Facultad de Ciencias
Departamento de Química Orgánica
CATALYTIC C−
C−H FUNCTIONALIZATION OF AROMATIC
AROMAT
NITROGEN COMPOUNDS DIRECTED BY THE
2--PYRIDYLSULFONYL GROUP
BEATRIZ URONES RUANO
Directores:
Dr. Juan Carlos Carretero Gonzálvez
Catedrático (UAM)
Dr. Ramón Gómez Arrayás
Profesor Titular (UAM)
Madrid, Mayo de 2013
This PhD Thesis has been done at the Department of Organic Chemistry at the
Universidad Autónoma de Madrid under the supervison of Prof. Dr. Juan Carlos Carretero and
Prof. Dr. Ramón Gómez Arrayás.
This work was supported by the Ministerio de Ciencia e Innovación (MICINN, CTQ200907791/BQU), the Ministerio de Economía y Competitividad (MINECO, CTQ 2012-35790) and
the Consejería de Educación de la Comunidad de Madrid (programme AVANCAT, S2009/PPQ1634). B.U. thanks the MICINN for a FPU predoctoral fellowship and N.R. for a contract
through her Marie Curie Career Integration Grant - CIG (CHAAS-304085).
It is difficult to overstate my gratitude to my Ph.D. supervisor, Prof. Juan Carlos Carretero,
who have helped and supported me along this long but fulfilling road.
To Ramón. whose expertise, understanding, and patience, added considerably to my
graduate experience. I appreciate his vast knowledge and skill in many areas and his guidence
in writing reports. Thanks for making things easier until the last minute.
A very special thanks goes out to Dr. Jorge Fernández Molina, without whose motivation
and encouragement I would not have considered to do a PhD. Also thank you very much for
being “tol rato tol tiempo en descontacto total” and never let me down.
When I started this adventure, my mum gave me a great advice: It’s going to be a hard
trip, so stick to people that loves you and support you! Maria, you are one of a kind! Thanks for
being my family in Madrid, support me, encourage me and also celebrate the good moments.
You have been a true friend all this time (esto es para siempre!).
Nuria, there isn’t enough words to thank you and to express all my gratitutde for everything
you have done for me. You were the last one arriving but you have became such a great friend.
THANK YOU for being just the way you are. You are the only few people that can me make me
laugh when I’m stressed…. Thanks for all your help and support and never let me down! I
couldn’t have done it without you, that’s for sure… I love you!!!
I must also acknowledge my colleagues in the Organic Chemistry Department for their
support and good moments, in special to the members of my research group for the exchanges
of knowledge, skills, and venting of frustration during my graduate program, which helped
enrich the experience.
Appreciation also goes out to those who provided me with helpful advice at times of critical
need; Nana, Ester, Mariona, Isa ….. Primi! Thanks for your permanent smile.
I would also like to thank my family for the support they provided me through my entire life
and in particular, I must acknowledge my grands without whose love, encouragement and faith,
I would not have embarked on this adventure.
“On ne voit bien qu'avec le coeur; l'essentiel est invisible pour les yeux”
Antoine de Saint-Exupéry, Le Petit Prince
“The whole problem with the world is that fools and fanatics are alsways so certain of
themselves and wisers full of doubts”
Bertrand Russell
To my family, in special to my grandparents
INDEX
Index
1.
Introduction...................................................................................................... 25
1.1.
Importance and challenges of C−H functionalization ...................................................................... 25
1.2.
General approaches for catalytic C−H Functionalization ................................................................ 27
1.3.
C−H functionalization via aryl-metal intermediates: use of directing groups.................................. 28
1.3.1.
Non-removable directing groups ........................................................................................... 33
1.3.2.
Removable, auxiliary directing groups .................................................................................. 35
1.4.
Precedents of our research group ................................................................................................... 45
1.5.
Research objectives and Thesis organization ................................................................................. 57
2.
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles .................... 63
2.1.
Importance of the 2,2’-biindole as structural motif .......................................................................... 63
2.2.
Synthesis of 2,2’-biindoles ............................................................................................................... 65
2.2.1.
Initial approaches to the 2,2’-biindole skeleton ..................................................................... 65
2.2.2.
Transition metal-catalyzed cross-coupling approach to 2,2’-biindoles................................. 69
2.2.3.
Oxidative homocoupling reaction .......................................................................................... 71
2.3.
Aim of the project.............................................................................................................................. 77
2.4.
Catalytic dehydrogenative homocoupling of indoles: synthesis of 2,2’-biindoles .......................... 79
2.4.1.
Screening of the catalytic system and the reaction conditions ............................................. 79
2.4.2.
Evaluation of the directing role N-(2-pyridyl)sulfonyl protecting group................................. 86
2.4.3.
Reaction scope....................................................................................................................... 88
2.4.4.
N-Deprotection via reductive desulfonylation reaction ......................................................... 92
2.4.5.
Mechanistic proposal ............................................................................................................. 92
2.4.6.
Intramolecular version: oxidative coupling of bis(1H-indol-3-yl)methanes........................... 93
2.5.
3.
Conclusions ...................................................................................................................................... 97
C−H olefination of anilines and arylalkylamines ............................................ 101
3.1.
Importance of anilines and arylalkylamines................................................................................... 101
3.2.
Direct C−H olefination of acetanilides ............................................................................................ 102
3.2.1.
C−H olefination of N-aryl ureas............................................................................................ 113
3.2.2.
C−H olefination of N-sulfonylanilines ................................................................................... 118
3.2.3.
Rh-catalyzed C−H olefination of aromatic amines .............................................................. 119
3.3.
C−H olefination of aryl alkylamines ................................................................................................ 125
3.4.
Aim of the project ............................................................................................................................ 129
3.5.
C−H ortho-olefination reaction of N-sulfonyl aniline derivatives ................................................... 132
3.5.1.
C−H olefination of N-methyl anilines: optimization studies ................................................. 132
3.5.2.
Structural versatility of the N-alkyl group ............................................................................. 136
3.5.3.
Structural versatility of the alkene coupling parter .............................................................. 143
3.5.4.
Structural variations at the aniline counterpart .................................................................... 145
3.5.5.
Application to indole synthesis ............................................................................................. 147
3.6.
Tether elongation: C−H olefination of arylalkylamines .................................................................. 149
3.6.1.
C−H olefination of benzylamines ......................................................................................... 151
3.6.2.
C−H olefination of phenethylamines and γ-arylpropylamines ............................................. 157
3.7.
Deprotection .................................................................................................................................... 163
3.7.1.
3.8.
4.
Attempts to isolate the palladacycle .................................................................................... 164
Conclusions..................................................................................................................................... 167
C−H di-ortho-olefination of carbazoles ...........................................................173
4.1.
Importance of carbazoles ............................................................................................................... 173
4.2.
Synthesis of carbazoles .................................................................................................................. 175
4.2.1.
C−C bond formation: metal-catalyzed cyclization of diarylamine derivatives (route a) ..... 176
4.2.2.
C−N bond formation: cyclization of 2-aminobiphenyl derivatives (route b) ........................ 184
4.2.3.
Direct functionalization of the carbazole skeleton: functionalization at C1/C8 positions ... 191
4.3.
Aim of the project ............................................................................................................................ 196
4.4.
Results and discussion ................................................................................................................... 198
4.4.1.
N-sulfonanylation of the NH-carbazole ................................................................................ 198
4.4.2.
Screening of the reaction conditions.................................................................................... 198
4.4.3.
Evaluation of the role of the N-(2-pyridyl)sulfonyl directing/protecting group..................... 202
4.4.4.
Di-ortho olefination ............................................................................................................... 204
II
4.4.5.
Olefin scope for the Pd -catalyzed di-olefination ................................................................ 205
4.4.6.
Substrate scope ................................................................................................................... 207
4.4.7.
C−H olefination of other nitrogen-containing compounds................................................... 214
4.4.8.
Deprotection of olefinated N-(2-pyridyl)sulfonyl carbazoles and indolines ........................ 218
4.5.
5.
Conclusions .................................................................................................................................... 220
Aerobic copper-catalyzed ortho-halogenation of anilines .............................. 225
5.1.
Introduction: sustainable catalytic C−H functionalization .............................................................. 225
5.2.
Coupling reactions under aerobic conditions ................................................................................ 225
5.3.
Aerobic Cu-catalyzed C−H functionalization ................................................................................. 227
5.3.1.
Base-promoted Cu-catalyzed C−H functionalization .......................................................... 228
5.3.2.
C−H activation of relatively inert aryl C−H bonds................................................................ 232
5.4.
Ortho-halogenated reactions of anilines derivatives ..................................................................... 241
5.5.
Aim of the project............................................................................................................................ 248
5.6.
Results and discussion .................................................................................................................. 249
5.6.1.
First attempts in Cu-catalyzed ortho-halogenation of anilines............................................ 249
5.6.2.
Development of a more benign copper-catalyzed protocol for the ortho-halogenation of
anilines
253
5.6.3.
Evaluation of the effect of the N-directing/protecting group ............................................... 258
5.6.4.
Structural versatility of the aniline in the ortho-chlorination reaction .................................. 260
5.6.5.
Expanding the reaction to bromination and iodination ........................................................ 265
5.6.6.
Ortho-substituted substrates: Development of the N-(2-pyrimidyl)sulfonyl directing group
269
5.6.7.
Deprotection ......................................................................................................................... 274
5.6.8.
Application to indole synthesis............................................................................................. 274
5.7.
6.
Conclusions .................................................................................................................................... 278
Experimental section ..................................................................................... 285
6.1.
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles: synthesis of 2,2’-biindoles .... 285
6.1.1.
General methods .................................................................................................................. 285
6.1.2.
Typical procedure for the synthesis N-(2-pyridyl)sulfonyl indole derivatives: .................... 285
6.1.3.
II
General procedure for the Pd -catalyzed dehydrogenative homocoupling to 2,2’-biindoles:
290
6.1.4.
Synthesis of 2,3’-biindoles via PdII-catalyzed dehydrogenative homocoupling ................. 292
6.1.5.
Deprotection of N,N’-bis(2-pyridilsulfonyl)-2,2’-biindolyl (2) to afford free NH-biindole 41.293
6.1.6.
Intramolecular homocoupling reaction ................................................................................. 294
6.2.
C−H olefination of anilines and arylalkylamines ............................................................................ 297
6.2.1.
General methods .................................................................................................................. 297
6.2.2.
Typical procedure for N-sulfonylation of anilines ................................................................ 298
6.2.3.
Synthesis of the starting functionalized N-alkyl anilines: .................................................... 300
6.2.4.
General procedure for N-sulfonylation of N-methyl-N-(2-pyridyl)sulfonyl arylalkylamines 304
6.2.5.
General procedure for the C−H alkenylation reaction ......................................................... 309
6.2.6.
General procedure for the Zn-promoted reductive N-desulfonylation: ............................... 325
6.2.7.
Synthesis of indoles from N-(methoxycarbonyl)methyl-substituted olefinated adducts:
cyclization-deprotection-aromatization. .......................................................................................................... 326
6.3.
C−H di ortho-olefination of carbazoles ........................................................................................... 329
6.3.1.
General methods .................................................................................................................. 329
6.3.2.
Synthesis of the starting carbazoles and derivatives .......................................................... 329
6.3.3.
C−H alkenylation reaction .................................................................................................... 335
6.3.4.
Zn-promoted reductive N-desulfonylation............................................................................ 342
6.3.5.
Mg-promoted reductive N-desulfonylation ........................................................................... 343
6.3.6.
Oxidative aromatization ........................................................................................................ 344
6.4.
Aerobic copper-catalyzed ortho-halogenation of anilines ............................................................. 345
6.4.1.
General methods .................................................................................................................. 345
6.4.2.
Typical procedure for the N-sulfonylation of anilines. ......................................................... 346
6.4.3.
General procedures for the copper-catalyzed ortho-halogenation ..................................... 354
6.4.4.
Typical procedure for the Mg-promoted N-desulfonylation ................................................. 369
6.4.5.
Typical procedure for the synthesis of 2-substitued NH-indoles from ortho-bromo-
substituted N-(2-pyridil)sulfonyl anilines: Sonogahira coupling/cyclization/deprotection.............................. 370
6.4.6.
Intramolecular isotopic kinetic effect .................................................................................... 371
6.4.7.
Regioselectivity in the ortho-chlorination process............................................................... 373
Appendix I: Publications..................................................................................................................377
And in the CD attached:
Appendix II: NMR spectra collection
Appendix II-A: NMR spectra chapter 2
Appendix II-B: NMR spectra chapter 3
Appendix II-C: NMR spectra chapter 4
Appendix II-D: NMR spectra chapter 5
Standard Abbreviations and Acronyms
Standard Abbreviations and Acronyms
Ac: acetyl
AcOH: acetic acid
Ac2O: acetyl anhydride
Ar: aryl
Bn: benzyl.
BQ: 1,4-benzoquinone
CAN: ceric ammonium nitrate
δ: chemical shift in parts per million
DCE: 1,2-dichloroethane
DCM: dicloromethane
DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DMA: dimethylacetamide
DMAP: 4-(N,N-dimethylamino)pyridine
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
EI: electron impact
EM: elemental mass
ESI: electrospray ionization
EWG: electron-withdrawing group
[F+]: N-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate
FAB: fast atom bombardment
GC: gas chromatography
HQ: hydroquinone
21
Hz: hertz
M: molar (moles per liter)
MS: mass spectrometry; molecular sieves
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
NIS: N-iodosuccinimide
Ns. 4-nitrobenzenesulfonyl (nosyl)
SET: single electron transfer
TAA: tert-amyl alcohol
TBHP: tert-butyl hydroperoxide
TBPB: tert-butyl perbenzoate
temp: temperature
TEMPO: 2,2,6,6-trimethylpiperidin-1-oxyl
Tf: trifluoromethanesulfonyl (triflyl)
TFA: trifluoroacetic acid
THF: tetrahydrofuran
TLC: thin-layer chromatography
Ts: para-toluenesulfonyl (tosyl)
22
Chapter 1:
Introduction
23
24
Chapter 1
1.
Introduction
1.1. Importance and challenges of C−
C−H functionalization
The ultimate aim of Organic Synthesis is to assemble a given organic compound
(target molecule)) from readily available starting materials and reagents in the most
efficient way.1 Consequently, one
one of the main goals in modern organic chemistry is to
increase efficiency and minimizze
e chemical waste. The term atom economy has been
coined to describe such a goal.2 One of the most atom economic processes is the
transformation of a non-activated
activated carbon-hydrogen (C−H) bond into a C−C
C or
C−heteroatom bond. Non-activated
activated C−H
C
bonds are ubiquitous in organic molecules.
molecules
Therefore, the development of selective, energy-efficient
energy
chemistry for the conversion
of C−H
H bonds into useful functional groups is leading to a paradigm shift in Organic
Synthesis (Scheme 1.1).3 The
he application of C−H
H functionalization technologies is
fascinating from the notion that a C−H
C
bond can be viewed as a latent functional
equivalent of an active functional group. In contrast to conventional synthesis that
often requires numerous chemical operations to link two molecules together, metalmetal
catalyzed C−H functionalization has tremendous potential in streamlining the
synthesis of complex molecules.4
Scheme 1.1
1
K. C. Nicolaou, J. S. Chen in Classics in Total Synthesis III: Further Targets, Strategies, Methods;
Methods
Wiley-VCH, Weinheim, 2011.
2
B. M. Trost, Acc. Chem. Res. 2002,, 35, 695.
3
R. G. Bergman, Nature 2007, 446,, 391.
391
4
For reviews on the application of C−H
C
functionalization to the total synthesis of complex molecules:
a) K. Godula, D. Sames, Science 2006,
2006 312, 67; b) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc.
Rev, 2011, 40, 1885; c) D. Y.-K.
K. Chen,
Chen S. W. Youn, Chem. Eur. J. 2012, 18, 9452.
25
Introduction
The functionalization of unactivated C−H bonds, however, remains a tremendous
challenge.5 This is due to: (1) The high pKa values (>35) and bond dissociation
energies (375 – 440 kcal/mol) of typical unfunctionalized C−H bonds, as well as their
“paraffin” nature, as they possess neither low lying HOMOs nor high lying LUMOs; (2)
Over-oxidation of functionalized products is often thermodynamically favored; (3)
Difficulty in functionalizing a single C−H bond with high regiocontrol within a complex
structure which contains many types of C−H bonds.
This is a very large, diverse, and highly active field. As consequence, the aim of
this introductory chapter is not to provide a comprehensive sampling of the vast
literature. Several excellent general review articles have been published on various
aspects of this field, some fairly recently.6 Our goal in this chapter is to convey some
general background and insight to help the reader to appreciate and put into context
the research of this thesis. Subsequent chapters of this manuscript provide a wider
coverage of the current state of art of the particular reaction that has been studied.
Therefore, in this chapter we place our emphasis on C−H functionalization of arenes,
a common feature of the research described in this manuscript, with discussion of
C(sp3)−H and other C−H bonds being outside of the general scope of this Thesis.
5
For a review on direct transformations of sp2 C−H bonds: a) D.-G. Yu, B.-J. Li, Z.-J. Shi, Tetrahedron
2012, 68, 5130. See also: b) B. A. Arndtsen, R. G. Begman, T. A. Mobley, T. H. Peterson, Acc.
Chem. Res. 1995, 28, 154; c) M. Tobisu, N. Chatani, Angew. Chem. Int. Ed. 2006, 45, 1683.
6
For general reviews on metal-catalyzed C−H functionalization: a) W. D. Jones, Science 2000, 287,
1942; b) J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507. See also the February 2010 and March
2011 issues of Chem. Soc. Rev., the April 2011 issue of Chem. Rev. and the June 2012 issue of Acc.
Chem. Res. For selected reviews: c) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011,
40, 1885. d) J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740. e) K. M.
Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. f) P. B. Arockiam, C. Bruneau,
P. H. Dixneuf, Chem. Rev. 2012, 112, 5879; g) J. J. Mousseau, A. B. Charette, Acc. Chem. Res.
2013, 46, 412.
26
Chapter 1
1.2. General approaches for catalytic C−
−H Functionalization
Different
transition
metal
complexes
are
capable
of
catalytic
activation/functionalization of C−H bonds. These catalysts can operate within two
very different general mechanistic manifolds: (1) Cleaving unactivated C−H bonds to
furnish carbometallated intermediates (C−[M]), which can be then transformed into
the desired products (C−FG) by treatment with appropriate reagents (R−X, Scheme
1.2, a); (2) Cleaving the C−H bond by insertion of metal-oxo or metalcarbenoid/nitrenoid species7 (Scheme 1.2, b). In the latter case, a C–H bond within
the substrate is not converted into a C–[M] bond for its subsequent functionalization.
Rather these processes rely on the formation of high energy species on the metal
center, which are then able to insert into the C–H bonds of the substrate.
Scheme 1.2
The research discussed in this thesis focuses mainly on the first method. Hence,
the discussion hereafter is focused in that area. The latter approach is outside of the
scope of this thesis and will thus not be discussed.
7
For reviews on catalytic C–H functionalization by metal carbenoid and nitrenoid insertion, see: a) H.
M. L. Davies, J. R. Manning, Nature 2008, 451, 417; b) H. M. L. Davies, D. Morton, Chem. Soc. Rev.
2011, 40, 1857.
27
Introduction
1.3. C−
−H functionalization via aryl-metal intermediates: use of directing
groups
In 1968, Fujiwara and Moritani disclosed the first catalytic C−H activation
reaction with Pd(OAc)2 in which benzene (as solvent) was added to styrene to afford
diphenylethylene (Scheme 1.3).8,9
Pd(OAc)2 (10 mol%)
H
+
Ph
Cu(OAc)2 or AgOAc (10 mol%)
Ph
O2 (50 atm), AcOH, 80 ºC
45%
Scheme 1.3
As shown in Scheme 1.4a, the mechanism involved the electrophilic palladation
of arene ring with a PdII catalyst to generate the arylpalladium intermediate I.
Subsequent carbopalladation of the olefin led to the alkylpalladium complex II that
underwent syn-β-H elimination to yield the styrenyl product and Pd0. The final step of
the catalytic cycle was oxidation of Pd0 to PdII using Cu salts, Ag salts, benzoquinone,
O2, and peroxides, among other oxidants examined. In an alternative mechanism, the
PdII catalyst was proposed to coordinate to the olefin, which enhanced its
electrophilicity and propensity to undergo nucleophilic addition with electron-rich
aromatic rings (Scheme 1.4b).10 The resulting intermediate II was intercepted in this
pathway.
8
a) Y. Fujiwara, I. Moritani, M. Matsuda, S. Teranishi, Tetrahedron Lett. 1968, 9, 3863; b) Y.
Fujiwara, I. Moritani, S. Danno, R. Asano, S. Teranishi, J. Am. Chem. Soc. 1969, 91, 7166.
9
For previous studies using stoichiometric PdII, see: a) I. Moritani, Y. Fujiwara, Tetrahedron Lett.
1967, 8, 1119; b) Y. Fujiwara, I. Moritani, M. Matsuda, Tetrahedron, 1968, 24, 4819; c) Y. Fujiwara, I.
Moritani, M. Matsuda, S. Teranishi, Tetrahedron Lett. 1968, 9, 633.
10
E. M. Beck, M. J. Gaunt, Top. Curr. Chem. 2010, 292, 85.
28
Chapter 1
Scheme 1.4
This early report by Moritani and Fujiwara demonstrated the impressive reactivity
of palladium(II) in activating aryl C−H bonds. However, two major drawbacks largely
hampered the application of this catalytic reaction. First, a large excess of the arene
was required (often used as the solvent). Second, there was a lack of control in the
regioselectivity when monosubstituted benzene derivatives such as toluene or
29
Introduction
anisole were used, generally resulting in the formation of undesirable mixtures of
regioisomeric products (Scheme 1.5).11
Scheme 1.5
In response to these problems, the development of ligand-directed C−H
activation6,12 has proved to be essential to address the challenges of improving
reactivity and controlling regioselectivity.13 This strategy involves the use of
11
Y. Fujiwara, I. Moritani, R. Asano, Tetrahedron 1969, 25, 4815.
12
For a recent account on controlling regioselectivity in C−H bond functionalization: a) S. R. Neufeldt,
M. S. Sanford, Acc. Chem. Res. 2012, 45, 936. For a recent review on removable directing groups in
metal catalysis: b) G. Rousseau, B. Breit, Angew. Chem., Int. Ed. 2011, 50, 2450.
13
Another mode of substrate-controlled regioselectivity involves the activation of C−H bonds in
substrates containing halogen substituents. The transition metal catalysts are brought adjacent to the
C−H bond of interest for selective cleavage via oxidative addition of the carbon-halogen (C−X) bond,
thereby generating organometallic intermediates as the requisite active catalysts prior to C−H. For
selected reviews, see: a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; b) M.
Catellani, E. Motti, N. Della Ca, Acc. Chem. Res. 2008, 41, 1512. A dramatic example on the efficient
application of this strategy was described by Fagnou and co-workers in the total synthesis of
Allocolchicine (see Scheme below).
30
Chapter 1
substrates bearing a coordinating functional group (L in Scheme 1.6) that can
reversibly chelate to the transition metal and brings it in proximity to the unactivated
C−H bond, thereby facilitating its cleavage (activation). The resulting cyclometalated
complex II formed upon C−H cleavage could then react with proper reagents to afford
ortho-functionalized products.
Scheme 1.6
The first report of ligand-directed C−H functionalization appeared in 1963 using
stoichiometric amounts of the transition metal. Kleiman and Dubeck discovered that
Cp2Ni could activate C–H bonds in azobenzene (Scheme 1.7).14 In 1965, Cope and
Siekman demonstrated that PdCl2 and K2PtCl4 showed an analogous reactivity.15
This total synthesis was based on a Pd-catalyzed intramolecular biaryl forming step between an aryl
halide and a donor Ar−H species. The in situ generated catalytic Pd0 species undergoes oxidative
addition to the aryl halide to form the PdII-aryl species that facilitates the activation of the aryl C−H
donor to assemble the biaryl–PdII intermediate prior to reductive elimination. See also: c) L.-C.
Campeau, M. Parisien, M. Leblanc , K. Fagnou, J. Am. Chem. Soc. 2004, 126, 9186; d) M. Leblanc,
K. Fagnou, Org. Lett. 2005, 7, 2849; e) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am.
Chem. Soc. 2006, 128, 581. For a review of C−H functionalization in natural product synthesis: f) L.
McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885. For another example of a total
synthesis, e.g. Trauner’s synthesis of rhazinilam, see: g) A. L. Bowie Jr., C. C. Hughes, D. Trauner,
Org. Lett. 2005, 7, 5207; h) A. L. Bowie Jr., D. Trauner, J. Org. Chem. 2009, 74, 1581.
14
J. P. Kleiman, M. Dubeck, J. Am. Chem. Soc. 1963, 85, 1544.
15
A. C. Cope, R. W. Siekman, J. Am. Chem. Soc. 1965, 87, 3272.
31
Introduction
Scheme 1.7
The pioneering catalytic directed C−H functionalization was reported by Murai
and co-workers, who 30 years later demonstrated that [Ru(PPh3)3(CO)2] and
[Ru(PPh3)3(CO)H2] were able to catalyze the insertion of olefins into the ortho-C−H
bonds of aromatic ketones (Scheme 1.8).16
Scheme 1.8
As shown in Scheme 1.9, the reaction mechanism proposed by Murai involved
the chelation-directed C−H bond activation by the ketone group to form the
cyclometallated ruthenium(0) hydride complex III, followed by olefin insertion and
reductive elimination to yield the product.17
16
S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda, N. Chatani, Nature 1993,
366, 529.
17
a) M. Sonoda, F. Kakiuchi, A. Kamatani, N. Chatani, S. Murai, Chem. Lett. 1996, 109; b) F.
Kakiuchi, H. Ohtaki, M. Sonoda, N. Chatani, S. Murai, Chem. Lett. 2001, 918; c) F. Kakiuchi, S.
Murai, Acc. Chem. Res. 2002, 35, 826.
32
Chapter 1
Scheme 1.9
Since this initial report, many groups have expanded the scope of this strategy to
include a variety of directing groups, which can be classified conventionally as
belonging to one of two principal classes: removable or non-removable (auxiliary)
groups.
1.3.1. Non-removable directing groups
In particular, nitrogen and oxygen-bearing structural units have been most
extensively utilized for transition-metal catalyzed C−H bond cleavage (Scheme 1.10).
Scheme 1.10
Especially, nitrogen played a vital role in chelation-induced activation reactions.
For example, pyridine was one of the classic directing groups, and the types of
reactions performed on 2-phenylpyridines range from C−C bond forming reactions
33
Introduction
such as arylation with aryl halides,18 hypervalent iodine reagents19 or arenes,20
oxidative Heck reactions or alkylation with organoboron,21 to carbon-heteroatom
(C−X) bond formation such as halogenation,22 acetoxylation23 or fluorination.24 For
example, the pyridine moiety in 2-phenylpyridine was discovered by Sanford and coworkers to be an efficient directing group for Pd(OAc)2-catalyzed ortho-acetoxylation
using PhI(OAc)2 as stoichiometric oxidant (Scheme 1.11).23 This reaction was
proposed to proceed through a PdII/PdIV catalytic cycle where the hypervalent iodine
reagent oxidized a cyclometallated PdII intermediate to PdIV species from which C−O
beyond-forming reductive elimination released the product.
18
a) D. Shabashov, O. Daugulis, Org. Lett. 2005, 7, 3657; b) L. Ackermann, A. Althammer, R. Born,
Synlett 2007, 2833.
19
D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am. Chem. Soc. 2005, 127, 7330.
20
K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904.
21
a) X. Chen, C. E. Goodhue, J. Q. Yu, J. Am. Chem. Soc. 2006, 128, 12634; b) B. F. Shi, N. Maugel,
Y. H. Zhang, J. Q. Yu, Angew. Chem., Int. Ed. 2008, 47, 4882.
22
a) A. R. Dick, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126, 2300; b) D. Kalyani, M. S.
Sanford, Org. Lett. 2005, 7, 4149; c) D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford, Org. Lett.
2006, 8, 2523; d) D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford, Tetrahedron 2006, 62, 11483.
23
A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62, 2439.
24
a) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc. 2006, 128, 7134. For a review on
catalysis for C−H fluorination and trifluoromethylation, see: b) T. Furuya, A. S. Kamlet, Tobias Ritter,
Nature, 2011, 471, 470.
34
Chapter 1
Scheme 1.11
1.3.2. Removable, auxiliary directing groups
The use of pyridine and similar structures as directing group to functionalize C−H
bonds is restricting from a practical standpoint since many molecules of interest do
not contain such directing group or its further manipulation requires extensive
destruction of the core structure.25 To overcome this problem, temporary auxiliary
directing groups that are easily removable after C−H functionalization have recently
emerged.
Important criteria for the efficiency of such catalyst-directing groups are: i) ease
of installation of the directing group; ii) efficient control over the reactivity/selectivity;
and iii) ease of removal from the substrate.
To avoid or minimize the impact of the requirement of two extra unproductive
steps involving the installation and removal of the directing group from the substrate,
in some cases the directing group is also a protecting group (with dual
protecting/directing role) or a source of chemical diversity, allowing its further
transformation into new functionalities. This concept will be illustrated below with
some remarkable examples extracted from the literature.
25
A. M. Kearney, C. D. Vanderwal, Angew. Chem., Int. Ed. 2006, 45, 7803.
35
Introduction
Daugulis and co-workers have demonstrated that a carboxylate substituent may
be used as a directing group in the direct palladium-catalyzed ortho-arylation of free
benzoic acids (Scheme 1.12).26 The possibility of a subsequent decarboxylation step
makes this sequence synthetically equivalent to the regioselective arylation of
unfunctionalized arenes. Likewise, it offers the possibility of a tandem reaction
development by using carboxylate functionality in subsequent Heck and Suzuki
couplings.
Scheme 1.12
The use of an aryl iodide as the coupling partner required stoichiometric amounts
of silver acetate for iodide removal in acetic acid as solvent. This method was
applicable to the arylation of electron-rich to moderately electron-poor benzoic acids
and tolerated chloride and bromide substituents on both coupling partners. This
method most likely proceeded through a PdII-PdIV coupling cycle.
The coupling with aryl chlorides was effected in the presence of cesium
carbonate as base, n-butyl-di-1-adamantylphosphine as ligand (BuAd2P), in DMF as
solvent. This protocol was suitable for both electron-rich and electron-poor benzoic
26
H. A. Chiong, Q.-N. Pham, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 9879.
36
Chapter 1
acids and mechanistic studies pointed toward the heterolytic C−H bond cleavage as
the turnover-limiting step.
Importantly, it was demonstrated that the arylation products could be
decarboxylated using the method developed by Goossen and co-workers,27 in the
presence of CuO/quinoline in NMP (Scheme 1.13).
Scheme 1.13
Yu and co-workers as well as Miura and co-workers have also used carboxylic
acids and their salts as highly effective directing groups for both Pd- and Rhcatalyzed C−H activation.28
The dialkylhydrosilyl function has been devised by Hartwig and Boebel as an
auxiliary directing group in the Ir-catalyzed ortho-borilation of arenes, phenols and Nalkylanilines.29 The reaction occurs with complete ortho-regiocontrol in all cases
under the conditions depicted in Scheme 1.14. The mechanism implied the formation
of an Ir−Si bond rather than the formation of a silaborane intermediate. The directing
group could be removed upon exposure to a source of fluoride ions.
27
a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662: For a review, see: b) L. J.
Goossen, N. Rodríguez, Chem. Soc. Rev. 2011, 40, 5030.
28
a) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B. Saunders, J.-Q Yu, J. Am. Chem.
Soc. 2007, 129, 3510; b) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10, 1159; c) M.
Yamashita, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11, 2337; d) S. Mochida, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2010, 12, 5776; e) S. Mochida, K. Hirano, T. Satoh, M. Miura, J. Org.
Chem. 2011, 76, 3024.
29
T. A. Boebel, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 7534.
37
Introduction
Scheme 1.14
Also related to this strategy, the groups of Gevorgyan30 and shortly after Ge31
reported independently the use of Si−OH group in directed oxidative C−H
alkenylation. Gevorgyan and co-workers equipped phenols with a silanol group and
the PdII-catalyzed ortho-alkenylation proceeded in good to excellent yields adopting
the previously described Yu’s conditions (Scheme 1.15).32 The silanol group was
removed with TBAF to afford ortho-alkenylated phenols. Owing to the steric demand
of the silicon atom decorated with two tert-butyl groups, the regioselectivity was
complete even for unsymmetrically substituted phenols. Not surprisingly, electron-rich
arenes and electron-poor alkenes were the optimal combination.
30
a) C. Huang, B. Chattopadhyay, V. Gevorgyan, J. Am. Chem. Soc. 2011, 133, 12406. For a silanol-
directed C−H oxygenation, see: C. Huang, N. Ghavtadze, B. Chattopadhyay, V. Gevorgyan, J. Am.
Chem. Soc. 2011, 133, 17630.
31
C. Wang, H. Ge, Chem. Eur. J. 2011, 17, 14371.
32
Y. Lu, D.-H. Wang, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 5916.
38
Chapter 1
Scheme 1.15
Ge and co-workers described a related PdII-catalyzed alkenylation of toluenederived silanols (Scheme 1.16).31 Yields were generally good and the scope ranged
from electron-rich to electron-poor arenes. The reaction worked efficiently when
electron-poor alkenes were used as coupling partners. Smooth “deprotection” of the
alkenylated benzylic silanols yielded the parent toluenes.
Scheme 1.16
39
Introduction
Directing groups based in a coordinating nitrogen-atom are very common in C−H
functionalization reactions. For example, 2-pyrazol-5-ylaniline (pza-H2) has been
used as an easily attachable and detachable directing group for the ortho-C−H
functionalization of aromatic organoboronic acids. Suginome and co-workers reported
a one-pot procedure for the Ru-catalyzed ortho-C-H silylation of arylboronic acids
with triethylsilane. The reaction took place with good yields and complete regiocontrol
(Scheme 1.17).33 It tolerated aromatic systems bearing both electron-donating or
electron-withdrawing substituents. The auxiliary directing group was easily introduced
by condensation of the boronic acid with the 2-pyrazol-5-ylaniline and was efficiently
removed from the final products under acidic conditions.
Scheme 1.17
In 2006, Sames and co-workers described a ruthenium-catalyzed α-arylation of
2-substituted pyrrolidines and piperidines with aryl boronic esters based on the use of
34
an amidine directing group (Scheme 1.18).
33
H. Ihara, M. Suginome, J. Am. Chem. Soc. 2009, 131, 7502.
34
S. J. Pastine, D. V. Gribkov, D. Sames, J. Am. Chem. Soc. 2006, 128, 14220.
40
Chapter 1
Scheme 1.18
The directing group facilitated the insertion of the ruthenium metal into the
C(sp3)−H bond. The resulting metal hydride was then transformed into the
corresponding metal-aryl complex via a metal-alkoxide intermediate (Scheme 1.19).
The final reductive elimination generated the C−C bond in the product and
regenerated the ruthenium catalyst. A wide range of aryl and heteroaryl boronic
esters were compatible with the reaction conditions employed. Although good yields
and diastereoselectivities were obtained with pyrrolidine substrates, extension of this
method to piperidine systems was less successful. Removal of the amidine function
from the product was possible although using rather harsh conditions.
Scheme 1.19
41
Introduction
The metal-coordinating 2-pyridyl unit has been widely employed as directing
group in many transition metal-catalyzed transformations.
35
For example, Yoshida
and co-workers has shown the efficiency of the dimethyl(2-pyridyl)silyl group in a vast
variety of functionalizations.
36
More recently, Gervorgyan and co-workers have
illustrated that the pyridyldiisopropylsilyl (PyDipSi) group was an efficient silicontethered directing group to allow the efficient palladium(II)-catalyzed functionalization
of aromatic C−H bonds (Scheme 1.20).
In particular, it proved to be very efficient in the ortho-acetoxylation/pivaloxylation
and ortho-halogenation of arenes. The reaction in the presence of 2.0 equiv of
PhI(OR)2 (R = Ac, Piv), in combination with AgOAc as bystanding oxidant system,
provided a variety of acetoxylated and pivaloxylated aromatic compounds in good
yields and excellent regiocontrol (Scheme 1.20a).37 On the other hand, the
combination of PhI(OAc)2 (1.5 equiv) with 2.0 equiv of NXS (X = Cl, Br, I) furnished
the corresponding ortho-halogenated arenes with excellent levels of reactivity and
38
selectivity (Scheme 1.20b).
This directing group could efficiently be “traceless”
cleaved by treatment with AgF in methanol, or converted into a variety of other
functional groups such as iodide or boronates. Also, the pyridyldiisopropylsilyl
(PyDipSi) group was used in the Hiyana-Denmark-type cross-coupling reaction with
iodoarenes, providing the access to biaryl derivatives.
35
For selected examples related to 2-pyridyl protecting group in transition metal-catalyzed reactions,
see: a) S. Nakamura, H. Nakashima, H. Sugimoto, N. Shibata, T. Toru, Tetrahedron Lett. 2006, 47,
7599; b) S. Nakamura, H. Sano, H. Nakashima, K. Kubo, N. Shibata, T. Toru, Tetrahedron Lett. 2007,
48, 5565; c) H. Tatamidani, K. Yokota, F. Kakiuchi, N. Chatani, Org. Lett. 2006, 8, 2519; d) P. H. Bos,
A. J. Minnaard, B. L. Feringa, Org. Lett. 2008, 10, 4219; e) P. H. Bos, B. Macia, M. A. FernándezIbáñez, A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem. 2010, 8, 47; f) J.-N. Desrosiers, W. S.
Bechara, A. B. Charette, Org. Lett. 2008, 10, 2315.
36
For a general review: a) K. Itami, K. Mitsudo, T. Nokami, T. Kamei, T. Koike, J.-I. Yoshida, J.
Organomet. Chem. 2002, 653, 105. For recent examples: b) T. Kamei, K. Itami, J.-I. Yoshida, Adv.
Synth. Catal. 2004, 346, 1824; c) K. Itami, Y. Ohashi, J.-I. Yoshida J. Org. Chem. 2005, 70, 2778.
37
N. Chernyak, A. S. Dudnik, C. Huang, V. Gevorgyan, J. Am. Chem. Soc. 2010, 132, 8270.
38
A. S. Dudnik, N. Chernyak, C. Huang, V. Gevorgyan, Angew. Chem. Int. Ed. 2010, 49, 8729.
42
Chapter 1
Scheme 1.20
As another example of a directing group bearing a pyridine unit, Chatani and coworkers reported the first example of a catalyst system based on nickel that took
advantage of chelation assistance. This work described the use of the N-(2pyridyl)methyl directing group in the Ni-catalyzed oxidative cycloaddition of aromatic
amides with alkynes (Scheme 1.21, a).39 The same concept has been extended to
the carbonylation of non-activated C(sp3)−H of aliphatic amides, in this case using
Ru3(CO)12 as the catalyst (Scheme 1.21, b).40 The activation of methyl groups was
favoured over methylenes, and the reaction featured a wide functional group
tolerance. In both transformations, the 2-pyridylmethylamino unit was crucial for the
reaction to proceed due to its coordination to the metal through the nitrogen atoms of
both pyridyl and amide functions. The final removal of the directing group was
effected by reaction with LDA followed by bubbing O2 and hydrolysis to afford the NHquinolone.
39
H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011, 133, 14952.
40
N. Hasegawa, V. Charra, S. Inoue, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011, 133, 8070.
43
Introduction
Scheme 1.21
More recently, in 2012, Huang and co-workers reported that triazenes were a
class of effective directing groups for oxidative Heck coupling reactions (Scheme
1.22).41 The presence of two electronegative nitrogen atoms contiguous to the C−N
bond attached to the arene attenuates the directing group-substrate bonding, thereby
allowing its easy cleavage under ambient conditions and enabling a number of
synthetic manipulations.42,43 Removal of this directing group was achieved by
41
C. Wang, H. Chen, Z. Wang, J. Chen, Y. Huang, Angew. Chem. Int. Ed. 2012, 51, 7242.
42
For an account on this chemistry, see: C. Wang, Y. Huang, Synlett 2013, 24, 145.
43
Independently, the ortho-selective trifluoromethylation of phenyltriazenes with AgCF3 has been
recently reported: A. Hafner, S. Bräse, Angew. Chem. Int. Ed. 2012, 51, 3713.
44
Chapter 1
treatment with BF3.OEt2 at room temperature, yielding the corresponding Ar−H in
quantitative yields.
Scheme 1.22
1.4. Precedents of our research group
In 2004 our research group started a new research line oriented to explore the
potential of heteroarylsulfonyl groups (especially the 2-pyridylsulfonyl group) as
temporary auxiliary directing groups in transition metal-catalyzed reactions. It was
rapidly found that this group promoted a dual effect: i) it usually enhanced the
reactivity and selectivity of the process by means of pre-association of the metalcatalyst to the N-pyridyl unit, and ii) after the reaction, the sulfonyl group could be
readily removed under mild conditions.
Along this line, a pioneering example was the development of a chelationassisted, transition metal-catalyzed protocol for the sequential multiarylation of cyclic
allyl sulfones. As shown in Scheme 1.23, the metal-coordinating ability of the 2pyridyl group on the sulfone promoted the otherwise difficult intermolecular Heck
monoarylation and diarylation of trisubstituted alkenes, as well as the coppercatalyzed allylic arylation with Grignard reagents.44,45 The role of the metal
44
T. Llamas, R. Gómez Arrayás, J. C. Carretero, Adv. Synth. Catal. 2004, 346, 1.
45
Introduction
coordinating 2-pyridylsulfonyl group was crucial to accomplish this goal, as proven by
the fact that the corresponding tosyl or phenyl sulfonyl derivatives were inert in this
reaction, even under harsh reaction conditions.
Scheme 1.23
On the other hand, combining the N-(2-pyridyl)sulfonyl group as directing group
with a chiral organometallic catalyst has led to the development of new asymmetric
catalytic processes. Thus, our research group described in 2004 the first catalytic
protocol for the enantioselective conjugated addition of carbon nucleophiles to α,βunsaturated sulfones.46 An exhaustive screening of different directing groups
confirmed that N-(2-pyridyl)sulfonyl was optimal for the Rh-catalyzed conjugated
addition of boronic acids to vinyl sulfones using (S,S)-Chiraphos as the most
appropriate chiral ligand. The products were all isolated with excellent yields and high
enantiomeric excesses (76-92% ee, Scheme 1.24). The method could be applied to
E- and Z-substrates and tolerated a wide variety of substituents at the β-position to
45
For the Heck arylation of α,β-insaturated 2-(N,N-dimethylamino)phenyl sulfones, see: a) P.
Mauleón, I. Alonso, J. C. Carretero, Angew. Chem. Int. Ed. 2001, 40, 1291; b) P. Mauleón, A. A.
Nuñez, I. Alonso, J. C. Carretero, Chem. Eur. J. 2003, 9, 1511; c) I. Alonso, M. Alcami, P. Mauleón, J.
C. Carretero, Chem. Eur. J. 2006, 12, 4576. For the reaction of N-(2-pyridyl)sulfonyl
azabenzonorbornadienes with cuprates, see: d) R. Gómez Arrayás, S. Cabrera, J. C. Carretero, Org.
Lett. 2005, 7, 219; e) R. Gómez Arrayás, S. Cabrera, J. C. Carretero, Synthesis 2006, 1205.
46
a) P. Mauleón, J. C. Carretero, Org. Lett. 2004, 6, 3195; b) P. Mauleón, I. Alonso, M. Rodríguez
Rivero, J. C. Carretero, J. Org. Chem. 2007, 72, 9924.
46
Chapter 1
the sulfone, as well as in the boronic acid. The elimination of the 2-pyridylsulfonyl
group through a Julia-Kocienski-type reaction opened a new path to optically active
alkenes substituted at the allylic position. This methodology has been extended to the
construction of stereogenic quaternary centers through the enantioselective addition
of boronic acids to α,β-unsaturated-β,β-disubstituted-(2-pyridyl)sulfones (88-99%
ee).47
Scheme 1.24
Another important reaction that rivalizes with the asymmetric conjugate addition
is the Cu-catalyzed conjugate reduction of β,β-disubstituted Michael-type acceptor
olefins. Since the first protocol described by Buchwald and workers in 1999,48 this
reaction has experienced a dramatic growth, being applied to a variety of α,βunsaturated carbonyl compounds.49 Our group has been pioneer on incorporating
vinyl sulfones into the arsenal of electrophiles that efficiently participates in this
process.50 Again, the use of the N-(2-pyridyl)sulfonyl group was key to overcome the
weaker Michael acceptor character that characterizes the vinyl sulfones in
comparison to the corresponding α,β-unsaturated dicarbonylic compounds (Scheme
47
P. Mauleón, J. C. Carretero, Chem. Commun. 2005, 4961.
48
D. H. Apella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121,
9473.
49
For a review in the topic, see: S. Rendler, M. Oestreich, Angew. Chem. Int. Ed. 2007, 46, 498.
50
T. Llamas, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2007, 46, 3329.
47
Introduction
1.25). In fact, analogues phenyl vinyl sulfones proved to be inert under the optimized
reaction conditions. The use of CuCl/tBuONa/(R)-BINAP as the chiral catalytic
system (5 mol%) and PhSiH3 as hydride source allowed the reduction of a broad
range of β-alkyl-β-aryl-substituted and β,β-dialkyl-substituted α,β-unsaturated 2pyridylsulfones in excellent chemical yields and with excellent enantioselectivities
(typically 90–94% ee). These enantioenriched sulfones were versatile intermediates
in the preparation of a wide variety of functionalized chiral compounds.
Scheme 1.25
This
concept
has
been
extended
to
reactions
of
coordinating
N-
(heteroaryl)sulfonyl imines. These new electrophiles have proven to be extremely
reactive compared to traditional N-tosyl imines. An example of this strategy has been
the development of a very general protocol for the synthesis of diaryl amines and
dialkyl amines based on the Friedel-Crafts reaction of N-(2-pyridyl)sulfonyl imines
with electron-rich aromatic and heteroaromatic compounds (Scheme 1.26).51 In this
reaction, the presence of the coordinating group was essential for stopping the
process in the mono-addition product, whereas the analogue N-Ts or N-aryl imines
provided exclusively the double addition products under identical conditions.52 The
scope of the reaction was very broad with regard to both imine and nucleophile
51
J. Esquivias, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2006, 45, 629.
52
For selected examples, see: a) J. Hao, S. Taktak, K. Aikawa, Y. Yusa, M. Hatano, K. Mikami,
Synlett 2001, 1443; b) B. Ke, Y. Qin, Q. He, Z. Huang, F. Wang, Tetrahedron Lett. 2005, 46, 1751.
48
Chapter 1
components, tolerating a wide variety of aromatics and heteroaromatics derivatives.
The deprotection of the sulfonamides was very efficient under mild conditions.
This method allowed an in situ second electrophilic aromatic substitution with a
different nucleophilic arene species (Ar3−H) promoted by the same Lewis acid
catalyst. This sequential addition of two arenes to the N-(2-pyridyl)sulfonyl imine
constituted the first one-pot synthesis of unsymmetrical triarylmethanes. DFT
theoretical studies of the second Friedel-Crafts reaction have shown that the different
reactivity of the N-(2-pyridyl)sulfonyl imine could be due to the different coordinating
mode of this imine to the metal, in comparison to the typical N-tosyl derivatives.53
Scheme 1.26
The same strategy has been applied to the development of the first general
protocol for the direct alkylation of imines with alkylzinc halides.54 This type of
alkylating reagents is very attractive because of their easy preparation, high
compatibility with a wide variety of functional groups and easy availability. However,
53
I. Alonso, J. Esquivias, R. Gómez-Arrayás, J. C. Carretero, J. Org. Chem. 2008, 73, 6401.
54
J. Esquivias, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2007, 46, 9257.
49
Introduction
their attenuated nucleophilic character has hampered their addition to imines.55 In the
presence of a catalytic amount of Cu(OTf)2 (1-5 mol%) the N-(2-pyridyl)sulfonyl
imines of aromatic and heteroaromatic aldehydes shown unprecedented high
reactivity towards the direct addition of a wide variety of alkyl zinc bromide reagents
(Scheme 1.27). The N,N-bidentate character of 2-pyridylsulfonyl imines with respect
to metal coordination was proven by an X-ray crystallographic study of the CuI
complex of the N-(2-pyridyl)sulfonyl imine of chalcone, and it was suggested as the
origin of the exceptional reactivity displayed by these substrates. The deprotection of
the sulfonamide group took place under mild reductive conditions, compatible with
many sensitive functional groups.
Scheme 1.27
The high reactivity offered by the N-(8-quinolyl)sulfonyl group led to the
development of the first example of catalytic asymmetric inverse-electron-demand
55
Our group has also described the copper-catalyzed asymmetric conjugate addition of dialkyl zinc
reagents with α,β−insaturated ketimines (80-90% yield, 70-80% ee): J. Esquivias, R. Gómez Arrayás,
J. C. Carretero J. Org. Chem. 2005, 68, 8120.
50
Chapter 1
Diels-Alder reaction of N-sulfonyl-1-aza-1,3-dienes.56 Up to that date, this reaction
required harsh conditions (high temperatures and high pressure) due to the low
reactivity of the 1-azadienes. This hampered the development of asymmetric
versions.57 Among the numerous chiral catalysts employed, the combination of
Ni(ClO4)2·6H2O/DBFOX-Ph (10 mol%) provided the best results, affording the
corresponding piperidines in good yields, with excellent endo-selectivity and high
enantioselectivities (typically in the range of 80-91% ee, Scheme 1.28).
Scheme 1.28
The CuI-Fesulphos-catalyzed (10 mol%) asymmetric Mannich reaction of
glycinate Schiff bases with N-(8-quinolyl)sulfonyl imines was reported by our group as
an efficient approach to α,β−diamino esters (Scheme 1.29).58 This type of amino
acids are very attractive targets in organic synthesis because of their wide range
56
J. Esquivias, R. Gómez Arrayás, J. C. Carretero, J. Am. Chem. Soc. 2007, 129, 1480.
57
The presence of an ester group in the 4-position of the 1-azadiene has allowed the development of
a catalytic versión of the process using chiral auxiliaries: R. C. Clark, S. S. Pfeiffer, D. L. Boger, J.
Am. Chem. Soc. 2006, 128, 2587.
58
J. Hernández-Toribio, R. Gómez Arrayás, J. C. Carretero, J. Am. Chem. Soc. 2008, 130, 16150.
51
Introduction
biological significance and high versatility as synthetic building blocks.59 A thorough
study on the influence of the imine protecting group in the reaction outcome revealed
the superiority of the 8-quinolylsulfonyl group over the N-Boc and other N-arylsulfonyl
or N-heteroarylsulfonyl moieties.
Up to date, a major limitation of the previous approaches was that they were
applicable only for the selective preparation of syn-configured products. This
important limitation was solved independently by the group of Hou60 and ours. An
additional distinctive feature of our catalyst system was that it allowed the
construction of α,β-diaminoacids with a tetrasubstituted carbon stereocenter at C-α in
a highly diastereo- and enantiocontrolled manner. A variety of aryl and heteroaryl
aldimines, including the challenging imine derived from 3-pyridinecarboxaldehyde,
proved to be excellent electrophilic substrates. The sequential amino deprotection of
the α,β-aminoester adducts could be effected under mild conditions and reasonable
yields.
Scheme 1.29
59
a) A. Viso, R. Fernández de la Pradilla, A. García, A. Flores, Chem. Rev. 2005, 105, 3167; b) A.
Ting, S. E. Schaus, Eur. J. Org. Chem. 2007, 5797; c) R. Gómez Arrayás, J. C. Carretero, Chem.
Soc. Rev. 2009, 38, 1940.
60
X.-X. Yan, Q. Peng, Q. Li, K. Zhang, J. Yao, X.-L. Hou, Y.-D. Wu, J. Am. Chem. Soc. 2008, 130,
14362.
52
Chapter 1
The modification of the steric and electronic properties of the α-iminoester used
as starting materials made possible the inversion of the diastereoselectivity (from anti
to syn), keeping the high asymmetric induction of the process. Accordingly, it was
achieved the access to α,β-diamino acid derivatives of syn configuration with high
diastereoselectivities and enantiomeric excesses, starting from ketimines (instead of
aldimines) from the glycinate derivatives of benzophenones poor in electrons
(Scheme 1.30).61
Scheme 1.30
Very recently, our group has demonstrated that the activating effect of the 2pyridylsulfonyl unit (and related sulfur-based groups) in metal-mediated reactions
could be applied to challenging Pd-catalyzed C−H activation processes. This concept
was first investigated in the PdII-catalyzed regioselective C2-alkenylation of N-(2pyridyl)sulfonyl indoles and pyrroles.62 The coordinating ability of the N-(2pyridyl)sulfonyl group was critical for inducing C−H activation with complete
regiocontrol at the less favoured C2-position, likely through formation of the
palladacycle I (Scheme 1.34). For instance, the N-Ts protected indole led to less than
20% conversion under identical conditions, whereas the low conversion and
61
J. Hernández-Toribio, R. Gómez Arrayás, J. C. Carretero, Chem. Eur. J. 2010, 16, 1153.
62
A. García-Rubia, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2009, 48, 6511.
53
Introduction
regiocontrol observed for the 3-pyridylsulfonyl group made unlikely the high reactivity
and selectivity observed to originate from electronic effects.
Both, electron-poor and non-activated alkenes were applicable, with the
participation
of
1,2-disubstituted
alkenes
and
1,3-dienes
being
particularly
noteworthy. On the other hand, both electron-withdrawing and electron-donating
substituents were tolerated at different positions of the indole core (Scheme 1.31)
Scheme 1.31
This method was also applicable to the functionalization of pyrroles (Scheme
1.32). Monosubstituted, disubstituted, as well as unsymmetrical 2,5-disubstituted
pyrroles could be obtained by small variations in the reaction conditions (temperature
and reaction time).
54
Chapter 1
Scheme 1.32
Removal of the N-(2-pyridyl)sulfonyl group from indoles and pyrroles was readily
achieved by reductive cleavage with Zn or Mg to give 2-alkenyl- or 2-alkyl-substituted
heteroarenes, respectively (Scheme 1.33).
Scheme 1.33
In an attempt to isolate the presumed palladacycle intermediate (type I or related
species), the N-(2-pyridyl)sulfonyl indole 1 was heated (60 ºC) with 1.2 equiv of
55
Introduction
Pd(OAc)2 in AcOH for 18 h. Instead of the palladacycle, the 2,2’-biindolyl 2 was
cleanly formed and isolated in 71% yield (Scheme 1.34). We speculated that due to
the facile C2-palladation in the absence of the alkene component, the palladacycle I
evolved by formation of a C2-palladated bi-indolyl intermediate II which would afford
2 via reductive elimination.
Scheme 1.34
56
Chapter 1
1.5. Research objectives and Thesis organization
The possibility of direct introduction into arenes of a new functionality via direct
C−H bond transformation is a highly attractive strategy, owing to the ubiquitous
nature of C−H bonds in organic substances. Methods involving directing groups have
received significant attention because they enable the efficient and site-selective
functionalization of a C−H bond. However, despite huge advances, a number of
challenges, especially concerning the reactivity, selectivity and cost-effectiveness,
still remain to be solved.
Our group has introduced the 2-pyridyl sulfonyl moiety (and related sulfur-based
groups) as a new type of removable metal-coordinating directing group in metalcatalyzed reactions of unsaturated sulfones and N-sulfonyl imines. Very recently, this
activating effect was also extended to a challenging C−H activation reaction: the Pdcatalyzed regioselective C2-alkenylation of N-(2-pyridyl)sulfonylindoles and pyrroles.
The enhanced reactivity and regiocontrol provided by these coordinating
heteroarylsulfonyl groups open very appealing scenarios for developing novel
methodologies in C−H activation processes that could significantly contribute to the
state of the art in the field. Therefore, the aim of this Thesis is to explore and evaluate
the extension of this “N-heteroarylsulfonyl activation” to other heteroaromatic systems
and less activated nitrogen-containing arenes, as well as to study other types of
C(sp2)−H functionalizations such as dehydrogenative arylations or halogenations.
The development of less expensive and more sustainable catalyst systems is also an
important goal of this research for improving practicality. These general objectives
have been organized into four chapters covering more specific goals as follows:
Chapter 2 presents the development of the first protocol for the intermolecular
cross-dehydrogenative homocoupling of indoles at C2 to give 2,2’-biindoles using
palladium-catalysis. Achieving high regiocontrol in intermolecular dehydrogenative
homocoupling of 2,3-unsubstituted indoles is a major obstacle, especially at the less
activated C-2 position. The presence of a N-(2-pyridyl)sulfonyl directing group could
ensure high reactivity and complete regioselectivity.
57
Introduction
Chapter 3 describes a general procedure for the selective Pd-catalyzed direct
C−H olefination of aniline derivatives that expands the current scope to difficult-toactivate substrates, most notably N-alkylated and ortho-substituted compounds. The
ortho-olefination of more challenging substrates such as benzylamines, βarylethylamines and γ-arylpropyamines will be also explored.
Chapter 4. Despite the significance of carbazole in pharmacy and material
science, examples on direct C−H functionalization of this privileged unit remained
undocumented. In this chapter, the high directing ability displayed by N-(2pyridyl)sulfonyl group will be studied in the PdII-catalyzed aryl C−H ortho alkenylation
of carbazole derivatives. The application of this procedure to related heterocyclic
systems, such as indolines, will be also explored.
58
Chapter 1
Chapter 5. As mentioned earlier, one of the persistent challenges in direct C−H
functionalization reactions is the application of more sustainable and environmentally
benign catalysts. To address this challenge, recent strategies have identified to use
low-toxic metal catalyst (e.g., Cu or Fe) in combination with O2 as the oxidant. Within
this context, in this chapter the compatibility of the aerobic Cu-catalyzed orthohalogenation of aniline derivatives with our 2-pyridylsulfonyl group activation strategy
will be explored.
59
60
Chapter 2:
Catalytic oxidative homocoupling of N-(2pyridyl)sulfonylindoles
61
62
Chapter 2
2.
Catalytic
oxidative
homocoupling
of
N-(2-
pyridyl)sulfonylindolesImportance of the 2,2’-biindole as structural motif
The biindole skeleton (two indole units connected directly by a C−C bond) is an
important structural motif frequently found in pharmaceuticals and functional
materials.63 Among this family of compounds, the 2,2’-biindolyl is a structural element
of particular importance because of its abundance and chemical properties. This
motif is present in the dyes indigo and Tyrian purple, known from ancient time (Figure
2.1).64
Figure 2.1
Moreover, this structural framework is also present in the core of indolo[2,3α]carbazoles which are extremely important natural products because of their broad
range of potent biological activities. The powerful and varied biological activities of
these systems endow them with many potential therapeutic applications, particularly
as anticancer agents and in the treatment against several neurodegenerative
diseases (Figure 2.2).65
63
G. Abbiati, A. Arcadi, E. Beccalli, G. Bianchi, F. Marinelli, E. Rossi, Tetrahedron 2006, 62, 3033;
and references cited therein.
64
J. Bergman, E. Koch, B. Pelcman, Tetrahedron 1995, 51, 5631.
65
For recent reviews of the synthesis and biological activity of indolo[2,3-α]carbazoles and related
carbazole alkaloids, see: a) T. Janosik, N. Wahlströmb, J. Bergman, Tetrahedron 2008, 64, 9159; b)
A. W. Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112, 3193.
63
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
Figure 2.2
The juxtaposition of the two nitrogens in 2,2’-biindolyls has been also exploited in
the construction of various ligand systems [Figure 2.3, a].66 This structural motif is
also of current interest due to its use as precursors for the synthesis of anion sensing
architectures, finding its applicability as fluorimetric sensors for anions [Figure 2.3,
b].67
Figure 2.3
As
another
application
of
2,2’-biindilyls,
alkyne-linked
biindole-
and
indolocarbazole-containing macrocycles bind selectively anions through hydrogenbonding interactions. In fact, they function as chemosensors capable of distinguishing
between different anions, as it has been demonstrated on the basis of the 1H NMR
chemical shifts of the corresponding complexes (Figure 2.4).68
66
D. St. C. Black, Synlett 1993, 246.
67
L. Capelli, P. Manini, A. Pezzella, A. Napolitano, M. d’Ischia, J. Org. Chem. 2009, 74, 7191.
68
P. A. Gale, Chem. Commun. 2008, 4525; and references cited therein.
64
Chapter 2
Figure 2.4
2.2. Synthesis of 2,2’-biindoles
2.2.1. Initial approaches to the 2,2’-biindole skeleton
However, although a wide variety of methods for the synthesis of indoles and
indole derivatives is available,69 2,2’-biindoles are relatively inaccessible compounds.
Few routes are available for their synthesis, and most of the reported procedures
require harsh conditions and are correspondingly plagued by low yields.
Functionalization of indoles at the 2-position, particularly the construction of 2,2’biindoles, is a synthetic challenge due to the lower inherent electron density of the
indole system at the C2-position compared to that at the C3-position.70 Consequently
many examples of C2-functionalization rely on indole derivatives having either a
protecting group or a blocking substituent at the more reactive C3-position.
The parent 2,2'-biindole was first synthesized by Madelung from the N,N’-bis(otolyl)oxamide, using the reaction which now bears his name (Scheme 2.1, a).71 The
reaction is based on the intramolecular cyclization of N-acylated-ortho-alkylanilines,
69
For recent reviews in the synthesis of indoles, see: a) G. R. Humphrey, J. T. Kuethe, Chem. Rev.
2006, 106, 2875; b) K. Krüger, A. Tillack, M. Beller, Adv. Synth. Catal. 2008, 350, 2153; c) J.
Barluenga, F. Rodríguez, F. J. Fañanás, Chem. Asian J. 2009, 4, 1036; d) J. J. Song, J. T. Reeves,
D. R. Fandrick, Z. Tan, N. K. Yee, C. H. Senanayake, Arkivok, 2010, 1, 309; e) S. A. Patil, R. Patil, D.
D. Miller, Curr. Med. Chem. 2011, 18, 615; f) S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol.
Chem. 2011, 9, 641; g) Z. Shi, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 9220.
70
D. J. Koza, W. B. Euler, Heter. Comm. 1999, 5, 399.
71
a) W. Madelung, Ber. 1912, 45, 1128; b) W. Madelung, Ann. Chem. 1914, 405, 58.
65
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
readily available by condensation between ortho-toluidine with oxalyl chloride, in the
presence of a strong base at elevated temperatures. However, the yield was very low
(26%) and the reaction conditions (sodium n-amylate/360 °C) were harsh, limiting the
applicability of the method when the desired 2,2’-biindole has sensitive substituents.
Bergman and co-workers improved the yield (80%) by changing the base, but this
method still requires a strong base and high temperatures (Scheme 2.1, b).64 The
useful scope of the synthesis is, therefore, limited to molecules which can survive
strongly basic conditions.
Scheme 2.1
In 1980, Bergman and Eklund became interested in the 2,2’-biindole skeleton
because these electron-rich systems displayed strong electron-donor capacity and
because their potential applications were so far unexplored.72 In order to study this
structural motif, they needed a ready access to the starting material and at that point
the Madelung cyclization seemed to be the only route available. Therefore, they
studied some copper- and palladium-promoted coupling reactions of simple indoles
for the assembly of the 2,2’-biindole skeleton.
For the copper-promoted coupling, the following sequence was used: lithiation of
indole at C2 with n-butillithium followed by transmetallation with CuCl2, gave a
copper(II) complex that after reductive elimination led to the 2,2’-biindole skeleton
(Scheme 2.2). Following this procedure, N,N’-dimethyl-2,2’-biindole was obtained
from N-methyl indole in good yield (73%). However, when this protocol was applied to
an indole bearing a typical electron-withdrawing N-protecting group such as N72
J. Bergman, N. Eklund, Tetrahedron 1980, 36, 1439.
66
Chapter 2
phenylsulfonyl, the reaction was found to be much less efficient, providing the
corresponding N-SO2Ph-protected 2,2’-biindole in only 23% yield. Nevertheless, this
product enabled the access to the free NH-2,2’-biindole upon alkaline deprotection of
the two sulfonamide groups. The yield of this last step was not provided in the
manuscript.
Scheme 2.2
The direct oxidative coupling of either N-methyl indole or NH-indole with an
stoichiometric amount of palladium acetate did not afford any shortcut to obtain the
2,2’-biindole skeleton. Instead, a very complex mixture that contained small amounts
of 3,3’- and 2,3’-coupled products (but no 2,2’-isomer) was detected. The applicability
of a Pd(OAc)2-induced oxidative coupling was elegantly solved by this group with the
development of an intramolecular variant (Scheme 2.3). The method involved an
initial step to form the 1,1’-carbonyl biindole, which was obtained in moderate yield
(41%) by reaction of indole with carbonyldiimidazole. Then, the 2,2’-biindole core was
assembled in good yield (84%) by palladium-mediated coupling at the 2- and 2’positions. This coupling was more facile due to its intramolecular nature (the carbonyl
tether played an important role fixing the geometry of the coupling, leading to less
negative entropies of activation), thereby avoiding the formation of other
regioisomers. To the best of our knolewdge, this protocol represented the first
example effective for the synthesis of the 2,2-biindole skeleton via a dehydrogenative
67
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
coupling. Finally, alkaline hydrolysis released the free NH-2,2’-biindole in good yield
(89%).
Scheme 2.3
Despite this advance,73 the need of a stoichiometric amount of palladium acetate
made this procedure little amenable for large-scale synthesis from economical and
environmental standpoints. Attempts to render the reaction catalytic in palladium by
addition of various co-oxidants such as Ac2O, MnO2 or Cu(OAc)2 resulted in no
significant improvement of the yield.74
73
For an intramolecular cyclation of a symmetrical diaminodiyne, in the presence of a strong base, to
give the 2,2’-biindole skeleton, see: C. Koradin, W. Dohle, A. L. Rodriguez, B. Schmid, P. Knochel,
Tetrahedron 2003, 59, 1571.
74
C. A. Merlic, Y. You, D. M. McInnes, A. L. Zechman, M. M. Miller, Q. Deng, Tetrahedron 2001, 57,
5199.
68
Chapter 2
2.2.2. Transition
metal-catalyzed
cross-coupling
approach
to
2,2’-
biindoles
Although methods based on transition-metal-catalyzed coupling of aryl halides
with aryl-metals have emerged as versatile tools for the synthesis of biaryls over the
past decades,75 few examples are found for the construction of the biindole skeleton.
To our knowledge, only the group of Merlic has developed a transition-metal
catalyzed cross-coupling approach for the synthesis of 2,2-biindoles.74 In particular, a
Suzuki reaction between 2-iodoindole and a 2-indolyl boronate was successfully
applied for the preparation of unsymmetrical 2,2’-biindoles. The starting 2-iodoindole
was formed using the method reported by Bergman and Venemalm, consisting of a
selective ortho-lithiation (at C2-position) of the in situ generated N-carboxylindole and
subsequent iodination with 1,2-diiodoethane.76 Then, the resulting 2-iodoindole was
easily N-alkylated or N-protected with several groups before it was converted in situ
to the corresponding 2-indolyl boronic ester via iodo/lithium exchange and trapping of
the resulting anion with trimethyl borate. Using modified Suzuki conditions, the in situ
prepared boronic ester was coupled with 2-iodoindole to afford unsymmetrical 2,2biindoles in reasonable yields (51-61%, Scheme 2.4).
75
For a recent review on traditional cross-coupling reactions, see: C. C. C. Johansso Seechurn, M. O.
Kitching, T. J. Colacot, V. Snieckus, Ang. Chem. Int. Ed. 2012, 51, 5062.
76
J. Bergman, L. Venemalm, J. Org. Chem. 1992, 57, 2495.
69
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
Scheme 2.4
Other palladium catalyzed cross-coupling reactions were also investigated by
this research group (Scheme 2.5). The Stille cross-coupling reaction of the Ncarboxylindol-2-yl tin derivative II and 2-iodo-N-methylindole resulted less efficient
than the Suzuki coupling, providing the corresponding 2,2’-biindole derivative in only
41% yield. Surprisingly, the Negishi approach was found not applicable for the
synthesis of the 2,2’-biindolyl system; the reaction of N-methylindol-2-yl zinc chloride
with 2-iodoindole resulted in the protonated product N-methylindole (Scheme 2.5).
This byproduct was proposed to arise from the protonation of the zinc reagent by the
unprotected 2-iodoindole coupling partner.
70
Chapter 2
Scheme 2.5
Attempts to couple the protected N-benzenesulfonylindol-2-yl boronic acid
resulted in the recovery of the protonated product N-benzenesulfonylindole. Identical
negative result was obtained when the N-benzenesulfonylindol-2-yl zinc chloride was
subjected to the Negishi-type coupling with 2-iodoindole (Scheme 2.6).
Scheme 2.6
2.2.3. Oxidative homocoupling reaction
As we have seen in the former section, traditional cross-coupling strategies such
as Stille or Suzuki reactions have provided solutions to the catalytic synthesis of 2,2’biindoles. However, these strategies relied on pre-activated electrophiles (halides or
pseudohalides) and organometallic nucleophiles as coupling partners. An enduring
objective in the construction of basic skeletons of heterocyclic molecules is the
search for new reactions that proceed with similar efficacy and selectivity upon
71
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
employing readily available non-preactivated starting materials such as heterocycles
themselves. This activation involves a two-fold C−H bond functionalization of
heteroarenes through a dehydrogenative coupling.77
Despite the fact that more and more research groups are trying to put their
efforts in this challenging area due to its interest from the green and sustainable
chemistry ideals,78 at the outset of our work the application of this approach to the
synthesis of biindoles remained undocumented. In 2010, almost simultaneously to
the publication of our work, two examples of dehydrogenative homocoupling of
indoles to afford biindoles appeared in the literature. None of them provided access
to the 2,2-biindole framework.
Zhang and co-workers described in 2010 a palladium-catalyzed oxidative
homocoupling of indoles, leading to 2,3’-biindoles.79 Under mild conditions (DMSO,
room temperature) and in the presence of a stoichiometric copper oxidant, various Nsubstituted indoles yielded the corresponding 2,3’-biindole typically in high efficiency
and with excellent regioselectivity (Scheme 2.7). The 2,2’- and 3,3’-isomers were not
observed under the reaction conditions. As mentioned, CuII-based oxidants provided
optimal results whereas silver(I) reagents such as AgOAc, Ag2CO3 and Ag2O were
found to be ineffective. Only trace amounts of products were observed when K2S2O8,
CuO or O2 were used as oxidants.
77
For selected examples of dehydrogenative indole arylation, see: a) D. R. Stuart, K. Fagnou,
Science 2007, 316, 1172; b) D. R. Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
12072; c) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn, B. DeBoef, Org. Lett. 2007, 16, 3137.
78
Reviews on metal-catalyzed C−H functionalization: a) J. A. Labinger, J. E. Bercaw, Nature 2002,
417, 507; b) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417. See also the February 2010 and
March 2011 issues of Chem. Soc. Rev., the April 2011 issue of Chem. Rev. and the June 2012 issue
of Acc. Chem. Res. For selected reviews: c) J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem.
Soc. Rev. 2011, 40, 4740; d) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885;
e) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788; f) P. B. Arockiam, C.
Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879.
79
Z. Liang, J. Zhao, Y. Zhang, J. Org. Chem. 2010, 75, 170.
72
Chapter 2
N-Methyl, N-benzyl and N-phenyl substitution were well tolerated, providing in all
cases the homocoupling products in good yield. However, electron-withdrawing Nprotecting groups, as in the case of N-acetylindole, were non-competent in this
transformation. With regard to substitution at the benzene ring of the indole moiety,
the reaction tolerates both electron-rich and moderately electron-poor substituents,
the former proceeding with higher yields. In the case of strongly electron-poor
indoles, the reactivity in the homocoupling process dropped markedly, although it
could be partially restored by enhancing the temperature and extending the reaction
time.
Regarding the regioposition of the substituents, higher yields were obtained for
the C5-, C6- and C7-substituted indoles. However, substitution at the C4-position
resulted in lower yields, possibly due to steric hindrance.
Scheme 2.7
The authors invoked a plausible Pd(0)/Pd(II) catalytic cycle to account for the
experimentally observed 2,3’-selectivity in the homocoupling reaction (Scheme 2.8).
The electrophilic palladation was proposed to first occur at the more reactive C3position of indole. A subsequent migration of the C3-PdX bond to the C2-position
73
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
would lead to the formation of intermediate I.80 This intermediate would then undergo
electrophilic palladation with a second indole molecule at the more nucleophilic C3
position, to form intermediate II. The following reductive elimination would generate
the 2,3’-biindole product. The released formed Pd(0) would be then oxidized to Pd(II)
by the Cu(II) salt in the system to furnish the catalytic cycle.
Scheme 2.8
Almost simultaneously, Shi and co-workers described an alternative and
complementary palladium-catalyzed oxidative homocoupling of indoles, allowing the
construction of the 3,3’-biindole skeleton.81
This group based his work on tuning the selectivity of the dimerization of indole
derivatives to afford the 3,3’-dimer by using different additives and oxidants, in
particular silver salts, which had been reported before to have a pronounced impact
80
a) B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc. 2005, 127, 8050; b) N. P. Grimster, C.
Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. Int. Ed. 2005, 44, 3125.
81
Y. Li, W.-H. Wang, S.-D. Yang, B.-J. Li, C. Fengab, Z.-J. Shi, Chem. Commun. 2010, 46, 4553.
74
Chapter 2
on the regioselectivity in the direct functionalization of indole derivatives.82 Notably,
AgNO3 was found to modulate the regioselectivity favoring the formation of the 3,3’dimeric indole scaffold, although the exact role of the silver salt was not well
understood at this stage. In contrast to the above Zhang’s procedure towards 2,3’linked indoles,83 unprotected indoles also underwent dimerization in the presence of
MgSO4, which was previously considered to tune the reactivity of free NH-indoles.80a
In general, electron-deficient and electron-rich indoles worked effectively,
although a slight change of the reaction conditions, for example, concentration of the
substrate, reaction temperature and the presence or absence of AcOH, was
necessary to achieve high efficiency for different substrates (Scheme 2.9).
H
2 R
R1
N
Pd(TFA)2 (10 mol%)
R2
AgNO3
2
N
R1
(AcOH), (MgSO4)
DMSO
R2
N
R1
1
1
R
N
R
N
R1
N
R2
R2
R2
R2
N
R1
R1 = H, 54%
R1 = Me, 72%
R1 = Bn, 69%
N
R1
R1 = H, R2 = CO2Me, 50%
R1 = Me, R2 = Br, 79%
R1 = Me, R2 = Me, 61%
N
R1
R1 = H, R2 = 4-CHO, 84%
R1 = Me, R2 = 6-Cl, 73%
R1 = Me, R2 = 7-OMe, 72%
Scheme 2.9
82
a) S. Yanagisawa, T. Sudo, R. Noyori, K. Itami, J. Am. Chem. Soc. 2006, 128, 11748; b) D. R.
Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129, 12072; c) S. Potavathri, A. S. Dumas,
T. A. Dwight, G. R. Naumiec, J. M. Hammann, B. DeBoef, Tetrahedron Lett. 2008, 49, 4050.
83
After our work was published, Liang and co-workers described a metal-free iodine-promoted
regioselective C−C bond formation, yielding 2,3-biindoles: Y.-X. Li, K.-G. Ji, H.-X. Wang, S. Ali, Y.-M.
Liang, J. Org. Chem. 2011, 76, 744.
75
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
These authors also proposed a plausible mechanistic pathway based on the
initial C3-palladation of the indole derivative via electrophilic substitution (intermediate
I). Then, another molecule of indole would undergo a second electrophilic substitution
at C3 by intermediate I to form intermediate II, which produced the 3,3’-linked
oxidative coupling product by the release of a proton and reductive elimination
(Scheme 2.10).
Scheme 2.10
76
Chapter 2
2.3. Aim of the project
Because of their biological and structural significance, the development of new
methods for the synthesis of 2,2’-biindoles remains an important ongoing challenge.
In this regard, the intermolecular oxidative homocoupling of indoles can be envisaged
as the most straightforward tool for the assembly of biindolyl systems. Surprisingly,
however, at the outset of our work this strategy remained undocumented.
One of the most challenging issues in dehydrogenative cross-coupling of indoles
has demonstrated to be the control of the reacting site.77 Indeed, direct coupling of
two indoles units at their C2-position to give 2,2’-biindoles appears to be the most
difficult connection. This is likely due to the higher nucleophilic character of the C3position of indole derivatives compared to their C2-position, thereby directing
electrophilic palladation at C3. To address this challenge, we considered that the
excellent ability of the N-(2-pyridyl)sulfonyl group as regiocontrolling unit for
functionalization of indoles at C2 could also enable the development of a general
catalytic procedure for the intermolecular dehydrogenative coupling of indoles to
access 2,2’-biindole systems.
In fact, as already mentioned in the Introduction of this Thesis (Chapter 1), in an
attempt to isolate the intermediate complex resulting from cyclopalladation at C2,
treatment of N-(2-pyridyl)sulfonyl indole 1 with a stoichiometric amount of Pd(OAc)2 in
AcOH led to the clean formation of 2,2’-biindole after 18 h at 60 ºC, isolated in 71%
yield. Therefore, the aim of this project is to develop a catalytic variant of this
homocoupling reaction under oxidative conditions (Scheme 2.11).
77
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
Scheme 2.11
Although, we will focus in the intermolecular version of the reaction because of
its greater impact, the intramolecular version will also be studied as a direct route to
polycyclic structures containing the 2,2’-biindole skeleton. In this regard, the
dehydrogenative intramolecular coupling of bis(1H-indol-3-yl)methanes to give
tetracyclic diindole structures with fixed coplanar S-cis conformation (with both
nitrogens pointing to the same side of the molecule) represents an attractive starting
point (Scheme 2.12).
Scheme 2.12
78
Chapter 2
2.4. Catalytic dehydrogenative homocoupling of indoles: synthesis of 2,2’biindoles
2.4.1. Screening of the catalytic system and the reaction conditions
a) Screening of the oxidant
Taking as starting point the palladium-mediated formation of the N,N’-bis(2pyridylsulfonyl)-2,2’-biindole 2 mentioned in the Introduction Chapter, we began our
study under the same conditions (AcOH, 60 ºC, 22 h) but using a catalytic amount of
Pd(OAc)2 (10 mol%) and a stoichiometric amount of a terminal oxidant, needed for
rendering this transformation catalytic with respect to the palladium salt. In this
regard, our initial choice was Cu(OAc)2 (1.5 equiv) since it previously provided good
results in the PdII-catalyzed direct C2-alkenylation of N-(2-pyridyl)sulfonyl indoles and
pyrroles described by our group.84 As shown in Scheme 2.13, the Pd(OAc)2-catalyzed
homocoupling reaction of N-2(pyridyl)sulfonyl indole 1 led to a very low conversion
(<10%), along with a very poor regiocontrol (2/3 = 40:60) in favour of the undesired
2,3’-biindole product 3. This result highlighted the challenges associated to the
development of a catalytic variation of this reaction related to the lower inherent
electron density of the indole system at the C2-position in comparison to that at the
C3-position.
Scheme 2.13
To overcome this discouraging start, and in light of the known critical role of the
nature of the co-oxidant in both the reactivity and regioselectivity of many C−H
84
A. García-Rubia, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2009, 48, 6511.
79
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
functionalizations, we decided to carry out a exhaustive screening of metal-based
and non metal-based oxidants. The experimental results are summarized in Table
2.1.
Table 2.1: Screening of the co-oxidant
Yield (%)
[a]
Entry
Co-oxidant
1
- (only O2)
< 10
40:60
2
Cu(OCOCF3)2
< 10
60:40
3
Cu(OTf)2
40
>98:<2
4
Ce(SO4)2
29
>98:<2
[c]
Selectivity 2:3
5
AgNO3
0
6
AgOAc
10
<2:>98
7
FeCl3
< 10
25:75
8
9
PhI(OAc)2
Benzoquinone
10
Oxone
11
tBuOOH
--
[c]
--
-
[d]
--
-
[d]
--
< 10
40:60
0
[b]
1
[a] Conversion yield (from the H NMR spectra); [b] Determined by 1H NMR
spectroscopy of the reaction mixture; [c] The starting material was recovered; [d]
Complex mixture.
The use exclusively of oxygen as ideal terminal oxidant proved to be ineffective
(entry 1, <10% conversion). Among the other copper(II) salts explored, CuII
trifluoroacetate did not produce any significant positive effect, except for a slight
increase of selectivity towards the 2,2’-biindole assembly 2 (entry 2, 2/3 = 60:40). In
contrast, the use of Cu(OTf)2 resulted in a higher conversion (entry 3, 40%
conversion) and, more importantly, complete regiocontrol in the formation of the
80
Chapter 2
desired 2,2-biindole skeleton (2/3 = >98:<2). Identical reaction outcome, yet in lower
conversion (entry 4, 29% conversion) was observed when using Ce(SO4)2 as oxidant.
Despite their proven ability as oxidants in C−H activation, silver or iron salts showed
very low reactivity in this transformation (entries 5-7), although the complete opposite
regioselectivity achieved with AgOAc was remarkable (entry 6, 2/3 = <2:>98).85
Finally, a survey of non-metal based species such as PhI(OAc)2 (entry 8),
benzoquinone (entry 9), oxone (entry 10) or t-BuOOH (entry 11) did not allow us to
identify any competent oxidant for this process.
Therefore, Cu(OTf)2 was chosen as the optimal oxidant for the homocoupling of
N-(2-pyridyl)sulfonyl indole 1 since it provided complete regiocontrol and higher
conversions among all the oxidants tested.
b) Optimization of the reaction work-up
Likely due to the metal-coordinating nature of the 2,2-biindole product 2, bearing
two N-(2-pyridyl)sulfonyl groups, a very polar solid was obtained after a simple
aqueous work-up of the reaction mixture. When isolated, this product proved to be
85
This complete regiocontrol in the formation of the 2,3’-biindole 3 when using AgOAc as co-oxidant
drew our attention towards the development of a general, complementary method for the efficient
access to 2,3’-biindolyl systems, which, to date, remained undocumented. For instance, we observed
that increasing the reaction temperature to 100 ºC (8 h) resulted in a clean formation of 3 with
complete 2,3’-regiocontrol, albeit still in a low 20% conversion (see Scheme below). However,
increasing the amount of AgOAc to 3.0 equiv did not give any improved result. Unfortunately, Zhang
and co-workers reported their Pd(OTFA)2-catalyzed intermolecular homocoupling approach to 2,3’biindoles (see reference 79) while we were performing these optimization studies The appearance of
this literature precedent discouraged us to continue investigating this mode of connection of biindolyl
and centred our focus on the 2,2’-regioselective homocoupling.
H
H
N
SO2Py
1
Pd(OAc)2 (10 mol%)
AgOAc (1.5 equiv)
AcOH, O2, 100 ºC, 8 h
selectivity 2/3 = <2:>98
conversion yield (3): 20%
N
SO2Py
N
SO2Py
3: 2,3'-biindole
81
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
non-soluble in the majority of the common polar organic solvents, which made
extremely difficult its purification and structural determination.
Understanding that this observation was due to the formation of a stable
biindolyl-CuII complex, we envisaged that introducing an extra-step in the work-up
procedure consisting of washing the organic solution of the crude reaction mixture
with aqueous ammonium hydroxide solution (NH4OH)86 could deliver the Cu-free
biindole product. To our delight, this was indeed the case and the 2,2’-biindole 2 was
obtained in good yield (68%) after diluting the reaction mixture with ethyl acetate and
successive washings with aqueous NH4OH and saturated aqueous NH4Cl, and then
filtering through a pad of Celite with a thin layer of silica gel on the top. This work-up
was even more necessary in the case of biindoles bearing electron-rich substituents,
which turned out to be quite unstable. Proof of this unstability was found when they
were purified by column chromatography, observing that the yields dramatically
decreased.
c) Solvent screening
Having identified Cu(OTf)2 as the best co-oxidant, we next explored the influence
of the nature of the solvent in the reaction (Table 2.2). Among all the different
solvents tested, only acidic solvents were found to be suitable for the reaction (entries
1-3). Thus, acetic and propionic acids provided higher conversions (40% and 44%
respectively, entries 1 y 2), while the reaction in trifluoroacetic acid yielded the
desired homocoupling product 2 in a much lower conversion (14%, entry 3). By
contrast, other protic polar solvents such as tert-amyl alcohol (entry 4) or non-protic
polar solvents such as DMA (entry 5), DMSO (entry 6) and acetonitrile (entry 7),
resulted in less than 10% conversion or full recovery of the starting material.
Likewise, a mixture of a polar solvent (DMA) with an acid (10 equiv of TFA, entry 8)
or a 1:1 mixture of acetonitrile and acetic acid (entry 9), led to full recovery of the
starting material.
86
For the use of NH4OH as demetalating agent for Cu-complexes of nitrogen-heterocycles, see: J. D.
Megiatto Jr., D. I. Schuster, Org. Lett. 2011, 13, 1808.
82
Chapter 2
Table 2.2: Solvent screening
Entry
Solvent
1
AcOH
40
2
EtCOOH
44
3
TFA
14
4
TAA
0
[b]
5
DMA
0
[b]
6
DMSO
0
[b]
7
CAN
8
DMA+TFA (10 equiv)
0
[b]
9
MeCN:AcOH (1:1)
0
[b]
[a] Conversion yield (from the crude
starting material was recovered.
Yield (%)
[a]
<10
1
H NMR); [b] The
d) Reaction temperature
Because of the low reactivity observed at 60 ºC, even under prolonged reaction
times (22 h), we decided to rise the reaction temperature to 100 ºC in the two
solvents that gave better yields: acetic acid and propionic acid. In both cases, a
dramatic increase of the reactivity was observed. In fact, the homocoupling of 1
reached full conversion in acetic acid, after only 12 h. As expected, similar behavior
(91% conversion) was observed in propionic acid as solvent (Scheme 2.14).
83
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
Scheme 2.14
A more accurate measurement of the reaction time led us to find out that 8 h
were sufficient for completion while shorter reaction times resulted into incomplete
reactivity. For example, a 50% conversion was observed after 4 h reaction at 100 ºC.
e) Screening of the palladium(II) precatalyst
Next we explored different palladium(II) salts as precatalysts in the model
homocoupling reaction of 1, fixing the rest of optimized parameters. These results are
summarized in Table 2.3. As expected, the reaction didn’t work at all in the absence
of any palladium salt, recovering the starting material unaltered (entry 1).
Table 2.3: Screening of the palladium(II) catalyst
II
Entry
Pd catalyst
Yield (%)
1
-
0
2
Pd(OAc)2
100
3
Pd(OTFA)2
66
4
PdCl2
30
5
PdCl2(CH3CN)2
1
-
[a]
[b]
[c]
[a] Conversion yield (from the H NMR spectra); [b] The starting material
was recovered; [c] Complex mixture.
84
Chapter 2
Among all the palladium(II) salts tested, the best result was obtained with
Pd(OAc)2, as it turned out to be the only palladium salt promoting full conversion of
the starting material into the desired biindole 2 (entry 2). Pd(OTFA)2 or PdCl2 also
afforded the desired product 2 with complete regiocontrol, but in lower conversions
(66% y 30% respectively, entries 3 and 4). Interestingly, PdCl2(CH3CN)2 resulted to
be totally ineffective, affording a complex reaction mixture (entry 5). Remarkably, the
2,3’- or 3,3’-biindole products were not detected in the reaction mixture in any case,
thus highlighting the crucial role of Cu(OTf)2 in controlling the regioselectivity to favour
the 2,2’-linkage.
f)
Importance of the aerobic conditions
Having identified the optimal palladium catalyst, we next evaluated the
importance of the aerobic conditions. When the reaction was run under strict nitrogen
atmosphere, only 20% of conversion to the desired 2,2’-biindole 2 was achieved in
the model homocoupling reaction of 1 (Scheme 2.15), evidencing the important
cooperative role of molecular oxygen as oxidant together with Cu(OTf)2 (1.5 equiv) to
obtain full conversions.
Scheme 2.15
As summary of these initial studies, optimized conditions were established
entailed the treatment of 1 with 10 mol% Pd(OAc)2 and 1.5 equiv of Cu(OTf)2 as cooxidant, in AcOH as solvent under an O2 atmosphere (1 atm) for 8-12 h.
85
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
2.4.2. Evaluation of the directing role N-(2-pyridyl)sulfonyl protecting
group.
a) Synthesis of indoles with potentially coordinating protecting groups
In order to evaluate the role of the protecting/directing group in this
dehydrogenative homocoupling reaction, a variety of removable N-sulfonyl groups
with different steric, electronic and coordinating properties were needed. For that
purpose, the free indole (4) was efficiently derivatized into a variety of products as
shown in Scheme 2.16.
Scheme 2.16
These protection reactions were carried out following the typical procedure for Nsulfonylation of indole derivatives: NH-deprotonation of indole 4 with NaH as a base
in THF at 0 ºC, followed by addition of the corresponding aryl-, heteroaryl- or N,Ndimethysulfamoyl chloride.84 The corresponding protected products (1 and 5-9) were
obtained in all cases as bench-stable solids and in acceptable to good yields (4076%). All the corresponding sulfonyl chlorides used in the N-sulfonylation reaction of
86
Chapter 2
indole were commercially available, except for the 2-pyridylsulfonyl chloride. This
reactant was readily prepared according to the literature procedure,87 involving
oxidation of 2-mercaptopyridine with sodium hypochlorite in sulfuric acid (Scheme
2.17). The resulting 2-pyridylsulfonyl chloride was subjected immediately to the
reaction with indole 4 because of its relative instability.
Scheme 2.17
To evaluate the effect of a non-sulfonyl protecting group, the N-Boc derivative 10
was also prepared in an excellent yield, following the described protocol (96%,
Scheme 2.18).88
Scheme 2.18
b) Evaluation of the effect of the N-protecting/directing group
The synthetized indoles (1 and 5-10), bearing a potentially coordinating
protecting group (PG), along with the free indole (4) and N-methyl indole (11) as
control substrates, were examined under the optimized conditions. The results
summarized in Table 2.4 highlight the unique efficiency of the N-(2-pyridyl)sulfonyl
group in the homocoupling reaction comparing to the rest of protecting groups
evaluated. In fact, the homocoupling reaction did not take place when using an indole
87
S. Diltz, G. Aguirre, F. Ortega, P. J. Walsh, Tetrahedron: Asymm. 1997, 8, 3559.
88
L. F. Silva Jr., M. V. Craveiro, M. T. P. Gambardella, Synthesis 2007, 3851.
87
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
with any of the other protecting groups. Only traces of a possible homocoupling
product 16 were detected when the N-(8-quinolyl)sulfonyl indole was subjected to the
optimized reaction conditions.
Table 2.4: Optimization of the N-protecting/directing group
Entry
Indole
PG
Product
Yield (%)
1
4
H
12
-
[b]
2
11
Me
13
-
[b]
3
1
(2-pyridyl)SO2
2
100 (68)
4
5
Ts
14
0
[d]
5
6
(2-thienyl)SO2
15
0
[d]
6
7
(8-quinolyl)SO2
16
~10
7
8
p-Ns
17
0
8
9
NMe2SO2
18
-
[b]
9
10
Boc
19
-
[b]
[a]
[c]
[d]
[a] Conversion yield (from the 1H NMR spectra); [b] Complex mixture; [c] Isolated
yield after chromatography; [d] The starting material was recovered.
2.4.3. Reaction scope
After
the
optimal
reaction
parameters
had
been
established
for
the
regiocontrolled 2,2’-homocoupling, we explored the scope of the reaction with regard
to the electronic and steric variations of the substituents at the indole counterpart.
For that purpose, a set of variously substituted indoles were N-sulfonylated with
2-pyridylsulfonyl chloride following the same standard protocol previously used for the
parent N-(2-pyridyl)sulfonyl indole 1 (see Scheme 2.16). The corresponding N-(2-
88
Chapter 2
pyridyl)sulfonyl protected indoles were obtained in all cases in good yields as benchstable solids (71-85%), regardless of the electron-rich or electron-poor nature of the
substitution (Scheme 2.19). Even the 7-aza-indole 31 was formed in good yield.
NaH
PySO 2Cl
R
N
H
R
N
O S
27-33
O
THF, 0 ºC--rt, 18 h
20-26
MeO
F
N
SO2Py
Br
N
SO2Py
27, 82%
N
N
SO2Py
28, 85%
MeO2C
29, 79%
N
SO2Py
30, 79%
CN
N
N
SO2Py
31, 73%
Me
N
SO2Py
32, 71%
N
SO2Py
33, 76%
Scheme 2.19
Next, these indoles were tested in the oxidative homocoupling reaction. As
shown in Scheme 2.20, the reaction tolerated electronically varied substitution at C5
and C6 of the indole unit. Both electron donating (OMe) and moderate electronwithdrawing (F) groups were well tolerated (products 34 and 35, 64% and 66% yield,
respectively). Although this tendency would fall off with the 5-bromo-substituede
indole (product 40, 50% conversion). By contrast, a strong electron-deficient ester
group had a clear detrimental effect on reactivity, leading to the complete recovery of
the starting material unaltered, even under prolonged reaction times. We attribute the
lack of reactivity of this substrate to its much lower activation towards aromatic
electrophilic substitution. Unexpectedly, a methyl group at the C7-position or a cyano
substituent at C4 dramatically altered the reactivity, obtaining complex reaction
mixtures due to the prevalence of decomposition products. This protocol was not
applicable either to the 7-aza-indole derivative 31, which proved to be inert under the
89
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
reaction conditions. In this case, the coordinating nature of the “extra” pyridyl nitrogen
could be responsible for this behavior, causing unproductive substrate-catalyst
interactions.
Scheme 2.20
On examining indoles with substituents at C5, we found that the 5-bromoindole
29 was significantly less reactive than 28, providing product 40 with only 50%
conversion after 12 h at 100 ºC. However, this product was highly attractive because
the resultant bromine on the biindolyl product could easily be manipulated, thus
providing a flexible handle for further functionalization.
90
Chapter 2
Consequently, we embarked in a more thorough optimization of the reaction
conditions (Table 2.5). Regarding the reaction temperature, only a slight improvement
of the conversion was observed when the temperature was raised up to 120 ºC (60%
conversion, entry 2). A further increase to 140 ºC had a deleterious effect due to the
appearance of unidentified by-products in the reaction mixture (30% conversion by
1
H NMR, entry 3). Fortunately, exploring higher loadings of the palladium precatalyst
resulted in critical improvement of reactivity. In fact, a 77% conversion was observed
when using 20 mol% of Pd(OAc)2 after 12 h at 100 ºC (entry 4). Moreover, we noticed
that the conversion yield correlated positively with the reaction time. Thus, extending
the reaction time to 30 h resulted in an improved 86% conversion (entry 5), the
reaction requiring 46 h for reaching full conversion (entry 6). It is important to note
that despite the reaction was a very clean process, the chromatographic separation
of the product from trace amounts of unidentified by-products resulted in reduced
yields of the dibrominated biindole 40 upon isolation (60% isolated yield). This trend
has been recurrently observed in most of the homocoupling reactions.
Table 2.5: Further optimization for the synthesis of 5,5’-dibromo-2,2’-biindolyl
40
Entry
Temp.
Pd
II
Reaction
Conversion
(%)
[a]
Yield
(mol%)
time (h)
1
100
10
12
50
2
120
10
12
60
3
140
10
12
4
100
20
12
77
47 (54)
[d]
5
100
20
30
86
53 (60)
[d]
6
100
20
46
100
30
(%)
[b]
(ºC)
[c]
62
91
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
[a] Conversion yield (from the 1H NMR spectra); [b] Isolated yield after chromatography; [c] Byproducts were observed; [d] Yield based on recovered starting material.
2.4.4. N-Deprotection via reductive desulfonylation reaction
The feasibility of the cleavage of the two N-(2-pyridyl)sulfonyl groups of the 2,2’biindolyl system led us to realize the full synthetic utility of our method. As an
example, compound 2 was treated with excess of Mg turnings in MeOH, affording the
free NH 2,2’-biindole 41 in 54% yield (route a, Scheme 2.21). On the other hand, 2,2’biindole 2 was also deprotected using Zn/NH4Cl/THF although prolonged reaction
time was required (48 h) to obtain a similar yield (52%, route b, Scheme 2.21).
Scheme 2.21
2.4.5. Mechanistic proposal
As already suggested for the Pd-catalyzed C2-olefination reaction of N-(2pyridyl)sulfonyl indoles, the significant activation brought about by the 2-PySO2 group
suggests an auxiliary-controlled direct cyclopalladation at the C2 of indole, facilitated
by the coordination of palladium(II) to the nitrogen in the 2-pyridylsulfonyl group to
form a six-membered ring. The resulting palladacycle I would evolve by forming a C2
palladated bisindolyl intermediate II which would afford the 2,2’-biindolyl skeleton
through a reductive elimination step (Scheme 2.22).
92
Chapter 2
Scheme 2.22
2.4.6. Intramolecular
version:
oxidative
coupling
of
bis(1H-indol-3-
yl)methanes
Assuming that the intramolecular version of this reaction would be much more
favourable than the intermolecular homocoupling, we decided to explore the
feasibility of the oxidative intramolecular coupling of bis(1H-indol-3-yl)methanes to
give tetracyclic diindole structures (Scheme 2.23). We settled on this type of starting
materials because of their ready availability through a double Friedel-Craft reaction
between the corresponding indole and a carbonyl compound in the presence of a
Lewis or Brönsted acid catalyst.89 Moreover, the final products are structurally
interesting because of their fixed coplanar S-cis conformation (with both nitrogens
pointing to the same side of the molecule).
89
a) C. Ramesh, J. Banerjee, R. Pal, B. Das, Adv. Synth. Catal. 2003, 345, 557. b) Yadav, J. S.;
Reddy, B. V. S.; Sunitha, S. Adv. Synth. Catal. 2003, 345, 349.
93
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
Scheme 2.23
a)
Synthesis of bis-indoles
Because of the pronounced electron-rich nature of their pyrrolic ring, indoles are
very reactive towards electrophilic substitution at C3 when subjected to the reaction
with carbonyl compounds in the presence of a suitable Lewis- or Brönsted-acid
catalyst. This reaction typically results in the formation of a bis(indolyl)methane as a
result of an initial Friedel-Crafts alkylation to give the corresponding (3indolyl)methanol derivative, which undergoes a second Friedel-Crafts alkylation
assisted by the acid catalyst with another molecule of indole. In accordance to this
route, bis-indole derivative 42 was prepared following a literature procedure89a and it
was isolated in 78% yield (Scheme 2.24). In this case, the N-protection with 2pyridylsulfonyl chloride (2.6 equiv) was not fully completed, affording almost an
equimolar mixture of the mono- and disulfonylated bis-indolyl derivatives 43 (26%
yield) and 44 (32% yield), respectively (Scheme 2.24).
Scheme 2.24
94
Chapter 2
However, we decided to investigate the behaviour of compounds 43 and 44 in
the Pd-catalyzed homocoupling reaction before making efforts trying to optimize the
efficiency and selectivity of this N-sulfonylation reaction.
b) Intramolecular oxidative coupling reaction
Initially, the 3,3’-bis indole derivative 43 was submitted to the optimized
conditions found for the dehydrogenative intermolecular homocoupling reaction: 10
mol% Pd(OAc)2, 1.5 equiv of Cu(OTf)2, under O2 atmosphere and using acetic acid
as solvent at 100 ºC. Unfortunately, the reaction didn’t take place at all and the
starting material was recovered unaltered (Scheme 2.25). This lack of reactivity was
attributed to a relatively strong coordination of the copper(II) salt, used as
stoichiometric oxidant, with the two pyridinyl nitrogens of the 2-pyridylsulfonyl groups.
This hypothesis is in accordance with the previously observed formation of an
insoluble solid in the crude reaction mixture (see optimization studies, section 2.4.1b)
which was attributed to the formation of a CuII-complex.
Scheme 2.25
To overcome this problem, the Cu(OTf)2 was replaced by cerium(IV) sulfate as
co-oxidant. Although in the initial optimization studies for the homocoupling reaction
we saw it was an efficient oxidant, in this case only the starting bis-indolyl methane
43 was detected in the crude reaction mixture by 1H NMR.
We next explored the reactivity of compound 44, bearing only one of its indolyl
nitrogen atom protected with the N-(2-pyridyl)sulfonyl group (Scheme 2.26). In this
case, after two hours of reaction at 100 ºC, a mixture of two new products 46 and 47
was obtained in a 40:60 relative ratio. After complete elucidation by NMR and EM
95
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
analysis, product 46 was identified as the 3-cyclohexenyl-N-(2-pyridyl)sulfonyl indole
while product 47 was found to be the 3-phenyl-N-(2-pyridyl)sulfonyl indole. Longer
reaction time (12 h) afforded exclusively compound 47 as the major component of the
mixture, which was isolated in good yield (76%). This result suggested that
compound 47 was formed in situ from the indole derivative 46 under the reaction
conditions.
Scheme 2.26
Mechanistically, the formation of the 3-cyclohexenyl indole derivative 46 from the
bis-indole 44 could be envisaged as the result of a retro-Friedel-Crafts reaction upon
activation at C3 with a Lewis acid followed by elimination to form the alkene.
Additionally, the formation of 3-phenyl indole 47 can be explained by in situ
aromatization of 46 under the oxidative conditions employed (Scheme 2.27).
Scheme 2.27
96
Chapter 2
2.5. Conclusions
We have developed a practical procedure for the catalytic oxidative
intermolecular homocoupling of indole derivatives leading to 2,2’-biindolyl systems.
This reaction implies a completely regiocontrolled two fold C−H bond functionalization
without requiring pre-activation at the reactive site or blocking the more reactive C3
position
of
the
idole
moiety.
To
our
knowledge,
catalytic
intermolecular
dehydrogenative homocoupling occurring exclusively at the C2 position of indole had
not been reported before.
Importantly, the efficiency of the reaction, in terms of both chemical yields and
the exquisite regiocontrol, strongly depends on the use of a N-(2-pyridyl)sulfonyl
group as both protecting and directing group, and the choice of Cu(OTf)2 as terminal
oxidant. The key role played by the N-(2-pyridyl)sulfonyl group has been attributed to
the stabilization of a presumed cyclopalladated intermediate involving the
coordination of the pyridyl nitrogen to the palladium.
Reaction parameters proved also to be an important factor for catalytic activity,
their optimization requiring intense screening studies. Optimal conditions were
established using Pd(OAc)2 as precatalyst (10 mol%), Cu(OTf)2 as the co-oxidant (1.5
equiv) under O2 atmosphere, in acetic acid as solvent and at 100 ºC. Under these
reaction conditions, 2,2’-biindoles are obtained with good yields and complete
regiocontrol, for a variety of substituted indoles. It is remarkable that the presence of
a bromine atom is also compatible with this catalytic system, which provide flexible
handle for subsequent product derivatization.
97
Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles
SO2Py
Pd(OAc)2 (10 mol%)
N
Cu(OTf)2 (1.5 equiv)
H
R
R
R
N
SO2Py
N
AcOH, O2, 100 ºC, 12 h
SO2Py
SO2Py
SO2Py
N
N
N
SO2Py
F
N
SO2Py
68%
66%
SO2Py
MeO
F
SO2Py
Br
N
N
OMe
SO2Py
64%
N
N
Br
SO2Py
62%
The easy reductive cleavage of the two N-(2-pyridyl)sulfonyl groups on the
resulting 2,2’-biindolyl systems under smooth conditions (Mg turnings in MeOH at
room temperature) led us to demostrate the full synthetic utility of our method.
Desulfonyl deprotection of the N,N’-protected 2,2-biindole motif (Mg turnings in
MeOH) afforded the free NH-biindole in acceptable yield.
98
Chapter 3:
C−H olefination of anilines and arylalkylamines
99
100
Chapter 3
3.
C−
−H olefination of anilines and arylalkylaminesImportance of anilines and
arylalkylamines
Aniline is the parent molecule of a vast family of aromatic amines. Since its
discovery in 1826 it has become one of the most important building blocks in
chemistry. In fact, aniline and alkylarylamine derivatives are privileged structures that
are ubiquitous in nature and can be often found as key components in
pharmaceutically active compounds.1 They embrace an important class of molecular
building blocks used as intermediates in many different fields of applications, such as
isocyanates, rubber processing chemicals, dyes and pigments, and agricultural
chemicals.90 Therefore, there is much interest in the synthesis of substituted aniline
and alkylarylamine derivatives. Figure 3.1 shows some representative examples of
this important family of compounds.
Figure 3.1
90
The Chemistry of Groups, Anilines. Part 1, Patai Series: The Chemistry of Functional; Z.
Rappoport, Ed. Willey: Chichester, UK, 2007.
101
C−H olefination of anilines and arylalkylamines
As we stated in the Introduction Chapter, the combination of transition metalcatalysis and a suitable directing group is a useful strategy to functionalize a
particular C−H bond in the presence of opposing steric and/or electronic factors,
thereby enabling the efficient construction of carbon–carbon or carbon–heteroatom
bonds with the desired regiocontrol. Regarding the direct functionalization of anilines,
the most commonly used N-protecting groups for this type of transformations are
amides (acetamide), carbamates and ureas, while sulfonamides have been rarely
used. In the following section, we will discuss the literature precedents related to the
direct C−H alkenylation of these aromatic systems, which have been classified on the
basis of the protecting group at the amino functionality. With respect to the catalyst,
palladium has been the typically used transition-metal, although recently other metals
such as rhodium have also been employed.
3.2. Direct C−
−H olefination of acetanilides
A number of protocols have been reported to be efficient for the metal-catalyzed
ortho-olefination of acetanilide derivatives with high regioselectivity.
In the early 1980s, Horino and Inue reported the ortho-alkenylation of
acetanilides prior formation of their cyclopalladation complexes.91 Reaction of
acetanilide with stoichiometric amounts of Pd(OAc)2 in refluxing toluene gave
complex I in good isolated yields (63-68%, Scheme 3.1). This complex reacted with
various olefins (such as methyl vinyl ketone, methyl acrylate, acrylonitrile or styrene)
in the presence of triethylamine in refluxing toluene to afford the corresponding 2substituted vinylacetanilides in aceptable yields (Scheme 3.1).
91
H. Horino, N. Inue, J. Org. Chem. 1981, 46, 4416.
102
Chapter 3
Scheme 3.1
Different acetanilides bearing electron-donating groups (such as methyl or
methoxy groups) or electron-withdrawing groups (such as acyl or ester groups) at
para- or meta-positions were well tolerated, leading to the corresponding orthoolefinated acetanilides in good yields after this two-step process. In the case of metasubstituted amides, the carbopalladation occured at the less hindered ortho-position.
In sharp contrast, acetanilides with ortho-substituents did not react with Pd(OAc)2
under these conditions, thus highlighting the high sensitivity of this reaction to steric
effects. To explain this failure, the authors proposed that the coordination of
palladium with the amide group might be an important factor, and the orthosubstituent could be occupying a sterically encumbering conformation causing a nonideal substrate-Pd interaction for carbometalation. Along the same line, Nmethylacetanilide did not undergo ortho-palladation with PdCl2 or with Pd(OAc)2
under the optimized conditions, presumably because of its increased steric
requirements.
These results suggested that the amide group must be able to assume its
tautomeric form in order to be able to form the ortho-palladacycle. In fact, formation of
complex II has been reported instead of the ortho-palladation complex in the reaction
of thioacetanilide with Na2PdCl4 (Figure 3.2).92
92
H. Alper, J. K. Currie, J. Organomet. Chem. 1979, 168, 369.
103
C−H olefination of anilines and arylalkylamines
Figure 3.2
However, despite the significance of this C−H functionalization reaction, the
requirement of a stoichiometric amount of a palladium(II) salt represents a major
drawback that limited the development of synthetic applications.
In 2002, de Vries, van Leeuwen and co-workers notably improved this reaction
describing the first catalytic version of this reaction.93 Thus, a new protocol for the
oxidative coupling of acetanilides and electron-deficient olefins was developed using
catalytic amounts of Pd(OAc)2 (2 mol%) and benzoquinone (BQ) as oxidant, under
mild conditions (AcOH as solvent at room temperature).
The use of other oxidants, such as H2O2 or Cu(OAc)2, gave significantly lower
conversions in comparison to benzoquinone. The authors proposed that BQ was not
only an oxidant but also served as a ligand that stabilized the active Pd species
formed during the catalytic cycle. However, the addition of more than 1.0 equiv of BQ
did not improve the yield significantly.
Addition of inorganic acids (HCl, H2SO4) had a large detrimental effect on the
catalytic performance. This effect was attributed to the coordination of the halide to
the Pd(II) center, thereby decreasing its electrophilicity and blocking its catalytic
activity. By contrast, the presence of a substoichiometric amount (0.5-1.0 equiv) of ptoluenesulfonic acid (TsOH) had a large beneficial effect, although larger amounts of
TsOH did not improve the yields. De Vries and van Leeuwen proposed that the
beneficial effect of TsOH was due to the increased electrophilicity of Pd(OTs),
resulting in faster metalation of the aromatic C−H bond.
93
M. D. K Boele, G. P. F. van Strijdonck, A. H. M. de Vries, P. C. J. Kamer, J. G. de Vries, P. W. N.
M. van Leeuwen, J. Am. Chem. Soc. 2002, 124, 1586.
104
Chapter 3
Regarding the alkene counterpart, only n-butyl acrylate was used. On the other
hand, substituents on the aromatic moiety of the acetanilide substrate significantly
influenced the efficiency of the coupling reaction. Electron-withdrawing substituents
gave lower conversions than electron-donating groups. As expected by the authors
due to the known sensitivity of this reaction to steric effects, ortho-substitution
hampered the reaction, providing low conversions of the alkenylated products
(Scheme 3.2). In agreement with this observation, minor amounts (<1%) of ortho-diolefination was only observed in some few cases, indicating disfavored electronic and
steric properties of the product to undergo a second substitution. Also disfavoured by
steric effects, the reaction of N-methylacetanilide gave no conversion at all.
Scheme 3.2
Mechanistic studies were driven in order to understand the mechanism of this
oxidative coupling. In first place, competition studies of a series of para-substituted
anilides of diverse electronic properties revealed that electron-rich arenes reacted
significantly faster than electron-neutral or electron-deficient acetanilide derivatives
+
(ρ = 2.2, Figure 3.3).
Me
HN
Me
O
HN
>
Me
O
HN
=
OMe
Me
O
HN
O
>>
CF3
Figure 3.3
105
C−H olefination of anilines and arylalkylamines
The reaction exhibited a considerable intramolecular kinetic isotope effect (kH/kD
= 3), indicating slow C−H bond activation (Scheme 3.3). Besides, the dimeric orthopalladated anilide complexes were tested in the reaction with n-butyl acrylate and the
outcome revealed that the reaction rate was at least an order of magnitude higher
when using the preformed complexes compared with the in situ generated catalysts.
The authors proposed an electrophilic substitution reaction pathway involving slow
electrophilic attack of cationic [PdOAc]+ species on the π-system of the arenes.
Scheme 3.3
The productive catalytic cycle of this particular reaction has been delineated
more recently by Brown et al. based on experimental data, NMR analysis and single
crystal diffraction studies (Scheme 3.4).94 Being aware of the fact that electron-rich
acetanilides were more favored substrates than electron-poor derivatives, a
conventional
electrophilic
substitution
mechanism
was
considered.
Kinetic
experiments showed the rate of the reaction to be first order in anilide and Pd(OAc)2,
but independent of [p-benzoquinone], alkene or p-TsOH. It was also observed that
formation of the palladacycle and its reaction with alkenes took place after the
displacement of acetate by tosylate at the palladium center. Therefore, Pd(OAc)2 was
first converted into a more electrophilic palladium species for effective catalysis,
defining the main role of the added p-TsOH as essential component in the reaction
mixture (whereas acetate was found to be dispensable).
It was concluded that the palladacycle intermediate, formed in the rate-limiting
stage by reaction with an electrophilic palladium entity, was directly involved in the
catalysis. Given that a stoichiometric amount of BQ was required in the absence of
94
W. Rauf, A. L. Thompson, J. M. Brown, Dalton Trans. 2010, 39, 10414.
106
Chapter 3
any co-oxidants, it was generally accepted that it participated directly in the process
as a two-proton, two-electron acceptor. However, the precise mechanism of the
catalyst regeneration step from the palladium hydride by the oxidant was not wellunderstood.
Scheme 3.4
Realizing that the original report by de Vries and van Leeuwen did not include
any example of anilide derivatives containing halogen substituents, in 2005, Prasad
and co-workers successfully applied this protocol to the olefination of a variety of
halogenated acetanilides. Moreover, this adapted procedure required an increase
amount of TsOH from 0.5 equiv to 1.0 equivalent.95 They demonstrated that the
presence of a halogen (F, Cl, Br or I) at the meta- or para-positions did not interfere in
the ortho C−H activation (Scheme 3.5).
95
G. T. Lee, X. Jiang, K. Prasad, O. Repič, T. J. Blacklock, Adv. Synth. Catal. 2005, 347, 1921.
107
C−H olefination of anilines and arylalkylamines
Scheme 3.5
In 2007, Jutand and co-workers rendered the protocol described by de Vries and
van Leewen93 catalytic in benzoquinone (10 mol%) and eluded the use of p-TsOH as
additive.96 For that purpose, an electrochemical oxidation (anode) was applied to
regenerate the benzoquinone from the reduced hydroquinone formed in each
catalytic cycle, the electrons playing then the role of co-oxidant. Indeed, it was also
possible to start with a catalytic amount of hydroquinone since it was oxidized at the
anode into benzoquinone. However, the cost of this improvement was that the
amount of Pd(OAc)2 needed to be increased to 10 mol% (while de Vries/Van
Leeuwen’s system used only 2 mol%).
The authors proposed the following mechanism for this electrochemical Hecktype reaction (Scheme 3.6).
96
C. Amatore, C. Cammoun, A. Jutand, Adv. Synth. Catal. 2007, 349, 292.
108
Chapter 3
Scheme 3.6
In the same year, Liu, Guo and co-workers, in order to avoid the use of
benzoquinone in the above-mentioned protocol for the ortho-selective C−H olefination
of acetanilides, devised a greener variation that replaced the oxidant by a catalytic
amount of Cu(OAc)2 in the presence of molecular oxygen as terminal oxidant.97
These authors also found that TsOH had some important influence on the reaction,
suggesting that the reason for this beneficial effect was that TsO− could increase the
electrophilicity of the Pd(II) center by replacing an AcO− ligand and therefore causing
a faster activation of the C–H bond. However, this modification towards a more
sustainable process resulted in a decrease of the reactivity, being only applicable to
97
J.-R. Wang, C.-T. Yang, L. Liu, Q.-X. Guo, Tetrahedron Lett. 2007, 48, 5449.
109
C−H olefination of anilines and arylalkylamines
anilide derivatives bearing electron-donating substituents and requiring higher
temperatures (60 ºC) (Scheme 3.7).
Scheme 3.7
These authors also found that the N-methyl-N-phenylacetamide didn’t provide
the desired product even after longer reaction time, evidencing that the presence of
an N-methyl group completely blocked the C–H activation (Scheme 3.8). It was
suggested that the nitrogen atom (or the amide oxygen in a deprotonated amide)
should be deeply involved in the Pd-mediated C–H activation process, presumably by
coordinating to the metal.
Scheme 3.8
In 2010, Lipshutz’s group disclosed a new protocol for the effective orthoolefination of acetanilides that was effective in water at room temperature, without
requiring addition of external acid.98 A cationic palladium(II) salt was used for this
purpose, in the presence of a suitable surfactant (PTS, polyoxyethanyl α-tocopheryl
sebacate), and a mixture of BQ (1.0 equiv) and AgNO3 (2.0 equiv) as oxidants. The
reaction proved to be limited in scope. Reactions of m-alkoxy-functionalized anilide
98
T. Nishikata, B. H. Lipshutz, Org. Lett. 2010, 12, 1972.
110
Chapter 3
derivatives with acrylates proceed smoothly to the less hindered ortho-position.
Unexpectedly, the isomeric p-alkoxy analogues were found to be unreactive. This
protocol could also be successfully applied to urea derivatives (Scheme 3.9).
Scheme 3.9
Also in 2010, Youn and co-workers described a protocol for the selective orthoalkenylation of acetanilides using Pd(OAc)2 as catalyst (5 mol%), K2S2O8 as oxidant
(1.0 equiv), in a 4:1 mixture of TFA/CH2Cl2 as solvent, at room temperature.99 Not
only acrylates but also other activated olefins (N,N-dimethylacrylamide or methyl vinyl
ketone) proceeded smoothly to afford the corresponding 2-alkenylacetanilides in
moderate to good yields.
Anilides bearing electron-donating or electron-withdrawing substituents were well
tolerated, giving cross-coupling products in moderate to good yields. For metasubstituted acetanilides the reaction took place at the sterically less hindered aryl
C−H bond. The applicability of this protocol for electron-deficient substrates is
remarkable, because they were found to be less reactive when using the previously
mentioned reported Pd-catalyzed Fujiwara–Moritani protocol.93-99 Furthermore, orthosubstituted acetanilides were also competent substrates, providing the di-orthosubstituted products in good yields (Scheme 3.10).
99
B. S. Kim, C. Jang, D. J. Lee, S. W. Youn, Chem. Asian J. 2010, 5, 2336.
111
C−H olefination of anilines and arylalkylamines
Scheme 3.10
Hii and co-workers also focused on the development of a “greener” and
environmentally more sustainable set of conditions for the ortho-olefination of
acetanilides.100 This group envisioned that this reaction could be realized under
ambient and homogeneous conditions while avoiding hazards associated with
handling toxic BQ and hydroquinone (HQ). Thus, they found out that tert-butyl
perbenzoate (TBPB) could be an effective substitute for benzoquinone, allowing the
reaction to be carried out at room temperature in acetic acid as solvent.
It had been previously suggested that TBPB regenerated the PdII directly from
palladium hydrides (resulting from the β-hydride elimination) by O−O bond cleavage
via a six-membered transition state, the perbenzoate acting as a hydrogen acceptor
(Scheme 3.11, bottom).101 This could imply that the regeneration of the catalyst might
occur without involving the generation of a Pd0 intermediate, which is known to
display a strong tendency to undergo deactivation through the formation of metal
clusters.
However, Hii and co-workers observed the deposition of a small amount of Pd
black even at room temperature. This was avoided by the addition of a small amount
of Cu(OAc)2 (5 mol%) as a co-catalyst to reoxidize Pd0 to PdII. The optimized reaction
100
X. Liu, K. K. (Mimi) Hii, J. Org. Chem. 2011, 76, 8022.
101
J. Tsuji, H. Nagashima, Tetrahedron 1984, 40, 2699.
112
Chapter 3
conditions were applied to the reaction of different acetanilides with butyl acrylate.
The pattern of reactivity was found to be comparable to previous reactions performed
using BQ as an oxidant: higher yields were obtained with electronically neutral or
electron-rich anilides, while the reaction with an electron-poor aromatic substrate was
sluggish (Scheme 3.11).
Scheme 3.11
3.2.1.
C−
−H olefination of N-aryl ureas
Although less used than the acetamide, the urea motif is another common
directing group that has provided excellent results in the ortho-functionalization of
aniline derivatives.
Brown and co-workers described the ortho-olefination of N,N-dimethyl-N’-aryl
ureas with butyl acrylate using the catalytic system described by de Vries and van
Leeuwen for the ortho-olefination of acetanilides [Pd(OAc)2/BQ/TsOH].102 The authors
conducted competitive reactivity studies between anilides and N-aryl ureas,
stablishing that the latter were more reactive. They also noted that palladacycles
were formed faster from aryl ureas than from anilides. According to the authors, this
102
W. Rauf, A. L. Thompson, J. M. Brown, Chem. Commun. 2009, 3874.
113
C−H olefination of anilines and arylalkylamines
was important since the turnover-limiting step for the overall reaction was the
formation of palladacycle. Nevertheless, it should be noticed that these experiments
were carried out in acetone as solvent, and the results obtained were compared with
the results found in literature,93 whereas the alkenylation reaction of anilides was
performed in acetic acid or acetic acid/toluene as solvent. Therefore, the palladium
intermediates involved could differ (Scheme 3.12).
Scheme 3.12
Lloyd-Jones, Booker-Milburn and co-workers found out that the reaction of Nethyl-N’-phenyl urea with α-methylstyrene, in toluene, with PdCl2(MeCN)2 (10 mol%)
as catalyst, gave surprisingly the indoline shown in Scheme 3.13, although in a very
low yield (10%).103
Scheme 3.13
The authors envisioned that the generation of the indoline could proceed via an
interrupted Heck-type process. After the urea-directed ortho-cyclopalladation and
103
C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagné, G. C. Lloyd-Jones, K. I. Booker-Milburn, J.
Am. Chem. Soc. 2008, 130, 10066.
114
Chapter 3
migratory insertion of the olefin, the resulting PdII-complex intermediate would react
with de NH group from the urea motif instead of evolving through the typical β-hydride
elimination to afford the indoline via cyclization.
This discovery prompted the research team to optimize this new reaction
pathway by switching the substrate from α-methyl-styrene to an electron-deficient
diene such as (E)-ethyl penta-2,4-dienoate, in this case leading to a C2-alkenyl
indoline derivative. The desired indoline derivative was isolated with low yield (37%
after 24 h at 50 ºC) when the usual mixture toluene/AcOH was used as solvent. It
was found that p-TsOH was a necessary additive, whereas water was detrimental for
the reaction. Finally, the reaction in THF in the presence of molecular sieves or Ac2O
as drying agents afforded the C2-alkenylated indoline in an improved 82% yield.
These optimized conditions were successfully applied to the reaction of several
aniline derivatives with different electron-deficient dienes, except for the case of
aromatic substrates substituted with electron-withdrawing groups, for which reduced
reaction rates and yields were observed (Scheme 3.14). Ortho-substitution inhibited
the reaction, possibly because an ortho-substituent would prevent the urea moiety
from adopting a conformation suitable for Pd-complexation and/or ortho C−H
insertion.
Scheme 3.14
The requirement for TsOH in the reaction medium suggested the in situ
formation of a reactive palladium mono- or bis-tosylate species from the Pd(OAc)2
115
C−H olefination of anilines and arylalkylamines
precatalyst. Indeed, when (MeCN)2Pd(OTs) (10 mol%) was used as catalyst in the
absence of added TsOH, the reaction took place in good yield (85%). These results
demonstrated that aromatic C−H bond activation could occur under mild conditions,
that was, relatively non acidic conditions and 50 ºC for 2-4 h, when highly electrophilic
PdII species were used as catalyst.
The authors proposed the catalytic cycle shown in Scheme 3.15. It is noteworthy
that although these were oxidative reaction conditions, no oxidation of indolines to the
corresponding indoles was observed.
Scheme 3.15
More recently, and after our work was published, Yu and co-workers described
an efficient method for the selective ortho-olefination of N-alkyl-N’-aryl ureas using
the catalytic system developed by de Vries-van Leeuwen.104 Urea derivatives bearing
electron-donating or withdrawing substituents were well tolerated, giving crosscoupling products in moderate to good yields. Substitution in the nitrogen of the urea
motif was also well tolerated (R2, Scheme 3.16).
104
L. Wang, S. Liu, Z. Li, Y. Yu, Org. Lett. 2011, 13, 6137.
116
Chapter 3
NHR2
HN
NHR2
O
CO2Bu
+
R1
1.2 equiv
HN
HN
Pd(OAc)2 (10 mol%)
BQ (1.0 equiv)
TsOH (30 mol%)
AcOH, 60 ºC
HN
CO2Bu
R1
NHR2
HN
O
HN
CO2Bu
O
HN
O
CO2Bu
O
CO2Bu
R1
R1 = p-Me, 90%
R1 = p-OMe, 86%
R1 = p-CF3, 82%
75%
R2 = H, 46%
R2 = Bz, 72%
Scheme 3.16
These authors also proposed a plausible mechanistic pathway involving initial
coordination of PdII to the NH of the urea moiety and subsequent cyclopalladation at
the ortho-position to afford an aryl-PdII metastable complex, stabilized by coordination
to the urea motif (Scheme 3.17). Then, olefin insertion would take place followed by
β-hydride elimination of the intermediate to produce the E-olefinated products.
Finally, p-benzoquinone would oxidize the reduced Pd0 to the PdII oxidation state.
Scheme 3.17
117
C−H olefination of anilines and arylalkylamines
3.2.2. C−
−H olefination of N-sulfonylanilines
To the best of our knowledge, the only example found in literature of a protocol
for the direct ortho-olefination of N-sulfonylanilines was described by Miura and coworkers in 1998.105 In particular, N-arylsulfonyl derivatives of 2-phenylaniline were
found to react efficiently with acrylate esters to give phenanthridine derivatives. The
appropriate catalytic system was: Pd(OAc)2 as catalyst (5 mol%), Cu(OAc)2 as
oxidant (5 mol%), and molecular sieves in dry DMF under air. The presence of a
base was also needed (NaOAc, 0.5 equiv) for achieving high conversions.
Various activated olefins such as acrylates, acrylamides or acrylonitrile
performed well in this reaction. An electron-withdrawing group (e.g. Cl) in the
benzenesulfonyl moiety seemed to enhance the reactivity (Scheme 3.18).
O O
N S
H
+
Cl
Pd(OAc)2 (5 mol%)
Cu(OAc)2.H2O (5 mol%)
R
3.0 equiv
NaOAc (0.5 equiv)
MS 4A, DMF, air
100-120 ºC
O O
S 4-ClC H
6 4
R
O O
S 4-ClC H
6 4
N
O O
S 4-ClC H
6 4
N
CO2Bu
97%
O O
S 4-ClC H
6 4
N
N
CONMe2
76%
CN
38%
Scheme 3.18
The authors proposed that the ArSO2NH group would direct the initial orthopalladation step of the benzene ring at the ortho-position, to afford the
heteropalladacycle I, whose subsequent intermolecular reaction with the alkene
would finally release the ortho-olefinated product (Scheme 3.19, path a). Later on,
Muzart and Le Bras suggested an alternative mechanistic pathway involving the
105
M. Miura, T. Tsuda, T. Satoh, S. Pivsa-Art, M. Nomura, J. Org. Chem. 1998, 63, 5211.
118
Chapter 3
formation of complex II, which would evolve to the reaction product via a Heck-type
reaction (Scheme 3.19, path b).106
Scheme 3.19
Independently from the reaction pathway, the acidic nature of the NH protons of
the arylsulfonyl group is a crucial factor since the catalytic oxidative coupling did not
proceed with 2-phenylaniline or N-benzylideneaniline as substrates. If the alkene
bears an electron-withdrawing group, an aza-Michael-type reaction occurs after the
C−H alkenylation reaction.
3.2.3. Rh-catalyzed C−
−H olefination of aromatic amines
Although palladium catalysis has captured the focus of most of the research
effort in the Fujiwara-Moritani reaction of aromatic amines with olefins, several
research groups have recently discovered that other transition metal-based catalysts
are also competent in this transformation. Specifically, rhodium often allows lower
106
J. Le Bras, J. Muzart, Chem. Rev. 2011, 111, 1170.
119
C−H olefination of anilines and arylalkylamines
catalytic loadings than palladium as well as complementary selectivities and olefin
scope.107
In 2009, Satoh, Miura and co-workers found out that catalytic amounts of
(Cp*RhCl2)2 induced the oxidative ortho-olefination of N-phenylpyrazoles, 2phenylpyridines and related compounds with various alkenes (such as acrylates and
styrenes) in the presence of a copper oxidant.108 Interestingly, this catalyst system
allowed for a sequential double ortho-olefination with two different alkenes, enabling
the acces to di-ortho-olefinated arenes in good yields (Scheme 3.20).
Scheme 3.20
The mechanistic cycle proposed for this transformation implies a RhIII/RhI
catalytic cycle similar to the one proposed in PdII/Pd0 catalysis: ortho-methalation,
olefin insertion, β-H elimination and re-oxidation of the catalyst (Scheme 3.21).
107
After our work was published, a Ru-catalyzed oxidative C−H olefination of anilides and
benzamides in water has been developed: L. Ackermann, L. Wang, R. Wolfram, A. V. Lygin, Org.
Lett. 2012, 14, 728.
108
N. Umeda, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2009, 74, 7094.
120
Chapter 3
Scheme 3.21
More recently, Glorius and co-workers developed a related Rh-catalyzed
oxidative olefination of acetanilides using a cationic rhodium salt, generated in situ
from the combination of (Cp*RhCl2)2 (0.5 mol%) and a silver salt (AgSbF6, 2 mol%),
in the presence of Cu(OAc)2 (2.1 equiv) as the terminal oxidant in tert-amyl alcohol at
120 ºC.109 The reaction proceeded smoothly with acrylates and less activated olefins
such as styrenes (Scheme 3.22). Even an ortho-vinylation took place under mild
pressure of ethylene (2 bar), although higher catalytic loading was required for this
particular case (2.5 mol% [Rh]).
Scheme 3.22
109
F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9982.
121
C−H olefination of anilines and arylalkylamines
The reaction tolerated the presence of both electron-rich and electron-poor
substituents, at para- and meta-positions (Scheme 3.22). Importantly, halide
substitution was well tolerated, both in the acetanilide and in the styrene. Thus,
valuable brominated products could be formed efficiently with no proto-debromination
or Heck coupling products, allowing further functionalization through other crosscoupling reactions. However, ortho-methyl-acetanilide was less reactive (51%
isolated yield), compared to the electronically analogous product meta-methyl
acetanilide that gave the ortho-olefinated product in high yield (88%). The authors
attributed this decrease in the reactivity to the steric hindrance between the amide
directing group and the CH3 substituent at the ortho-position, thus disturbing the
planarity of the intermediate complex (Scheme 3.23). Similarly, N-methyl-acetanilide
only led to 13% conversion of the expected ortho-olefination product with styrene.
Scheme 3.23
This ortho-steric effect might also account for the fact that the transformation was
virtually stopped at the mono-olefination stage. In other words, the second C−H
activation was disfavored compared to the first one because of the difficulty for the
directing group to access a conformation coplanar with the aromatic ring due to steric
hindrance caused with the stilbene functional group on the other ortho position. Thus,
a
planar
conformation
of
the
acetanilide
seemed
important
for
effective
cyclometalation.
One year later, in 2011, the group of Glorius developed a Rh-catalyzed orthoolefination reaction of aniline derivatives using a N-methoxy urea as an oxidizing-
122
Chapter 3
directing group.110 The authors envisioned that the N−O bond could act as internal
oxidant.111 As the oxidant was pre-installed in the substrate, this strategy benefited
from milder reaction conditions, thereby allowing broader scope of substrates.
However, it was found that in this case the oxidation was not exclusively internal,112
being necessary to use a second equivalent of the substrate (N-methoxy-N’-aryl
urea) as external oxidant. One equivalent served as the substrate, whereas the other
equivalent was used as organic oxidant; the alkene being the limiting reagent. Due to
the Michael acceptor character of the olefin, after initial olefination step, a 6-exo azaMichael addition took place to afford dihydroquinazolinones (Scheme 3.24).
H
N
H
N
R
O
(2.0 equiv)
H
N
OMe
EWG
EWG = CN, 44%
EWG = SO2Ph, 69%
OMe
H
N
(Cp*RhCl2)2 (2.5 mol%)
R
NaOAc (30 mol%)
t-BuOH, 70 ºC, 18 h
O
N
OMe
EWG
H
N
O
N
EWG (1.0 equiv)
R
O
N
O
N
OMe
CO2Et
R = NO2, 71%
R = Me, 77%
R
H
N
R
O
N
OMe
CO2Et
R = Cl, 61%
R = OMe, 73%
H
N
OMe
CO2Et
R = Me, 60%
R = Br, 64%
Scheme 3.24
The reaction proceeded smoothly with a variety of olefins such as acrylates,
methyl vinyl ketone, acrylonitrile or sulfonates. Regarding the electronic effects of
substituents in para-position, the reaction tolerated the presence of electronwithdrawing and electron-donating groups, although for electron-rich aromatic
systems a higher reaction temperature was required. Regardless of their electronic
110
J. Willwacher, S. Rakshit, F. Glorius, Org. Biomol. Chem. 2011, 9, 4736.
111
For a recent mini-review on internal oxidants in C−H bond activation, see: F. W. Patureau, F.
Glorius, Angew. Chem. Int. Ed. 2011, 50, 1977.
112
For an example of full internal oxidation in ortho-functionalization of N-methoxybenzamides, see:
S. Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc. 2011, 133, 2350.
123
C−H olefination of anilines and arylalkylamines
nature, substituents at the meta-position afforded the desired cyclized products in
good yields and high regioisomeric ratios (13:1 to >24:1), favouring the activation of
the less hindered C−H bond. Substitution at the ortho-position was also compatible
with the reaction conditions. It is also noteworthy that all tested halogen substituents
(Br, Cl, F) on the aromatic ring were amenable to the reaction, not being detected the
corresponding Heck-products from oxidative addition.
To gain insights into the mechanism of this transformation, a series of deuteriumlabeling and kinetic competition experiments were carried out. The use of tBuOD as
solvent, under otherwise identical reaction conditions, resulted in 89% deuterium
incorporation at the two ortho-positions, indicating that the C−H bond activation step
was reversible under the reaction conditions (Scheme 3.25).
H
N
H
N
O
D
OMe
(Cp*RhCl2)2 (2.5 mol%)
NaOAc (30 mol%)
t-BuOD, 70 ºC, 18 h
D
N
D
N
D
OMe
O
ortho-incorporation: 89% (1H NMR analysis)
Scheme 3.25
On the other hand, a competition experiment between deuterated and nondeuterated substrates revealed an intermolecular kinetic isotope effect (kH/kD) of 2.7
at low conversion (20%), suggesting that C−H bond activation was involved in the
rate-determining step of the catalytic cycle (Scheme 3.26).
Scheme 3.26
124
Chapter 3
Furthermore, based on their observation that electron-poor substrates generally
reacted faster than electron-rich urea substrates, the authors suggested that C−H
bond activation was most likely occuring via a concerted metallation-deprotonation
mechanism (CMD). In the absence of NaOAc, the reaction did not work, showing the
crucial role of the acetate ion in the reaction.
Finally, reductive cleavage of the N−O bond was readily achieved by treatment
of the obtained aza-Michael addition product with SmI2 at room-temperature,
affording the free dihydroquinazolinone in good yield (89%, Scheme 3.27), thereby
expanding the synthetic utility of the reported transformation.
Scheme 3.27
3.3. C−
−H olefination of aryl alkylamines
Although the ortho-cyclopalladation complex with N,N-dimethylbenzylamine was
reported in 1966 by Cope and Friedrich,113 the reactivity of such complex with styrene
was disclosed by Tsuji in 1969 without experimental details.114 Six years later, Julia
and co-workers reported the reaction of a similar cyclopalladated complex with ethyl
acrylate.115
113
A. C. Cope, E. C. Friedrich, J. Am. Chem. Soc. 1966, 90, 909.
114
Unpublished results from J. Tsuji, K. Ohno, cited in J. Tsuji, Acc. Chem. Res. 1969, 2, 144, note
67.
115
M. Julia, M. Duteil, J. Y. Lallemand, J. Organomet. Chem. 1975, 102, 239.
125
C−H olefination of anilines and arylalkylamines
More than a quarter of a century later, in 2007, the first catalytic procedure was
developed by Shi and co-workers.116 After intense screening optimization studies,
including Pd(0) reoxidants (CuII salts, O2, BQ, PhI(OAc)2) and solvents, the optimal
conditions were: PdCl2 (5 mol%) as catalyst, Cu(OAc)2 as oxidant (1.0 equiv) and 16
equiv of AcOH in CF3CH2OH as solvent. Various olefins such as acrylates and
acrylamide were successfully coupled, although less activated olefins such as
styrene failed to react. With regard to substitution at the arene counterpart, the
catalyst system tolerated the presence of electron-withdrawing and electron-donating
groups, even in the ortho-positions. The olefination of other benzylamine derivatives
with N-alkyl groups different than NMe2 provided low yields.
Aside from the interest of dimethylbezylamines as structural subunits found in
some bioactive molecules,117 this method could not be applied to the synthesis of
other nitrogen-derivatives. The NMe2 group cannot be considered as a protected
amino group. Therefore, as synthetic application, the N,N-dimethylaminomethyl unit
was transformed into a methyl group by hydrogenolisis (H2, Pd/C) to provide access
to 3-(o-tolyl)propanoic acid derivatives, which are also interesting structural motifs
(Scheme 3.28). Both transformations (ortho-olefination and hydrogenolisis) could be
combined in one vessel to offer a much more environmentally benign process.
Scheme 3.28
116
G. Cai, Y. Fu, Y. Li, X. Wan, Z. Shi, J. Am. Chem. Soc. 2007, 129, 7666.
117
a) J. M. Fevig, J. Cacciola, J. Buriak, K. A. Rossi, R. M. Knabb, J. M. Luettgen, P. C. Wong, S. A.
Bai, R. R. Wexler, P. Y. S. Lam, Bioorg. Med. Chem. Lett. 2006, 16, 3755; b) H. F. Kung, S. Newman,
S.-R. Choi, S. Oya, C. Hou, Z.-P. Zhuang, P. D. Acton, K. Ploessl, J. Winkler, M.-P. Kung, J. Med.
Chem. 2004, 47, 5258.
126
Chapter 3
After mechanistic studies, it has been proposed that the role of the AcOH is most
likely to tune the concentration of the free amine moiety in order to promote the Pdcatalyzed C−H cleavage. In this case, the use of cationic PdII-complexes such as
Pd(CH3CN)4(BF4)2 in the absence of AcOH resulted in very poor yields.
To confirm the key role of the N,N-dimethylaminomethyl group in controlling the
reactivity and regioselectivity of the process, palladacycle I was prepared using
stoichiometric amounts of PdII. Hence, it was confirmed the stabilization of the orthometalation intermediate by coordination with the tertiary amine through a fivemembered metallacycle. This palladacycle could catalyze ortho-olefination in
excellent efficiency under the standard conditions (Scheme 3.29), thus suggesting
that it could be a key intermediate during this catalytic cycle. Moreover, the authors
performed some deuterium-labeling studies which revealed an intermolecular isotope
effect (kH/kD) of 2.2. Consequently, they postulated that the cleavage of the C−H bond
at the ortho-position was involved in the rate-determining step.
Scheme 3.29
In 2007, Yu and co-workers reported the PdII-catalyzed ortho-alkenylation of
homobenzyl and bis-homobenzyl sulfonamides using AgOAc as reoxidant in a
DMF/ClCH2CH2Cl mixture. This protocol provided an access to structural motifs of
high relevance in medicinal chemistry.118 Triflamide was found to be the optimal
sulfonamide group. A cyclopalladation was suggested as the initial step;
phenethylamine derivatives leading to a 6-membered ring palladacycle, whereas the
bis-homobenzylic
sulfonamides
would
evolve
through
a
7-membered
ring
palladacycle. Both electron-deficient (such as acrylates) and less activated olefins
118
J.-J. Li, T.-S. Mei, J.-Q. Yu, Angew. Chem. Int. Ed. 2008, 47, 6452.
127
C−H olefination of anilines and arylalkylamines
(such as styrenes) were reactive (Scheme 3.30). Although dialkenylated products
were formed in some cases, their formation was decreased in the presence of
NaH2PO4. Vinyl ketones provided tetrahydroisoquinolines via a tandem C−H
alkenylation/aza-Michael addition. Hence, this olefination cyclization reaction could
be envisaged as an approach to the isoquinoline skeleton complementary to the wellestablished Pictet–Spengler condensation and the Bischler–Napieralski cyclization.
Interestingly, unlike these latter two strategies that often require at least two electrondonating groups at the aromatic ring, the reaction developed by Yu did not require
electron-donating groups on the aryl rings. Another important feature of this
transformation was its wide functional tolerance, being compatible with sensitive
groups such as trifluoromethylsulfonate (OTf).
Scheme 3.30
128
Chapter 3
3.4. Aim of the project
Despite great advances made in the C−H ortho-olefination reaction of aniline and
arylalkylamine derivatives, there are still important challenges to be solved. For
instance, one of the main limitations refers to the structural versatility of the process:
few methods have demonstrated to tolerate a wide range of olefin coupling partners
(the vast majority are restricted to the use of acrylates). With regard to the aromatic
substitution, the structural limitation is a consequence of the significant electronic and
steric sensitivity. Thus, anilides substituted with strong electron-withdrawing groups
or with ortho-substituents showed generally poor reactivity. Also, due to steric
demands, the reaction is currently limited to NH-anilide derivatives; the presence of
an alkyl substituent at the nitrogen inhibits the reaction. Another issue to be solved is
the lack of protocols allowing di-ortho-olefination (except for some isolated
examples).
With this general view of the state-of-art of the reaction, we envisioned to apply
the concept of C−H functionalization assisted by a directing N-(heteroaryl)sulfonyl
group to aniline derivatives. Thus, our main objective would be to broaden the
structural scope of the reaction to difficult-to-activate substrates, focusing on N-alkyl
aniline derivatives, which have been, so far, reported to be unreactive substrates in
this reaction. Along the same line, another challenge that needed to be addressed
would be the double C−H ortho-alkenylation of this type of compounds, which implies
solving the poor reactivity showed by ortho-substituted aniline derivatives (Scheme
3.31).
Scheme 3.31
129
C−H olefination of anilines and arylalkylamines
The presence of an alkyl group (R1) onto the nitrogen, especially if it is
functionalised, is important because it provides flexible handles for further
functionalization of the final products. As an illustration, we envisioned that a direct
synthetic application for this alkenylation protocol could be the synthesis of indole
derivatives from an aniline derivative containing an adequately functionalized N-alkyl
group (e.g. methoxycarbonyl methyl group) as shown in Scheme 3.32.
Scheme 3.32
Another structural limitation generally found in C−H functionalization processes
assisted by directing groups is that the length of the tether connecting the
coordinating unit to the substrate plays a critical role in the efficiency of the reaction.
In contrast, there have been only isolated examples of successful reactions where
different tether lengths satisfied geometrical requirements to generate reactive
metallacyclic complex intermediates.119 In fact, in the vast majority of cases, longer or
shorter tethers provided insufficient or lack of reactivity. To push further the limits of
this coupling reaction and to expand the substrate scope, we planned to test the
structural flexibility of this method with regard to the tether length. A direct
consequence of elongating the tether length was the formation of palladacycles of
increased ring-sizes. Therefore, in case of achieving this goal, the process could find
applicability to benzylamine (n = 1), phenethylamine (n = 2) and γ-arylpropylamine
(n = 3) derivatives (Scheme 3.33).
119
D.-H. Wang, K. M. Engle, B.-F. Shi, J.-Q. Yu, Science 2010, 327, 315.
130
Chapter 3
Scheme 3.33
Surprisingly, in none of the already existing protocols for the ortho-olefination of
aniline derivatives, the selective deprotection of the amino group without altering the
conjugated alkene motif (typically acrylate) has been described. The reason could be
that harsh (strongly basic) conditions were typically needed for the deprotection of
amides and ureas. By contrast, one of the advantages associated to the use of N(heteroaryl)sulfonyl directing group was the easy deprotection of the amino group
under mild reductive conditions, compatible with the labile conjugated olefin moiety
present in the products. In the case of homologated substrates (n ≥1), this
deprotection would enable the construction of nitrogen containing heterocycles
relevant from synthetic and medicinal chemistry standpoints.
Scheme 3.34
Before entering into the “results and discussion” section of this chapter, it must
be noted that this research project aimed to address the above-mentioned challenges
has constituted the point of intersection of two Ph.D. Theses, both focussing on
catalytic C−H functionalization. Nevertheless, each student’s contribution is clearly
specified along the presentation/discussion of the results.
131
C−H olefination of anilines and arylalkylamines
3.5. C−
−H ortho-olefination reaction of N-sulfonyl aniline derivatives
3.5.1. C−
−H olefination of N-methyl anilines: optimization studies
In light of the previous good results obtained with the use of the N-(2pyridyl)sulfonyl group in the C(2)-alkenylation of indoles and pirroles120 as well as in
the homocoupling reaction of indoles,121 we began our optimization studies choosing
the Pd(OAc)2-catalyzed olefination of N-methyl-N-(2-pyridyl)sulfonyl aniline (I) with
butyl acrylate as the model reaction. At the outset of our study, acetic acid was
chosen as solvent because it has been proposed in the literature that the presence of
weak acids enhanced the electrophilic nature of the active palladium(II) species,
favouring electrophilic palladation processes.122 We envisioned that this effect could
compensate the weaker nucleophilic character of aniline derivatives compared to that
of indole or pyrrole derivatives. The optimization of the reaction parameters for this
model reaction (catalyst, oxidant, solvent, temperature…) and the choice of the most
suitable protecting group were carried out by Alfonso García Rubia.
120
A. García-Rubia, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2009, 48, 6511.
121
A. García-Rubia, B. Urones, R. Gómez Arrayás, J. C. Carretero, Chem. Eur. J. 2010, 16, 9676.
122
A. D. Ryabov, Inorg. Chem. 1987, 26, 1252.
132
Chapter 3
Table 3.1: Screening of the oxidant
Entry
Oxidant
1
Cu(OAc)2
5
2
O2
4
3
t-BuOOH
4
K 2 S2 O 8
13
5
Oxone
37
6
PhI(OAc)2
58
7
Ce(SO4)2
65
8
+
[F ]
Yield (%)
0
[a]
[b]
100 (78)
[c]
[a] Conversion yield (from the 1H NMR spectra); [b] The
starting material was recovered unaltered; [c] Isolated yield
after column chromatography.
Fixing those variables, a variety of oxidants typically used in C−H olefination
were examined in a first place. In this study, two equivalents of oxidant were used
and all reactions were stopped after 12 h. The results summarized in Table 3.1
highlighted the important role played by the oxidant in the reaction. This strong
dependence of the reactivity on the nature of the oxidant has been recurrently
observed in other C−H functionalization protocols. Most of the oxidants tested,
including copper(II) salts, molecular oxygen, potassium persulfate or peroxides gave
very low reactivity (entries 1-4, <15%). Higher conversions were achieved using
stronger oxidants such as oxone (entry 5, 37%), PhI(OAc)2 (entry 6, 58%) or
cerium(IV) sulphate (entry 7, 65%). However, a stronger organic oxidant such as Nfluoro-2,4,6-trimethylpyridinium
trifluoromethanesulfonate
([F+])
resulted
highly
effective, providing the desired ortho-alkenylated product II with complete conversion
and in 78% isolated yield after column chromatography. It is remarkable the complete
133
C−H olefination of anilines and arylalkylamines
ortho-regiocontrol observed in all cases, likely due to the coordinating nature of the 2pyridylsulfonyl protecting group.
Table 3.2: Screening of the solvent
Entry
Solvent
Yield (%)
1
DMF
0
[b]
2
DMSO
0
[b]
3
1,4-Dioxane
65
4
Toluene
80
5
AcOH
100 (78)
[a]
[c]
[a] Conversion yield (from the 1H NMR spectra); [b] The
starting material was recovered unaltered; [c] Isolated yield
after column chromatography.
With regard to the solvent, polar and aprotic solvents such as DMF and DMSO
did not give any reaction (entries 1 and 2, 0% conversion yield), recovering unaltered
the starting aniline. Less polar solvents such as 1,4-dioxane (entry 3, 65% conversion
yield) gave better reactivity although the best results were achieved in toluene (entry
4, 80% conversion yield) and, especially, in AcOH (100% conversion yield, 87%
isolated yield).
To evaluate the role of the N-(2-pyridyl)sulfonyl as protecting/directing group in
this reaction, structurally diverse N-protecting groups were surveyed for the
alkenylation of N-methylaniline with butyl acrylate under the optimized conditions
(Table 3.3).
134
Chapter 3
Table 3.3: Evaluation of the effect of the directing/protecting group
Entry
Protecting Group
Yield
[a]
(PG)
(%)
1
Boc
__
2
Ts
0
[c]
3
p-Ns
0
[c]
4
(8-quinolyl)-SO2
0
[c]
5
(2-pyridyl)- SO2
78
[b]
[a] Isolated yield after column chromatography; [b] A complex
mixture was observed (1H NMR); [c] Only starting material
detected (1H NMR).
The N-Boc derivative led to a complex reaction mixture (entry 1), suggesting that
this protecting group was too labile under the reaction conditions. Switching to a N-Ts
or a N-Ns group led to the recovery of the starting material unaltered after 24 h
(entries 2 and 3), and an identical disappointingly result was also obtained with the
potentially coordinating N-(8-quinolyl)sulfonyl-protected aniline. These results were in
sharp contrast with the complete conversion observed in the case of the 2pyridylsulfonyl aniline I, providing the ortho-olefinated product in 78% isolated yield.
The key role played by the 2-pyridylsulfonyl group was likely due to the stabilization
of the cyclopalladated intermediate by N-coordination.
At this point, the work of Alfonso García Rubia focused on the exploration of the
structural scope of this reaction with regard to the substitution at both the alkene and
the aniline counterpart (these results are not included in this manuscript). Within the
same context, the present Thesis embarked on studying the structural versatility at
the N-alkyl group, paying special attention to the compatibility with synthetically
versatile functional groups, as shown in the next point.
135
C−H olefination of anilines and arylalkylamines
3.5.2. Structural versatility of the N-alkyl group
a) Synthesis of the starting functionalized N-alkyl anilines
For the development of future synthetic applications, it was very interesting to
examine the structural versatility of this olefination reaction with regard to the alkyl
chain at the nitrogen of the aniline and functional group tolerance. For that purpose,
the variously substituted N-alkyl-N-(2-pyridyl)sulfonyl anilines (3-7) were designed as
substrates containing several functional groups (Scheme 3.35). All of these
substrates were prepared from the same intermediate 2 by applying different
protocols found in the literature.
Scheme 3.35
Methyl (E)-3-(N-phenylpyridine-2-sulfonamido)acrylate 3 was prepared by
conjugate addition of N-(2-pyridyl)sulfonyl aniline 2 with methyl propiolate in the
presence
of
N-methylmorpholine
(NMM)
(MeCN, 0 °C). 123
The
desired
β-
aminoacrylate derivative 3 was obtained as a mixture of geometric isomers with
acceptable
stereoselectivity
[(E)/(Z)
=
80:20].
After
separation
by
flash
chromatography, the major diastereoisomer of E-configuration of the N-sulfonyl
enaminoate E-3 was isolated in good yield (67%, Scheme 3.36).
123
M. Barbazanges, C. Meyer, J. Cossy, Org. Lett. 2007, 9, 3245.
136
Chapter 3
Scheme 3.36
The N-acylation reaction of sulfonamide 2 with trans-crotonyl chloride led to the
clean formation of the (E)-N-phenyl-N-(2-pyridyl)sulfonyl-2-butenamide 4, in the
presence of triethylamine as base in dichloromethane (85% isolated yield, Scheme
3.37).124
O
PyO2S
NH
Cl
(1.4 equiv)
Et3 N (2.0 equiv)
O
PyO2S
N
CH2Cl2, rt, 30 min
2
4, 85%
Scheme 3.37
The N-(homoallyl)-substituted derivative 5 was readily synthesized by Nalkylation of N-(2-pyridyl)sulfonyl aniline 2 with 4-bromo-2-pentene (1.1 equiv) using
K2CO3 (1.5 equiv) as base and in DMF at 40 ºC. The resulting N-(but-3-en-1-yl)-Nphenylpyridine-2-sulfonamide 5 was isolated in 70% isolated yield (Scheme 3.38).125
124
M. R. Jeddeloh, J. B. Holden, D. H. Nouri, M. J. Kurth, J. Comb. Chem. 2007, 9, 1041.
125
V. A. Rassadin, A. A. Tomashevskiy, V. V. Sokolov, A. Ringe, J. Magull, A. de Meijere, Eur. J. Org.
Chem. 2009, 2635.
137
C−H olefination of anilines and arylalkylamines
Scheme 3.38
Similarly, sulfonamide 2 underwent N-alkylation with methyl 2-bromoacetate or
with 2-bromoacetonitrile, under similar reaction conditions used for the preparation of
5 (in the presence of K2CO3 as base, in acetonitrile at room temperature). The
resulting N-alkyl sulfonamides 6 and 7 were isolated in high yields (98% and 87%,
Scheme 3.39).
Scheme 3.39
b) Ortho-olefination of sulfonamides 3-7
N-alkyl anilines 3-7 were subjected to the reaction with butyl acrylate (2.0 equiv)
under the optimized reaction conditions previously found for the model compound Nmethyl-N-(2-pyridyl)sulfonyl aniline I: Pd(OAc)2 as catalyst (10 mol%), [F+] as oxidant
(2.0 equiv), in AcOH at 110 ºC for 12 h. Disappointingly, the reaction of the
enaminoate derivative 3 led to a complex reaction mixture in which the N-(2pyridyl)sulfonyl aniline 2 was detected (roughly in 20% by NMR) (Scheme 3.40).
138
Chapter 3
Scheme 3.40
Unfortunately, comparable negative results were obtained in the reaction of the
N-sulfonyl crotonamide 4 and the N-homoallyl derivative 5 with butyl acrylate under
identical reaction conditions, presumably due to decomposition of the starting
sulfonamides (Scheme 3.41).
Scheme 3.41
In contrast and to our delight, the desired ortho-alkenylated aniline derivative 8
was cleanly formed with full conversion when the glycinate derivative 6 was
submitted to the optimized reaction conditions with methyl acrylate as the coupling
partner, being isolated in 89% yield after chromatographic purification (Scheme 3.42).
This was not the case of the N-(cyanomethyl) sulfonamide 7, which did not react at
all. Even after 12 h, 7 was recovered unaltered.
139
C−H olefination of anilines and arylalkylamines
Scheme 3.42
Understanding that the decomposition products largely observed in the reaction
of substrates 3-5 could be due to their sensitivity to the acidic conditions used, we
decided to undertake a brief solvent screening to identify non acidic solvents
compatible with this olefination reaction. Therefore, a reaction of glycinate 6 with
methyl acrylate was performed in several solvents (Table 3.4). While no reaction was
observed in MeCN (entry 1), the use of toluene allowed the reaction to give the
desired olefinated product 8 in moderate conversion (entry 2, 50%). It would be with
DCE when product 8 was formed with complete conversion, isolated in 91% yield
(entry 3), providing a suitable solvent alternative to AcOH.
Table 3.4: Short screening of the solvent
Entry
Solvent
Yield (%)
1
MeCN
0
2
Toluene
3
DCE
[a]
[b]
50
100 (91)
[c]
[a] Conversion yield (from the 1H NMR spectra); [b]
The starting material was recovered unaltered; [c]
Isolated yield after column chromatography.
140
Chapter 3
As both AcOH and DCE gave good results, a comparative study of efficiency in
terms of catalyst loading and temperature was run in the reaction of glycinate 6 with
methyl acrylate in these two solvents under shorter reaction time (4 h). These results
are summarized in Table 3.5.
Table 3.5: Study of catalyst loading and temperature
Entry
Pd(OAc)2
Solvent
(mol%)
Temperature
Yield
(ºC)
(%)
[a]
1
10
AcOH
110
100 (89)
[b]
2
10
DCE
110
100 (91)
[b]
3
5
AcOH
110
100 (85)
[b]
4
5
DCE
110
100 (86)
[b]
5
5
AcOH
80
95
6
5
DCE
80
95
[a] Conversion yield (from the
chromatography.
1
H NMR spectra); [b] Isolated yield after column
The main conclusion obtained from this Table is that the results with DCE as
solvent nicely parallel those observed in AcOH, both solvents being equally effective.
The loading of Pd(OAc)2 precatalyst could be reduced to 5 mol% without significant
impact in the reaction conversion (measured by 1H NMR) affording comparable yields
of the desired ortho-alkenylated product 8. A decrease of the temperature from 110
ºC to 80 ºC resulted in incomplete conversions when using both DCE and AcOH, a
small amount of unreactive starting material being detected in both cases in the crude
reaction mixture (95% conversion).
Having established that AcOH and DCE provided comparable yields, the latter
was chosen for future scope investigation because of its higher functional group
tolerance. On the other hand, although it was demonstrated that the catalyst loading
141
C−H olefination of anilines and arylalkylamines
could be reduced to 5 mol% without appreciable loss of chemical efficiency, a 10
mol% was maintained for practical reasons and reliability of the results due to the
small scale experiments.
Unfortunately, the reaction of the more sensitive substrates 3-5 with methyl
acrylate using DCE instead of AcOH under otherwise identical optimized conditions
also resulted in the formation of complex reaction mixtures.
At this stage, having demonstrated that this new protocol for ortho-olefination
reaction of anilines was compatible with the presence of functionalized N-alkyl
substituents, we decided to continue investigating the reaction scope as well as the
potential synthetic applications. First, noticing that the N-(methoxycarbonyl)methyl
group contains a carbonyl group that could also play a directing role in the C−H
olefination reaction, we begun by determining the directing ability of the ester group.
For that purpose, the corresponding N-tosyl derivative 11 was readily synthesized
following a similar sequence employed for the preparation of its analogue substrate 6
(Scheme 3.43). Interestingly, no reaction was observed when the N-tosyl derivative
11 was evaluated for ortho-alkenyation under the standard reaction conditions,
showing the strong reliance on the presence of the N-(2-pyridyl)sulfonyl group.
Ts
NH2
1
Ts
N
NH
Ts
TsCl (1.2 equiv)
Br
CO2Et
(2 equiv)
pyridine (1.2 equiv)
THF, 0 ºC--rt
K2CO3 (1.5 equiv)
MeCN, rt
CO2Et
H
+
10, 76%
Pd(OAc)2 (10 mol%)
CO2Me
(5.0 equiv)
N
[F ] (2.0 equiv)
DCE, 110 ºC, 18 h
12
Scheme 3.43
CO2Et
11, 82%
+
11
142
Ts
N
CO2Et
CO2Me
Chapter 3
3.5.3. Structural versatility of the alkene coupling parter
By using these optimized conditions, we next explored the alkene scope of the
reaction. The results are summarized in Scheme 3.44.
Scheme 3.44
Not only acrylates but a variety of monosubstituted electrophilic alkenes (2.0
equiv) reacted efficiently with the N-(2-pyridyl)sulfonyl aniline 6, leading to the
corresponding mono-alkenylated products in high isolated yields (Scheme 3.44,
typically ≥80%). Although an excess of the olefin was used in all cases, the diolefinated product was never detected by NMR. Using acrylonitrile as coupling
partner,
the
mono-olefinated
product
14
was
obtained
as
a
mixture
of
diastereoisomers (Z-14/E-14 = 50:50), which unfortunately could not be separated by
column chromatography. The absence of diastereoselectivity in this case could be
owed to the lower steric side of the cyano group compared to the rest of activating
groups examined. Other alkenes bearing electron-withdrawing groups such as phenyl
vinyl sulfone and dimethyl vinylphosphonate showed high reactivity, yielding
exclusively the product of E-configuration with complete diasterocontrol (13 and 15,
83% and 93% yield respectively). At this point we confirmed that the catalyst loading
could be reduced to 5 mol% in the case of the reaction with methyl acrylate and
phenyl vinyl sulfone without affecting the reactivity and obtaining similar yields after
4 h of reaction (Scheme 3.45, products 8 and 13, 91% and 83% yields, respectively).
For the rest of alkenes, incomplete conversions were attained even after longer
143
C−H olefination of anilines and arylalkylamines
reaction times (8 h, Scheme 3.45), therefore indicating that 10 mol% of the
palladium(II) catalyst was required for achieving complete conversions in these
cases.
Scheme 3.45
Unfortunately, other activated alkenes proved to be much less efficient as
coupling partners in the reaction with aniline 6. For example, the reaction with acrylic
acid resulted in 50% conversion, while N,N-dimethylacrylamide, 3-buten-2-one, or
(E)-methyl crotonate were totally unreactive (the starting aniline was recovered). In
contrast, the reaction of 6 with a less electrophilic alkene such as styrene led to a
30% conversion (Scheme 3.46).
Scheme 3.46
144
Chapter 3
3.5.4. Structural variations at the aniline counterpart
To evaluate the effect of the substitution at the aromatic ring of the aniline
derivative, a series of N-aryl-N-(2-pyridyl)sulfonyl glycinates bearing electronwithdrawing and electron-donating groups at ortho-, meta- and para-positions were
synthesised following the same two-step procedure to that previously used to prepare
the parent substrate 6 (Scheme 3.47). Thus glycinates 31-37 were obtained in good
yields from N-sulfonylation reaction of the corresponding anilines and subsequent Nalkylation with methyl bromoacetate, in the presence of K2CO3 as base, in acetonitrile
as solvent. All compounds were isolated as bench-stable solids.
Scheme 3.47
These different substituted anilines were submitted to the C−H olefination
protocol with methyl acrylate as the coupling partner. As shown in Scheme 3.48, a
broad range of para- and meta-substituted aryl rings with diverse steric and electronic
properties (ether, halide and ester groups) could be readily exploited in this
procedure, affording the corresponding olefinated product in yields typically above
70%. The wide tolerance of functional groups, as well as variations in the substitution
145
C−H olefination of anilines and arylalkylamines
pattern at the aromatic ring was remarkable and rather unusual for this type of
transformation.
Scheme 3.48
Halides such as chloride and bromide survived under the reaction conditions,
with no Heck-type coupling or proto-dehalogenation being detected (products 38 and
42). For example, the para-chloro substituted derivative 38 was isolated in good yield
(79%), while the meta-bromo substituted aniline 34 was less reactive, providing only
50% conversion. In spite of this low conversion, the desired brominated product 42
was isolated in an acceptable 46% yield after chromatographyc purification, and 47%
of the starting material was recovered. This feature was important since halogens
substituents are versatile handles for further transformations via transition metalcatalyzed cross-coupling. High regiocontrol was observed in meta-substituted
146
Chapter 3
anilines, favoring the C−H functionalization at the sterically less hindered orthoposition (products 40 and 42, 67% and 46% yield). Notably, 2-naphthalenamine
derivative was also amenable to the olefination reaction, which proceeded with high
selectivity at the more accessible ortho-position (product 41, 84% yield). It is
important to note the excellent catalyst performance with challenging aniline
substrates, including those bearing a strong electron-withdrawing substituent (e.g.
CO2Me group, product 39, 73% yield). Unfortunately, aniline derivatives substituted at
ortho-positions with both electron-donating (OMe, aniline 31) or electron-withdrawing
groups (F, aniline 32) did not show any reactivity, recovering the starting aniline
unaltered in both cases.
3.5.5. Application to indole synthesis
In
these
products,
both
the
ortho-alkenyl
group
and
the
N-
(methoxycarbonyl)methyl offered high versatility as building blocks. As an illustrative
synthetic application, a three-step synthesis was designed to transform the olefinated
aniline products containing a N-CH2CO2Me group into functionalized indoles (Scheme
3.49).
147
C−H olefination of anilines and arylalkylamines
Scheme 3.49
The indoline skeleton was readily assembled as a 1:1 diastereomeric mixture by
intramolecular Michael addition of the ester-stabilized carbanion generated in situ
with LHMDS (THF, 0 ºC). The crude product was subjected to reductive
desulfonylation under mild basic conditions upon treatment with magnesium turnings
(MeOH, room temperature, and sonication). Aromatization with DDQ (CH2Cl2, room
temperature) of the resulting NH-indoline afforded the corresponding indole in
acceptable overall yield (generally 58-63%) after chromatographic purification. As
exceptions, the compound 46, resulting from ortho-olefination with acrylonitrile, and
the meta-methoxy substituted acrylate 40 provided the corresponding indole
derivatives in low yields (products 46 and 50, 28% and 26% yield, respectively). In
the former case, this unsatisfactory conversion could be attributed to the lower
reactivity as Michael acceptor displayed by α,β-unsaturated nitrile derivatives
compared to acrylates. The same argument is also applicable to the latter case, since
the methoxy substituent is located at para-position with regard to the carbon directly
148
Chapter 3
attached to the conjugated alkene, resulting in higher electron density at the β-carbon
of the acrylate moiety, thereby attenuating its electrophilic character.
It is important to note that this Mg-promoted N-sulfonyl deprotection was
compatible with sensitive functional groups such as halides or esters (products 48
and 49). In the case of aniline 13, bearing an α,β-unsaturated phenylsulfone as
Michael-acceptor group, the application of this sequence of reactions led to 3-methylsubstituted indole 47 due to concomitant both N- and C-desulfonylation with
Mg/MeOH (63% overall yield for the 3 steps).
3.6. Tether elongation: C−
−H olefination of arylalkylamines
While exploring suitable N-alkyl groups for the model C−H olefination reaction of
aniline derivatives with butyl acrylate, we became interested in the N-benzyl
protected substrate 52. This compound was readily prepared from commercially
available N-benzyl-N-phenylamine (51) by N-sulfonylation with 2-pyridylsulfonyl
chloride under the usual conditions (73% yield, Scheme 3.50).
Scheme 3.50
149
C−H olefination of anilines and arylalkylamines
Unexpectedly, the Pd-catalyzed reaction of 52 with n-butyl acrylate under the
standard reaction conditions led to the diolefinated product 53, in which both aromatic
rings had undergone mono-olefination at their ortho-position (Scheme 3.51).126
Scheme 3.51
The formation of product 53 clearly suggested that the directing ability of the 2pyridylsulfonyl group could be extended through longer tethers. As a consequence,
126
At this point, we briefly explored the intramolecular deshydrogenative cross-coupling of this type of
compounds as a potential efficient method for the assembly of tricyclic nitrogen systems such as 54.
Screening of different oxidants and solvents led to the recovery of the starting material in all cases
(see Scheme below).
Considering that this failure in the cyclization could be due to the fact that the palladacycle was too
rigid, the more flexible derivative 55 was also prepared and studied in this intramolecular
dehydrogenative coupling. Unfortunately, as in the previous case, after screening different oxidants
and solvents, the starting material was recovered unaltered.
150
Chapter 3
our focus was turned to test the applicability of this methodology to the C−H
alkenylation of arylalkylamines. Having already demonstrated the versatility of this
protocol to the N-alkyl substitution, in these studies we considered only a methyl as
model alkyl-substituent at the nitrogen functionality.
3.6.1. C−
−H olefination of benzylamines
The N-methyl-N-(2-pyridyl)sulfonyl benzylamine 58 was synthesised in good
yield from commercially available N-methyl benzylamine (57), following the described
N-protection protocol with 2-pyridylsulfonyl chloride and pyridine as base.
Correspondingly, for comparative purposes, the N-tosyl derivative 59 was also
synthesised under identical conditions except for using tosyl chloride instead of 2pyridylsulfonyl chloride (Scheme 3.52).
Scheme 3.52
The alkenylation reaction of N-methyl-N-(2-pyridyl)sulfonyl benzylamine 58 with
n-butyl acrylate under the optimized conditions led to a mixture of 80:20 of mono- and
di-olefinated products 60 and 61, respectively. This outcome demonstrated the high
reactivity displayed by this substrate, similar to that of electron-rich aniline derivatives
(Scheme 3.53).
151
C−H olefination of anilines and arylalkylamines
Scheme 3.53
To address the problem of mono- versus di-substitution selectivity, we undertook
a brief screening of the oxidants that proved to be effective in this reaction, on the
basis of our previous experience in other aryl C−H functionalization processes, where
the reactivity was efficiently tuned by the proper choice of the oxidant, resulting in an
excellent control of the mono- versus di-substitution selectivity.127 These results are
summarized in in Table 3.6.
Table 3.6: Short screening of oxidants
Yield (%)
[a]
Ratio 60:61
Entry
Oxidant
1
[F ]
100
80:20
2
K2 S2 O 8
15
>98:<2
3
Ce(SO4)2
27
>98:<2
4
PhI(OAc)2
39
75:25
+
1
[a] Conversion yield (from the H NMR spectra).
Weaker oxidants such as K2S2O8 and Ce(SO4)2 showed very low reactivity (lower
than 30%, entries 2 and 3), although the olefination product was formed with
127
See, for instance: A. García-Rubia, M. A. Fernández-Ibáñez, R. Gómez Arrayás, J. C. Carretero,
Chem. Eur. J. 2011, 17, 3567.
152
Chapter 3
complete mono-selectivity. In contrast, the use of PhI(OAc)2 caused a loss in the
mono-selectivity (mono-/di- = 75:25, entry 4) even at low conversions (39%
conversion after 8 h). Finally, complete selectivity (>95:<5) in favour of the monoolefination product was achieved by simply adjusting the amount of butyl acrylate to
1.1 equiv. As shown in Scheme 3.54 product 60 was isolated in 81% yield under
these conditions.
Scheme 3.54
The key directing role of the 2-pyridylsulfonyl unit was again demonstrated by the
lack of reactivity displayed by the related N-tosyl protected benzylamine 59, only the
starting material being detected in the reaction mixture (Scheme 3.55).
Scheme 3.55
a) Substitution at the alkene partner
To evaluate the scope with regard to the alkene partner, several electrondeficient olefins were surveyed for the olefination of benzylamine derivative 58. Due
to the different reactivity of each olefin, the number of equivalents of this reactant
needed to be adjusted between 1.1 and 2.0 for maximizing the selectivity in the
mono-alkenylated product. As shown in Scheme 3.56, good yields were obtained in
the reaction of 58 with vinyl phenyl sulfone, vinyl phenyl sulfonate and vinyl
phosphonate (71-80%). Instead, the reaction with acrylonitrile resulted in low
153
C−H olefination of anilines and arylalkylamines
conversion (product 66, 35% conversion yield by 1H NMR analysis). In the latter case,
increasing the amount of either alkene or oxidant did not improve the conversion.
Other alkenes such as styrene and N,N-dimethyl acrylamide did not react.
Scheme 3.56
b) Versatility at the benzylamine counterpart
The study of the substitution at the arene ring of the benzylamine counterpart
was carried out by Alfonso Garcia Rubia, as part of his Thesis. These results are
summarized in Scheme 3.57.
The ortho-olefination reaction of variously substituted benzylamines with butyl
acrylate gave results less homogenous than those previously obtained with N-alkylanilines derivatives. For example, para-substituted derivatives with Me or F groups
gave the mono-olefinated products in good yields using 1.1 equiv of acrylate
(products III and IV, 72% and 81%, respectively), whereas other para-substituted
derivatives (e.g. OMe, Br and CF3) showed an increased reactivity, even when 2.0
equiv of butyl acrylate were used (products V-VII, 35%-41% yield).
High regiocontrol was observed in meta-substituted benzylamines, favoring the
C−H functionalization at the sterically less hindered ortho-position and providing the
desired ortho-alkenylated products in good yields (76-78%). One exception was the
154
Chapter 3
meta-fluor derivative, which led to a 2:1.5 mixture of regioisomers of which the major
component of the mixture was identified as the isomer X.
Ortho-methoxy and ortho-methyl-substituted derivatives gave the corresponding
di-ortho-substituted derivatives in good yields (products XI and XII, 72% and 81%,
respectively). However, ortho-halogenated substituted derivatives (e.g., F or Br)
showed a lack of reactivity even when 3.0 equiv of oxidant were used.
Finally,
1-napthyl
and
2-napthyl-methylamine
derivatives
led
to
the
corresponding ortho-alkenylated products with complete regiocontrol at the less
hindered position (products XIII and XIV, 83% and 50%, respectively).
155
C−H olefination of anilines and arylalkylamines
Scheme 3.57
156
Chapter 3
3.6.2. C−
−H olefination of phenethylamines and γ-arylpropylamines
The outstanding flexibility showed by the N-(2-pyridyl)sulfonyl group with regard
to the tether length, prompted us to go one step further and explore substrates with
even longer tethers. This study was performed working together in collaboration with
Alfonso García Rubia. First, by the typical N-sulfonylation protocol, the N-methyl-N(2-pyridyl)sulfonyl derivatives of phenethylamine (product 68, 85% yield), γphenylpropylamine (product 71, 79%) and δ-phenylbutylamine (product 73, 77%)
were efficiently prepared (Scheme 3.58). Besides, N-tosyl derivative of the N-methyl2-phenylethanamine 69 was also prepared in order to evaluate the effect of the
protecting group.
NH
N
SO2Ar
ArSO2Cl (1.2 equiv)
pyridine (1.2 equiv)
THF, 0 ºC--rt
68, Ar = 2-Py, 85%
69, Ar = 4-MeC6H4, 88%
67
NH
H
N
PyO2S
N
N
PySO2Cl (1.2 equiv)
PySO2Cl (1.2 equiv)
pyridine (1.2 equiv)
THF, 0 ºC--rt
pyridine (1.2 equiv)
THF, 0 ºC--rt
71, 79%
70
SO2Py
72
73, 77%
Scheme 3.58
A
clean
reaction
was
observed
when
N-methyl-N-(2-pyridyl)sulfonyl
phenethylamine (68) was combined with butyl acrylate under standard conditions to
give the corresponding alkenylated product 74 in good yield (87%, Scheme 3.59). As
occurred in the case of the N-methyl benzylamine derivative, the higher reactivity
displayed by the N-methyl-N-(2-pyridyl)sulfonyl phenethylamine (58) made necessary
to adjust the amount of butyl acrylate to 1.1 equiv in order to minimize the formation
157
C−H olefination of anilines and arylalkylamines
of diolefinated products. Once more, the key directing role of the 2-pyridylsulfonyl unit
was confirmed by the lack of reactivity of the related N-tosyl protected substrate 69.
Scheme 3.59
Even the γ-phenylpropylamine derivative 71 underwent the alkenylation reaction
providing the corresponding product 76, with 78% yield. In this case 3.0 equiv of
oxidant were needed in order to achieve full conversion (Scheme 3.60).
Scheme 3.60
Unfortunately, N-methyl-4-(phenylbutyl)amine derivative 72 did not react, even
with excess of butyl acrylate and 3.0 equiv of oxidant. The starting N-protected amine
72 was recovered unaltered after 12 h reaction, revealing the limitation of the method
with respect to the tether length (Scheme 3.61).
158
Chapter 3
Scheme 3.61
c) Versatility at the alkene
Next, a study of the alkene versatility was carried out using phenethylamine
derivative 68 as the model substrate. As shown in Scheme 3.62, a variety of olefins,
not only acrylates but also alkenes substituted with sulfone, sulfonate, phosphonate
and even nitrile groups were well tolerated in the alkenylation reaction. The
corresponding mono-olefinated products were obtained in good yields in all cases
(products 78-82, 79-89% yield). It is remarkable the high reactivity of the substrate
74, only requiring 1.1 equiv of the alkene counterpart to afford full conversion.
Scheme 3.62
159
C−H olefination of anilines and arylalkylamines
The high reactivity displayed by this substrate allowed us to carry out the double
C−H olefination reaction in the presence of an excess of the alkene. Di-orthoolefinated products were obtained in good yields with a variety of olefins (Scheme
3.63, products 83-86, 79-89%).
Scheme 3.63
Because of the good results obtained in the double C−H olefination leading to
symmetrical di-olefinated products, we envisioned that it could then be possible the
installation of two different alkenes at the two ortho-positions of the arene via
sequential double C−H alkenylation, leading therefore to unsymmetrical di-orthoolefinated products. To our delight, this was indeed the case, as demonstrated in the
second ortho-olefination reaction performed on the acrylate derivative 74 with phenyl
vinyl sulfone (3.0 equiv) to afford the product 87 with two different types of Michael
acceptor olefins (vinyl sulfone/acrylate) in 80% yield (Scheme 3.64). However, the
level of efficiency in the second ortho-olefination process was found to be much lower
in the reaction with acrylonitrile, leading to a modest conversion (product 88, 36%
isolated yield, 60% yield in converted product).
160
Chapter 3
Scheme 3.64
b) Structural versatility with regard to aromatic substituion
The versatility of the reaction with regard to electronic and steric modifications in
the arene ring was also studied. For that purpose, a variety of differently substituted
derivatives were prepared (Scheme 3.65).
Scheme 3.65
161
C−H olefination of anilines and arylalkylamines
These derivatives were submitted to the olefination reaction with butyl acrylate
as the coupling partner (Scheme 3.66). The olefination reaction proved to be rather
general (yields typically above 70%) regardless of the electron-donating (Me, OMe)
or electron-withdrawing (F) nature of the attached groups and the substitution pattern,
including ortho-substituted arenes. For the para- (products 105-106, 75-80%) and
meta-substituted (products 107-108, 81-84%) derivatives only 1.1 equiv of alkene
was needed to achieve complete conversion, affording the mono-alkenylated
products in good yields. In the latter case, the substitution occurred with high
regiocontrol at the less sterically hindered ortho-position. Similarly, the 2-naphtyl
derivative 104 afforded the mono-olefinated product 109 with good yield (75%) and
complete regiocontrol at C3. Interestingly, ortho-substituted derivatives also showed
a high reactivity (products 110-112, 77-86%), although in these cases 2.0 equiv of
butyl acrylate were needed to ensure full conversion.
162
Chapter 3
Scheme 3.66
3.7. Deprotection
Finally, the easy reductive removal of the N-(2-pyridyl)sulfonyl directing group
under smooth acidic conditions led us to realize the full synthetic utility of this method
towards the access to different nitrogen-containing skeletons (Scheme 3.67). We had
previously found that simple treatment of the N-(2-pyridyl)sulfonamide product with
excess of Zn powder in a 1:1 mixture of THF and saturated aqueous NH4Cl at room
temperature allowed the smooth N-deprotection, leading to the corresponding free
amino derivative. In contrast, the N-deprotection with magnesium turnings in MeOH
occured with concomitant reduction of the conjugated double bond.
163
C−H olefination of anilines and arylalkylamines
Applying the Zn-based deprotection to the ortho-alkenylated products in the
homologous series was very interesting, allowing the construction of nitrogencontaining heterocycles relevant from synthetic and medicinal chemistry standpoints.
For example, the N-desulfonylation reaction of sulfonamide products possessing one
or two carbons between the nitrogen atom and the aryl moiety, simultaneously
triggers the cyclization of the free amines under the reaction conditions, leading to
isoindoline (product 113) and tetrahydroisoquinoline (114) bicyclic frameworks in
synthetically useful yields (73-78%, Scheme 3.67).
Scheme 3.67
3.7.1. Attempts to isolate the palladacycle
Unfortunately, up to date, attempts to prepare and isolate the orthocyclopalladated intermediate of the aniline derivative XV by reaction of several N-(2pyridyl)sulfonyl
aniline,
benzylamine
or
phenethylamine
derivatives
with
a
stoichiometric amount of Pd(OAc)2 have been unsuccessful, recovering the starting
material unaltered in the vast majority of the cases (Scheme 3.68).
164
Chapter 3
Scheme 3.68
Although we had then no experimental proof related to the coordination of the 2pyridylsulfonyl activating group to the palladium, a reasonable explanation for the
outstanding flexibility observed with regard to the tether length between the amine
moiety and the aromatic ring is shown in Figure 3.4. While for the aniline derivatives,
the formation of a seven-membered palladacycle was viable128 (intermediate XV), for
the homologous series, the stabilization of the corresponding palladacycles
intermediates could imply the coordination of the metal not only to the pyridine
nitrogen but also to the amine nitrogen. Therefore, bicyclic species would be formed:
two five-membered rings for the benzyl amine derivatives (intermediate XVI), a fivemembered ring fused with a six-membered ring for phenethylamine derivatives
(intermediate XVII) and finally a fused 7/5 bicyclic species for phenethylamine
derivatives (intermediate XVIII). This extra stabilizating effect should not be effective
for palladacycles of more than seven-membered, which is in agreement with the
literature
and
would
explain
the
fact
that
N-methyl-N-(2-pyridyl)sulfonyl-4-
phenylbutylamine derivative did not show any reactivity (in this case the fused bicyclic
palladacycle would be 8/5 in ring size).
128
G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem. 2011, 123, 1416; Angew. Chem. Int. Ed. 2011,
50, 1380.
165
C−H olefination of anilines and arylalkylamines
Figure 3.4
Currently, computational studies are carrying out with Prof. Peter Fristrup
(Technical University of Denmark) to study the viability and stability of the proposed
palladacycles intermediates XV-XVIII along with obtaining a complete mechanistic
picture of this reaction, including a justification for the need of a strong oxidant such
as [F+]. In fact, the stabilization energies of the palladacycles have already been
calculated by this group, confirming our hypothesis: fused palladacycles XVI, XVII
and XVIII are more stable than simple palladacycle XV (Scheme 3.69)
Scheme 3.69
166
Chapter 3
3.8. Conclusions
1) We have developed the first palladium-catalyzed C−H olefination reaction of
N-alkyl aromatic amines. One of the most important features of this catalytic system
is its unprecedented structural versatility. In fact, not only simple N-methyl anilines
but also a functionalized N-alkyl group such as a N-(methoxycarbonyl)methyl group is
well tolerated. The method also features wide tolerance with regard to the substitution
at the alkene partner, as well as steric and electronic variations at the arene moiety,
including difficult-to-activate substrates, such as substrates bearing strong electrondeficient groups. The corresponding ortho-olefinated products were generally
obtained in high yields (typically ≥ 70%), complete regiocontrol and excellent levels of
(E)-diastereoselectivity.
2) Together with this remarkable structural tolerance, an exceptional flexibility
with regard to the tether length connecting the arene unit to the directing unit has
167
C−H olefination of anilines and arylalkylamines
enabled the extension of this reaction to other type of aromatic amines such as
benzylamine derivatives (one-carbon longer tether), phenethylamine derivatives (twocarbon longer tether) and γ-arylpropylamine derivatives (three-carbon longer tether),
showing comparable reactivity.
168
Chapter 3
3) The high reactivity of this catalytic system has allowed us to solve another
important limitation of this reaction: its applicability to double C−H olefination, thereby
enabling the access to di-ortho-substituted products. Apart from the symmetrical diortho-alkenylated products, a sequential double olefination with two different olefins
has been achieved, leading to unsymmetrical di-ortho-alkenylated products with two
different types of Michael acceptor olefins.
4) Both the ortho-alkenyl group and the possibility of having a functionalized
group at the nitrogen (e.g., N-CH2CO2Me) provided the resulting products with high
versatility as building blocks. As an application of the synthetic potential of this
method, a simple three steps transformation of the olefination products into
functionalized indoles has been devised. The corresponding indole derivatives are
generally
obtained
in
acceptable
overall
yield
(58-63%),
after
a
single
chromatographic purification.
169
C−H olefination of anilines and arylalkylamines
Moreover, the easy N-desulfonylation of the amino group in the olefinated
products enabled a direct access to highly functionalized nitrogen-containing
heterocycles
relevant
tetrahydroisoquinolines.
170
in
medicinal
chemistry,
such
as
isoindolines
and
Chapter 4:
C−H di-ortho-olefination of carbazoles
171
172
Chapter 4
4.
C−
−H di-ortho-olefination of carbazolesImportance of carbazoles
Carbazoles are a distinguished class of aromatic heterocyclic nuclei, prevalent
as structural motifs in various synthetic materials and naturally occurring alkaloids
(Figure 4.1, structure of carbazole).129
Figure 4.1
The properties imported by the carbazole motif have also found applications in
material
science
131
polymers
as
optoelectronic
and synthetic dyes.
132
or
luminescent
materials,130
conducting
In fact, they are known for their intense
luminescence and they are widely used in organic light-emitting diodes (OLEDs) as
blue, green, red, and white emitters, depending on the substitution of the carbazole
core.133 In recent years, carbazole-containing ligands have been demonstrated to be
129
For recent reviews of the synthesis and biological activity of carbazoles, see: a) A. W. Schmidt, K.
R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112, 3193; b) I. Bauer, H.-J. Knölker, Top. Curr. Chem.
2012, 309, 203; c) J. Roy, A. K. Jana, D. Mal, Tetrahedron 2012, 68, 6099.
130
a) G. Bubniene, T. Malinauskas, M. Daskeviciene, V. Jankauskas, V. Getautis, Tetrahedron 2010,
66, 3199; b) H.-Y. Wang, F. Liu, L.-H. Xie, C. Tang, B. Peng, W. Huang, W. J. Wei, Phys. Chem. C
2011, 115, 6961; c) W.-L. Gong, F. Zhong, M. P. Aldred, Q. Fu, T. Chen, D.-K. Huang, Y. Shen, X.-F.
Qiao, D. Ma, M.-Q. Zhu, RSC Advances 2012, 2, 10821; d) H. Huang, Y. Wang, B. Pan, X. Yang, L.
Wang, J. Chen, D. Ma, C. Yang, Chem. −Eur. J. 2013, 19, 1828.
131
For selected references, see: a) Y. Morisaki, J. A. Fernandes, N. Wada, Y. Chujo, J. Polym. Sci. A:
Polym. Chem. 2009, 47, 4279. b) O. D. Is, F. B. Koyuncu, S. Koyuncu, E. Ozdemir, Polymer 2010,
51, 1663; c) N. Dubey, M. Leclerc, J. Polym. Sci. B: Polym. Phys. 2011, 49, 467.
132
a) E. M. Barea, C. Zafer, B. Gultekin, B. Aydin, S. Koyuncu, S. Icli, F. F. Santiago, J. Bisquert, J.
Phys. Chem. C 2010, 114, 19840; b) K. Srinivas, C. R. Kumar, M. A. Reddy, K. Bhanuprakash, V. J.
Rao, L. Giribabu, Synth. Met. 2011, 161, 96.
133
R. M. Adhikari, D. C. Neckers, J. Org. Chem. 2009, 74, 3341, and references cited therein.
173
C−H di-ortho-olefination of carbazoles
effective as anion receptors134 [Figure 4.2, a] as well as ligands in asymmetric
catalysis [Figure 4.2, b].135
Figure 4.2
As a core skeleton for naturally occurring alkaloids, carbazoles prominently
embody a wide range of plant natural products (Figure 4.3). A large number of them
are endowed with revelant biological activities, which include antitumor, psychotropic,
antiinflammatory, antihistaminic, antibiotic, and anti-oxidative activities.129 Moreover,
the carbazole moiety is considered as one of the pharmacophores in the
cardiovascular pharmaceuticals carvedilol136 and carazolol,137 which are used in the
treatment of hypertension, ischemic heart disease and congestive heart failure.
134
M. J. Chmielewski, M. Charon, J. Jurczak, Org. Lett. 2004, 6, 3501.
135
T. Niwa, M. Nakada, J. Am. Chem. Soc. 2012, 134, 13538; and references cited therein.
136
N. Senthilkumar, Y. S. Somannavar, S. B. Reddy, B. K. Sinha, G. K. A. S. S. Narayan, R. Dandala,
K. Mukkanti, Synth. Commun. 2010, 41, 268.
137
E. A. Dubois, J. C. van den Bos, T. Doornbos, P. A. P. M. van Doremalen, G. A. Somsen, J. A. J.
M. Vekemans, A. G. M. Janssen, H. D. Batink, G. J. Boer, J. Med. Chem. 1996, 39, 3256.
174
Chapter 4
Figure 4.3
4.2. Synthesis of carbazoles
Due to the unique structural features and biological activities of carbazole
derivatives, the development of efficient synthetic methods to prepare such
compounds continues being a subject of intense research. Among the repertoire of
synthetic methods currently available, transition-metal-catalyzed C−C or C−N bond
forming reactions are the most powerful and attractive ones, considering that the
starting materials could be easily prepared with synthetic convergence and
practicality. In recent years, C−H bond functionalization strategies have been
incorporated to the synthesis of carbazoles. Within this context, two main approaches
have
been
used
functionalization:
138
138
for
the
assembly of
the
carbazole
skeleton
via
C−H
i) the metal-catalyzed cyclization of diarylamine derivatives (C−C
For selected examples of cyclization of halogenated diarylamines to carbazoles, see: a) L.-C.
Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581; b) L.-C. Campeau, P.
Thansandote, K. Fagnou, Org. Lett. 2005, 7, 1857; c) R. B. Bedford, C. S. J. Cazin, Chem. Commun.
2002, 2310. For an intramolecular photo-stimulated synthesis of carbazoles from 2-chloro
diarylamines: M. E. Budén, V. A. Vaillard, S. E. Martin, R. A. Rossi, J. Org. Chem. 2009, 74, 4490.
175
C−H di-ortho-olefination of carbazoles
bond formation, route a, Scheme 4.1); ii) the metal-catalyzed cyclization of 2aminobiphenyl derivatives (C−N bond formation, route b, Scheme 4.1).
Scheme 4.1
4.2.1. C−
−C bond formation: metal-catalyzed cyclization of diarylamine
derivatives (route a)
In 1975, Åkermark and co-workers reported for the first time the synthesis of
carbazoles via a palladium-mediated oxidative intramolecular cyclization of N,N-diaryl
amines under reflux of acetic acid (Scheme 4.2).139
Scheme 4.2
This transformation tolerated a wide range of substituents but it was mainly
limited to the synthesis of 3-substituted carbazoles. The use of N,N-diaryl amines
bearing a strong electron-withdrawing group (e.g. NO2) required 2.0 equiv of
palladium. The oxidative cyclization was believed to proceed via electrophilic attack
of palladium(II) at the ortho-positions of the two aromatic rings to afford a
diarylpalladium(II) intermediate, which underwent reductive elimination to generate
the carbazole product and palladium(0). Despite this palladium(II)-mediated oxidative
For a one-pot synthesis of carbazoles via coupling reaction of anilines with 1,2-haloarenes: L.
Ackermann, A. Althammer, Angew. Chem. Int. Ed. 2007, 46, 1627.
139
B. Åkermark, L. Eberson, E. Jonsson, E. Petterson, J. Org. Chem. 1975, 40, 1365.
176
Chapter 4
cyclization was later applied to the convergent total synthesis of a range of
structurally different carbazole alkaloids,129 the need of stoichiometric amounts of
palladium(II) acetate was a serious drawback that limited the development of truly
efficient synthetic applications.
The evolution of this palladium-mediated reaction, described over more than 30
years ago, to a catalytic version did not take place until 1994, when Knölker and coworkers found out that the cyclization of 2-anilino-1,4-naphthoquinone to obtain
benzo[b]carbazoles could be rendered catalytic in palladium by using an equimolar
amount of copper(II) acetate as oxidant (Scheme 4.3).140
Scheme 4.3
Soon later, Åkermark and co-workers designed a similar palladium-catalyzed
protocol for the cyclization of arylaminoquinones to give carbazoloquinones using
tert-butyl hydroperoxide as the terminal oxidant, in acetic acid at 90 ºC (Scheme
4.4).141 Although the yields were good for a broad range of arylaminoquinones, when
this protocol was applied to diphenylamine to obtain carbazole as the product, the
yield dramatically decreased to 30%.
140
H.-J. Knölker, N. O’Sullivan, Tetrahedron 1994, 50, 10893.
141
B. Åkermark, J. D. Oslob, U. Heuschert, Tetrahedron Lett. 1995, 36, 1325.
177
C−H di-ortho-olefination of carbazoles
Scheme 4.4
Few years later, in 1999, the same authors described a more environmental
friendly protocol for this palladium-catalyzed cyclization of arylaminoquinones using
molecular oxygen as the oxidant, under otherwise identical reaction conditions.142
When they applied this protocol to diphenylamine to obtain the carbazole core, the
reactivity was higher than the observed when tert-butyl hydroperoxide was used the
terminal oxidant (61%, route a, Scheme 4.5). In fact, changing the palladium(II) salt
for a more electrophilic catalyst (palladium(II) trifluoroacetate) and adding 10 mol% of
Sn(OAc)2 resulted in a slight increase of the reactivity, isolating the desired carbazole
in 66% yield (route b, Scheme 4.5). However, the authors did not study the structural
scope of the reaction with regard to the substitution at the diphenylamino moiety.
Scheme 4.5
142
H. Hagelin, J. D. Oslob, B. Åkermark, Chem. Eur. J. 1999, 5, 2413.
178
Chapter 4
Nonetheless, when this palladium-catalyzed cyclization protocols were applied in
a concrete step of a total synthesis with fully substituted N,N-diaryl amines, only
decomposition was observed when the substructures contained alkoxy substituents
conjugated with the nitrogen. Presumably, the decomposition can be explained
through oxidative pathways involving the formation of quinone imines as
intermediates.143 This could be the reason why literature references to the
preparation of polyoxygenated carbazoles by cyclodehydrogenation of diarylamines
are scarce and give moderate yields.144
It wasn’t until recently when this reaction has received fresh impetus, allowing
extending the scope to obtain differently substituted carbazoles. In 2007, Ohno and
co-workers developed a one-pot carbazole synthesis from anilines and aryl triflates
via palladium-catalyzed N-arylation (Buchwald-Hartwig N-arylation) followed by biaryl
oxidative coupling in the presence of molecular oxygen or air (Scheme 4.6).145
Regarding the substitution in the triflate and in the aniline, the best combination was
the coupling between electron-rich triflates (3- or 4- substituted) and 4-substituted
electron-deficient anilines. Thus, 2- and/or 4-substitutes carbazoles were obtained in
moderate to good yields. It is remarkable that in many cases, N-arylation proceeded
almost quantitatively, suggesting that the yield of the carbazoles was mainly
dependent on the reactivity of the C−H activation step of the resulting diarylamines.
143
144
V. Sridharan, M. A. Martín, J. C. Menéndez, Synlett 2006, 15, 2375.
For two recent examples, giving 32% and 43% yields, respectively, see: a) G. Lin, A. Zhang,
Tetrahedron Lett. 1999, 40, 341; b) H.-J. Knölker, J. Knöll, Chem. Commun. 2003, 1170.
145
a) T. Watanabe, S. Ueda, S. Inuki, S. Oishi, N. Fujii, H. Ohno, Chem. Commun. 2007, 4516; b) T.
Watanabe, S. Oishi, N. Fujii, H. Ohno, J. Org. Chem. 2009, 74, 4720.
179
C−H di-ortho-olefination of carbazoles
Scheme 4.6
In 2008, Fagnou and co-workers developed a protocol for the palladium(II)catalyzed oxidative cyclization of diarylamines to carbazoles in the presence of a
catalytic amount of a base (K2CO3, 10 mol%) using air atmosphere as the terminal
oxidant, in pivalic acid as solvent at 110 ºC.146 Initially, their study was focused in the
known challenging electron-rich diarylamines, which have been described to
decompose through oxidative pathways.143 Besides, these conditions also permitted
the efficient coupling of substrates bearing electron-withdrawing groups, although in
the latter case was limited to 3-substitued carbazoles (Scheme 4.7).
146
B. Liégault, D. Lee, M. P. Huestis, D. R. Stuart, K. Fagnou, J. Org. Chem. 2008, 73, 5022.
180
Chapter 4
Scheme 4.7
Catalytic cycle for the oxidative cyclization
All together, the literature precedents reveal that the scope of this palladiumcatalyzed cyclization was very dependent on the substitution pattern and cannot be
apply for the synthesis of carbazoles with any kind of substitution and/or with groups
of different electronic properties. The catalytic cycle for this transformation remained
unknown until very recently, when it was depicted by Knölker and co-workers in
2012.147 The Scheme 4.8 shows the generally accepted mechanism for the oxidative
coupling leading to biaryl bond formation by palladium(II)-catalyzed double C−H bond
activation.
147
T. Gensch, M. Rönnefahrt, R. Czerwonka, A. Jäger, O. Kataeva, I. Bauer, H.-J. Knölker, Chem.
Eur. J. 2012, 18, 770.
181
C−H di-ortho-olefination of carbazoles
Air
Cu+
Pd(OAc)2
Cu2+
N
I H
1. Electrophilic
Substitution
AcOH
4. Reoxidation
Pd0L2
L Pd L
OAc
N
H
III
2. Cyclopalladation
N
H
II
3. Reductive
Elimination
L
L
Pd
AcOH
N
H
IV
Scheme 4.8
The first step was assumed to be an electrophilic palladation of the diarylamine I
(SE reaction by an electrophilic Pd species), generating a palladium(II) III complex. In
the same line as Åkermark proposed,139 the authors anticipated that the second C−H
bond activation proceeded via a cyclopalladation leading to a palladacycle IV. Finally,
reductive elimination of a palladium(0) species from the palladacycle IV with
concomitant C−C coupling generates the biaryl compound II. To come to a catalytic
process, the palladium(0) species had to be reoxidized to palladium(II) by an external
oxidant [e.g., copper(II) and air or directly air].
However, the crucial C−C coupling reaction that generates the biaryl bond could
be explained by at least three different mechanisms (Scheme 4.9).
182
Chapter 4
Scheme 4.9
The first route (a) would proceed via the palladacycle IV, which represents a
palladium(II) intermediate. Moreover, for the cyclopalladation leading to IV three
alternative mechanisms have been considered:148 i) second electrophilic palladation
(SE), ii) concerted σ-bond metathesis, or iii) concerted metalation–deprotonation
(CMD) pathway. Recent findings based on kinetic data support the CMD pathway for
the second C−H bond activation.149 In any case, reductive elimination provides the
biaryl compound II and palladium(0). The second route (b) involves an intramolecular
oxidative addition, leading to a palladacycle V, which is a palladium(IV) complex.
Reductive elimination would lead to the biaryl II. The third route (c) consists of an
intramolecular carbopalladation and it has been suggested by Ohno and coworkers.145b However, the palladium complex VI initially resulting from this process
would have the wrong stereochemistry for the β-hydride elimination to the carbazol II
and would require a previous epimerization.
148
D. R. Stuart, K. Fagnou, Science 2007, 316, 1172.
149
a) X. Bugaut, F. Glorius, Angew. Chem. 2011, 123, 7618; Angew. Chem. Int. Ed. 2011, 50, 7479;
b) L. Ackermann, Chem. Rev. 2011, 111, 1315; c) A. N. Campbell, E. B. Meyer, S. S. Stahl, Chem.
Commun. 2011, 47, 10257.
183
C−H di-ortho-olefination of carbazoles
In their work, Knölker and co-workers provided direct evidence for the
cyclopalladation route (a) by the isolation of palladacycle IV whose structure was
unequivocally determined by X-ray diffraction analysis. This complex IV was
transformed into the corresponding biaryl II by reductive elimination of palladium(0) in
acetic acid under air at 80 ºC for 30 min. Moreover, the palladacycle IV was
demonstrated to be catalytically competent in this reaction, likely by generating the
catalytically active palladium(II) species required for the oxidative cyclization that lead
to the carbazole II.
4.2.2. C−
−N bond formation: cyclization of 2-aminobiphenyl derivatives
(route b)150
In 2005, Buchwald and co-workers disclosed a new method for the oxidative
cyclization of 2-acetamidobiphenyl derivatives (or ortho-arylated acetanilides) under
palladium(II)-catalysis in combination with Cu(OAc)2/O2 as terminal oxidant to
efficiently produce a series of carbazoles (Scheme 4.10).151
Scheme 4.10
150
For a palladium-catalyzed annulation of arynes by substituted 2-haloacetanilides to obtain N-
acetylcarbazoles, see: C. Lu, N. A. Markina, R. C. Larock, J. Org. Chem. 2012, 77, 11153.
151
W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 14560.
184
Chapter 4
The reaction tolerated the presence of electron-donating and withdrawing groups
at different positions in both aromatic rings with little influence in the reactivity. Thus,
2-, 3- and 4-substituted carbazoles were obtained in good yields, although only a
single example was provided of synthesis of carbazole derivatives substituted at the
C1 position (adjacent to the nitrogen) from the cyclization of ortho-substituted orthoarylated acetanilides.
The scope of the process was limited to functional groups compatible with the
use of Cu(OAc)2 as oxidant. For example, polar coordinating groups such as nitro-,
cyano- or thioether functionalities were found to be incompatible and the coupling
reaction essentially met with failure. However, the same research group managed to
overcome this limitation.152 They found out that when dimethyl sulfoxide (DMSO) was
used as the solvent under an atmosphere of oxygen, Cu(OAc)2 was not necessary
and carbazoles with challenging substitution were obtained in similar yields, yet an
increased catalyst loading of 10 mol% was required (Scheme 4.11). The authors
proposed that presumably in this case, DMSO was acting as a ligand facilitating the
direct oxidation of Pd0 to PdII with oxygen.
Scheme 4.11
Regarding to the nature of the amine protecting group, sulfonamide-based biaryl
amides underwent the cyclization with comparable efficiency than the corresponding
152
W. C. P. Tsang, R. H. Munday, G. Brasche, N. Zheng, S. L. Buchwald, J. Org. Chem. 2008, 73,
7603.
185
C−H di-ortho-olefination of carbazoles
acetamide. In contrast, 2-aminobiphenyl derivatives with other amides as Nprotecting groups such as benzamide or carbamates, such as the N-Boc group,
provided much lower yields of the desired products with an easily removable amide
group. The N-pentafluoropropionamide derivative was found to be inert under the
reaction conditions (Scheme 4.12).
Scheme 4.12
Shi and co-workers successfully used the protocol for the C−N coupling
developed by Buchwald, combined with their own procedure for the synthesis of
ortho-arylated acetanilides by cross-dehydrogenative coupling reaction. Thus, the
carbazoles core could be constructed from anilides and simple arenes through
double C−H functionalization, with a Pd-based catalyst in a highly chemo- and
regioselective manner, in a process free of halogenated and metal-containing
reagents (Scheme 4.13).153
Scheme 4.13
153
B.-J. Li, S.-L. Tian, Z. Fang, Z.-J. Shi, Angew. Chem. Int. Ed. 2008, 47, 1115.
186
Chapter 4
In 2008, Gaunt and co-workers developed a related PdII-catalyzed process for
the intermolecular C−H amination of 2-aminobiphenyl derivatives that operated at
extremely mild reaction conditions (toluene, room temperature) using Pd(OAc)2 as
the catalyst (5 mol%), PhI(OAc)2 as the oxidant (1.2 equiv).154 Under these optimized
conditions, substrates bearing simple N-alkyl, N-benzyl and N-allyl motifs performed
well in the reaction, providing the desired carbazoles in good yields (Scheme 4.14).
Scheme 4.14
As shown in Scheme 4.15, the reaction tolerated the presence of electrondonating and electron-withdrawing groups in both rings independently of their
position, and they observed that electron-rich substrates reacted faster than electrondeficient substrates. Gaunt elegantly postulated a PdII/PdIV catalytic cycle, attributing
the success of this protocol to the facile reductive elimination of aminoaryl
palladium(IV) intermediates, leading to C−N bond formation.
154
J. A. Jordan-Hore, C. C. C. Johansson, M. Gulias, E. M. Beck, M. J. Gaunt, J. Am. Chem. Soc.
2008, 130, 16184.
187
C−H di-ortho-olefination of carbazoles
Scheme 4.15
More recently, in 2011, Youn and co-workers also reported a Pd-catalyzed
intramolecular oxidative C−H amination of N-Ts-2-arylanilines that involves a directed
C−H activation followed by a subsequent C−N bond formation via a PdII/PdIV
process.155 The reaction proceeded at room temperature, representing an
improvement of the protocol developed by Buchwald and co-workers, which needed
elevated temperatures and prolonged reaction time. Besides, to promote the
formation of PdIV species, oxone was used as a nontoxic, environmentally benign
oxidant, more attractive than PhI(OAc)2 (which led to a formation of a toxic
stoichiometric byproduct, PhI) in Gaunt’s protocol. However, Gaunt’s and Youn’s are
complementary approaches since the former is better suited for substrates containing
electron-donating N-alkyl substituent whereas the latter works best for N-sulfonylated
derivatives. The reaction tolerated well the presence of both electron-donating and
electron-withdrawing substituents in the 2-aryl moiety, although an increased loading
of the palladium catalyst (10 mol%) was needed for electron-withdrawing substituents
at the aniline aromatic ring (Scheme 4.16).
155
S. W. Youn, J. H. Bihn, B. S. Kim, Org. Lett. 2011, 13, 3738.
188
Chapter 4
Scheme 4.16
In this context, while much effort has been spent in the development of Pdcatalyzed oxidative C−H/N−H couplings, alternative and/or complementary methods
using more practical metal catalysts such as Cu species or metal free conditions has
been less investigated.
In 2011, Chang and co-workers developed an intramolecular oxidative C−N
bond-forming reaction of N-substituted 2-amidobiphenyls for the synthesis of
carbazoles under Cu-catalysis and mild reaction conditions.156 Surprisingly, it was
observed that the cyclization took place readily also under metal-free conditions,
although product yields were generally lower in the latter case. For the coppercatalyzed protocol, it was found that the best conditions were: Cu(OTf)2 as the
catalyst (5 mol%), PhI(OAc)2 as the oxidant (1.5 equiv), in 1,2-dichloroethane as the
solvent, at 50 ºC. For the metal-free protocol, PhI(OAc)2 was replaced by bis(trifluoroacetoxy)iodobenzene, [PhI(OTFA)2], which could be used alone as an
oxidant for the corresponding carbazole synthesis. In both cases, the presence of
CF3COOH (3.0 equiv) as an additive increased the yields. (Scheme 4.17).
156
S. H. Cho, J. Yoon, S. Chang, J. Am. Chem. Soc. 2011, 133, 5996.
189
C−H di-ortho-olefination of carbazoles
Scheme 4.17
Based on their observations, the authors postulated a reactivity pattern of
sulfonamidobiphenyl substrates: it could be generalized that the electronic influences
of substituents on the “right” and “left” aryl sides were complementary to each other
under for both Cu-catalyzed and metal-free conditions. Thus, high product yield was
obtained with substrates bearing electron-donating groups (R2) at the “right” phenyl
part and/or electron-withdrawing substituents (R1) at the amido-containing “left” aryl
side. In contrast, poor reactivity was found with substrates having electronwithdrawing groups (R2) at the “right” phenyl side and/or electron-donating
substituents (R1) at the “left” amidoaryl position (Scheme 4.18).
Scheme 4.18
Antonchick and co-workers developed an atom-economical, environmentally
friendly organocatalytic method for the preparation of carbazoles through C−H
190
Chapter 4
amination reaction.157 For this metal-free approach, initially stoichiometric amounts of
PhI(OAc)2 (1.1 equiv) was used as oxidant, in a polar solvent, hexafluro-2-propanol
(HFIP), at a concentration of 0.05 M (dilution of the reaction was found to be a key
feature). Under these conditions, N-tosyl-9H-carbazole and N-acetyl-9H-carbazole
were obtained in moderate to good yields, 68% and 81% respectively. To render the
reaction catalytic in the oxidant by in situ oxidation of iodo(I)arenes to
iodine(III)species, 2,2’-diiodo-4,4’,6,6’-tetramethylbiphenyl (1, 10 mol%) was used
instead of PhI(OAc)2, along with AcOH as additive. In this case, a mixture of CH2Cl2
and HFIP was used as a solvent, maintaining the dilution. In general, the reaction
tolerated well the presence of substituents with different electronic and steric
properties in various positions, yielding the substituted carbazoles in moderate to
good yields (Scheme 4.19).
Scheme 4.19
4.2.3. Direct functionalization of the carbazole skeleton: functionalization
at C1/C8 positions
The direct functionalization of the carbazole skeleton is an efficient alternative
approach to those described previously. This strategy largely relies on the
electrophilic aromatic substitution reaction. Since carbazole is activated towards
electrophiles at its 3,6-positions, functionalization at C3 and/or C6 is the reactivity
157
A. P. Antonchick, R. Samanta, K. Kulikov, J. Lategahn, Ang. Chem. Int. Ed. 2011, 50, 8605.
191
C−H di-ortho-olefination of carbazoles
pattern generally available through this reaction.158 However, this reactivity
represents a strong limitation for the development of new application of carbazole
chemistry. For example, with respect to carbazole-based materials, nearly all the
previous literature has focused on substitution at 3,6-positions and at the N-position.
This is because the N-position can be easily functionalized by N-alkylation and
Ullman
reaction,159
while
3,6-functionalization
is
readily
accessed
through
electrophilic substitution. In contrast, functionalization at C1 and C8 remains
uncharted.130c The absence of research on C1/C8 substituted-carbazoles is due to
the lack of methods for their synthesis. The following examples illustrate this current
limitation.
a) C1/C8 functionalization through electrophilic aromatic substitution
Because of the higher nucleophilic character of its C3 and C6 positions, the
electrophilic substitution at C3 and/or C6 positions constitutes an efficient approach
for the functionalization of the carbazole core. However, substitution at the less
activated C1 and C8 positions typically requires prefunctionalization/”protection” of
the 3,6-positions. For example, Jurczak and co-workers became interested in the 1,8diaminocarbazole as a direct precursor to prepare 1,8-diamidocarbazoles, which they
envisioned could effectively bind anions.134 However, they found a synthetic problem
while achieving their goal: the synthetic route for 1,8-diaminocarbazole available in
the literature was very lengthy and impractical.160 For that reason, they established
the 1,8-diamino-3,6-dichlorocarbazole as a more convenient parent compound
because it had been previously prepared by Muzik and co-workers in a 3-step
sequence involving: i) chlorination of the carbazole, which took place at the more
nucleophilic 3- and 6-position; ii) electrophilic nitration which occurs selectively at C1
158
a) F. Dierschke, A. C. Grimsdale, K. Müllen, Synthesis 2003, 2470; b) Y. Maegawa, Y. Goto, S.
Inagaki, T. Shimada, Tetrahedron Lett. 2006, 47, 6957; c) G. G. K. S. N. Kumar, K. K. Laali,
Tetrahedron Lett. 2013, 54, 965.
159
W. Jiang, L. Duan, J. Qiao, G. Dong, D. Zhang, L. Wang, Y. Qiu, J. Mater. Chem. 2011, 21, 4918.
160
K. Takahashi, H. Eguchi, S. Shiwaku, T. Hatta, E. Kyoya, T. Yonemitsu, S. Mataka, M. Tashiro, J.
Chem. Soc. Perkin Trans. 1 1988, 1869.
192
Chapter 4
and C8; and iii) catalytic hydrogenation (Scheme 4.20). Indeed, they observed that
selective chlorination of the carbazole was a difficult step that still needed to be
improved, because of the difficult-to-handle conditions used (gaseous chlorine). Their
found that using sulfuryl chloride as chlorinating agent, the 3,6-dibromocarbazole was
obtained in 60% yield.
Scheme 4.20
Very recently, Nakada and co-workers faced a similar problem when developing
a new family of chiral ligands based on 1,8-(bisoxazolyl)carbazole structural unit.135
This type of chiral ligands displayed non porphyrine-like properties and catalysed the
asymmetric epoxidation of (E)-alkenes with excellent enantioselectivities.161 Before
being able to functionalize the C1 and C8 positions, the more nucleophilic C3 and C6
positions had to be blocked with a phenyl substituent in a two-step sequence
consisting of electrophilic iodiation and subsequent standard Suzuki-coupling reaction
with phenyl boronic acid. Then, a second electrophilic iodination took place at the
161
For the synthesis of 1,8-(bisoxazolyl)carbazole ligands, see: a) M. Inoue, T. Suzuki, M. Nakada, J.
Am. Chem. Soc. 2003, 125, 1140. For selected references of their application in asymmetric
catalysis: b) T. Suzuki, A. Kinoshita, H. Kawada, M. Nakada, Synlett 2003, 570; c) M. Inoue, M.
Nakada, Org. Lett. 2004, 6, 2977; d) M. Inoue, M. Nakada, Angew. Chem. Int. Ed. 2006, 45, 252; e)
M. Inoue, M. Nakada, Heterocycles 2007, 72, 133; f) M. Inoue, T. Suzuki, A. Kinoshita, M. Nakada,
Chem. Rec. 2008, 8, 169.
193
C−H di-ortho-olefination of carbazoles
desired C1 and C8 allowing the access to the target compounds after installing the
oxazolyl moiety (Scheme 4.21).
Scheme 4.21
b) C1-functionalization through ortho-directed lithiations
The lithiation of the free NH-carbazole is difficult and very low yields of C1
substituion product are invariably obtained, deuteration being the sole exception.162
However, certain N-directing groups make carbazole-lithiation synthetically useful.
The best of these groups appeared to be pyrrolidin-1-ylmethyl (Scheme 4.22).163 This
method could be applied to a wide range of electrophiles with varied efficiency to
afford aminal-directed functionalized products at C1 in moderate to good yields.
Hydrolysis of the pyrrolidinomethyl protecting group was readily achieved during the
work-up by gently warming the reaction mixture for a few minutes in the presence of
dilute aqueous hydrochloric acid. The C1-substituted NH-carbazole derivatives were
obtained in good yields (68-86%).
162
A. Hallberg, A. R. Martin, J. Heterocycl. Chem. 1984, 21, 837.
163
A. R. Katritzky, G. W. Rewcastle, L. M. Vazquez de Miguel, J. Org. Chem. 1988, 53, 794.
194
Chapter 4
Scheme 4.22
195
C−H di-ortho-olefination of carbazoles
4.3. Aim of the project
Despite the significant process in the synthesis of functionalized carbazole
derivatives, limitations still remain with regard to the type of substitution pattern that
can be accessed, especially through catalytic approaches. In particular, accessing C1
and/or C8-substituted carbazoles has proven to be challenging using C−H cyclization
strategies from diarylamines (C−C bond formation) or from 2-aminobiphenyl
derivatives (C−N bond formation) due to the steric congestion next to the reactive
site, especially in the former case.
On the other hand direct functionalization of the carbazole skeleton is an
alternative approach perfectly suited for substitution at the more nucleophilic C3
and/or C6 positions. In contrast, functionalization at the less activated C1 and C8
positions typically requires “protection” at the 3,6-positions. A solution to this
regioselectivity problem came from the ortho-directed lithiation of N-pyrrolidin-1ylmethyl carbazole, allowing the synthesis of various regioespecifically substituted at
C1 and C8 carbazole derivatives. However, the disadvantage of this method lies in
the high reactivity and basicity of the alkyl lithium reagents required, which are often
incompatible with many standard functional groups.
Therefore, alternative pathways are needed for the catalytic regiocontrolled
functionalization of carbazoles, providing orthogonal selectivities to those currently
available, as well as other type of functionalization including the introduction of
sensitive and versatile groups, would be of great interest for expanding the scope of
carbazole synthesis.
In this context, in stark contrast to the tremendous progress made with related
nitrogen aromatic systems such anilines, methods for the catalytic direct C−H
functionalization of the carbazole core remained undocumented at the outset of this
work. 164 On the basis of the excellent structural flexibility previously observed in the
164
Only recently have the first two successful examples appeared. For the PdII-catalyzed direct ortho-
arylation of carbazoles bearing a N-(pyridin-2-yl) directing group with potassium aryltrifluoroborates,
196
Chapter 4
PdII-catalyzed
direct
olefination
of
N-alkyl-N-(2-pyridyl)sulfonyl
anilines
and
arylalkylamines, we hypothesized that this reaction could also extended to the C-H
functionalization of carbazole derivatives. In fact, the N-(2-pyridyl)sulfonyl carbazole
could be envisaged as a particular type of N-aryl N-(2-pyridyl)sulfonyl aniline
derivative. If successful, this reaction would enable a direct catalytic access to C1and/or C8-functionzalized carbazole derivatives (Scheme 4.23).
Scheme 4.23
Furthermore, this method could be also applied to related heterocyclic systems
with a fully saturated ring such as the saturated hexahydrocarbazole derivative or
indoline derivatives (Scheme 4.24).
Scheme 4.24
see:a) J.-H. Chu, C.-C. Wu, D.-H. Chang, Y.-M. Lee, M.-J. Wu, Organometallics 2013, 32, 272. For
the direct dehydrogenative C1−N carbazolation of NH-carbazoles by the cooperative action of Ru and
Cu catalysts, see: b) M.-L. Louillat, F. W. Patureau, Org. Lett. 2013, 15, 164.
197
C−H di-ortho-olefination of carbazoles
4.4. Results and discussion
4.4.1. N-sulfonanylation of the NH-carbazole
The N-(2-pyridyl)sulfonyl carbazole 2 was chosen as the model compound for
optimization studies of the different parameters of the C−H alkenylation reaction. As
shown in Scheme 4.25, N-(2-pyridyl)sulfonyl carbazole 2 was prepared following the
typical N-sulfonylation protocol, consisting of the N-H deprotonation of carbazole (1)
with NaH as a base in THF followed by addition of 2-pyridylsulfonyl chloride.
Scheme 4.25
4.4.2. Screening of the reaction conditions
We began our study by examining the C−H alkenylation reaction of N-(2pyridyl)sulfonyl carbazole 2 using n-butyl acrylate as the coupling partner, under the
same conditions that provided us the best results in the previously described PdIIcatalyzed direct ortho-alkenylation of N-alkyl N-(2-pyridyl)sulfonyl anilines. Thus,
under
catalytic
amount
of
Pd(OAc)2
(10
mol%),
using
N-fluoro-2,4,6-
+
trimethylpyridinium triflate as the oxidant ([F ], 2.0 equiv), in ClCH2CH2Cl as solvent
at 110 ºC, the reaction took place with an overall 93% conversion providing a mixture
of the mono- (3) and di-alkenylated (4) carbazoles (relative ratio of 2:3:4 of 7:16:77).
The major component of the mixture was the di-alkenylated product 4, which was
isolated in 42% yield after chromatographic purification (Scheme 4.26). In spite of this
initial poor mono- versus di-substitution selectivity, the complete ortho-control was
remarkable and encouraging.
198
Chapter 4
Scheme 4.26
With the aim of controlling mono-olefination selectivity, we carried out a deep
screening of metal-based and non-metal based oxidants, given the known strong
influence of the oxidant in both reactivity and selectivity in C−H olefination and other
functionalization reactions. The results obtained are summarized in Table 4.1.
199
C−H di-ortho-olefination of carbazoles
Table 4.1: Screening of the oxidant
Entry
1
Oxidant
+ [c]
[F ]
Ratio 2:3:4
Conv.
(%)
[a]
Yield [3/4,
(%)]
[b]
7:16:77
93
11/42
2
PhI(OAc)2
5:28:67
95
26/43
3
AgNO3
23:38:39
77
37/30
4
Ce(SO4)2
55:39:6
45
26/3
5
AgOAc
43:42:15
57
35/10
39:47:14
61
40/8
>98:<2:0
0
[e]
--
[e]
--
6
7
Ce(SO4)2
[d]
K2 S2 O 8
8
Cu(OAc)2
>98:<2:0
0
9
AgCO3
>90:<10:0
<10
--
10
AgF
>90:<10:0
<10
--
0
[e]
--
0
[e]
--
0
[e]
--
0
[d]
--
0
[d]
--
0
[d]
--
11
12
13
14
15
16
AgOTf
Ag2O
[f][g]
CAN
BQ
[h]
Tempo
Oxone
>98:<2:0
>98:<2:0
>98:<2:0
>98:<2:0
>98:<2:0
>98:<2:0
[a] Based on starting material recovered after chromatographic purification; [b] Isolated yield
after chromatography; [c] N-fluoro-2,4,6-trimethylpyridinium triflate; [d] 3 equivalents of
oxidant were used; [e] The starting material was recovered; [f] CAN: cerium ammonium
nitrate; [g] 1.2 equiv of oxidant were used; [h] 1,4-benzoquinone.
Among the many oxidants examined, only PhI(OAc)2 provided comparable
efficiency in terms of reactivity to the [F+] reagent. In fact, both oxidants led to very
similar levels of unpractical mono- versus di-substitution selectivity (entry 2). The use
of AgNO3 resulted in lower conversion (77%), but roughly an equimolar mixture of
200
Chapter 4
mono- and diolefinated product was obtained (37% isolated yield of 3 and 30%
isolated yield of 4, entry 3). Ce(SO4)2 and AgOAc were found to be less active
oxidants in this reaction, both leading to conversions close to 50% (entries 4 and 5).
However, still in these cases a significant amount of the diolefinated product at C1
and C8 was formed (3-10%). In fact, when the amount of Ce(SO4)2 was increased
from 2.0 to 3.0 equivalents, the increased conversion (61%) was accompanied by an
increase in the relative ratio of diolefination product (entry 6). Finally, it is worth
mentioning that many oxidant species that have been reported to be highly effective
in a wide variety of C−H functionalization reactions were unproductive, highlighting
the critical role of this component of the catalytic system (entries 7-16).
With the best two oxidants identified in the previous study, control of the monoolefination selectivity was attempted by using reduced equivalents of either the
acrylate or the oxidant. As shown in the results summarized in Table 4.2, both effects
caused a decrease in the reactivity. However, the formation of significant amounts of
the disubstitution product 4 in all cases even at decreased conversions suggested a
similar reactivity of both the starting carbazole 2 and the mono-olefination product 3.
Therefore, we turned our focus to the development of a protocol for the di-olefination
reaction of carbazole regiospecifically at its C1 and C8 positions.
201
C−H di-ortho-olefination of carbazoles
Table 4.2: [F+] vs PhI(OAc)2
Entry
Equiv. of
Oxidant
Equiv. of
alkene
1
2.0
2
2.0
3
+ [c]
[F ]
PhI(OAc)2
4
2.0
5
2.0
Conv.
oxidant
2:3:4
[a]
2.0
7:16:77
93
11/43
(%)
Yield [3/4
(%)]
[b]
2.0
5:28:67
95
26/43
+ [c]
2.0
30:28:42
70
20/22
+ [c]
1.0
34:25:41
66
19/23
1.0
40:43:17
60
36/11
[F ]
1.1
Ratio
[F ]
PhI(OAc)2
[a] Based on starting material recovered after chromatographic purification; [b] Isolated yield after
chromatography; [c] N-fluoro-2,4,6-trimethylpyridinium triflate.
4.4.3. Evaluation
of
the
role
of
the
N-(2-pyridyl)sulfonyl
directing/protecting group
To evaluate the role of the N-(2-pyridyl)sulfonyl protecting/directing group, a set
of carbazole derivatives having different potentially coordinating groups at the
nitrogen were also prepared. Thus, the N-tosyl carbazole derivative 5 was readily
accessed by N-sulfonylation reaction with tosyl chloride under identical conditions
compared to that used in the case of 2 (Scheme 4.27).
Scheme 4.27
202
Chapter 4
For testing also non-sulfonyl protecting groups, we considered the N-acetyl
carbazole 6, commercially available, and the N-Boc carbazole 7. The latter was
prepared in excellent yield, following a previously described protocol (quantitative
yield, Scheme 4.28).165
Scheme 4.28
The N-protected synthetized carbazoles (2, 5 and 7), bearing a potentially
coordinating protecting group (PG), along with commercially available NH- (1) and Nacetyl (6) carbazole derivativess were examined in the reaction with butyl acrylate
(2.0 equiv), under catalytic amounts of Pd(OAc)2 (10 mol%), using N-fluoro-2,4,6trimethylpyridinium triflate ([F+], 2.0 equiv) as the oxidant, in ClCH2CH2Cl as solvent
at 110 ºC. The results are collected in Table 4.3.
165
V. Diep, J. J. Dannenberg, R. W. Franck, J. Org. Chem. 2003, 68, 7907.
203
C−H di-ortho-olefination of carbazoles
Table 4.3: Evaluation of the N-directing/protecting group
[a]
Entry
PG
Conv. (%)
Yield [3/4 (%)]
1
H (1)
-
[c]
--
[c]
--
2
Boc (7)
-
3
Ac (6)
<5
--
4
Ts (5)
<5
--
5
−SO2(2-pyridyl) (2)
93
11/42
[b]
[a] Based on starting material recovered after chromatographic purification; [b]
Isolated yield after chromatography; [c] Complex reaction mixture.
Both the unprotected NH-carbazole (1) and the N-Boc derivative 7 led to a
complex mixture of products (entries 1 and 2), with the latter result suggesting that
the Boc protecting group is too labile under the reaction conditions. Switching to an
N-Ac group (substrate 6) or an N-Ts group (5) resulted in the full recovery of the
unreacted starting material, even after 24 h (entries 3 and 4). These results, showing
the complete lack of reactivity displayed by the parent NH-carbazole (1) and the Nprotected
derivatives (5-7)
highlighted
the
unique
efficiency of
the N-(2-
pyridyl)sulfonyl group in the C−H alkenylation reaction of carbazoles comparing to the
rest of protecting groups evaluated.
4.4.4. Di-ortho olefination
In contrast to the poor control for mono-olefination, high diolefination selectivity in
the model reaction of 2 with butyl acrylate under otherwise identical conditions was
achieved by simply adjusting the excess of alkene (4.0 equiv) and oxidant (3.0 equiv).
These results are summarized in Table 4.4.
204
Chapter 4
Table 4.4: Di-ortho olefination
Entry
1
2
Oxidant
+ [c]
[F ]
PhI(OAc)2
Ratio 2:3:4
Conv. (%)
[a]
Yield [3/4 (%)]
0:0:>98
>98
0/64
5:15:80
95
16/58
[b]
[a] Based on starting material recovered after chromatographic purification; [b] Isolated yield
after chromatography; [c] N-fluoro-2,4,6-trimethylpyridinium triflate.
The use of [F+] resulted in a clean di-olefination reaction, providing the C1/C8disubstituted carbazole derivative 4 in 64% isolated yield (entry 1), whereas
PhI(OAc)2 was found to be slightly less reactive. In the latter case although the dialkenylated product 4 was the major component of the reaction mixture, small
amounts of the mono-alkenylated product 3 and of the unaltered starting carbazole 2
were also present (entry 2).
At this point, it is important to note that although the 1H NMR of the crude
reaction mixture using [F+] as oxidant was rather clean, showing mainly the
diolefinated product, the difficulty in its complete chromatographic separation from the
trace amounts of unidentified by-products resulted in a diminished moderate 64%
yield.
4.4.5. Olefin scope for the PdII-catalyzed di-olefination
By using the optimized conditions for the di-olefination, we next explored the
scope of the reaction with regard to the alkene. The results are summarized in
Scheme 4.29.
205
C−H di-ortho-olefination of carbazoles
Scheme 4.29
In addition to n-butyl acrylate, other monosubstituted electrophilic alkenes, such
as phenyl vinyl sulfone or ethyl vinyl ketone, were also capable reactants in the
model diolefination reaction with carbazole 2, leading to the corresponding
dialkenylated products 8 and 9 in good isolated yields (64% and 80%, respectively).
Interestingly, styrene derivatives bearing electron-withdrawing substituents (NO2 or
CF3) at the para-position of the phenyl ring were also found to be excellent coupling
partners (products 10 and 11, 80% and 91% yield respectively). Unfortunately,
styrene itself provided poor reactivity (mixtures of mono- and diolefinated products in
60% conversion); and the same mixture was obtained when acrylonitrile was used as
coupling partner (Scheme 4.30). Acrylamide and methyl crotonate did not react, the
starting material was recovered unaltered.
206
Chapter 4
Scheme 4.30
4.4.6. Substrate scope
The evaluation of the scope of the reaction with regard to the substitution at the
carbazole nucleus required the N-sulfonylation of carbazole derivatives. Thus,
carbazoles derivatives were N-protected following the typical N-sulfonylation protocol
(N-H deprotonation of carbazole (1) with NaH and subsequent addition of the in situ
prepared 2-pyridylsulfonyl chloride, Scheme 4.31). This was the case of the
commercially available 2,3,4,9-tetrahydro-1H-carbazole (14) and the 3-bromo-9Hcarbazole (16). Although the latter carbazole wasn’t commercially available, it was
readily prepared by electrophilic bromination of the NH-carbazole 1 with Nbromosuccinimide (1.0 equiv) in DMF, which occured cleanly at the more reactive C3
position.166 The obtained 3-bromo-9H-carbazole (16, 75% isolated yield) was
submitted to the N-sulfonylation protocol, yielding the 3-bromo-N-(2-pyridyl)sulfonyl9H-carbazole 17 in 89%.
166
A. Midya, Z. Xie, J.-X. Yang, Z.-K. Chen, D. J. Blackwood, J. Wang, S. Adams, K. P. Loh, Chem.
Commun. 2010, 46, 2091.
207
C−H di-ortho-olefination of carbazoles
Scheme 4.31
a) Oxidative cyclization of 2-N-(2-pyridyl)sulfonyl biphenyl derivatives
Unfortunately, the very limited number of substituted carbazole derivatives that
are commercially available prompted us to find a reliable method for the preparation
of N-(2-pyridyl)sulfonyl carbazoles by adapting any of the existing protocols. Among
the catalytic methods described in the introduction of this chapter, we focused on the
intramolecular C−H amination of 2-aminobiphenyl derivatives. These method has
been proven especially well suited for substrates bearing an strong electronwithdrawing N-protecting group (Scheme 4.32).
Scheme 4.32
Furthermore, this approach would allow us to explore the influence of the metalcoordinating N-(2-pyridyl)sulfonyl group in the key C−H activation/cyclization step.
Another attractive issue that we considered was that both metal-promoted and metalfree conditions were available for the cyclization through intramolecular C−H
amination. The required N-(2-pyridyl)sulfonyl 2-aminobiphenyl derivatives should be
readily available by applying the already described Suzuki cross-coupling between 2-
208
Chapter 4
bromoanilines and arylboronic156 followed by standard N-sulfonylation reaction of the
resulting aminobiphenyl products (Scheme 4.33).167
Scheme 4.33
To explore the feasibility of this route, we first attempted the synthesis of two
substituted carbazoles derivatives with different electronic properties, the 3methoxycarbazole derivative 18 and the 2-chlorocarbazole derivative 19. Thus, the
Suzuki coupling between the commercially available 2-bromoaniline and the
corresponding substituted boronic acid (3-methoxy boronic acid and 4-chloro boronic
acid), under previously reported reaction conditions led clearly to the already
described 3’-methoxy-2-amino biphenyl A and 4’-chloro-2-amino biphenyl B. After
subjecting them to N-sulfonylation with 2-pyridylsulfonyl chloride in pyridine, the
corresponding N-(2-pyridyl)sulfonyl-2-aminobiphenyl derivatives I and II were isolated
in good yields after precipitation from diethyl ether (Scheme 4.34).
Scheme 4.34
167
For the synthesis of analogous N-(2-p-toluene)sulfonyl-2-aminobiaryls, see reference 155.
209
C−H di-ortho-olefination of carbazoles
For the next C−H amination/cyclization step we tested the palladium-catalyzed
protocol developed by Youn and co-workers, which proved to be highly efficient for
analogous N-tosyl-2-aminobiphenyl derivatives.155 Indeed, this procedure has shown
the best performance when the electron-donating groups were present at the orthoaryl substituent of the aniline moiety. Accordingly, substrate I should be well suited for
applying this catalytic system, however it was found to be inert under Youn’s
optimized conditions. The starting material was recovered without observing even
traces of the desired carbazole 18 (Scheme 4.35).
Scheme 4.35
Understanding that this failure must be due to the incompatibility of the PdIIcatalyst with the NH-SO2Py group, we decided to move on to another type of catalyst
system. In this regard, it must be noted that similar incompatibility was observed in
the ortho-olefination of anilines derivatives, where an N-alkyl group was required for
the reaction to proceed while the NH-SO2Py-aniline derivative resulted unreactive.
Therefore, we decided to examine the Cu-catalyzed procedure developed by
Chang and co-workers, also compatible with N-sulfonyl protecting groups.156
Gratifyingly, the reaction of the N-(2-pyridyl)sulfonyl-2-(3’-methoxyphenyl)aniline I
under the reporter conditions resulted in the clean formation of the desired carbazole
product 18, albeit in low conversion (37% isolated yield, Scheme 4.36). However,
when N-(2-pyridyl)sulfonyl 2-(4’-chlorophenyl)aniline II was submitted to the reaction
conditions, the biaryl derivative was recovered unaltered (Scheme 4.36). Heating or
adding an acid (CF3COOH; as reported by the authors to increase the yield in some
cases with electron-withdrawing substituents) did not change the outcome of the
reaction.
210
Chapter 4
Scheme 4.36
As a consequence, we tested the organocatalytic version of this reaction
developed by Antonchick’s group.157 The first optimized conditions by this group were
used: PhI(OAc)2 as the oxidant (1.1 equiv), at room temperature, in hexafluoro-2propanol (HFIP, 0.05 M) as solvent. Under these conditions, N-(2-pyridyl)sulfonyl-2amino derivatives I and II were tested, and gratifyingly, both gave the desired
carbazoles 18 and 19, although the yields were moderate (Scheme 4.37).
Scheme 4.37
Despite these low conversions, the reaction proved to be scalable to provide
enough material to continue with the study of the scope of the C−H olefination
reaction. Therefore, this method was selected for the preparation of a variety of
functionalized carbazole derivatives.
211
C−H di-ortho-olefination of carbazoles
Once identified a suitable method for the assembly of N-(2-pyridyl)sulfonyl
carbazole derivatives, it was applied to the preparation of substrates substituted with
various groups of different electronic and steric properties. The two-step sequence
(Suzuki coupling, N-sulfonylation) leading to N-(2-pyridyl)sulfonyl-2-aminobiphenyl
derivatives for substrates I-VI is depicted in Scheme 4.38. Both electron-donating and
electron-withdrawing substituents were well tolerated, regardless of the position of
the substituent in the boronic acid coupling partner or in the aniline.
Scheme 4.38
Next, the biphenylamines I-VI were subjected to the organocatalytic oxidative
intramolecular C−H amination, which took place with acceptable conversion in two on
the four new cases examined, leading to several carbazole derivatives bearing
electronically modified varied substituents with different substitution pattern in 3768% yield (products 18-21, Scheme 4.39). Unexpectedly, the 3’-trifluoromethyl-2aminobiphenyl and the 3,5-dimethyl-2-aminobiphenyl derivatives were completely
unreactive under these conditions.
212
Chapter 4
Scheme 4.39
b) Sustrate scope of the C−H di-olefination reaction
This structurally diverse set of functionalized carbazole derivatives (17-20) was
surveyed for the C−H olefination reaction with butyl acrylate as the model olefin
(Scheme 4.40). In general, both electron-rich and electron-deficient substrates
performed well in this reaction, thereby enabling the construction of polysubstituted
carbazoles in acceptable yields (24-27, 48-66% yield). Of special importance,
carbazoles containing halogen atoms, including bromine and chlorine, were also
compatible with this catalytic system (25 and 26). This observed orthogonal reactivity
relative to the Pd0-catalyzed cross-coupling chemistry could be useful for subsequent
product derivatization. As expected, a blocking fluorine substituent at C1 in substrate
20 caused exclusive mono-olefination at C8 (product 27, 66% yield), and only 2.0
equiv of alkene and oxidant were needed.
213
C−H di-ortho-olefination of carbazoles
Scheme 4.40
4.4.7. C−
−H olefination of other nitrogen-containing compounds
Regarding the alkenylation of related heterocyclic systems, the more sterically
congested N-(2-pyridyl)sulfonyl benzo[b]carbazole reacted at the less hindered ortho
site with complete regiocontrol to give the monoolefinated derivative 28 (64% yield).
In this case, also two equivalents of alkene and oxidant were needed to obtain full
conversions.
Likewise,
the
successful
use
of
the
partially
saturated
hexahydrocarbazole derivative turned out to be viable, producing exclusive orthomonoolefination at the aromatic ring in high yield (product 29, 84%). In this latter case
the oxidant was switched to PhI(OAc)2, because the stronger [F+] led to a complex
reaction mixture (Scheme 4.41).
214
Chapter 4
Scheme 4.41
The encouraging result obtained in the mono-alkenylation of the partially
saturated hexahydrocarbazole derivative 15 drew our attention to other nitrogencontaining coumpounds, which are also relevant in synthetic and medicinal
chemistry. For example, indoline derivatives are a common motif prevalent in many
natural products and pharmaceutical targets.168 Besides, the direct catalytic C7−H
olefination of the indoline skeleton has been only scarcely documented.169 In an
attempt to expand the substrate scope of this transformation, we became interested
in the homologous derivative tetrahydroquinoline and also in phenoxazine, important
structural motif that possess antitumoral properties (Figure 4.4).170
168
For recent examples of indoline synthesis: G. He, C. Lu, Y. Zhao, W. A. Nack, G. Chen, Org. Lett.
2012, 14, 2944, and references cited therein.
169
a) C. S. Yi, S. Y. Yun, J. Am. Chem. Soc. 2005, 127, 17000. For the intramolecular C7−H arylation
of indolines via a metal-free, single electron transfer mechanism, see: b) S. De, S. Ghosh, S. Bhunia,
J. A. Sheikh, A. Bisai, Org. Lett. 2012, 14, 4466. For the observation of 2,7-disubstitution in the Pdcatalyzed C−H olefination of indoles: c) G. Fanton, N. M. Coles, A. R. Cowley, J. P. Flemming, J. M.
Brown, Heterocycles 2010, 80, 895. For a directed ortho-lithiation approach to C7-substituted indoles:
d) C. G. Hartung, A. Fecher, B. Chapell, V. Snieckus, Org. Lett. 2003, 5, 1899.
170
H. Prinz, B. Chamasmani, K. Vogel, K. J. Böhm, B. Aicher, M. Gerlach, E. G. Günther, P. Amon, I.
Ivanov, K. Müller, J. Med. Chem. 2011, 54, 4247.
215
C−H di-ortho-olefination of carbazoles
Figure 4.4
a) N-sulfonylation of different nitrogen containing compounds
The corresponding N-(2-pyridyl)sulfonyl-protected parent derivative of each of
the three heteroaromatic compound mentioned above were readily prepared under
our standard N-sulfonylation reaction with 2-pyridylsulfonyl chloride. The three
products (31, 33 and 35) were isolated in good yields as bench-stable solids
(Scheme 4.42).
Scheme 4.42
216
Chapter 4
b) Reactivity towards C−H olefination
Unfortunately, when N-(2-pyridyl)sulfonyl-1,2,3,4-tetrahydroquinoline 31 was
submitted to the optimized conditions, the starting material was recovered unaltered.
A similar result was obtained when PhI(OAc)2 was used as the oxidant.
Scheme 4.43
The reaction of the N-(2-pyridyl)sulfonyl-10H-phenoxazine 33 with butyl acrylate
under the optimized reaction conditions was also unsuccessful, in this case resulting
in a very complex mixture, presumably due to decomposition of the starting material
(Scheme 4.44). A similar result was obtained when PhI(OAc)2 was used as the
oxidant.
Scheme 4.44
Pleasingly and in sharp contrast, the reaction of the N-(2-pyridyl)sulfonyl indoline
(35) with butyl acrylate (2.0 equiv) under the standard reaction conditions (but
reducing the amount of oxidant to 2.0 equiv) produced the alkenylated product at C7
38 in 80% isolated yield (Scheme 4.45). Besides, a comparable yield was obtained
when PhI(OAc)2 was used as the oxidant.
217
C−H di-ortho-olefination of carbazoles
Scheme 4.45
4.4.8. Deprotection of olefinated N-(2-pyridyl)sulfonyl carbazoles and
indolines
The easy reductive removal of the 2-pyridylsulfonyl group under mild conditions
to generate the free NH-carbazoles led us to confirm the full synthetic utility of this
method. Interestingly, the sulfonyl cleavage could be directed to the selective
formation of either alkenyl- or alkyl-substituted free carbazoles, depending on the
reducing agent used (Scheme 4.46). Simple treatment of derivative 4 with an excess
of Zn powder in a 1:1 mixture of THF and saturated aqueous NH4Cl at room
temperature led to the corresponding free carbazole 39 in 93% yield without affecting
the sensitive acrylate moiety. Instead, treatment of 4 with magnesium turnings
(MeOH, rt, sonication) afforded the dialkylated free carbazole 40 (75% yield).
Scheme 4.46
218
Chapter 4
These complementary deprotection protocols could also be applied with
comparable efficiency to the indoline derivative 38, as exemplified in its
transformation into the desulfonylated products 41 and 42 (Scheme 4.47). In the
latter case, the deprotection simultaneously triggered the cyclization of the free NHindoline under the reaction conditions to give the tricyclic compound 42.171 The easy
aromatization of this product with DDQ furnished the pyrroloquinolinone framework of
43, which is found in some biologically relevant indole based alkaloids,169b,172 and
whose derivatives are known to show unusual photosensitizing properties.173
Scheme 4.47
171
For the synthesis of 40 and its use as an intermediate in the synthesis of a potent and selective
CYP11B1 inhibitor for the treatment of Cushing’s syndrome, see: L. Yin, S. Lucas, F. Maurer, U.
Kazmaier, Q. Hu, R. W. Hartmann, J. Med. Chem. 2012, 55, 6629.
172
D. W. Robbins, T. A. Boebel, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 4068.
173
Pyrrolo[3,2,1-ij]quinolin-4-one (42) has been previously prepared using a ketene cyclization under
flash vacuum pyrolysis conditions (at 950 ºC): H. McNab, D. J. Nelson, E. J. Rozgowska, Synthesis
2009, 2171. See references cited therein for photophysical properties of this type of system.
219
C−H di-ortho-olefination of carbazoles
4.5. Conclusions
1) We have developed the first palladium-catalyzed C−H olefination reaction of
carbazoles leading to regiocontrolled C1/C8 di-olefinated products. The N-(2pyridyl)sulfonyl group has proved to be an efficient directing and readily removable
protecting group for this transformation.
This protocol was not only applicable to conventional mono-substituted alkenes
such as acrylates, sulphones and ketones, but also to styrene derivatives bearing
electron-withdrawing
substituents,
affording
the
corresponding
di-olefinated
carbazoles in good yields.
2) This palladium-catalyzed di-olefination protocol could be applied to various
substituted carbazoles affording the desired products in good yields, tolerating the
presence of electron-donating and electron-withdrawing groups in different positions
of the carbazole core. Remarkably, the partially saturated hexahydrocarbazole
220
Chapter 4
derivative also performed well in this reaction conditions, affording the monoolefinated corresponding product in good yield (84%).
3) Other nitrogen-containing compounds such as and the indoline surveyed the
reaction conditions, affording the mono-alkenylated product in good yield (80%). It is
noteworthy that the direct catalytic C7-olefination of the indoline has been only
scarcely documented.
221
C−H di-ortho-olefination of carbazoles
4) The easy reductive removal of the 2-pyridylsulfonyl group under mild
conditions to generate the free NH-carbazole derivatives led us to demonstrate the
full synthetic utility of our method. In fact, depending on the conditions used, the diortho-alkenylated (Zn-promoted deprotection) and the di-ortho-alkylated (Mgpromoted deprotection) NH-carbazole derivatives could be obtained in good yields.
5) These N-desulfonylation protocols could be also successfully applied to the
C7-alkenylated indoline derivative. Under Zn-promoted deprotection the alkenylated
NH-indoline was cleanly obtained, while under Mg-promoted deprotection a
cyclization reaction took place in situ after deprotection. The tryciclyc compound thus
obtained underwent smoothly aromatization in the presence of DDQ to afford
pyrroloquinolinone, a relevant heterocyclic system.
222
Chapter 5:
Aerobic copper-catalyzed ortho-halogenation of anilines
223
224
Chapter 5
5.
Aerobic
copper-catalyzed
ortho-halogenation
of
anilinesIntroduction:
sustainable catalytic C−
−H functionalization
Despite impressive levels of efficiency and selectivity accomplished, after
decades of intense research, the selective transformation of ubiquitous but inert C−H
bonds to other functional groups is still far-reaching practical implications in complex
total synthesis. Therefore, there are still important limitations that need to be solved.
For example, most of the reported methods for C−H functionalization rely on
complexes of expensive and toxic transition metals such as Pd, Pt, Rh, Ir or Ru in
combination with stoichiometric amounts of highly oxidizing metal- and non metalbased species [e.g., CuII, AgI, PhI(OAc)2] that are often incompatible with some
functional groups. In some cases, the cost and environmental incompatibilities
represent a strong limitation in the use of these catalyst systems. Therefore, the
development of new reagents and catalysts that are efficient, environmentally benign
and easily accessible toward specific C−H bond functionalization is currently an
important area of research in chemical science. In this regard, catalyst systems
based on non-toxic metals such as Cu or Fe that are effective under aerobic
conditions can clearly contribute to solve this problem.
5.2. Coupling reactions under aerobic conditions
The selective oxidation of C−H bonds and the use of molecular oxygen as a
stoichiometric oxidant represent two prominent challenges in organic chemistry.
However, their combination results into attractive academic and industrial prospects
and an enormous effort is behind to establish aerobic metal-catalyzed C−H
functionalizations as versatile synthetic tools. In addition to the inherent advantages
to C−H functionalizations processes, molecular oxygen is the ideal oxidant because
of its abundance, low cost and lack of toxic by-products (Scheme 5.1).174,175 In fact,
174
a) A. N. Campbell, S. S. Stahl, Acc. Chem. Res. 2012, 45, 851. For reviews on metal-catalyzed
aerobic cross-coupling reactions, see: b) S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400; c) K. M.
Gligorich, M. S. Sigman, Angew. Chem. Int. Ed. 2006, 45, 6612. For a review on C−H bond
oxidations: d) T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 2011, 50, 3362.
225
Aerobic copper-catalyzed ortho-halogenation of anilines
O2 is considered as “the quintessential oxidant for chemical synthesis” and it exhibits
a highly atom-efficient oxidant per weight.176
Scheme 5.1
In this line and within the field of homogeneous catalysis, palladium-catalyzed
C−H functionalization processes are perhaps the most versatile methods for selective
aerobic oxidation of organic molecules, and they include methods ranging from
alcohol oxidation to oxidative C−C, C−N and C−O bond formation. However, many of
the latter methods are not compatible with the use of O2 as the sole stoichiometric
oxidant and, instead, other oxidants such as PhI(OAc)2, benzoquinone, CuII or AgI,
are required to achieve catalytic turnover. Mechanistic studies suggest that these
oxidants are often required to promote reductive elimination of the product from the
Pd center through the formation of high-valent intermediates.177 New palladium
catalyst systems may be capable of overcoming this limitation,178 but another
complementary solution may involve the use of other transition-metal catalysts. In
175
For the use of O2 as oxidant in C−H bond functionalization, see: a) X.-I. Murahashi, D. Zhang,
Chem. Soc. Rev. 2008, 37, 1490; b) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; c) Z. Shi, C. Zhang, C.
Tanga, N. Jiao, Chem. Soc. Rev. 2012, 41, 3381; d) A. N. Campbell, S. S. Stahl, Acc. Chem. Res.
2012, 45, 851.
176
177
S. S. Stahl, Science 2005, 309, 1824.
For reviews on high-valent Pd chemistry, see: a) K. Muñiz, Angew. Chem. 2009, 121, 9576;
Angew. Chem. Int. Ed. 2009, 48, 9412; b) L.-M. Xu, B.-J. Li, Z. Yang, Z.-J. Shi, Chem. Soc. Rev.
2010, 39, 712; c) P. Sehnal, R. J. K. Taylor, I. J. S. Fairlamb, Chem. Rev. 2010, 110, 824.
178
For recent progress in addressing this problem, see: a) Y.-H. Zhang, J.-Q. Yu, J. Am. Chem. Soc.
2009, 131, 14654; b) J. Zhang, E. Khaskin, N. P. Anderson, P. Y. Zavalij, A. N. Vedernikov, Chem.
Commun. 2008, 3625; c) A. N. Campbell, P. B. White, I. A. Guzei, S. S. Stahl, J. Am. Chem.Soc.
2010, 132, 15116; d) G. Brasche, J. García-Fortanet, S. L. Buchwald, Org. Lett. 2008, 10, 2207.
226
Chapter 5
particular, recent advances in homogeneous copper catalysis highlight opportunities
to achieve selective aerobic oxidative functionalization of C−H bonds.
5.3. Aerobic Cu-catalyzed C−
−H functionalization
Copper is a vital element in living systems. Most copper-enzymes oxidize
organic substrates under mild conditions.174b The diversity and function of
copper/oxygen enzymes has inspired the design of synthetic copper systems for
oxidation catalysis to the point that it has demonstrated to be a versatile oxidant in
oxidative coupling reactions, many of which can be rendered catalytic in Cu by
employing O2 as the terminal oxidant.
In spite of this, Cu-catalyzed aerobic C−H bond functionalization has only
recently emerged as a powerful synthetic tool for developing new pathways that
complement those based on noble metals. These transformations resemble the
organometallic C−H oxidation reactions mediated by 2nd and 3rd row transition
metals. However, from a mechanistic standpoint, the Cu-catalyzed aerobic C−H
oxidation might represent a departure from the cyclometalated intermediate typically
proposed in most ligand-directed aryl C−H functionalization and could allow
introducing new modes of activation that could enable the access to unique reactivity
and selectivity. In fact, CuII has often proposed to serve as one-electron oxidant,179
initiating a single electron transfer (SET) process wherein cation-radical intermediates
are involved.180
179
For a review on the reactivity of radical cations, see: a) M. Schmittel, A. Burghart, Angew. Chem.
Int. Ed. 1997, 36, 2550. For examples of SET mechanism in Cu-promoted reactions, see: b) X. Ribas,
C. Calle, A. Poater, A. Casitas, L. Gómez, R. Xifra, T. Parella, J. Benet-Buchholz, A. Schweiger, G.
Mitrikas, M. Solà, A. Llobet, T. D. Stack, J. Am. Chem. Soc. 2010, 132, 12299; c) S. E. Creutz, K. J.
Lotito, G. C. Fu, J. C. Peters, Science 2012, 338, 647.
180
For intermediacy of CuIII complexes in C−H activation: a) B. Yao, D. X. Wang, Z. T. Huang, M. X.
Wang, Chem. Commun. 2009, 2899; b) L. M. Huffman, A. Casitas, M. Font, M. Canta, M. Costas, X.
Ribas, S. S. Stahl, Chem. Eur. J. 2011, 17, 10643. For a review on high-valent Cu-catalysis: c) A. J.
Hickman, M. S. Sanford, Nature 2012, 484, 177
227
Aerobic copper-catalyzed ortho-halogenation of anilines
In this area, much work has been directed to the Cu-catalyzed functionalization
of acidic C−H bonds (pka <35) or α-functionalization of tertiary amines via oxidation to
iminium ions.181 In contrast, base-free activation of relatively inert C−H bonds by Cucatalysts has been seldom explored.
In this section we will not attempt to present an extensive review of Cu-catalyzed
C−H activation but instead provide an overview of aerobic reactions focusing more
precisely on the advances made for the functionalization of inert arenes.
5.3.1. Base-promoted Cu-catalyzed C−
−H functionalization
A common strategy for obtaining site selectivity in copper-catalysed C−H
functionalization reactions relies on the use of substrates that have a significant
electronic or steric predisposition for metalation at a specific site. On this basis,
alkynes, 1,2-azoles and polyfluorinated arenes are typical substrates for basepromoted Cu-catalyzed C−H functionalization processes as they all share similar
relatively high C−H bond acidities (the pKa values of pentafluorobenzene,
benzoxazole, benzothiazole, and phenylacetylene are 21, 24, 27, and 28.8,
respectively, Figure 5.1).
Figure 5.1
For example, in 2008 Stahl and co-workers reported the areobic Cu-catalyzed
direct amidation of terminal alkynes with a wide range of nitrogen nucleophiles. 182,183
181
For α-functionalization of tertiary amines via oxidation to iminium ion: O. Baslé, C.-J. Li, Chem.
Commun. 2009, 4124.
182
T. Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 833.
228
Chapter 5
The corresponding ynamides were obtained in good yields when using an excess of
the amine nucleophile (5.0 equiv) under a catalyst system composed of CuCl2 (20
mol%), Na2CO3 (2.0 equiv) and pyridine (2.0 equiv), in toluene under an O2
atmosphere (Scheme 5.2). This excess of the amine helps to minimize the quantity of
Glaser alkyne homocoupling byproduct.
Scheme 5.2
The authors invoked a simplified mechanism involving the sequential activation
of alkyne C−H and nucleophile N−H groups at a CuII center, followed by C−N bond
formation to give via reductive elimination the ynamide product (Scheme 5.3). Details
of the C−N coupling process and aerobic reoxidation of the catalyst were not
addressed.
183
For other selected alkyne hetero-functionalization reactions, see: a) C. Zhang, N. Jiao, J. Am.
Chem. Soc. 2010, 132, 28; b) Y. Gao, G. Wang, L. Chen, P. Xu, Y. Zhao, Y. Zhou, L.-B. Han, J. Am.
Chem. Soc. 2009, 131, 7956; c) L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2010, 132, 7262; d) L. Chu,
F.-L. Qing, J. Am. Chem. Soc. 2010, 132, 7262.
229
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.3
Mori and co-workers further extended this methodology to the oxidative
intermolecular coupling of benzothiazole with N-methylaniline under the following
optimized conditions: Cu(OAc)2 (20 mol%), PPh3 (40 mol%), NaOAc (4.0 equiv), at
140 ºC in xylenes under an O2 atmosphere. The substrate scope tolerated
benzoxazoles and benzimidazoles, which were effectively coupled with aromatic and
even aliphatic amines (Scheme 5.4).184,185
Scheme 5.4
184
185
D. Monguchi, T. Fujiwara, H. Furukawa, A. Mori, Org. Lett. 2009, 11, 1607.
For selected references of related functionalization of 1,2-azoles, see: a) Q. Wang, S. L.
Schreiber, Org. Lett. 2009, 11, 5178; b) S.-I. Fukuzawa, E. Shimizu, Y. Atsuumi, M. Haga, K. Ogata,
Tetrahedron Lett. 2009, 50, 2374; c) D. Zhao, W. Wang, F. Yang, J. Lan, L. Yang, G. Gao, J. You,
Angew. Chem. Int. Ed. 2009, 48, 3296; d) S. Guo, B. Qian, Y. Xie, C. Xia, H. Huang, Org. Lett. 2011,
13, 522; e) Y. Li, Y. Xie, R. Zhang, K. Jin, X. Wang, C. Duan, J. Org. Chem. 2011, 76, 5444.
230
Chapter 5
Accordingly, Su and co-workers demonstrated that an identical strategy could be
applied for the C−H amination of perfluorinated arenes and heteroarenes using
Cu(OAc)2 (20 mol%), tBuOK (2.5-4 equiv) and TEMPO (50 mol%) under an oxygen
atmosphere in DMF, at 40 ºC.186,187 The substrate scope encompassed tetra- and
pentafluoroarenes that underwent coupling with various electron-deficient anilines in
moderate to good yields (Scheme 5.5).
Scheme 5.5
In addition to C−H aminations, alkynes, 1,2-azoles and polyfluoroanes have
being also derivatized through processes involving copper-catalyzed aerobic C−H
activation and its subsequent coupling with a wide range of other Nu-H nucleophiles,
as well as through copper-catalyzed homo- and cross-coupling reactions.188
As an example, Daugulis and co-workers reported an aerobic copper-catalyzed
Glaser-Hay-type deprotonative method for the homocoupling of electron-deficient
(hetero)aromatics, using only 1-3 mol% CuCl2 and a Zn/Mg amide base (e.g.,
186
H. Zhao, M. Wang, W. Su, M. Hong, Adv. Synth. Catal. 2010, 352, 1301.
187
For a copper-catalyzed sulfoximation of polyfluoroarenes, see: M. Miyasaka, K. Hirano, T. Satoh,
R. Kowalczyk, C. Bolm, M. Miura, Org. Lett. 2011, 13, 359.
188
For selected references, see: a) Y. Li, J. Jin, W. Qian, W. Bao, Org. Biomol. Chem. 2010, 8, 326;
b) Y. Wei, H. Zhao, J. Kan, W. Su, M. Hong, J. Am. Chem. Soc. 2010, 132, 2522; c) M. Kitahara, K.
Hirano, H. Tsurugi, T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 1772; d) N. Matsuyama, M. Kitahara,
K. Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 2358.
231
Aerobic copper-catalyzed ortho-halogenation of anilines
iPrMgCl.LiCl, tetramethylpiperidine and ZnCl2) in THF at room temperature under an
oxygen atmosphere. In most cases, the corresponding arene homodimers could be
obtained with good yields (Scheme 5.6).189
Scheme 5.6
All these selected examples were chosen to highlight a wealth of new C−H
oxidation reactions involving substrates with relatively acidic C−H bonds that are
nowadays emerging as powerful synthetic tools. These reactions closely resemble
Glaser–Hay couplings (oxidative deprotonative alkyne dimerization under aerobic
conditions); however, they employ substrates and achieve transformations for which
the Glaser–Hay analogy was not previously recognized.
5.3.2. C−
−H activation of relatively inert aryl C−
−H bonds
In contrast, the use of aerobic Cu-catalysis for the base-free activation of
relatively “inert” aryl C−H bonds (e.g., those Ar−H with pka>35) has been seldom
explored and only a few examples can be found in literature. These examples can be
189
H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2009, 131, 17052
232
Chapter 5
clasified into (a) the intermolecular coupling (based on a directing group) and (b) the
intramolecular coupling, also called oxidative annulation.
a) Chelate-directed C−H oxidative couplings
In an elegant pioneering example, Yu and co-workers demonstrated in 2006 the
II
Cu -catalyzed
190
derivatives.
intermolecular
aerobic
ortho-functionalization
of
2-arylpyridine
They found that the 2-pyridyl group could act as directing group in CuII-
catalyzed C−H functionalization as it does with other transition metals. Indeed, the
reaction of 2-phenylpyridine with Cu(OAc)2 (1.0 equiv) and H2O (1.0 equiv) in MeCN
under O2 (1 atm) at 130 °C for 36 h gave the ortho-hydroxylated product in 67% yield
(Scheme 5.7). This reaction tolerated the presence of electron-withdrawing and
electron-donating groups at the para-position of the aryl ring, but required a
stoichiometric amount of CuII. Labeling experiments using H218O in the absence of O2
showed that the oxygen atom from Cu(OAc)2 was incorporated into the orthohydroxylated product. The authors proposed that the first step involved the formation
of the acetoxylated product, which underwent rapid hydrolysis under the reaction
conditions catalyzed by the intramolecular pyridyl group.
Scheme 5.7
The reaction could be carried out with a catalytic amount of Cu(OAc)2 (10 mol%)
by performing the reaction in a mixture of acetic acid and acetic anhydride, but in this
190
X. Chen, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 6790.
233
Aerobic copper-catalyzed ortho-halogenation of anilines
case resulted in formation of a mixture of the mono- and di-ortho-acetoxylated
products was unavoidably obtained (Scheme 5.8).
Scheme 5.8
During the screening of reaction conditions for this acetoxylation reaction, the
authors found that the reaction of 2-phenylpyridine with 20 mol% of Cu(OAc)2 in
Cl2CHCHCl2 under an oxygen atmosphere gave the di-ortho-chlorinated product in
92% isolated yield. Owing to the importance of aryl halides, the report largely focused
on ortho-chlorination reactions, showing that a variety of 2-arylpyridines could be
chlorinated: when the aryl ring or the pyridine had an ortho-substituent, the reaction
stopped in the mono-chlorinated products. For the rest of substitution patterns, dichlorinated products were obtained. Electron-withdrawing groups attached to the aryl
ring resulted in low conversions (Scheme 5.9). In this reaction the solvent served as
an in situ source of the chloride nucleophile.191,192
191
In 2010, Cheng and co-workers described another C−H functionalization of 2-arylpyridines by
Cu(OAc)2-catalysis (10 mol%) using alkyl and aryl anhydrides as the coupling partner providing either
di-ortho-acyloxy- or di-ortho-chlorinated products: a) W. Wang, F. Luo, S. Zhang, J. Cheng, J. Org.
Chem. 2010, 75, 2415; b) W. Wang, C. Pan, F. Chen, J. Cheng, Chem. Commun. 2011, 47, 3978.
192
For a protocol of chlorination using an excess of LiCl as chlorinating agent, see: S. Mo, Y. Zhu, Z.
Shen, Org. Biomol. Chem. 2013, 11, 2756.
234
Chapter 5
Scheme 5.9
By using Cu(OAc)2, yet in stoichiometric amount (1.0 equiv), in combination with
other nucleophilic sources, different types of functionalities could be introduced in the
ortho-position of the aryl ring (Scheme 5.10). For bromination, the nuclephilic source
of bromine was Br2CHCHBr2, used as solvent.
Scheme 5.10
235
Aerobic copper-catalyzed ortho-halogenation of anilines
The authors proposed a radical-cation pathway to explain the data obtained from
their mechanistic studies (Scheme 5.11). A single electron transfer (SET) from the
aryl ring to the coordinated CuII leading to the cation-radical intermediate I was
proposed to be the rate-limiting step. The lack of reactivity of biphenyl suggested that
the coordination of CuII to the pyridine was necessary for the SET process. The
observed ortho-selectivity was explained by an intramolecular anion transfer from a
nitrogen-bound Cu(I) “ate” complex I.193
Scheme 5.11
Almost simultaneously with the publication of Yu’s protocol, Chatani and coworkers reported the chelate-directed amination of 2-phenylpyridine derivatives with
aniline using a stoichiometric amount of Cu(OAc)2.194 The electronic nature and the
positions of the substituents on the phenyl ring had a significant effect on the efficacy
on the reaction; ortho-substitution resulted in a significant decrease in the reactivity.
Regarding the substitution in the aniline, a methoxy substituent, regardless of its
position, inhibited the reactivity. Nevertheless, the overall yields ranged from poor to
moderate, recovering part of the starting material (Scheme 5.12).
193
The authors also postulated an alternative mechanism: an electrophilic attack of the pyridyl-
coordinated CuII on the aryl ring could take place in a manner similar to that of the Pb(TFA)4-mediated
oxidation of aryl C−H bonds. The subsequent loss of a proton would give an unusual cyclometalated
aryl Cu(II) complex that could undergo reductive elimination to give the functionalized products and
Cu0.
194
T. Uemura, S. Imoto, N. Chatani, Chem. Lett. 2006, 35, 842.
236
Chapter 5
Scheme 5.12
Ohno and co-workers described the use of tetrahydropyrimidine rather than
pyridine as a directing group to achieve ortho-hydroxylation using stoichiometric
amounts of Cu(OAc)2.195 Because the ortho-hydroxylated product was difficult to
isolate, triphosgene was added in the reaction mixture to obtain the tricyclic product I
as its protected form (Scheme 5.13). Substitution in the aryl ring was only studied at
the para-position, and electron-donating groups gave better reactivities than electronwithdrawing groups.
195
T. Mizuhara, S. Inuki, S. Oishi, N. Fujii, H. Ohno, Chem. Commun. 2009, 3413.
237
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.13
This protocol was also applicable to copper-promoted ortho-amination using
BocNH2 and TsNH2 as the coupling partners, affording the nitrogen-analogue
products in moderate yields (Scheme 5.14).
Scheme 5.14
Nicholas and co-workers recently reported an efficient Cu(OAc)2-catalyzed
amidation of 2-phenylpyridine using molecular oxygen as the terminal oxidant.196 A
variety of primary sulfonamides, carboxamides, and anilines participated in the
reaction, providing the desired amination products in moderate yields (Scheme 5.15).
196
A. John, K. Nicholas, J. Org. Chem. 2011, 76, 4158.
238
Chapter 5
Scheme 5.15
b) Oxidative annulation reactions
Buchwald, Nagasawa and Li independently reported the oxidative aerobic Cucatalyzed cyclization (hence intramolecular) of anilide derivatives with formation of
ortho C−N, C−O or C−C bonds to afford benzimidazoles, benzoxazoles and
indolinediones, respectively.
Buchwald and co-workers reported the aerobic oxidative cyclization of amidines
to give 2-phenyl-benzimidazoles under oxygen atmosphere, generating water as the
only direct waste product. The optimized conditions were: Cu(OAc)2 (15 mol%) and
AcOH (5.0 equiv), at 100 ºC in DMSO under an oxygen atmosphere (Scheme
5.16).197 This cyclization process tolerated the presence of both electron-donating
and electron-withdrawing substituents at 5-position of the benzimidazol, or in orthoand para-position in the 2-substituted phenyl ring.
197
G. Brasche, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 1932.
239
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.16
Almost simultaneously, Nagasawa and co-workers reported a similar protocol for
the preparation of benzoxazoles by aerobic cyclization of various benzanilides.198
Under the optimized conditions [Cu(OTf)2 (20 mol%) at 140 ºC in o-xylene under O2]
the desired benzoxazole products were obtained in high yields (Scheme 5.17). The
best results were reported for meta- or para-substituted benzanilides, while orthosubstituted substrates gave lower yields. Electron-withdrawing substituents resulted
in lower conversion, with recovered starting material reported in some cases.
Scheme 5.17
Finally, Li and co-workers reported an aerobic, copper-catalyzed oxidative C−H
acylation procedure for the preparation of indoline-2,3-diones (isatins) in an
intramolecular reaction that utilized two C−H bonds as the reaction partners (Scheme
198
S. Ueda, H. Nagasawa, Angew. Chem. 2008, 120, 6511; Angew. Chem. Int. Ed. 2008, 47, 6411.
240
Chapter 5
5.18).199 N-methyl-2-oxo-N-phenylacetamide could be cyclized in 90% yield using 20
mol% CuCl2 and 1 atm O2 in THF at 100 ºC. A range of formyl-N-aryl-formamides
could be cyclized, with electron-rich substrates affording higher yields than electrondeficient substrates.
Scheme 5.18
5.4. Ortho-halogenated reactions of anilines derivatives
Organic halides represent a very important class of organic compounds, both on
their own and due to the well-developed processes toward functionalization of
carbon–halogen bonds in the synthesis of valuable chemicals. Such an importance
has resulted in the development of numerous synthetic approaches for the
preparation of organic halides, some of these approaches becoming basic synthetic
organic tools.
In particular, halogenated anilines are important synthetic intermediates
endowed with many industrial applications,200 such as the manufacture of
polyurethanes, rubber chemicals, agricultural products and drugs, as well as versatile
precursors for the construction of a diverse range of heterocyclic frameworks.
199
B.-X. Tang, R.-J. Song, C.-Y. Wu, Y. Liu, M.-B. Zhou, W.-T. Wei, G.-B. Deng, D.-L. Yin, J.-H. Li, J.
Am. Chem. Soc. 2010, 132, 8900.
200
E. Baumgarten, A. Fiebes, A. Stumpe, React. Funct. Polym. 1997, 33, 71.
241
Aerobic copper-catalyzed ortho-halogenation of anilines
Such a prominence has resulted in the development of numerous synthetic
approaches for their preparation. Historically, due to the high reactivity of primary
amines, these compounds have been accessed through electrophilic halogenation of
their corresponding derivatized anilides.201 Even so, this widely used transformation
suffer from several notable disadvantages, such as the following: (i) the scope is
often limited to activated substrates, (ii) it is often plagued by over-halogenation of the
arene, (iii) only a limited set of arene substitution patterns can be accessed, and (iv)
multiple regioisomeric products are frequently obtained, resulting in decreased yields
and the requirement of tedious separations.202
As far as chloroanilines are concerned, they are typically synthetized by
hydrogenation of the corresponding chloronitrobenzenes.203 This process is far from
being simple since it is a challenge to avoid the concomitant hydrodechlorination
reaction while selectively reducing a nitro group in the same molecule.
Another important route to selectively halogenated anilines involves directed
ortho-lithiation (DoL) followed by quenching with an electrophilic halogen source. DoL
reactions have found application in the construction of a variety of complex
molecules. However, their broad utility remains limited by the requirement for strong
201
M. B. Smith, J. March, Advanced Organic Chemistry. Reactions, Mechanisms and Structure, 5th
edn. Willey, New York, 2001.
202
For electrophilic bromination of anilines, see: a) B. Das, K. Vetkateswarlu, M. Kroshnaiah, H.
Holla, Tetrahedron Lett. 2006, 47, 8693; b) B. Das, K. Vetkateswarlu, A. Majhi, V. Siddaiah, K. R.
Reddy, J. Mol. Catal. 2007, 267, 30; c) M. M. Heravi, N. Abdolhosseini, H. A. Oskooie, Tetrahedron
Lett. 2006, 46, 8959; d) M. J. Guo, L. Varady, D. Fokas, C. Baldino, L. Yu, Tetrahedron Lett. 2006,
47, 3889; e) B. M. Choudary, Y. Sudha, P. N. Reddy, Synlett 1994, 450; f) G. Rothenberg, J. H.
Clark, Green Chem. 2000, 2, 248; g) D. Roche, K. Prasad, O. Repic, T. J. Blacklock, Tetrahedron
Lett. 2000, 41, 2083; h) U. Bora, G. Bose, M. K. Chaudhuri, S. S. Dhar, R. Gopinath, A. T. Khan, B.
K. Patel, Org. Lett. 2000, 2, 247; i) N. Narender, P. Srinivasu, S. J. Kulkarni, K. V. Raghavan, Stud.
Surf. Sci. Catal. 2001, 135, 3745; j) K. V. V. Krishna Mohan, N. Narender, P. Srinivasu, S. J. Kulkarni,
K. V. Raghavan, Synth. Commun. 2004, 34, 2143; k) S. Singhal, S. L. Jain, B. Sain, J. Mol. Catal. A
2006, 258, 198; l) B. Ganchegui, W. Leitner, Green Chem. 2007, 9, 26.
203
D. He, H. Shi, Y. Wu, B.-Q. Xu, Green Chem. 2007, 9, 849.
242
Chapter 5
bases (resulting in reduced functional group tolerance) and by the relatively narrow
scope of suitable directing groups.
The above-mentioned clear limitations of these traditional methods for
halogenation of anilines clearly support the development of new, simple, and
complementary transition metal-catalyzed reactions for the selective halogenation of
anilines.
Within the field of C−H activation, a pioneering report by Sanford and co-workers
disclosed a highly regioselective palladium-catalyzed chlorination or bromination of
electron-deficient arenes, such as benzo[η]quinoline, using NBS/NCS as the
electrophilic halogen sources in CH3CN.204 On the basis of these preliminary studies,
Shi and co-workers later described a palladium-catalyzed protocol for the
regioselective ortho-chlorination of acetanilides, in the presence of Cu(OAc)2 (2.0
equiv) and CuCl2 (2.0 equiv) as oxidant and halogen source, respectively (DCE at 90
ºC).205 Other N-protecting groups (e.g., formyl, benzoyl, tosyl, trifluoroacetyl) were
tested, but only the pivalyl group was also found to be an appropriate protecting
group for this transformation, albeit with a slight decrease of the chlorination
efficiency. This protocol was applied to a range of para- and meta-substituted anilines
affording the ortho-chlorinated products in good yields for electron-donating groups
and moderate yields for electron-withdrawing groups. The regioselectivity of the
chlorination of meta-substituted acetanilides was dominated by steric effects, and
only the less hindered ortho-chlorinated acetanilides were systematically obtained
(Scheme 5.19).
204
A. R. Dick, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126, 2300.
205
X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang, Z. Shi, J. Am. Chem. Soc. 2006, 128, 7416.
243
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.19
Within the same work, this strategy was also extended to the construction of
C−Br bonds in relatively electron-rich acetanilides (Scheme 5.20). However, this
method would be later questioned by Bedford and co-workers who were not able to
reproduce the results here claimed.206
Ac
HN
H
R
Pd(OAc) 2 (10 mol%)
Cu(OAc)2 (2.0 equiv)
CuCl2 (2.0 equiv)
Ac
HN
Br
R
DCE, 90 ºC, 48 h
Ac
Ac
HN
Br
Me
Ac
HN
HN
Br
Me
66%
Br
MeO
OMe
OMe
OMe
90%
91%
Scheme 5.20
206
R. B. Bedford, M. F. Haddow, C. J. Mitchell, R. L. Webster, Angew. Chem. Int. Ed. 2011, 50, 5524.
244
Chapter 5
Subsequently, Bedford and co-workers described a new palladium-catalyzed
protocol for the direct ortho-clorination and –bromination of anilides using the
corresponding halosuccinimide as source of halogen.206 This protocol was applied to
anilides bearing an acetyl or a pivaloyl protecting group, and tolerated ortho-, metaand para-substitution with electron-donating and electron-withdrawing groups,
although the latter class of substituents only gave good ortho-selectivities when
attached at para-position (Scheme 5.21).
Scheme 5.21
Moreover, Glorious and co-workers have also demonstrated that the orthohalogenation of anilines is possible using a RhIII-catalyzed C−H bond activation
methodology. The particular advantage of this strategy is its compatibility with many
different, highly useful directing groups, which opens up new possibilities for the
synthesis of a panel of aromatic halides (Scheme 5.22).
245
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.22
Although impressive levels of efficiency, selectivity and functional group
tolerance have been accomplished in the palladium-catalyzed C−H halogenation
protocols, there are still important limitations that need to be solved, such us the use
of chlorinated solvents and/or strong acids, as well as the need for stoichiometric
amounts of a metal-co-oxidants [e.g., CuII]. Taking into consideration that mechanistic
studies suggest that these oxidants are required to promote reductive elimination of
the product from the Pd center through the formation of high-valent intermediates,177
new more active Pd catalyst systems may be capable of overcoming these
limitations. Nonetheless, a complementary and more sustainable, solution may
involve the use of other transition-metal catalysts. In particular, recent advances in
homogeneous copper catalysis highlight opportunities to achieve selective aerobic
oxidative functionalization of C−H bonds.207
Along this line, we have stated above that Cu-catalyzed aerobic oxidations are
emerging now as powerful alternatives. However, examples of Cu-promoted orthohalogenation are rare and have been exclusively applied to arenes with a non-
207
For non-aerobic Cu-catalyzed C−H functionalizations, see: a) R. J. Phipps, N. P. Grimster, M. J.
Gaunt, J. Am. Chem. Soc. 2008, 130, 8172; b) R. J. Phipps, M. J. Gaunt, Science 2009, 323, 1593; c)
C.-L. Ciana, R. J. Phipps, J. R. Brandt, F.-M. Meyer, M. J. Gaunt, Angew. Chem. Int. Ed. 2011, 50,
458; d) H. A. Duong, R. E. Gilligan, M. L. Cooke, R. J. Phipps, M. J. Gaunt, Angew. Chem. Int. Ed.
2011, 50, 463.
246
Chapter 5
removable 2-pyridyl (or a related heteroaryl) directing group. In their seminal work
mentioned above, Yu et al. reported the CuII-catalyzed ortho-halogenation of 2arylpyridines using X2CHCHX2 (X = Cl, Br) as halogen source.190 More recently, a
couple of reports have appeared using benzoyl chloride/Li2CO3191b or excess of
LiCl192 as chlorinating agents. In all cases, controlling mono- vs disubstitution was
found to be problematic.
This journey by the literature precedents clearly highlights that Cu-catalyzed
arene C−H functionalization strategies remain underdeveloped. The challenges are
likely due to significant changes in the mechanism of activation (different from
cyclometallation typically proposed under noble metal catalysis) and the lack of
suitable removable directing groups.
247
Aerobic copper-catalyzed ortho-halogenation of anilines
5.5. Aim of the project
In response to the increasing demand for sustainable methods in organic
synthesis, it is imperative to design catalytic methods for the functionalization of inert
aryl C−H bonds that allow replacing precious metal-based catalysts and
stoichiometric strong oxidants by cheap, non-toxic first row transition metals in
combination with O2 as terminal oxidant. In light of the environmental and economical
benefits of the Cu/O2 combination as catalyst system, we envisaged to explore
whether or not our “2-pyridylsulfonyl” activation could be extended to coppercatalyzed aerobic C−H functionalization of arenes.
Given the importance of halogenated anilines and the lack of reliable methods
for the general ortho-halogenation of anilines, we focused on the Cu-catalyzed
aerobic halogenation of N-(2-pyridyl)sulfonyl anilines as testing ground reaction to
test our hypothesis. In contrast to the previously reported Cu-catalyzed aerobic
halogenations, that are limited to arenes with a non-removable 2-pyridyl (or a related
heteroaryl) directing group, our methodology would notably contribute to increase the
chemical versatility and the current scope of this reaction (Scheme 5.23).
Scheme 5.23
248
Chapter 5
5.6. Results and discussion
5.6.1. First attempts in Cu-catalyzed ortho-halogenation of anilines
N-(2-pyridyl)sulfonyl aniline 1 was chosen as the model compound for the
optimization studies of the different parameters in the Cu-catalyzed C−H
halogenation reaction. Initially, we attempted the prospective ortho-chlorination of the
N-(2-pyridyl)sulfonyl aniline (1) adopting the conditions reported by Yu and coworkers for the selective ortho-chlorination of 2-phenylpyridine derivatives (20 mol %
CuCl2 in Cl2CHCHCl2, O2 atmosphere at 130 °C). The outcome of this first ex periment
was very satisfactory as the desired ortho-chloroaniline derivative 1-Cl was isolated
as the only product (78% yield), along with a tiny amount of starting material (Scheme
5.24). It is worth to remark that no di-ortho-chlorination occurred and no para-chloroaniline derivative arising from a SEAr mechanism was detected. Therefore, the
reaction was thus highly regio- and chemoselective.
Scheme 5.24
Nonetheless, although this result was very encouraging, some control
experiments were run in order to gain some insights about the reaction conditions.
They are summarized in Table 5.1.
249
Aerobic copper-catalyzed ortho-halogenation of anilines
Table 5.1: Optimization of the reaction conditions
o-Cl
Entry
Solvent
Oxidant
1
Cl2CHCHCl2
O2
Cl2CHCHCl2
O2
3
DCE
O2
20
4
DCE
- (N2)
<5
DCE
- (N2)
61
6
DCE
Ce(SO4)2
60
7
DCE
AgOAc
58
8
DCE
K2 S 2 O 8
56
9
DCE
PhI(OAc)2
63
2
5
[b]
[d]
(%)
p-Cl
[a]
(%)
38
62 (78)
[c]
[a]
di-Cl
(%)
-
-
-
-
-
-
[a]
[a] GC yields (n-hexadecane as internal standard); [b] 24 h reaction time; [c] Isolated yield; [d] 1.0
equiv of CuCl2.
First of all, we evaluated the reaction time (entry 1-2) and we found that only
38% conversion to the ortho-chlorinated product 1-Cl was achieved at shorter
reaction times (16 h, entry 1), being 62% of the starting material 1 still remaining in
the reaction mixture. Although the reactivity was slow, it is remarkable the selectivity
of the process, observing exclusively the ortho-regioisomer without even detecting
traces of the para-chlorinated isomer or any di-halogenated products. Prolonging the
reaction time to 24 h allowed us to achieve higher conversions, isolating the desired
product in good yield (78%, entry 2) and without observing traces of chlorinated sideproducts. The starting material was the only compound that was also detected in the
reaction mixture by GC and it was recovered unaltered by column chromatography.
250
Chapter 5
Next, to study whether the solvent of the reaction was the source of chlorine, we
changed
from
1,1,2,2-tetrachloroetane
(Cl2CHCHCl2)
to
1,2-dichloroethane
(ClCH2CH2Cl, DCE, entry 3) as solvent. When the reaction was thus performed, only
20% of the chlorinated aniline derivative was detected by GC analysis. This
percentage of chlorinated product could be attributed to the 20 mol% of CuCl2 that we
were using as Cu-catalyst. Therefore, it was confirmed that tetrachloroethane was
serving as the in situ source of the chloride in our model reaction.
When the reaction was performed in the absence of molecular oxygen, but under
inert conditions (nitrogen atmosphere), most of the starting sulfonamide 1 was
recovered unaltered even after prolonged reaction times (entry 4). This result
demonstrated the crucial role of O2 in rendering the reaction catalytic in copper by
recycling it through reoxidation. In fact, when the reaction was performed with
stoichiometric amount of CuCl2 under nitrogen atmosphere, the reaction proceeded
with the same selectivity, obtaining the ortho-chlorinated product in a very similar GCyield (61%, entry 5). Moreover, other oxidants such as Ce(SO4)2 (entry 6), AgOAc
(entry 7), K2S2O8 (entry 8) or PhI(OAc)2 (entry 9) also performed well in the reaction,
affording the desired ortho-halogenated product 1-Cl in good yields (56%-63% GC
conversions). However, oxygen remained as the best choice since, as we stated in
the introduction, it is considered as “the quintessential oxidant for chemical synthesis”
because of its abundance, low cost and lack of toxic by-products.
In order to evaluate the influence of the electronic nature of the substitution at
the aromatic ring on the reactivity and selectivity of the process, two para-substituted
sulfonamides were prepared: one bearing an electron-donating group (OMe,
sulfonamide 2) and the other bearing an electron-withdrawing group (CF3,
sulfonamide 3). Both sulfonamides were prepared by N-protection with 2pyridylsulfonyl chloride in the same conditions as for the sulfonamide derivative 1
from the corresponding commercially avaible anilines (Scheme 5.25).
251
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.25
Remarkably, this chlorination protocol could be applied in the ortho-chlorination
of both aniline derivatives, showing that, regardless of the electronic character of the
substituents, the reaction proceeded smoothly affording only the ortho-halogenated
products 2-Cl and 3-Cl with good yields (89%-94%, Scheme 5.26).
Scheme 5.26
Although no significant difference in isolated yield was observed, the electronic
nature of the substituents was a determining factor for the reaction rate. By analysing
the reaction after 16 h (Scheme 5.27), we found that the ortho-halogenation of 2, with
a para-methoxy substituent, proceeded much faster than the ortho-chlorination of 1,
without any substitution. An even more pronounced effect was noted when
comparing the reactivity of the aniline 3, with an electron-withdrawing parasubstituent (e.g. CF3), with the parent substrate (product 1-Cl). In this case, a much
lower conversion was observed in the former case, indicating a marked sensitivity of
the reaction rate to the electronic effects: the electron-poor substrates suffered from
252
Chapter 5
reduced reactivity in comparison to the electron-rich arenes, thereby requiring longer
reaction times to reach completion.
Scheme 5.27
5.6.2. Development of a more benign copper-catalyzed protocol for the
ortho-halogenation of anilines
With these encouraging results in hand, we next decided to embark on the
development of a more environmentally benign version of this oxidative coupling. So
far, the protocol described above required the use of the industrially disfavoured
1,1,2,2-tetrachloroethane as a solvent and one day heating at 130 °C for completion.
While any attempt of lowering the reaction temperature resulted in a decrease in the
yield, we decided to explore more sustainable solvents and more attractive sources
of chlorine. The most relevant results obtained in the refinement of the reaction
conditions are depicted in Table 5.2.
253
Aerobic copper-catalyzed ortho-halogenation of anilines
Table 5.2: Study of the source of chlorine
Entr
y
1
Reactio
Cl-
n time
sourc
Solvent
Cl2CHCHCl
(h)
e
24
-
2
p-Cl
o-Cl
(%)
(%)
[a]
[a
di-Cl
(%)
]
]
]
-
-
62(78)
[a
[b
2
DCE
1
NH4Cl
<5
-
-
3
DCE
1
LiCl
<5
-
-
4
DCE
1
NaCl
<5
-
-
5
DCE
1
CsCl
<5
-
-
6
DCE
24
LiCl
20
-
-
7
DCE
1
NCS
75
<7
<7
[a] GC yields (n-hexadecane as internal standard); [b] Isolated yield after column chromatography.
In this study, DCE was chosen as solvent to evaluate the use of alternative
chlorine sources such as NH4Cl, LiCl, NaCl and CsCl (entries 2-5). Indeed, a couple
of recent reports have demonstrated that benzoyl chloride/Li2CO3191b or excess of
LiCl192 could be employed as chlorinating agents in the copper-catalyzed orthohalogenation of 2-aryl pyridines. Unfortunately, none of the inorganic salts tested
proved to be efficient at all in our case. Only upon prolonging the reaction time to 24
h, the ortho-halogenated product 1-Cl could be detected in 20% of conversion (entry
6). As stated before, the chlorine-source in this case was attributed to the catalyst
(CuCl2), used in 20 mol%. Besides, 78% of the starting material was recovered after
chromatographic purification.
In sharp contrast, after only one hour of reaction, high conversion was observed
when N-chlorosuccinamide was used as chlorine source (entry 7), observing only
254
Chapter 5
11% of the starting material. Interestingly, the reaction maintained the high
regioselectivity to afford the ortho-chlorinated product as the major component of the
reaction mixture, along with tiny amounts of the para-regioisomer and the dichlorinated product.
NCS was therefore chosen as the chlorine source because it’s a cheap source of
chloride and it is easy to handle. We next performed a short screening of the reaction
conditions to further optimize the reaction parameters (Table 5.3).
Table 5.3: NCS as the chlorine-source
II
o-Cl
p-Cl
di-Cl
Temp.
Cu
(ºC)
(mol%)
1
130
20
75
<7
<7
2
100
20
70
12
15
3
100
10
<5
-
Entry
(%)
[a]
79 (95)
(%)
[b]
[a]
(%)
[a]
[a] GC yields (n-hexadecane as internal standard); [b] Isolated yield after column
chromatography.
N-chlorosuccinamide proved to be a more active chlorinating agent than
Cl2CHCHCl2, leading to complete conversion of 1 into 1-Cl after only 1 h at 130 ºC
(entry 1). Furthermore, the temperature could be reduced to 100 ºC without
appreciable loss of reactivity (entry 2). Moreover, the high reactivity displayed by this
method allowed the catalyst loading (CuCl2) to be reduced to 10 mol% (entry 3). In all
cases, very high selectivity was observed towards the ortho-mono-chlorinated
product 1-Cl and under these optimized conditions the desired product 1-Cl was
isolated in 95% yield after column cromatography.
255
Aerobic copper-catalyzed ortho-halogenation of anilines
Being aware that DCE wasn’t the best choice as green solvent, a short study of
the solvent was done in the model ortho-chlorination of 1 to give 1-Cl. The results are
shown in Table 5.4.
Table 5.4: Study of the solvent using NCS as the chloride-source
o-Cl
Entry
Solvent
Temp.
1
MeCN
100
79 (95)
2
THF
100
-
3
MeCN
80
(%)
p-Cl
[a]
(%)
[b]
[a]
di-Cl
(%)
[a]
<5
-
[c]
-
-
39
28
33
[a] Conversion yield (from the 1H NMR spectra); [b] Isolated yield after column
chromatography; [c] The starting material was recovered unaltered.
Satisfyingly, changing the solvent to the more industrially favoured MeCN208
while maintaining unaltered the rest of reaction parameters [NCS (1.2 equiv), CuCl2
(10 mol%), under an oxygen atmosphere at 100 °C] re sulted in full conversion to the
desired product. In fact, the 2-chlorinated sulfonamide 1-Cl was isolated in 95% yield
along with only trace amounts of the para-Cl derivative, no dichlorinated product was
detected (entry 1). Indeed, this solvent was a great choice because it was polar
enough so the reactants could be dissolved, allowing us to decrease the reaction
temperature to 100 ºC. With a less polar solvent such as THF, the starting material
was recovered unaltered (entry 2).
At this point of the optimization, it was found out that the temperature was
critical, since a further decrease of the temperature induced a loss in the
208
For a recent study on the importance of MeCN in the pharmaceutical industry, see: I. F.
McConvey, D. Woods, M. Lewis, Q. Gan, P. Nancarrow, Org. Process Res. Dev. 2012, 16, 612.
256
Chapter 5
regioselectivity. Thus, the reaction performed at 80 °C was associated to a complete
loss of the regioselectivity, affording a mixture of the three possible products in similar
ratios (entry 3). This result could be rationalized assuming that the Cu-catalyzed
directed ortho-chlorination reaction becomes too slow at temperatures below 100 ºC,
then being competitive the alternative uncatalyzed electrophilic aromatic substitution
pathway, resulting in a non-selective transformation.
Along the same line, any attempt to decrease the amount of CuCl2 to 5 mol %
resulted in the competitive formation of the para-Cl aniline derivative 1-(p)-Cl (o/p =
60:20, by GC), likely via the competitive electrophilic aromatic substitution pathway
(Scheme 5.28).
Scheme 5.28
To prove our hypothesis, the chlorination reaction of 1 was run in the absence of
the Cu-catalyst under otherwise identical conditions. This experiment led to the
exclusive formation of the para-chlorination product 1-(p)-Cl which was isolated in
90% yield after chromatography (Scheme 5.29, left). This result is also a dramatic
example of complementarity between the Cu-catalyzed and uncatalyzed reactions
(Scheme 5.29).
Scheme 5.29
257
Aerobic copper-catalyzed ortho-halogenation of anilines
5.6.3. Evaluation of the effect of the N-directing/protecting group
To evaluate the role of the N-(2-pyridyl)sulfonyl protecting/directing group, a set
of aniline derivatives having different potentially coordinating groups at the nitrogen
were also considered (products 4-6, Figure 5.2).
Figure 5.2
Likewise, it was also very interesting to investigate the role of the sulfonyl group
in the efficiency of the reaction. For that purpose, the 2-pyridylcarbonyl aniline 7, also
containing the heteroaryl coordinating unit but connected to the substrate by a
carbonyl group instead of a sulfonyl group, was also prepared following a previously
described protocol (Scheme 5.30).209 Activation of 2-picolinic acid with oxalyl chloride
and treatment of the resulting acid chloride with aniline led to the formation of the
desired product 7 in moderate yield (53%)
Scheme 5.30
The N-methyl-N-(2-pyridyl)sulfonyl aniline 8 was also prepared in order to study
the effect of the free hydrogen in the sulfonamido moiety and therefore, test the
tolerance of the reaction to N-alkyl substituents. The N-methyl-N-(2-pyridyl)sulfonyl
209
M. D. Markey, Y. Fu, T. R. Kelly, Org. Lett. 2007, 9, 3255
258
Chapter 5
aniline 8 was prepared from the commercially available N-methylaniline III following
the standard protocol for N-sulfonylation (Scheme 5.31).
Scheme 5.31
The set of N-protected anilines (4-8) was examined in the reaction using NCS
(1.2 equiv) as source of chloride, under catalytic amount of CuCl2 (10 mol%), and
using molecular oxygen as the final oxidant in acetonitrile as solvent at 100 ºC. The
results are summarized in Table 5.5.
Table 5.5: Influence of the N-directing/protecting group
Entry
PG
o-Cl (%)
1
SO2Py
79 (95)
2
Ts
3
[a]
[b]
p-Cl (%)
[a]
di-Cl (%)
<5
--
6
90
--
Ac
10
--
60
4
H
34
29
15
5
C(O)(2-Py)
12
69
18
6
Boc
7
N(Me)SO2Py
-
[a]
[c]
10
87
[a] GC yields (n-hexadecane as internal standard); [b] Isolated yield; [c] Decomposition.
259
Aerobic copper-catalyzed ortho-halogenation of anilines
This screening of protecting groups revealed that the 2-PySO2- group on the
nitrogen was uniquely effective for the formation of the ortho-chlorinated regioisomer
in a selective way. For instance, the NH-Ts aniline led to the para-chlorination
product with very high selectivity (entry 2), suggesting that the lack of the “directing”
2-pyridyl unit causes the background electrophilic chlorination to predominate. Along
the same line, the more activated acetanilide led mainly to the 2,4-dichlorination
product (entry 3), while the unprotected aniline produced a mixture of ortho- and
para-chloroaniline with very low selectivity, along with a significant amount of 2,4dichloroaniline (entry 4). Notably, the potentially coordinating 2-pyridylcarbonyl group
provided the para-chlorination regioisomer as the major product (entry 5),
emphasizing the cooperative directing role of both the sulfonyl and the 2-pyridyl
moieties. The N-Boc protecting group was too labile in the reaction conditions and a
very complex reaction mixture was obtained from substrate 6, presumably due to
decomposition products (entry 6). Finally, N-alkylation did not fit for this
transformation, as the N-(Me)(SO2Py)-aniline 8 provided only traces of the orthochlorinated product, leading almost exclusively to the para-substituted regioisomer
(entry 7).
5.6.4. Structural versatility of the aniline in the ortho-chlorination reaction
The versatility of the reaction with regard to electronic and steric modifications in
the aryl ring was also studied. For that purpose, a variety of differently substituted
anilines were efficiently N-protected following the standard protocol for the Nsulfonylation with 2-pyridylsulfonyl chloride (Scheme 5.32).
260
Chapter 5
PyO2S
NH2
NH
PySO2Cl (1.2 equiv)
R
R
pyridine (1.2 equiv)
THF, 0 ºC--rt
II-XV
2-4, 9-20
para-substituted anilines
PyO2S
PyO2S
NH
OMe
2, 89%
PyO2S
PyO2S
NH
Me
9, 94%
PyO2S
NH
Cl
12, 76%
PyO2S
NH
I
10, 89%
PyO2S
NH
F
13, 79%
NH
Br
11, 87%
PyO2S
NH
CF3
3, 76%
NH
CO2Me
14, 64%
meta-substituted anilines
PyO2S
NH
F
PyO2S
NH
iPr
15, 83%
PyO2S
NH
F3C
16, 80%
17, 73%
polyhalogenated anilines
PyO2S
NH
PyO2S
NH
Cl
Cl
I
18, 70%
PyO2S
NH
Cl
Br
19, 83%
Cl
20, 85%
Scheme 5.32
All these N-(2-pyridyl)sulfonyl aniline derivatives were next submitted to the
ortho-chlorination reaction under the optimized reaction conditions.
261
Aerobic copper-catalyzed ortho-halogenation of anilines
a) Ortho-chlorination of para-substituted aniline derivatives
Good to excellent yields of the desired ortho-chlorinated para-substituted
products were obtained with little or no competitive electrophilic halogenation
apparent in most cases (Scheme 5.33). Electron-rich substituents, such as MeO and
Me, were well tolerated, leading to the formation of the desired products with
excellent yields (product 2-Cl and 9-Cl, 89% and 78% yield, respectively). The
complete ortho-selectivity with regard to the amino group achieved in the case of the
para-methoxyaniline derivative 2 (product 2-Cl) is particularly noteworthy since it
contains two ortho-directing (electron releasing) groups (NHSO2Py and OMe).
Achieving this selectivity in para-methoxy anilides typically requires ortho-lithiation
strategies.210 Likewise, strongly electron-withdrawing groups such as CF3 and CO2Me
had no significant influence on this catalytic system (product 3-Cl and 14-Cl, 80%
and 86% yield, respectively). Regardless the electronic nature of the substitution the
corresponding ortho-chlorinated products were isolated in good to high yields. These
results are in contrast to the already known Pd-catalyzed examples that are
especially suited for electron-rich substrates.
210
See, for instance: a) D. E. Lizos, J. A. Murphy, Org. Biomol. Chem. 2003, 1, 117; b) P.
Thansandote, D. G. Hulcoop, M. Langer, M. Lautens, J. Org. Chem. 2009, 74, 1673; c) Y. Kobayashi,
J. Igarashi, C. Feng, T. Tojo, Tetrahedron Lett. 2012, 53, 3742.
262
Chapter 5
Scheme 5.33
b) Ortho-chlorination of meta-substituted aniline derivatives
In the case of meta-substituted substrates, the regioselectivity proved to be
sensitive to both steric and electronic issues (Scheme 5.34). For example, the metafluoro aniline 15 underwent chlorination at the more acidic ortho-C−H bond (that
flanked by the C−F bond) with complete regiocontrol (product 15-Cl). In contrast, a
bulky i-Pr group at the meta-position directs the chlorination to the less hindered
ortho-position (product 16-Cl). A meta-CF3 group, wich contributes to make more
acidic the ortho-C−H bond and is sterically more hindered than a fluorine substituent,
was not effective in controlling the regioselectivity, and two regioisomers of 17-Cl
were obtained in equal amounts.
263
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.34
c) Ortho-chlorination of polyhalogenated aniline derivatives
It is also important to stress the wide tolerance to halogen substitution (F, Cl, Br
or I), thereby allowing the selective access to Br/Cl- or I/Cl-substituted anilines,
endowed
with
orthogonal reactivity to
Pd-based
coupling
reactions.
Even
polyhalogenated substrates were suitable [Scheme 5.35, products (18-20)-Cl, 5864% yield].
Scheme 5.35
264
Chapter 5
5.6.5. Expanding the reaction to bromination and iodination
Expanding the scope to bromination was attempted by simply replacement of
NCS by NBS under identical reaction conditions (except for using CuBr2 instead of
CuCl2). Unfortunately, under these conditions, the reaction of the parent N-(2pyridyl)sulfonyl aniline 1 with NBS proved to be non-selective, affording a 1:1 mixture
of the para- and the ortho-brominated regioisomers (as detected by GC-analysis,
Scheme 5.36).
Scheme 5.36
In contrast, a clean ortho-bromination reaction was observed when the paraposition of the aromatic ring was blocked with either electron-donating (Me, OMe),
electron-withdrawing (CF3, CO2Me) or halogenated (F, Cl, Br, I) substituents (Scheme
5.37). This can be explained on the basis that NBS is a better reagent for the
electrophilic aromatic substitution, which is the side-reaction of our methodology.
Besides, because Br is larger than Cl, the ortho-substitution is expected to be more
difficult compared to the ortho-chlorination. As a result, the copper-catalyzed orthobromination protocol required longer reaction times and afforded slightly decreased
yields in comparison to to the copper-catalyzed ortho-chlorination procedure.
265
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.37
The meta-fluoro substituted aniline derivative 15, lacking a blocking group at the
para-position, was a special case, leading to the ortho-substituted product 15-Br in
good yield (64%) and with very high ortho-selectivity mainly at the position flanked by
both the amino- and fluoro-functionalities. In this case, no traces of the parasubstituted product were observed and only 10% of the other ortho-brominated
regioisomer was detected by GC (Scheme 5.38). In contrast, the meta-CF3
substituted aniline derivative led to a complex mixture of brominated regioisomers.
266
Chapter 5
Scheme 5.38
The 3,4-dichloroaniline derivative 20, having the para-position blocked, led to a
clean bromination at the less hindered ortho-position (product 20-Br, 60% yield,
Scheme 5.39)
Scheme 5.39
In contrast to the similar reactivity observed between the chlorination and
bromination reactions, the reaction with NIS was found to be slower. For instance, the
reaction of the parent substrate 1 led to a mixture of regioisomers, where the major
compound was the para-iodo aniline derivative (GC-analysis, Scheme 5.40).
267
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.40
Only good selectivity was attained in the iodination of electron-poor substrates
having the para-position blocked (products 3-I and 14-I). In these cases, a higher
catalyst loading of Cu(OAc)2 (20 mol%) and longer reaction time (16 h) were required
for achieving reasonable conversions (Scheme 5.41).
Scheme 5.41
In addition, similar results were observed when preforming the iodination using I2
as source of iodine (Scheme 5.42).
268
Chapter 5
Scheme 5.42
5.6.6. Ortho-substituted
substrates:
Development
of
the
N-(2-
pyrimidyl)sulfonyl directing group
While para- and meta-substitution were well tolerated, this protocol was not
applicable to the more sterically demanding ortho-substituted anilines, as
demonstrated in the chlorination of substrates 12-Cl and 9-Br (Scheme 5.43).
Scheme 5.43
269
Aerobic copper-catalyzed ortho-halogenation of anilines
To circumvent this problem, we found inspiration in the recent work by Gevorgian
and co-workers who demonstrated that the use of a Si-tethered 2-pyrimidyl (2-Pyr)
directing group enabled the Pd-catalyzed ortho-C−H oxygenation in ortho-substituted
aromatic substrates where the 2-Py-based group failed to induce functionalization.211
We therefore envisaged that the same concept could be applied to our case and,
thus, replacing the 2-pyridylsulfonyl group by a 2-pyrimidylsulfonyl group (2-PyrSO2)
could solve the problem of the low reactivity of ortho-substituted substrates, thereby
further increasing the synthetic applicability of the method.
With this idea in mind, the N-(2-Pyr)SO2-aniline derivatives 21-Cl and 22 were
prepared by N-sulfonylation with the corresponding 2-pyrimydylsulfonyl chloride,
generated in situ from 2-mercaptopyrimidine by oxidation with bleach (NaOCl),
according to a literature protocol212 and they were obtained in good yields (80% and
74%, respectively) as bench stable solids (Scheme 5.44).
211
A. V. Gulevich, F. S. Melkonyan, D. Sarkar, V. Gevorgyan, J. Am. Chem. Soc. 2012, 134, 5528
(see Scheme below).
212
S. W. Wright, K. N. Hallstrom, J. Org. Chem. 2006, 71, 1080.
270
Chapter 5
Scheme 5.44
Next, products 21-Cl and 22 were submitted to the standard optimized Cucatalyzed ortho-chlorination reaction, but increasing the catalyst loading to a 30 mol%
and the reaction time to 16 h (Scheme 5.45). The clean formation of the desired
products 21-Cl2 and 22-Cl under these sligthly modified conditions (isolated in 78%
and 80% yield, respectively) confirmed our starting hypothesis. Thus, the critical
improvement in reactivity provided by the N-2-pyrimidylsulfonyl group enabled the
access to ortho-disubstituted products.
271
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.45
Di-ortho chlorination reaction
Because
of
these
remarkable
results,
two
para-substituted
N-(2-
pyrimydil)sulfonyl aniline derivatives were also prepared following the same protocol
as the one used for the aniline derivatives 21-Cl and 22. The idea behind these
substrates was to investigate the capability of this new coordinating group to induce
di-ortho-chlorination
reaction
(Scheme
5.46).
The
N-sulfonylation
with
2-
pyrimidylsulfonyl chloride worked well in both cases, regardless of the electronic
properties of the substitution (products 21 and 23, 54% and 82% yield, respectively).
Even the para-fluoroaniline, with its nucleophilicity attenuated by the fluoride
substituent, provided an acceptable yield (product 21, 54% yield).
272
Chapter 5
Scheme 5.46
As expected, when these aniline derivatives (21 and 23) were submitted to the
reaction with an increased amount of NCS (2.4 equiv) under otherwise same reaction
conditions, the di-ortho-chlorinated derivatives were obtained with good yields,
considering the difficulty of the reaction (products 21-Cl2 and 23-Cl2, 58% and 85%
yield, respectively, Scheme 5.47).
Scheme 5.47
273
Aerobic copper-catalyzed ortho-halogenation of anilines
5.6.7. Deprotection
Finally, the easy reductive removal of the N-(2-pyridyl)sulfonyl directing group
under mild conditions led us to realize the full synthetic utility of this method enabling
the access to the free NH2-ortho-chlorinated anilines (Scheme 5.48). The free NH2anilines were obtained by a simple treatment of the N-(2-pyridyl)sulfonamide product
with magnesium turnings in MeOH at room temperature. Applying similar conditions,
the pyrimidyl-based directing group could be also removed yielding the corresponding
aniline with high yields. It is remarkable that the mild conditions required for the
cleavage of the directing group makes this method compatible with sensitive Ar−Cl
bonds.
Scheme 5.48
5.6.8. Application to indole synthesis
Both the halide and the NH functionalities provide products that offer high
versatility as building blocks, as illustrated in the efficient conversion of the
bromoaniline derivative 3-Br into the functionalized indol 27. The known palladiumcatalyzed anulation of 2-haloanilines with an alkyne213 (phenylacetylene in our case)
213
The preparation of indoles from ortho-haloanilines by condensation with an alkyne goes back at
least to 1963, when C. E. Castro of the University of California observed that coupling of 2-iodoaniline
with phenylacetylene-copper (Ph−C≡C−Cu) led, not to the diaryl alkyne, but to the 2-phenylindole: a)
C. E. Castro, R. D. Stevens, J. Org. Chem. 1963, 28 2163; b) C. E. Castro, E. J. Gaughan, D. C.
Owsley, J. Org. Chem. 1966, 31, 4071. More recent examples can be found in an excellent review on
274
Chapter 5
via tandem Sonogashira reaction/metal-catalyzed anulation generated the N-(2pyridyl)sulfonyl indole 26 in a very high yield (96%), which underwent smooth
deprotection under the standard protocol for N-desulfonylation, thus providing the
free NH-indole 27 in a very good overall yield.
NHSO2Py
Br
Ph
Et3N, p-xylene
CF3
R
Pd(PPh 3)4 (10 mol%)
(1.2 equiv)
3-Br
N
CuI (20 mol%)
100 ºC, 16 h
96%
Ph
F3C
26, R = SO2Py
27, R = H, 81%
Mg
Scheme 5.49
5.6.1. Mechanistic studies
Up to date, the mechanism for the CuII-catalyzed halogenation reaction is still not
well understood. In fact, from a mechanistic standpoint, Cu-catalyzed aerobic
oxidation reactions can be divided in two general ways of activation: i) singleelectron-transfer (SET) from the aromatic ring to the coordinated CuII to generate a
cation-radical intermediate (mechanism A, Scheme 5.50), and ii) a process similar to
that proposed for Pd-catalyzed C−H functionalization involving cyclometalation
(mechanism B, Scheme 5.50, either via a stepwise metalation and deprotonation
through a Wheland intermediate, or via a concerted metalation-deprotonation to form
directly the Aryl−Cu complex).
the synthesis of heterocycles via palladium-catalyzed oxidative addition: c) G. Zeni, R. C. Larock,
Chem. Rev. 2006, 106, 4644. For a general recent review on the synthesis of indoles, see: D. F.
Taber, P. K. Tirunahari, Tetrahedron 2011, 67, 7195.
275
Aerobic copper-catalyzed ortho-halogenation of anilines
Scheme 5.50
In order to gain mechanism insights, a series of experiments were carried out. In
first place, the reaction was run in the presence of commonly used radical
scavengers such as TEMPO or Galvinoxyl (1.0 equiv). In both cases it was observed
complete inhibition of the reaction, the starting sulphonamide 1 being recovered
unaltered (Scheme 5.51). These results strongly support a SET mechanism for this
reaction.
Scheme 5.51
Additionally, kinetic studies were carried out to determine the intramolecular
isotopic effect. In this pursuit, the monodeuterated aniline derivative 29 was prepared
following literature procedure214 (Scheme 5.52). 2-bromoaniline was subjected to
214
S.-H. Huang, J. M. Keith, M. B. Hall, M. G. Richmond, Organometallics 2010, 29, 4041.
276
Chapter 5
several exchange cycles with MeOD, for deuterium exchange of the NH2 group to
ND2, followed by treatment with a mixture of zinc dust and 10% NaOD in D2O to
afford the 2-bromoaniline-d3 28. In a final step, N-sulfonylation was carried with 2pyridylsulfonyl chloride following the standard protocol to give the mono-deuterated
aniline 29 with good overall yield (85% for the three-steps) and with a high deuterium
content of 95%-D (measured by 1H NMR).
Scheme 5.52
The aniline derivative 29 was submitted to the reaction with NCS under the
optimized conditions affording a mixture of products 29(H)-Cl and 29(D)-Cl in a 1:1
ratio (measured by 1H NMR-analysis, Scheme 5.53). This absence of intramolecular
kinetic isotopic effect suggests that the reaction mechanism is different from the Pdcatalyzed halogenation reactions, in which substantial isotope effects are typically
observed, and is also in line with the value described by Yu and co-workers
supporting a SET.
Scheme 5.53
Further mechanistic investigations to get a complete picture of the reaction
pathway are currently underway in our laboratory.
277
Aerobic copper-catalyzed ortho-halogenation of anilines
5.7. Conclusions
In summary, we have developed a practical and highly regioselective N(heteroaryl)sulfonyl-directed Cu-catalyzed aerobic ortho-C−H halogenation of aniline
derivatives. This new strategy provides complementary ortho-regioselectivities to that
of the classical electrophilic aromatic halogenation pathway.
General remarkable features of this new method include:
- The reaction proved to be very general for chlorination and bromination
- Very high mono-substitution selectivity
- Wide functional group tolerance at the aromatic ring, especially to other
halogenated substituents
- The use of these (heteroaryl)sulfonyl protecting/directing group allows their
facile removal under mild reaction conditions, enabling the development of useful
synthetic applications.
The advances accomplished, in a more detailed fashion, are listed below:
1) The N-(2-pyridyl)sulfonyl group proved to be an excellent protecting/directing
group for the ortho-mono-chlorination of aniline derivatives, providing good to
excellent yields with little or not competitive electrophilic halogenation apparent in
most cases. The reaction tolerates substrates bearing electron-donating or electronwithdrawing groups, being especially remarkable its compatibility with other halogens
such as Cl, Br or I, thereby leading to polyhalogenated products with orthogonal
reactivity relative to Pd0-catalyzed cross-coupling reactions.
278
Chapter 5
2) By just changing the source of halogen to the corresponding NBS and NIS,
under the same optimized conditions, this catalyst system could also be extended to
the regioselective ortho-bromination and ortho-iodination reactions. In the case of the
iodination, only para-substituted, electron-withdrawing substituted sulfonamides gave
good yields and selectivities for the desired ortho-iodinated products.
279
Aerobic copper-catalyzed ortho-halogenation of anilines
3) We have also introduced the (2-pyrimidyl)sulfonyl group (SO2Pyr) as a new
efficient directing group that solves the problem of the lack of reactivity displayed by
ortho-substituted
anilines
in
the
N-(2-PySO2)-directed
Cu-catalyzed
aerobic
chlorination reaction, thus enabling the access to di-ortho-substituted halogenated
anilines.
280
Chapter 5
This new directing group is also efficient for the double ortho-C−H chlorination of
anilines.
4) The easy reductive removal of both N-(2-pyridyl)sulfonyl and N-(2pyrimidyl)sulfonyl directing groups under mild conditions led us to realize the full
synthetic utility of this method allowing the access to the corresponding free NH2ortho-halogenated anilines in good yields.
281
Aerobic copper-catalyzed ortho-halogenation of anilines
5) Both the halide and the NH functionalities provide products that offer high
versatility as building blocks. As an application of the synthetic potential of this
method, the efficient conversion of the bromoaniline derivative 3-Br into the
functionalized indol 26 was realized. A tandem Sonogashira reaction/metal-catalyzed
cyclization, followed by the standard N-desulfonylation, afforded the free NH-indole
27, which was isolated in a very good overall yield.
NHSO2Py
Br
Ph
Et3N, p-xylene
CF3
3-Br
(1.2 equiv)
R
Pd(PPh 3)4 (10 mol%)
CuI (20 mol%)
100 ºC, 16 h
96%
N
Ph
F3C
26, R = SO2Py
27, R = H, 81%
Mg
6) Although a detailed mechanism of this copper(II)-catalyzed ortho-halogenation
protocol remains to be elucidated, preliminary insights suggest a SET pathway. For
example, the reaction was completely inhibited in the presence of commonly used
radical scavengers such as TEMPO or Galvinoxyl (1.0 equiv). On the other hand, the
absence of intramolecular kinetic isotopic effect suggests that the reaction
mechanism is different from the Pd-catalyzed halogenation reactions, in which
substantial isotope effects are typically observed, and is consistent with a radical
pathway.
282
Chapter 6:
Experimental section
283
284
Chapter 6
6.
Experimental
section
Catalytic
oxidative
homocoupling
of
N-(2-
pyridyl)sulfonylindoles: synthesis of 2,2’-biindoles
6.1.1. General methods
All the reactions were carried out in anhydrous solvents and under inert
atmosphere. Melting points were taken in open-end capillary tubes. NMR spectra
were recorded at 300 MHz (1H), 75 MHz (13C), at room temperature in CDCl3
[calibrated at 7.26 ppm (1H) and 77.0 ppm (13C)] unless otherwise indicated. Mass
spectra (MS) were determined at an ionizing voltage of 70 eV. Flash column
chromatography was performed using silica gel Merk-60 (230-400 mesh).
6.1.2. Typical procedure for the synthesis N-(2-pyridyl)sulfonyl indole
derivatives:
6.1.2.1. Synthesis of 2-pyridylsulfonyl chloride
To a solution of 2-mercaptopyridine (4.0 g, 36.0 mmol) in conc. H2SO4 (100 mL)
was added dropwise a commercially available bleach solution (roughly 5% NaOCl,
400 mL). The resulting mixture was stirred at 0 ºC for 15 min before it was extracted
with CH2Cl2 (2 x 25 mL). The combined organic phase was dried (Na2SO4) and
concentrated (caution: in a fume hood because of the presence of Cl2) to afford the 2pyridylsulfonyl chloride as a colorless oil. This compound is relatively unstable at
room temperature and it was immediately used without further purification. 1H NMR
(CDCl3, 300 MHz) δ: 8.85 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 8.07 (tt, J =
7.5, 1.3 Hz), 7.72 (ddd, J = 7.5, 4.6, 1.2 Hz, 1H).
285
Experimental section
Synthesis of N-(2-pyridylsulfonyl)indole (1). A mixture of indole (0.84 g,
7.15 mmol) and sodium hydride (240 mg, 10.01 mmol) was stirred
in THF at 0 ºC for 30 min. To the resulting solution was slowly
added at 0 ºC 2-pyridylsulfonyl chloride (1.9 g, 10.73 mmol) and
the resulting mixture was stirred at room temperature overnight.
The mixture was quenched with sat aq. NH4Cl solution (5 mL) and extracted with
EtOAc (3 x 10 mL). The combined organic phase was dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by flash
chromatography (n-hexane-EtOAc 9:1) to afford 7 as a pale yellow solid; yield: 1.48 g
(76%); mp = 60-62 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.63 (d, J = 4.4 Hz, 1H), 8.15 (d,
J = 7.9 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 3.6 Hz,
1H), 7.57 (d, J = 7.6 Hz, 1H), 7.47 (dd, J = 4.8, 7.1 Hz, 1H), 7.20-7.35 (m, 1H), 6.72
(d, J = 3.6 Hz, 1H).
C NMR (CDCl3, 75 MHz) δ: 155.4, 150.5, 138.1, 135.0, 130.8,
13
127.6, 127.3, 124.5, 123.5, 122.3, 121.4, 113.7, 108.9. ESI+ calcd. for C13H11N2O2S
(M+H)+: 259.0541; Found: 259.0538.
N-(4-Toluensulfonyl)indole (5): Following the typical procedure but using the
commercially available p-toluenesulfonyl chloride (1.5 equiv),
compound 5 was obtained after column chromatography (nhexane-EtOAc 9:1) as a white solid; yield: 71%; mp = 8586 ºC. 1H NMR (CDCl3, 300 MHz) δ: 7.99 (d, J = 8.1 Hz, 1H),
7.76 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 3.6 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.33-7.20
(m, 4H), 6.65 (d, J = 3.6 Hz, 1H), 2.33 (s, 3H).
C NMR (CDCl3, 75 MHz,) δ: 144.9,
13
135.4, 134.9, 130.8, 129.9(2C), 126.8(2C), 126.4, 124.6, 123.3, 121.4, 113.6, 109.1,
21.5. EI+ calcd. for C15H14NO2S (M+H)+: 272.0739; Found: 272.0747.
N-(2-Thienylsulfonyl)indole (6): Following the typical procedure but using the
commercially available 2-thiophenesulfonyl chloride (1.5 equiv),
N
SO2
S
compound 6 was obtained after column chromatography (nhexane-EtOAc 9:1) as a grey solid; yield: 70%; mp = 76-78 ºC.
1
H NMR (CDCl3, 300 MHz) δ: 8.02 (d, J = 8.2 Hz, 1H), 7.68 (d, J
= 3.6 Hz, 1H), 7.50-7.58 (m, 3H), 7.35 (m, 1H), 7.26 (m, 1H), 6.98 (t, J = 4.4 Hz, 1H),
286
Chapter 6
6.98 (d, J = 3.6 Hz, 1H).
C NMR (CDCl3, 75 MHz) δ: 138.3, 134.8, 133.5, 133.1,
13
130.9, 127.5, 126.2, 124.8, 123.7, 121.6, 113.7, 109.0. ESI+ calcd. for C12H9NO2S2
(M+H)+: 264.0147; Found: 264.0144.
N-(8-Quinolylsulfonyl)indole (7): Following the typical procedure but using the
commercially available 8-quinolinesulfonyl chloride (1.5 equiv),
compound 7 was obtained after column chromatography (nhexane-EtOAc 9:1) as a pale yellow solid; yield: 62%; mp =
178-180 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.85 (dd, J = 1.7, 4.2
Hz, 1H), 8.40 (dd, J = 1.4, 7.5 Hz, 1H), 8.01 ( d, J = 3.7 Hz, 1H), 7.98 ( dd, J = 1.7,
8.3 Hz, 1H). 7.87 (dd, J = 1.3, 8.2 Hz, 1H), 7.77 (dd, J = 0.8, 8.1 Hz, 1H), 7.50 (t, J =
7.6 Hz, 1H), 7.39 (dd, J = 1.4, 6.9 Hz, 1H), 7.30 (dd, J = 4.3, 8.3 Hz, 1H), 7.08 (m,
2H), 6.49 (dd, J = 0.6, 3.7 Hz, 1H).
13
C NMR (CDCl3, 75 MHz) δ: 151.4, 143.9, 136.2,
135.6, 134.8, 134.7, 132.0, 130.6, 129.5, 129.0, 125.2, 123.8, 122.8, 122.4, 121.1,
113.5, 106.2. ESI+ calcd. for C17H12N2O2S (M+H)+: 309.0692; Found: 309.0688.
N-(4-Nitrophenylsulfonyl)indole (8): Following the typical procedure but using the
commercially available 4-nitrobenzenesulfonyl chloride (1.5
equiv),
compound
8
was
obtained
after
column
chromatography (n-hexane-EtOAc 9:1) as a pale pink
solid, yield: 60%; mp = 106-109 ºC. 1H NMR (CDCl3, 300
MHz) δ: 8.26 (d, J = 8.8 Hz, 2H), 8.01 (dd, J = 8.5, 14.2 Hz, 3H), 7.55-7.53 (m, 2H),
7.31 (td, J = 6.4, 14.7 Hz, 2H), 6.73 (d, J = 3.5 Hz, 1H).
13
C NMR (CDCl3, 75 MHz)
δ:150.6, 143.4, 134.8, 131.9, 128.0 (2C), 126.0, 125.2, 124.5 (2C), 124.1, 121.8,
113.4, 110.7. FAB+ calcd. for C14H10N2O4S (M)+: 302.0361; Found: 302.0370.
N-(N’N’-Dimethylsulfonyl)indole (9): Following the typical procedure but using the
commercially
available
dimethylsulfamoyl
chloride
(1.5 equiv),
compound 9 was obtained after column chromatography (n-hexaneEtOAc 95:5) as a pale red solid; yield: 55%; mp =74-76 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 7.97 (dd, J = 0.4, 8.0 Hz, 1H), 7.60 (d, J = 7.0 Hz,
1H), 7.46 (d, J = 3.6 Hz, 1H), 7.35-7.23 (m, 2H), 6.64 (d, J = 3.6 Hz, 1H), 2.84 (s,
287
Experimental section
6H).
C NMR (CDCl3, 75 MHz) δ: 135.4, 129.9, 127.2, 124.2, 122.7, 121.2, 113.7,
13
106.7, 38.4 (2C). FAB+ calcd. for C10H12N2O2S (M)+: 224.0619; Found: 224.0627.
N-(2-Pyridylsulfonyl)-6-fluoroindole
(27):
Following
the
typical
procedure
compound 27 was obtained after column chromatography (nhexane-EtOAc 8:2) as a white solid; yield: 82%; mp = 105107 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.64 (d, J = 4.1 Hz, 1H),
8.16 (d, J = 7.9 Hz, 1H), 7.95 (dt, J = 1.5, 7.8 Hz, 1H), 7.78
(dd, J = 2.1, 9.6 Hz, 1H), 7.68 (d, J = 3.7 Hz, 1H), 7.45-7.55 (m, 2H), 7.03 (dt, J = 2.3,
9.0 Hz, 1H), 6.98 (d, J = 3.7 Hz, 1H).
C NMR (CDCl3, 75 MHz) δ: 162.4, 159.2,
13
155.3, 150.6, 138.2, 127.7, 122.3, 122.1, 112.1, 111.8, 108.5, 101.4, 101.1. ESI+
calcd. for C13H10FN2OS (M+H)+: 277.0447; Found: 277.0430.
N-(2-Pyridylsulfonyl)-5-methoxyindole (28): Following the typical procedure
compound 28 was obtained after column chromatography
(n-hexane-EtOAc 8:2) as a white solid; yield: 85%; mp =
96-98 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.61 (d, J = 0.9,
4.6 Hz, 1H), 8.11 (td, J = 0.9, 7.9 Hz, 1H), 7.90 (d, J = 9.1
Hz, 1H), 7.80 (dt, J = 1.7, 7.8 Hz, 1H), 7.65 (d, J = 3.8, 7.5 Hz, 1H), 7.46 (ddd, J =
1.1, 4.6, 7.6 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 2.4, 8.9 Hz, 1H), 6.62 (dd,
J = 0.8, 3.8 Hz, 1H), 3.85 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 156.6, 155.3, 150.4,
13
138.1, 131.8, 129.6, 128.1, 127.6, 122.2, 114.5, 113.6, 109.0, 103.7, 55.6. ESI+
calcd. for C14H13N2O2S (M+H)+: 273.0698; Found: 273.0687.
N-(2-Pyridylsulfonil)-5-bromoindole
(29):
Following
the
typical
procedure
compound 29 was obtained after column chromatography (nhexane-EtOAc 8:2) as a white solid; yield: 79%; mp = 8788 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.59 (d, J = 4.2 Hz, 1H),
8.10 (d, J = 7.9 Hz, 1H), 7.92-7.87 (m, 2H), 7.67-7.65 (m,
2H), 7.45 (ddd, J = 1.1, 4.7, 7.7 Hz, 1H), 7.38 (dd, J = 1.9, 8.8 Hz, 1H), 6.61 (d, J =
3.8 Hz, 1H).
288
C NMR (CDCl3, 75 MHz) δ: 155.3, 150.5, 138.2, 133.8, 132.5, 128.6,
13
Chapter 6
127.7, 124.0, 122.2, 117.0, 115.2, 108.1. FAB+ calcd. for C13H9N2O2SBr (M)+:
335.9568; Found: 335.9576.
N-(2-Pyridylsulfonyl)-6-methoxycarbonylindole
(30):
Following
the
typical
procedure compound 30 was obtained after column
chromatography (n-hexane-EtOAc 7:3) as a white solid;
yield: 79%; mp = 147-149 ºC. 1H NMR (CDCl3, 300 MHz)
δ: 8.70 (s, 1H), 8.62 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 7.9
Hz, 1H), 7.90-8.0 (m, 2H), 7.87 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (dd,
J = 4.7, 7.2 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 3.98 (s, 3H).
13
C NMR (CDCl3, 75 MHz)
δ: 167.2, 155.3, 150.6, 138.3, 134.6, 134.5, 130.4, 127.8, 126.5, 124.6, 122.4, 121.1,
115.4, 108.6, 52.2. FAB+ calcd. for C15H13N2O43S (M+H)+: 317.0596; Found:
317.0585.
7-Aza-N-(2-pyridylsulfonyl)indole (31): Following the typical procedure compound
31 was obtained after column chromatography (n-hexane-EtOAc
6:4) as a white solid; yield: 73%; mp =154-156 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.56 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.47
(dt, J = 7.9, 0.9 Hz, 1H), 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (td, J = 7.8, 1.7 Hz, 1H),
7.89 – 7.79 (m, 2H), 7.45 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.14 (dd, J = 7.9, 4.8 Hz,
1H), 6.64 (d, J = 4.0 Hz, 1H).
C NMR (CDCl3, 75 MHz) δ:155.6, 150.3, 147.6,
13
144.9, 138.1, 129.8, 127.8 (2C), 124.2, 123.1, 119.2, 105.6. FAB+ calcd. for
C12H10N3O2S (M+H)+: 260.0494; Found: 260.0491.
N-(2-Pyridylsulfonyl)-7-methylindole
(32):
Following
the
typical
procedure
compound 32 was obtained after column chromatography (nhexane-EtOAc 9:1) as a red solid; yield: 71%; mp = 50-52 ºC. 1H
NMR (CDCl3, 300 MHz) δ: 8.59 (dd, J = 0.9, 4.6 Hz, 1H), 8.10
(dd, J = 0.9, 7.9 Hz, 1H), 7.89 (dt, J = 1.7, 6.1 Hz, 1H), 7.79 (d, J
= 3.7 Hz, 1H), 7.45 (ddd, J = 1.1, 4.6, 7.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.12 (t, J
= 7.6 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.70 (d, J = 3.8 Hz, 1H), 2.56 (s, 3H).
13
C
NMR (CDCl3, 75 MHz) δ: 157.0, 150.3, 138.2, 134.9, 132.9, 130.0, 128.2, 127.4,
289
Experimental section
124.6, 123.8, 122.0, 119.4, 108.8, 21.9. ESI+ calcd. for C14H13N2O2S (M+H+):
273.0698; Found: 273.0682.
4-Cyano-N-(2-pyridylsulfonyl)indole
(33):
Following
the
typical
procedure
compound 33 was obtained after column chromatography (nhexane-EtOAc 8:1) as a yellow solid; yield: 76%; mp =163165 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.59 (ddd, J = 4.7, 1.8, 0.9
Hz, 1H), 8.29 (dt, J = 8.4, 0.9 Hz, 1H), 8.14 (dt, J = 7.9, 1.0 Hz,
1H), 7.93 (td, J = 7.8, 1.7 Hz, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.57 (dd, J = 7.5, 0.9 Hz,
1H), 7.49 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.37 (dd, J = 8.4, 7.6 Hz, 1H), 6.90 (dd, J =
3.7, 0.8 Hz, 1H).
C NMR (CDCl3, 300 MHz) δ: 155.3, 150.8, 138.5, 135.2, 132.5,
13
130.0, 128.2, 128.1, 124.5, 122.4, 118.6, 117.4, 107.1, 104.5. FAB+ calcd. for
C14H9N3O2S (M)+: 283.0415; Found: 283.0412.
Synthesis of tert-butyl-1-indole carboxylate (10).
Following the literature procedure,215 compound 10 was obtained as a yellow oil;
yield: 96%. 1H NMR (CDCl3, 300 MHz) δ: 8.15 (d, J = 8.1 Hz, 1H),
7.60 (d, J = 3.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.33-7.20 (m,
3H), 6.57 (d, J = 3.6 Hz, 1H), 1.68 (s, 9H).
13
C NMR (CDCl3,
75 MHz) δ: 149.8, 135.2, 130.6, 125.9, 124.2, 122.6, 120.9, 115.2,
107.3, 83.6, 28.2 (3C). EI+ calcd. for C13H16NO2 (M+H)+: 218.1175; Found: 218.1181.
6.1.3. General
procedure
for
the
PdII-catalyzed
dehydrogenative
homocoupling to 2,2’-biindoles:
A screw-capped test tube was charged with N-(2-pyridylsulfonyl)indole derivative
(0.2 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol) and Cu(OTf)2 (108.5 mg, 0.3 mmol) before
AcOH (2 mL) was added and O2 was bubbled into the mixture for 5 min. The mixture
was heated to 90-100 ºC for 8-46 h (indicated in each case) before it was allowed to
215
L. F. Silva Jr., M. V. Craveiro, M. T. P. Gambardella, Synthesis 2007, 3851.
290
Chapter 6
reach room temperature, then diluted with CH2Cl2 (20 mL) and washed successively
with NH4OH (2 x 10 mL), sat. aq solution of NH4Cl (10 mL) and sat. aq NaCl (10 mL).
The combined organic phase was dried (MgSO4) and concentrated in vacuo. The
residue was diluted with CH2Cl2 and passed through a pad of Celite with a thin layer
of silica gel on the top. The filtrate was concentrated to dryness to afford the
corresponding pure biindole derivative.
N,N’-Bis(2-pyridylsulfonyl)-2,2’-biindole (2): reaction time 8 h; brown-redish solid;
yield: 68%. mp = 257-259 ºC. 1H NMR (CDCl3, 300 MHz) δ:
8.55 (d, J = 4.5 Hz, 2H), 8.26 (d, J = 8.4 Hz, 2H), 7.90-7.75
(m, 4H), 7.53 (d, J = 7.7 Hz, 2H), 7.45-7.35 (m, 4H), 7.28-7.23
(m, 2H), 6.77 (s, 2H).
C NMR (CDCl3, 75 MHz) δ: 155.9
13
(2C), 150.1 (2C), 137.8 (2C), 137.6 (2C), 130.8 (2C), 128.3 (2C), 127.4 (2C), 125.4
(2C), 123.7 (2C), 122.6 (2C), 121.2 (2C), 115.6 (2C), 115.4 (2C). ESI+ calcd. for
C26H19N2O4S2 (M+H)+: 515.0848; Found: 515.0844.
6,6’-Difluoro-N,N’-bis(2-pyridylsulfonyl)-2,2’-biindole (34): reaction time 12 h;
redish solid; yield: 66%; mp = 230-232 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.56 (d, J = 4.8 Hz, 2H), 8.01 (dd, J
= 2.1, 10.3 Hz, 2H), 7.86-7.83 (m, 4H), 7.48-7.41 (m,
4H), 7.03 (dt, J = 2.3, 9.0 Hz, 2H), 6.73 (s, 2H).
13
C
NMR (CDCl3, 75 MHz) δ: 161.3 (d, JC-F = 242.2 Hz, 2C), 155.7 (2C), 150.2 (2C),
137.9 (2C), 130.8 (d, JC-F = 4.1 Hz, 2C), 127.6 (2C), 125.0 (d, JC-F = 1.6 Hz, 2C),
122.5 (2C), 121.9 (d, JC-F = 9.9 Hz, 2C), 114.9 (2C), 112.3 (d, JC-F = 24.4 Hz, 2C),
103.0 (d, JC-F = 29.0 Hz). EI+ calcd. for C26H17N4O4F2S2 (M+H)+: 551.0653; Found:
551.0654.
5,5’-Dimethoxy-N,N’-bis(2-pyridylsulfonyl)-2,2’-biindole (35): reaction time 7 h;
brown solid; yield: 64%; mp = 130-132 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.54 (d, J= 4.6 Hz, 2H), 8.15
(d, J=9.9 Hz, 2H), 7.85-7.77 (m, 4H), 7.40 (ddd, J=
1.7, 4.7, 6.6 Hz, 2H), 6.99 (dd, J= 2.7, 7.0, Hz, 4H),
291
Experimental section
6.72 (s, 2H), 3.82 (s, 6H).
C NMR (CDCl3, 75 MHz) δ: 156.6 (2C), 155.8 (2C), 150.0
13
(2C), 137.7 (2C), 132.3 (2C), 131.4 (2C), 129.7 (2C), 127.3 (2C), 122.5 (2C), 116.5
(2C), 115.4 (2C), 114.5 (2C), 103.4 (2C), 55.7 (2C). FAB+ calcd. for C28H23N4O6S2
(M+H)+: 575.1059; Found: 575.1051.
5,5’-Dibromo-N,N’-bis(2-pyridylsulfonyl)-2,2’-biindole (38): Pd(OAc)2 (20 mol%,
8.9 mg); reaction time 46 h; brown-redish solid; yield:
61%; mp= 268-269 ºC. 1H NMR (CDCl3, 300 MHz)
δ:8.54 (d, J = 4.6 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H),
7.84 (dd, J = 4.0, 1.1 Hz, 4H), 7.67 (d, J = 2.0 Hz, 2H),
7.53 – 7.38 (m, 4H), 6.71 (s, 2H).
13
C NMR (CDCl3,
75 MHz) δ: 155.6 (2C), 150.2 (2C), 137.9 (2C), 136.3(2C), 131.5 (2C), 130.4(2C),
128.4(2C), 127.6(2C), 123.8 (2C), 122.5 (2C), 117.2 (2C), 117.1(2C), 114.4 (2C).
FAB+ calcd. for C26H17N4O4S2Br2 (M+H)+: 670.9058; Found: 670.9059.
6.1.4. Synthesis of 2,3’-biindoles via PdII-catalyzed dehydrogenative
homocoupling
N,N’-Bis(2-pyridylsulfonyl)-2,3’-biindole (3):A screw-capped test tube was charged
with
N-(2-pyridylsulfonyl)indole
1.0 equiv),
Pd(OAc)2
(4.5 mg,
(51.7 mg,
0.02 mmol)
0.2 mmol,
and
AgOAc
(101.9 mg, 0.6 mmol, 3.0 equiv) before AcOH (2 mL) was
added and O2 was bubbled into the mixture for 5 min. The
mixture was heated to 90-100 ºC for 23 h
before it was
allowed to reach room temperature, then diluted with AcOEt (20 mL) and washed
successively with and sat. aq NaCl (10 mL). The combined organic phase was dried
(MgSO4) and concentrated in vacuo. The residue was purified by column
chromatography (CH2Cl2) affording the 2,3’-biindole 3 as a redish solid (12.4 mg, 24%
yield), recovering part of the starting material unalterted (23.2 mg). Yield in converted
product: 44%; 1H NMR (CDCl3, 300 MHz) δ: 8.62 (d, J = 4.2 Hz, 1H), 8.43 (d, J = 4.6
Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H),
292
Chapter 6
7.90 (dt, J = 1.5, 7.8 Hz, 1H), 7.79 (s, 1H), 7.62-7.60 (m, 2H), 7.52 (d, J = 7.6 Hz,
1H), 7.49-7.44 (m, 1H), 7.40-7.35 (m, 2H), 7.32-7.26 (m, 3H), 7.21-7.16 (m, 1H), 6.72
(s, 1H). 13C NMR (CDCl3, 75 MHz) δ: 155.5, 155.4, 150.4. 150.0, 138.4, 138.3, 137.5,
134.5, 131.9, 131.3, 129.8, 128.0, 127.7, 127.6, 127.3, 125.0, 124.9, 124.0, 123.7,
122.5, 122.3, 120.7, 120.6, 116.0, 114.0, 113.7. EI+ calcd. for C26H19N4O4S2 (M+H)+:
515.0842; Found: 515.0828.
6.1.5. Deprotection of N,N’-bis(2-pyridilsulfonyl)-2,2’-biindolyl (2) to afford
free NH-biindole 41.
Synthesis of NH-2,2’-biindole (41). A suspension of 2,2’-bisindolyl 2 (0.3 mmol,
153.3 mg) and Mg (290 mg, 12 mmol) in a 1:1 mixture of
THF:MeOH (15 mL) was stirred at 0 ºC for 5 min and then
under sonication at room temperature for 2 h. The mixture
was quenched with sat. aq. NaHCO3 and extracted with CH2Cl2. The combined
organic phase weas washed with sat. aq NaCl, dried (MgSO4), and concentrated
under reduced pressure. The residue was purified by flash cromatography
(hexane/EtOAc 5:1) to give 41 as a pale yellow solid (33.8 mg); yield: 54%; mp= 200202 ºC (decomposition). 1H NMR (acetone-d6, 300 MHz) δ: 7.60 (d, J = 7.7 Hz, 2H),
7.45 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.0 Hz, 2H), 7.07 (d, J = 7.1 Hz, 2H), 6.98 (s,
2H), 2.95 (bs, 2H).
C NMR (acetone-d6, 75 MHz) δ: 138.2 (2C), 132.4 (2C), 130.0
13
(2C), 122.8 (2C), 121.0 (2C), 120.6 (2C), 111.8 (2C), 99.5 (2C). EI+ calcd. for
C16H12N2 (M)+: 232.1000; Found: 232.1009.
293
Experimental section
6.1.6. Intramolecular homocoupling reaction
6.1.6.1. Synthesis of the starting material
3,3'-(cyclohexane-1,1-diyl)bis(1H-indole) (42). A screw-capped test tube was
charged
with
indole
(1.17 g,
10.0 mmol,
1.0 equiv),
ciclohexanone (1.03 mL, 10.0 mmol, 1.0 equiv), la resina ácida
Amberlist-15 resin (500 mg) and CH2Cl2 (25 mL). The reaction
mixture was stirred at 50 ºC for 12 h under inert atmosphere.
Once the reaction was completed (TLC monitoring), it was
allowed to reach room temperature, then diluted with AcOEt (20 mL) and filtered off
through celite, rinsing the filtrate cake with AcOEt (3 x 10 mL). The filtrate was
concentrated under reduced pressure and the residue was purified by flash
chromatography (n-hexane-EtOAc 9:1) to afford 42 as a yellow solid; yield: 1.22 g
(78%); mp = 94-96 ºC. 1H NMR (CDCl3, 300 MHz) δ: 7.87 (s, 2H), 7.59 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 8.1 Hz, 2H), 7.10-7.05 (m, 4H), 6.94-6.89 (m, 2H), 2.57 (t, J = 5.7
Hz, 4H), 1.68-1.60 (m, 6H).
13
C NMR (CDCl3, 75 MHz) δ: 137.1, 126.4, 123.7, 122.0,
121.5, 121.2, 118.5, 111.1, 39.6, 36.9, 26.8, 23.0. FAB+ calcd. for C22H22N2 (M)+:
314.1783; Found: 314.1779.
Bis[N-(2-pyridyl)sulfonyl-1H-indole-3-yl]cyclohexane (43) y 1-(1H-Indol-3-yl)-1(N-(2-pyridyl)sulfonyl-1H-indole-3-yl)cyclohexane
(44):
Under
nitrogen
atmosphere, bisindole-NH 42 (1 g, 3.2 mmol, 1.0 equiv) and NaOH (0.5 g,
12.7 mmol, 4.0 equiv) were stirred in 1,2-dicloroethane (15 mL) at 0 ºC for 5 min., 2pyridylsulfonyl chloride (1.5 g, 8.2 mmol, 2.6 equiv) was dissolved in 1,2-dicloroetano
(2 mL) and it was slowly added to the reaction mixture at 0 ºC. Upon completion of
the addition, the mixture was allowed to reach room temperature and it was stirred for
12 h. Water (25 mL) was added and the reaction mixture was extracted with CH2Cl2
(2 x 20 mL). The combained organic layers were washed with a saturated aqueous
solution of NaCl (15 mL), dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography (n-hexane-EtOAc 9:1) to afford the
monoprotected product 44 (465.8 mg, 32%), followed by the di-protect product 43
(491.3 mg, 26%).
294
Chapter 6
44: pale yellow solid; mp = 178-180 ºC; 1H NMR (CDCl3, 300 MHz) δ: 8.62 (d, J = 4.0
Hz, 1H), 8.07-7.95 (m, 3H), 7.84 (s, 1H), 7.72 (dt, J = 1.6, 7.8
Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.37-7.31 (m, 2H), 7.28-
N
H
N
SO2Py
7.21(m, 2H), 7.08 (dt, J = 7.06, 19.8 Hz, 2H), 6.93 (t, J = 7.4
Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 2.53-2.41 (m, 4H), 1.67-1.58
(m, 6H).
C NMR (CDCl3, 75 MHz) δ: 155.5, 150.4, 138.1,
13
137.1, 136.1, 130.5, 129.6, 127.5, 126.1, 124.7, 124.0, 122.8, 122.5, 122.3, 122.0,
121.6, 121.5, 121.1, 118.8, 113.8, 111.2, 39.2, 36.7, 26.8, 22.9. FAB+ calcd. for
C27H25N3O2S (M)+: 455.1667; Found: 455.1670.
43: pale yellow solid; mp = 222-224 ºC; 1H NMR (CDCl3, 300 MHz) δ: 8.61 (d, J = 4.0
Hz, 2H), 8.06 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H),
7.84-7.79 (m, 4H), 7.41 (dd, J = 4.7, 8.4 Hz, 2H), 7.30 (d, J =
8.0 Hz, 2H), 7.11-7.06 (m, 2H), 6.89-6.84 (m, 2H), 2.42-2.40
(m, 4H), 1.65-1.58 (m, 6H).
13
C NMR (CDCl3, 75 MHz) δ:
155.3, 150.3, 138.0, 135.8, 129.8, 128.0, 127.4, 124.7, 124.1,
122.7, 122.2, 121.6, 113.6, 38.9, 36.1, 26.5, 22.5. FAB+ calcd. for C32H28N4O4S2 (M)+:
596.1552. Found: 596.1560.
6.1.6.2. Attempts for intramolecular oxidative homocoupling Retro-FriedelCrafts reaction.
Synthesis of 3-(Cyclohex-1-enyl)-N-(2-pyridylsulfonyl)indole (46) and 3phenyl-N-(2-pyridylsulfonyl)indole (47). A screw-capped test tube was charged the
mono-protected bis-indole 44 (45.5 mg, 0.1 mmol, 1.0 equiv), Pd(AcO)2 (2.2 mg,
0.01 mmol, 10 mol%), Cu(OTf)2 (54.2 mg, 0.15 mmol, 1.5 equiv) before toluene
(1 mL) was added and O2 was bubbled into the mixture for 5 min. The mixture was
heated to 100 ºC for 3 h before it was allowed to reach room temperature, then
diluted with AcOEt (20 mL) and washed with sat. aq solution of NaCl (2 x 5 mL). The
combined organic phase was dried (MgSO4) and concentrated in vacuo. The residue
295
Experimental section
was purified by flash chromatography (n-hexane-EtOAc 8:2) to afford the retro
Friedel-Crafts product 46 (3.9 mg, 12%), followed by the oxidated 47 (6.2 mg, 19%).
46: colorless oil; 1H NMR (CDCl3, 300 MHz) δ: 8.60 (d, J = 4.3 Hz, 1H), 8.09 (d, J =
7.9 Hz, 1H), 8.02 (dd, J = 1.3, 7.2 Hz, 1H), 7.86 (dt, J = 1.8, 7.7 Hz,
1H), 7.80-7.77 (m, 1H), 7.56 (s, 1H), 7.43 (ddd, J = 1.0, 4.6, 7.6 Hz,
1H), 7.33-7.19 (m, 2H), 6.30-6.28 (m, 1H), 2.44-2.40 (m, 2H), 2.282.22 (m, 2H), 1.84-1.77 (m, 2H), 1.74-1.66 (m, 2H). FAB+ calcd. for
C19H18N2O2S (M)+: 338.4; Found: 338.1.
47: colorless oil; 1H NMR (CDCl3, 300 MHz) δ: 8.61 (d, J = 4.3 Hz, 1H), 8.15 (d, J=
7.9 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.89 (dt, J = 1.6, 7.8 Hz, 1H),
7.80-7.79 (m, 2H), 7.65-7.62 (m, 2H), 7.49-7.43 (m, 3H), 7.40-7.29
(m, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 155.4, 150.6, 138.1, 135.7,
133.1, 129.4, 128.9, 127.9, 127.6, 127.5, 124.8, 123.9, 123.8,
123.7, 122.3, 120.4, 114.1. FAB+ calcd. for C19H15N2O2S (M+H)+: 335.4; Found:
335.0.
296
Chapter 6
6.2. C−
−H olefination of anilines and arylalkylaminesGeneral methods
All the reactions were carried out in anhydrous solvents and under a nitrogen
atmosphere with exclusion of moisture from reagents, solvents and glassware using
standard techniques. Melting points were taken in open-end capillary tubes. NMR
spectra were recorded at 25 ºC using a 300 MHz spectrometer [300 MHz (1H),
75 MHz (13C)]. Chemical shifts (δ) are represented in parts per million, referenced to
residual protons in the NMR solvent [CDCl3 (unless otherwise specified): 1H NMR δ =
7.26 ppm (singlet);
C NMR δ = 77.0 ppm (triplet)]. Data are reported as follows:
13
chemical shift, multiplicity, coupling constant (J, in Hz) and integration. All
13
C NMR
spectra were obtained with complete proton decoupling. Mass spectra were
determined at an ionizing voltage of 70 eV. Flash column chromatography was
performed using 230-400 mesh ultra-pure silica gel.
297
Experimental section
6.2.2. Typical procedure for N-sulfonylation of anilines
Synthesis of N-phenylpyridine-2-sulfonamide (2). To a solution of aniline
(436.2 mg, 4.69 mmol) in THF (47 mL), cooled to 0 ºC and under N2
O O
S
HN
N
atmosphere, were successively added pyridine (683 µL, 8.44 mmol,
1.8 equiv,) and a solution of 2-pyridylsulfonyl chloride (1.0 g,
5.63 mmol, 1.2 equiv) in THF (2 mL). The resulting solution was
allowed to reach room temperature and it was stirred overnight, whereby a precipitate
was formed. The solid was filtered and discarded. To the filtrate was added water
(20 mL) and the THF was removed by evaporation at reduced pressure, yielding a
suspension of a white solid in the aqueous medium. The solid was filtered, washed
with toluene (2 x 5 mL) and dried under vacuum to give 7 as a white powder; yield:
1.0 g (92%); mp = 170-172 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.21 (bs, 1H), 8.68
(d, J = 4.7 Hz, 1H), 8.03-7.94 (m, 2H), 7.58 (m, 1H), 7.30-7.19 (m, 4H), 7.04 (t, J =
7.2 Hz, 1H).
C NMR (acetone-d6, 75 MHz): δ 158.0, 150.9, 139.1, 138.6, 129.8
13
(2C), 127.9, 125.3, 123.5, 121.9 (2C). ESI+ calcd. for C11H11N2O2S (M+H)+: 235.0535;
Found: 235.0537.
N-(2-Methoxyphenyl)pyridine-2-sulfonamide (24). White solid; yield: 50%; 1H NMR
(CDCl3, 300 MHz) δ: 8.67 (d, J = 4.2 Hz, 1H), 7.98 – 7.88 (m, 1H),
7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.56 (dd, J = 8.0, 1.7 Hz, 1H), 7.49 –
7.35 (m, 2H), 7.01 (td, J = 7.8, 1.7 Hz, 1H), 6.86 (td, J = 7.7, 1.5
Hz, 1H), 6.75 (dd, J = 8.1, 1.4 Hz, 1H), 3.71 (s, 3H).
N-(2-Fluorophenyl)pyridine-2-sulfonamide (25). White solid; yield: 96%; 1H NMR
(CDCl3, 300 MHz) δ: 8.74 (d, J = 4.9 Hz, 1H), 8.15 – 7.94 (m, 1H),
7.94 – 7.83 (m, 1H), 7.64 (dt, J = 7.2, 3.7 Hz, 1H), 7.51 (ddd, J = 7.2,
4.2, 1.5 Hz, 1H), 7.35 – 7.18 (m, 1H), 7.14 – 6.95 (m, 3H). ESI+ calcd.
for C11H10N2O2SF (M+H)+: 253.0441; Found: 253.0444.
298
Chapter 6
N-(3-Methoxyphenyl)pyridine-2-sulfonamide (26). White solid; yield: 83%; mp =
165-167 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.74 (d, J = 4.2 Hz, 1H),
8.16 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.82 (td, J = 7.7, 1.6 Hz, 1H),
7.46 (ddd, J = 7.5, 4.7, 0.9 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.826.77 (m, 2H), 6.62 (dd, J = 8.3, 1.9 Hz, 1H), 3.71 (s, 3H). 13C NMR
(CDCl3, 75 MHz) δ: 160.2, 156.2, 150.1, 138.1, 137.3, 129.9, 127.0, 123.2, 114.6,
111.5, 108.1, 55.3. ESI+ calcd. for C12H13N2O3S (M+H)+: 265.0641; Found: 265.0652.
N-(3-Bromophenyl)pyridine-2-sulfonamide (27). White solid; yield: 85%; 1H NMR
PyO 2S
(CDCl3, 300 MHz) δ: 8.73 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 7.7 Hz,
NH
1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.49 (ddd, J = 7.5, 4.8, 1.4 Hz,
1H), 7.39 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.14 (dd, J =
Br
7.8, 1.1 Hz, 1H), 7.11 – 7.03 (m, 1H). ESI+ calcd. for C11H10N2O2SBr
(M+H)+: 312.9640; Found: 312.9634.
N-(2-Naphthyl)pyridine-2-sulfonamide (28). Pale pink solid; yield: 89%; mp = 204206ºC. 1H NMR (DMSO-d6, 300 MHz) δ: 8.74 – 8.61 (m, 1H),
SO 2Py
NH
8.02 (dd, J = 3.8, 1.0 Hz, 2H), 7.76 (t, J = 9.9 Hz, 3H), 7.63 – 7.54
(m, 2H), 7.48 – 7.28 (m, 3H).
C NMR (DMSO-d6, 75 MHz) δ:
13
156.3, 150.1, 138.7, 135.3, 133.1, 129.9, 128.8, 127.4, 127.4, 127.1, 126.6, 124.9,
122.5, 120.4, 115.9. ESI+ calcd. for C15H13N2O2S (M+H)+: 285.0692; Found:
285.0692.
N-(4-Chlorophenyl)pyridine-2-sulfonamide (29). White solid; yield: 76%; mp = 182PyO2S
NH
184 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.08 (s,
1H), 7.92 – 7.81 (m, 2H), 7.49 (ddd, J = 7.1, 4.7, 1.4 Hz, 1H), 7.17 (s,
4H).
Cl
C NMR (CDCl3, 75 MHz) δ: 155.9, 150.1, 138.3, 134.7, 131.3,
13
129.3 (2C), 127.2, 124.1 (2C), 123.3. ESI+ calcd. for C11H10N2O2SCl
(M+H)+: 269.0146; Found: 269.0161.
299
Experimental section
Methyl 4-[N-(2-pyridyl)sulfonylamino]benzoate (30). White solid; yield: 40%; mp =
222-224 ºC. 1H NMR (DMSO-d6, 300 MHz) δ: 8.70 (d, J = 3.8 Hz,
1H), 8.09 (dt, J = 12.0, 4.0 Hz, 2H), 7.87 – 7.76 (m, 2H), 7.71 – 7.58
(m, 1H), 7.27 (d, J = 7.5 Hz, 2H), 3.77 (s, 3H).
13
C NMR (DMSO-d6,
75 MHz) δ: 165.6, 156.1, 150.2, 142.4, 138.9, 130.4, 127.6, 124.2,
122.5, 118.1, 51.8. ESI+ calcd. for C13H13N2O4S (M+H)+: 293.0590; Found: 293.0594.
4-Methyl-N-phenylbenzenesulfonamide
(10).
Compound
10
was
prepared
following the typical procedure from aniline (364 µL, 4.00 mmol) and 4methylbenzenesulfonyl chloride (915 mg, 4.80 mmol, 1.2 equiv) to give 4 as
a white solid; yield: 752 mg (76%); mp = 96-97 ºC. 1H NMR (acetone-d6,
300 MHz) δ: 8.90 (s, 1H), 7.67 (d, J = 8.3, 2H), 7.31 (d, J = 7.9, 2H), 7.26 –
7.16 (m, 4H), 7.13 – 7.00 (m, 1H), 2.35 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 144.0,
136.7, 136.2, 129.8, 129.4, 127.4, 125.4, 121.6, 21.6.
6.2.3. Synthesis of the starting functionalized N-alkyl anilines:
All these substrates were prepared from the N-phenylpyridine-2-sulfonamide (2)
following literature procedures.
Methyl (E)-3-(N-phenylpyridine-2-sulfonamido)acrylate (3). Following the literature
procedure,216 compound 3 was obtained after flash column
chromatography
(eluents
n-hexane-EtOAc
3:1),
as
a
colourless oil; yield: 67%. H NMR (CDCl3, 300 MHz) δ: 8.81
1
(d, J = 4.3 Hz, 1H), 8.44 (d, J = 13.8 Hz, 1H), 7.92 – 7.84 (m,
1H), 7.84 – 7.79 (m, 1H), 7.56 (ddd, J = 7.4, 4.7 Hz, 1.5, 1H), 7.45 – 7.32 (m, 3H),
7.01 (dt, J = 6.4, 1.9 Hz, 2H), 4.69 (d, J = 13.8 Hz, 1H), 3.69 (s, 3H).
216
M. Barbazanges, C. Meyer, J. Cossy, Org. Lett. 2007, 9, 3245.
300
Chapter 6
(E)-N-Phenyl-N-(2-pyridyl)sulfonylbut-2-enamide
procedure,
217
(4).
Following
the
literature
compound 4 was obtained as a white solid after
column chromatography (eluents n-hexane-EtOAc 2:1); yield:
85%. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (ddd, J = 4.6, 1.7, 0.8
Hz, 1H), 8.24 (dt, J = 7.8, 0.9 Hz, 1H), 7.92 (td, J = 7.8, 1.8 Hz,
1H), 7.71 – 7.54 (m, 2H), 7.48 (dq, J = 7.4, 1.5 Hz, 4H), 6.90 (dq, J = 15.2, 6.9 Hz,
1H), 5.56 (dd, J = 15.1, 1.6 Hz, 1H), 1.66 (dd, J = 6.9, 1.7 Hz, 3H).
N-(But-3-en-1-yl)-N-phenylpyridine-2-sulfonamide (5). Following the literature
procedure,218 compound 5 was obtained as a colourless oil after
column chromatography (eluents n-hexane-EtOAc 4:1); yield:
70%. 1H NMR (CDCl3, 300 MHz) δ: 8.76 (dd, J = 5.6, 1.5 Hz, 1H),
7.83 – 7.75 (m, 1H), 7.74 – 7.68 (m, 1H), 7.47 (ddd, J = 7.4, 4.8,
1.4 Hz, 1H), 7.32 – 7.24 (m, 3H), 7.17 – 7.08 (m, 2H), 5.92 – 5.64 (m, 1H), 5.03 (ddd,
J = 14.2, 3.5, 1.7 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 2.92 (d, J = 21.6 Hz, 1H), 2.26 (q,
J = 7.1 Hz, 2H).
6.2.3.1. Preparation of N-[(methoxycarbonyl)methyl]aniline derivatives.
Synthesis
PyO2 S
of
methyl
N-phenyl-N-[(2-pyridyl)sulfonyl]glycinate
suspension
N
CO2 Me
of
N-phenylpyridine-2-sulfonamide
(6).
(2)
To
a
(0.44 g,
1.89 mmol) and K2CO3 (390 mg, 2.83 mmol, 1.5 equiv) in CH3CN
(10 mL), at room temperature under nitrogen atmosphere, was
slowly added methyl bromoacetate (360 mL, 3.78 mmol,
2 equiv). The mixture was stirred at room temperature for 12-14 h before it was
concentrated under reduced pressure. The residue was dissolved in EtOAc (15 mL)
and washed successively with water (3 x 10 mL) and brine (10 mL). The combined
organic phase was dried (MgSO4) and concentrated to dryness. The residue was
purified by flash chromatography (n-hexane-EtOAc 4:1) to afford 9 as a pale yellow
217
M. R. Jeddeloh, J. B. Holden, D. H. Nouri, M. J. Kurth, J. Comb. Chem. 2007, 9, 1041.
218
V. A. Rassadin, A. A. Tomashevskiy, V. V. Sokolov, A. Ringe, J. Magull, A. de Meijere, Eur. J. Org.
Chem. 2009, 2635.
301
Experimental section
solid; yield: 560 mg (98%); mp = 91-92 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.73 (ddd, J
= 4.7, 1.6, 0.9 Hz, 1H), 7.87 – 7.65 (m, 2H), 7.48 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.24
(s, 5H), 4.70 (s, 2H), 3.68 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ: 169.3, 157.4, 150.0,
139.5, 137.8, 129.2 (2C), 128.9 (2C), 128.3, 126.9, 122.9, 54.1, 52.3. ESI+ calcd. for
C14H15N2O4S (M+H)+: 307.0747; Found: 307.0744.
Methyl
N-(2-methoxyphenyl)-N-[(2-pyridyl)sulfonyl]glycinate
(31).
Chroma-
tography eluent: n-hexane-EtOAc 1:1; pale yellow oil; yield:
89%; 1H NMR (CDCl3, 300 MHz) δ: 8.75 (ddd, J = 4.6, 1.7, 0.8
Hz, 1H), 7.82 (td, J = 7.7, 1.7, 1H), 7.74 – 7.66 (m, 1H), 7.63
(dd, J = 7.8, 1.8 Hz, 1H), 7.54 – 7.44 (m, 1H), 7.33 – 7.23 (m,
1H), 6.96 (td, J = 7.6, 1.3 Hz, 1H), 6.75 (dd, J = 8.3, 1.4 Hz, 1H), 4.62 (s, 2H), 3.69 (s,
3H), 3.34 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 169.8, 158.1, 155.7, 149.8, 137.4,
13
133.9, 130.3, 126.7, 126.4, 122.3, 120.9, 111.4, 55.1, 52.1, 51.9. ESI+ calcd. for
C15H17N2O5S (M+H)+: 337.0852; Found: 337.0864.
Methyl N-(2-fluorophenyl)-N-[(2-pyridyl)sulfonyl]glycinate (32). Chromatography
eluent: n-hexane-EtOAc 3:1; white solid; yield: 86%; 1H NMR
(CDCl3, 500 MHz) δ: 8.69 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.89 –
7.76 (m, 1H), 7.71 (dq, J = 8.5, 1.0 Hz, 1H), 7.61 – 7.45 (m, 2H),
7.31 – 7.20 (m, 1H), 7.13 – 7.04 (m, 1H), 7.01 – 6.90 (m, 1H),
4.59 (s, 2H), 3.62 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ: 168.8, 158.9 (d, JC-F = 252.0
Hz), 157.0, 150.0, 137.8, 133.0, 130.4 (d, JC-F = 8.1 Hz), 126.9, 126.2 (d, (d, JC-F =
11.7 Hz), 124.4 (d, JC-F = 3.7 Hz), 122.2, 116.3 (d, JC-F = 20.0 Hz), 52.5 (d, JC-F = 2.8
Hz), 52.1.
19
F NMR (CDCl3, 282 MHz) δ: -119.6. ESI+ calcd. for C14H14N2O4SF
(M+H)+: 325.0658; Found: 325.0654.
Methyl N-(3-methoxyphenyl)-N-[(2-pyridyl)sulfonyl]glycinate (33). Chromatography eluent: n-hexane-EtOAc 2:1; colourless oil; yield: 98%;
1
H NMR (CDCl3, 300 MHz) δ: 8.79 – 8.61 (m, 1H), 7.86 – 7.69
(m, 2H), 7.47 (ddd, J = 7.2, 4.7, 1.3 Hz, 1H), 7.12 (t, J = 8.1 Hz,
1H), 6.85 – 6.80 (m, 1H), 6.79 – 6.72 (m, 2H), 4.67 (s, 2H), 3.68
302
Chapter 6
(s, 3H), 3.66 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 169.1, 159.8, 157.2, 149.8, 140.4,
13
137.7, 129.6, 126.8, 122.8, 120.4, 114.5, 114.0, 55.1, 54.0, 52.1. ESI+ calcd. for
C15H17N2O5S (M+H)+: 337.0852; Found: 337.0859.
Methyl N-(3-bromophenyl)- N-[(2-pyridyl)sulfonyl]glycinate (34). Chromatography
eluent: n-hexane-EtOAc 2:1; colourless oil; yield: 94%; 1H NMR
(CDCl3, 300 MHz) δ: 8.88 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.04 –
7.96 (m, 1H), 7.95 – 7.89 (m, 1H), 7.65 (ddd, J = 7.4, 4.7, 1.4
Hz, 1H), 7.57 (t, J = 2.0 Hz, 1H), 7.53 (ddd, J = 7.8, 1.9, 1.1 Hz,
1H), 7.43 – 7.36 (m, 1H), 7.33 – 7.24 (m, 1H), 4.81 (s, 2H), 3.84 (s, 3H).
13
C NMR
(CDCl3, 75 MHz) δ: 169.1, 157.3, 150.2, 140.9, 138.1, 132.0, 131.6, 130.5, 127.8,
127.1, 123.0, 122.4, 54.0, 52.5. ESI+ calcd. for C14H14N2O4SBr (M+H)+: 386.9837;
Found: 386.9828.
Methyl N-2-naphthyl-N-[(2-pyridyl)sulfonyl]glycinate (35). Chromatography eluent
SO 2Py
N
CO2 Me
n-hexane-EtOAc 2:1; pale pink solid; yield: 91%; mp = 9091 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.78 (d, J = 4.4 Hz, 1H),
7.84 – 7.65 (m, 6H), 7.52 – 7.42 (m, 3H), 7.35 (dd, J = 8.8, 1.8
Hz, 1H), 4.82 (s, 2H), 3.69 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 169.2, 157.4,
13
150.0, 137.7, 136.7, 133.2, 132.6, 129.1, 128.1, 127.9, 127.5, 126.8, 126.7, 126.4,
126.3, 122.9, 54.2, 52.2. ESI+ calcd. for C18H17N2O4S (M+H)+: 357.0903; Found:
357.0916.
Methyl N-(4-chlorophenyl)-N-[(2-pyridyl)sulfonyl]glycinate (36). Chromatography
PyO2 S
N
CO2 Me
eluent: n-hexane-EtOAc 2:1; pale yellow solid; yield: 93%; mp =
86-88 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.74 (d, J = 4.7 Hz, 1H),
7.92 – 7.69 (m, 2H), 7.50 (ddd, J = 7.3, 4.7, 1.3 Hz, 1H), 7.23 (s,
Cl
J = 8.1 Hz, 4H), 4.67 (s, 2H), 3.69 (s, 3H). 13C NMR (CDCl3, 75
MHz) δ: 169.0, 157.3, 150.0, 138.0, 137.9, 134.3, 130.3 (2C), 129.4 (2C), 126.9,
123.0, 53.9, 52.4. ESI+ calcd. for C14H14N2O4SCl (M+H)+: 341.0357; Found: 341.0351.
303
Experimental section
Methyl 4-[N-(methoxycarbonyl)methyl-N-(2-pyridyl)sulfonyl]aminobenzoate (37).
PyO2 S
N
CO2 Me
Chromatography eluent: n-hexane-EtOAc 2:1; yellow solid; yield:
89%; mp = 76-78 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.72 (d, J =
4.4 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.82 (ddd, J = 20.8, 10.5,
4.4 Hz, 2H), 7.53 – 7.46 (m, 1H), 7.35 (d, J = 8.5 Hz, 2H), 4.73
CO2 Me
(s, 2H), 3.87 (s, 4H), 3.69 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 168.9, 166.1, 157.1,
150.0, 143.7, 137.9, 130.5 (2C), 129.4, 127.8 (2C), 127.0, 122.8, 53.5, 52.4, 52.2.
ESI+ calcd. for C16H17N2O6S (M+H)+: 365.0801; Found: 365.0816.
N-(Cyanomethyl)-N-phenylpyridine-2-sulfonamide (7). Following the general
procedure but using bromoacetonitrile, compound 7 was obtained
as a pale brown solid. Chromatography eluents: n-hexane-EtOAc
2:1; yield: 87%. 1H NMR (CDCl3, 300 MHz) δ: 8.81 (ddd, J = 4.6,
1.6, 0.9 Hz, 1H), 8.01 – 7.83 (m, 1H), 7.79 (dd, J = 7.8, 1.2 Hz, 1H),
7.56 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.34 (dd, J = 4.9, 2.0 Hz, 3H), 7.24 – 7.14 (m,
2H), 4.89 (s, 3H).
Ethyl N-phenyl-N-tosylglycinate (11). Following the general procedure but using
the commercially available tosyl chloride and ethyl bromoacetate,
compound 11 was obtained as a pale yellow solid. Chromatography
eluents: n-hexane-EtOAc 9:1; yield: 82%. 1H NMR (CDCl3, 300 MHz)
δ: 7.59 (d, J = 8.3 Hz, 2H), 7.40 – 7.13 (m, 7H), 4.43 (s, 2H), 4.19 (q,
J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). ESI+ calcd. for C17H20NO4S
(M+H)+: 334.1107; Found: 334.1121.
6.2.4. General
procedure
for
N-sulfonylation
of
N-methyl-N-(2-
pyridyl)sulfonyl arylalkylamines
The N-methyl-substituted substrates were prepared by reaction of the
corresponding commercially available N-alkylamine derivative with 2-pyridylsulfonyl
chloride (see Scheme below). Identical procedure was followed for the preparation of
the the N-benzyl aniline derivative 52. The N-tosyl derivatives 59 and 69, used in
304
Chapter 6
control experiments, were prepared following the same procedure as above using
commercially available p-toluenesulfonyl chloride.
To
a
solution
of
the
corresponding
commercially
available
N-methyl
arylalkylamine (5.0 mmol) and pyridine (720 µL, 7.5 mmol, 1.5 equiv) in THF (50 mL),
cooled to 0 ºC and under nitrogen atmosphere, was slowly added 2-pyridylsulfonyl
chloride (1.3 g, 7.5 mmol, 1.5 equiv). The resulting solution was allowed to reach
room temperature and stirred at room temperature overnight. The mixture was
quenched with sat aq. NH4Cl solution (10 mL) and extracted with EtOAc (3 x 20 mL).
The combined organic phase was dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography (SiO2, chromatography
eluent n-hexane-EtOAc 3:1), affording the corresponding N-2-pyridylsulfonyl
arylalkylamine.
N-Benzyl-N-phenylpyridine-2-sulfonamide (52). White solid; yield: 73%; mp = 7981 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.85 (d, J = 4.3 Hz, 1H),
7.82 (dt, J = 1.1, 7.7 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.53 (m,
1H), 7.35-7.15 (m, 9H), 7.07 (m, 1H), 5.14 (s, 2H).
13
C NMR
(CDCl3, 75 MHz) δ: 157.6, 150.1, 138.8, 137.8, 136.4, 129.2
(2C), 129.0 (2C), 128.6 (2C), 128.4 (2C), 128.0, 127.7, 126.8, 123.2, 57.0. ESI+
calcd. for C18H17N2O2S (M+H)+: 325.1011; Found: 325.1017.
N-Benzyl-N-methylpyridine-2-sulfonamide (58). White solid; yield: 89%; mp = 8890 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.74 (d, J= 4.5 Hz, 1H), 7.99 (d,
J= 7.8 Hz, 1H), 7.92 (dt, J= 1.6, 7.6 Hz, 1H), 7.51 (m, 1H), 7.49-7.26
(m, 5H), 4.45 (s, 2H), 2.80 (s, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
157.4, 150.1, 137.9, 136.0, 128.6 (2C), 128.3 (2C), 127.8, 126.5,
305
Experimental section
122.8, 55.0, 35.1. ESI+ calcd. for C13H15N2O2S (M+H)+: 263.0854; Found: 263.0850.
N-Benzyl-N-methyl-4-methylbenzenesulfonamide (59).219 Following the typical
procedure but using tosyl chloride (1.5 equiv) compound 59 was
obtained as a white solid; yield: 81%; mp = 86-88 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 7.67 (d, J = 8.2 Hz, 2H), 7.31-7.25 (m, 7H),
4.07 (s, 2H), 2.53 (s, 3H), 2.40 (s, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
143.5, 135.8, 134.7, 129.8 (2C), 128.7 (2C), 128.4 (2C), 127.9,
127.6 (2C), 54.2, 34.4, 21.6.
N-Methyl-N-(2-phenethyl)pyridine-2-sulfonamide (68). White solid; yield: 85%;
mp = 99-101 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.71 (d, J = 4.6 Hz,
1H), 7.96 (d, J = 7.6 Hz, 1H), 7.91 (dt, J = 1.5, 7.4 Hz, 1H), 7.49 (m,
1H), 7.34-7.22 (m, 5H), 3.53 (m, 2H), 2.98 (s, 3H), 2.93 (m, 2H).
13
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.0, 138.4, 137.9, 128.9
(2C), 128.6 (2C), 126.5 (2C), 122.6, 52.7, 36.1, 35.2. ESI+ calcd. for
C14H17N2O2S (M+H)+: 277.1011; Found: 277.1016.
N-Methyl-N-(2-phenethyl)-4-methylbenzenesulfonamide (69).220 Following the
typical procedure but using tosyl chloride (1.5 equiv) compound
69 was obtained as a pink solid; yield: 88%; mp = 77-79 ºC. 1H
NMR (CDCl3, 300 MHz) δ: 7.67 (d, J= 8.4 Hz, 2H), 7.33-7.20 (m,
7H), 3.28 (m, 2H), 2.87 (m, 2H), 2.77 (s, 3H), 2.44 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 144.3, 138.4, 134.9, 129.7 (2C),
128.8 (2C), 128.6 (2C), 127.4 (2C), 126.6, 51.8, 35.2 34.9, 21.5. ESI+ calcd. for
C16H20NO2S (M+H)+: 290.1215; Found: 290.1217.
219
a) D. A. Powell, G. Pelletier, Tetrahedron Lett. 2008, 49, 2495; b) D. A. Powell, H. Fan, J. Org.
Chem. 2010, 75, 2726.
220
H. Aikawa, S. Tago, K. Umetsu, N. Haginiwa, N. Asao, Tetrahedron 2009, 65, 1774.
306
Chapter 6
N-Methyl-N-[2-(4-methylphenyl)ethyl]pyridine-2-sulfonamide (97). White solid;
O O
Me
S
N
N
yield: 86%; mp = 84-86 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (d, J
= 4.4 Hz, 1H), 7.92 (d, J = 6.7 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H), 7.45
(m, 1H), 7.22 (m, 4H), 3.42 (m, 2H), 2.95 (s, 3H), 2.91 (m, 2H), 2.34
(s, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.4, 150.0, 137.8, 136.5,
13
135.2, 129.2 (2C), 128.7 (2C), 126.4, 122.6, 52.7, 36.0, 34.7, 21.0.
ESI+ calcd. for C15H19N2O2S (M+H)+: 291.1167; Found: 291.1162.
Me
N-Methyl-N-[2-(4-clorophenyl)ethyl]pyridine-2-sulfonamide
O O
S
Me
N
N
(98).
White
solid;
yield: 81%; mp = 97-99 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.66 (d,
J = 4.5 Hz, 1H), 7.92-7.85 (m, 2H), 7.45 (m, 1H), 7.23 (d, J = 8.4 Hz,
2H), 7.12 (d, J = 8.4 Hz, 2H), 3.49 (t, J = 7.2 Hz, 2H), 2.92 (s, 3H),
2.88 (t, J = 7.2 Hz, 2H).
13
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.0,
137.9, 136.8, 132.3, 130.2 (2C), 128.7 (2C), 126.5, 122.6, 52.5,
36.0, 34.5. ESI+ calcd. for C14H16ClN2O2S (M+H)+: 311.0621; Found:
Cl
311.0626.
N-Methyl-N-[2-(3-methylphenyl)ethyl]pyridine-2-sulfonamide (99). White solid;
yield: 79%; mp = 73-75 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.69 (m,
1H), 7.96-7.87 (m, 2H), 7.48 (m, 1H), 7.15 (m, 1H), 7.05- 7.00 (m,
3H), 3.50 (m, 2H), 2.97 (s, 3H), 2.88 (m, 2H), 2.34 (s, 3H).
13
C NMR
(CDCl3, 75 MHz) δ: 157.4, 149.9, 137.8, 136.0, 135.2, 129.2 (2C),
128.7 (2C), 126.4, 122.6, 52.7, 36.0, 35.1, 21.4. ESI+ calcd. for
C15H19N2O2S (M+H)+: 291.1167; Found: 291.1162.
N-Methyl-N-[2-(3-clorophenyl)ethyl]pyridine-2-sulfonamide (100). White solid;
O O
Me
S
N
N
yield: 84%; mp = 90-92 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (d,
J = 4.2 Hz, 1H), 7.93-7.80 (m, 2H), 7.46 (m, 1H), 7.20-7.15 (m, 3H),
7.09 (d, J= 5.5 Hz, 1H), 3.50 (s, 3H), 2.93 (s, 3H), 2.88 (m, 2H).
13
Cl
C NMR (CDCl3, 75 MHz) δ: 157.2, 150.0, 140.4, 137.9, 134.2,
129.8, 127.1, 126.7, 126.5, 122.6, 52.4, 36.1, 34.9. ESI+ calcd. for
C14H16ClN2O2S (M+H)+: 311,0621; Found: 311.0626.
307
Experimental section
N-Methyl-N-[2-(2-methoxyphenyl)ethyl)pyridine-2-sulfonamide (101). White solid;
yield: 83%; mp = 75-77 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.66 (d,
J = 3.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.86 (t, J = 7.4 Hz, 1H),
7.44 (m, 1H), 7.23-7.12 (m, 2H), 6.88-6.80 (m, 2H), 3.80 (s, 3H),
3.45 (m, 2H), 2.97 (s, 3H), 2.88 (m, 2H).
13
C NMR (CDCl3, 75 MHz)
δ: 157.5 (2C), 150.0, 137.8, 130.6, 127.9, 126.7, 126.3, 122.6,
120.6, 110.3, 55.3, 50.9, 25.9, 29.9. ESI+ calcd. for C15H19N2O3S (M+H)+: 307.1116;
Found: 307.1119.
N-Methyl-N-[2-(2-methylphenyl)ethyl)pyridine-2-sulfonamide (102). White solid;
yield: 76%; mp = 80-82 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (d,
J = 3.6 Hz, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H),
7.45 (m, 1H), 7.22 (s, 4H), 3.42 (2H, m), 2.99 (s, 3H), 2.91 (m, 2H),
2.34 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.4, 150.0, 137.8,
13
136.5, 136.3, 130.4, 129.5, 126.7, 126.4, 126.2, 122.6, 51.6, 36.1,
+
32.7, 19.3. ESI calcd. for C15H19N2O2S (M+H)+: 291.1167; Found: 291.1164.
N-Methyl-N-[2-(2-clorophenyl)ethyl]pyridine-2-sulfonamide (103). White solid;
yield: 85%; mp = 102-104 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.66 (m,
1H), 7.92 (d, J = 7.5 Hz, 1H), 7.87 (t, J = 6.5 Hz, 1H), 7.45 (t, J = 5.3
Hz, 1H), 7.33-7.16 (m, 4H), 3.50 (m, 2H), 3.04 (m, 2H), 2.97(s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.0, 137.9, 136.0, 134.0,
131.3, 129.5, 128.2, 127.1, 126.4, 122.6, 50.7, 36.1, 33.0. ESI+
calcd. for C14H16ClN2O2S (M+H)+: 311.0621; Found: 311.0622.
N-Methyl-N-(2-(naphthalen-2-yl)ethyl)pyridine-2-sulfonamide (104). Pale brown
solid; yield: 76%; mp = 90-92 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.63
(d, J = 4.6 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.83-7.74 (m, 4H), 7.62
(s, 1H), 7.47-7.38 (m, 3H), 7.32 (d, J = 8.4 Hz , 1H), 3.60 (m, 2H),
3.06 (m, 2H), 2.97 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 157.4,
149.9, 137.8, 135.9, 133.6, 132.3, 128.2, 127.6, 127.5, 127.3 (2C),
126.4, 126.1, 125.5, 122.6, 53.0, 36.1, 35.4. ESI+ calcd. for
308
Chapter 6
C18H19N2O2S (M+H)+: 327.1167; Found: 327.1169.
N-Methyl-N-(3-phenylpropyl)pyridine-2-sulfonamide (71). Colourless oil; yield:
79%. 1H NMR (CDCl3, 300 MHz) δ: 8.69 (d, J = 4.4 Hz, 1H), 7.94 (d,
J = 7.5 Hz, 1H), 7.88 (dt, J = 1.5, 7.3 Hz, 1H), 7.47 (m, 1H), 7.307.25 (m, 2H), 7.20-7.15 (m, 3H), 3.31 (m, 2H), 2.93(s, 3H), 2.67 (m,
2H), 1.89 (m, 2H).
C NMR (CDCl3, 75 MHz) δ: 157.2, 150.0, 141.4,
13
137.9, 128.4 (2C), 128.3 (2C), 126.4, 126.0, 122.7, 50.6, 35.5, 32.8,
+
29.6. ESI calcd. for C15H19N2O2S (M+H)+: 291.1167; Found: 291.1169.
N-Methyl-N-(4-phenylbutyl)pyridine-2-sulfonamide (73). Colourless oil; yield: 77%.
1
H NMR (CDCl3, 300 MHz) δ: 8.71 (d, J = 4.5 Hz, 1H), 7.97 (d, J =
7.7 Hz, 1H), 7.91 (t, J = 7.4 Hz, 1H), 7.50 (m, 1H), 7.33-7.29 ( m,
2H), 7.23-7.19 (m, 3H), 3.31 (m, 2H), 2.93 (s, 3H), 2.67 (m, 2H),
1.72-1.60 (m, 4H).
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.0,
13
142.1, 137.8, 128.4 (2C), 128.3 (2C), 126.4, 125.8, 122.7, 50.7,
35.6, 35.1, 28.1, 27.3. ESI+ calcd. for C16H21N2O2S (M+H)+:
305.1324; Found: 305.1328.
6.2.5. General procedure for the C−
−H alkenylation reaction
A screw-capped test tube was charged with the corresponding aniline derivative
(0.15 mmol),
Pd(OAc)2
(3.32 mg,
0.015 mmol,
10 mol%)
and
1-fluoro-2,4,6-
trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv). The mixture was placed
under nitrogen atmosphere before DCE (1.5 mL) and butyl acrylate (43 µL, 0.3 mmol,
2.0 equiv) were successively added. The mixture was heated to 110 ºC for 18 h, and
then it was allowed to reach room temperature, diluted with CH2Cl2 (10 mL) and
filtered through a pad of Celite. The filtrate was concentrated under reduced pressure
and the residue was purified by flash chromatography. Eluents would be specified in
each case.
309
Experimental section
Methyl
M eO2 C
(E)-3-{2-[N-(methoxycarbonyl)methyl-N-(2-pyridyl)sulfonyl-amino]N
phenyl}acrylate (8). Methyl acrylate (64 µL, 0.75 mmol,
SO2 Py
5.0 equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate
CO2 Me
(87 mg,
0.3vmmol,
2.0 equiv)
were
used.
Chromatography eluent: n-hexane-EtOAc 2:1. Pale
yellow solid; yield: 91%; mp = 152-153 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.79 (d, J =
4.6 Hz, 1H), 7.98 (d, J = 16.1 Hz, 1H), 7.84 (td, J = 7.7, 1.4 Hz, 1H), 7.73 (d, J = 7.8
Hz, 1H), 7.67 – 7.58 (m, 1H), 7.52 (dd, J = 7.0, 5.2 Hz, 1H), 7.38 – 7.24 (m, 3H), 6.34
(d, J = 16.1 Hz, 1H), 4.68 (d, J = 14.1 Hz, 2H), 3.80 (s, 3H), 3.70 (s, 3H). 13C NMR
(CDCl3, 75 MHz) δ: 168.8, 166.6, 156.9, 150.2, 140.0, 138.3, 137.8, 134.6, 130.8,
130.6, 129.1, 127.1, 126.9, 122.8, 119.9, 54.3, 52.2, 51.6. ESI+ calcd. for
C18H19N2O6S (M+H)+: 391.0958; Found: 391.0947.
Methyl
N-{[2-(E)-(phenylsulfonyl)vinyl]phenyl}-N-[(2-pyridyl)sulfonyl]glycinate
MeO2 C
N
(13). Phenyl vinyl sulfone (50 mg, 0.3 mmol, 2.0 equiv)
SO2 Py
SO2Ph
and
1-fluoro-2,4,6-trimethylpyridinium
triflate
(87 mg,
0.3 mmol, 2.0 equiv) were used. Chromatography eluent:
CH2Cl2-EtOAc 30:1; pale yellow solid; yield: 83%; mp =
204-206 ºC. H NMR (CDCl3, 300 MHz) δ: 8.82 (d, J = 4.6 Hz, 1H), 8.28 (d, J = 15.6
1
Hz, 1H), 8.04–7.96 (m, 2H), 7.84 (td, J = 7.8, 1.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H),
7.62 – 7.50 (m, 5H), 7.32 – 7.26 (m, 2H), 7.17 – 7.10 (m, 1H), 6.83 (d, J = 15.5 Hz,
1H), 4.68 (d, J = 34.6 Hz, 2H), 3.74 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 168.7,
13
156.9, 150.5, 140.6, 139.3, 139.1, 138.0, 133.6, 133.3, 131.5, 130.2, 129.4, 129.3,
129.2, 127.9, 127.7, 127.2, 123.0, 54.8, 52.5. ESI+ calcd. for C22H21N2O6S2 (M+H)+:
473.0835, Found: 473.0854.
(E)- and (Z)-Methyl N-{2-[(Z)-cyanovinyl]phenyl}-N-[(2-pyridyl)sulfonyl]-glycinate
(E-14
and
Z-14).
Acrylonitrile
(20 µL, 0.3 mmol, 2.0 equiv) and
1-fluoro-2,4,6-trimethylpyridinium
triflate (87 mg, 0.3 mmol, 2.0 equiv)
were used. Chromatographic purification (n-hexane-EtOAc 2:1) of the crude reaction
310
Chapter 6
mixture affords a 50:50 mixture of E-14 and Z-14 as a colourless oil; yield: 89%.
Small samples of pure E-14 and Z-14 could be isolated by partial but incomplete
chromatographic separation.
Data for E-14: 1H NMR (CDCl3, 300 MHz) δ: 8.74 (d, J = 4.0 Hz, 1H), 7.98 (d, J =
16.8 Hz, 1H), 7.80 (td, J = 7.7, 1.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.56 – 7.43 (m,
2H), 7.24 (ddd, J = 10.6, 9.8, 4.8 Hz, 2H), 7.03 (d, J = 7.3 Hz, 1H), 5.76 (d, J = 16.8
Hz, 1H), 4.63 (d, J = 64.2 Hz, 2H), 3.63 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 168.7,
156.7, 150.2, 146.9, 138.2, 138.0, 134.5, 131.6, 129.8, 129.3, 127.3, 126.3, 123.0,
117.9, 97.7, 54.5, 52.3. ESI+ calcd. for C17H16N3O4S (M+H)+: 358.0856; Found:
358.0866.
Data for Z-14: 1H NMR (CDCl3, 300 MHz) δ: 8.78 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 7.8
Hz, 1H), 8.04 (d, J = 12.2 Hz, 1H), 7.85 (td, J = 7.8, 1.7 Hz, 1H), 7.72 (d, J = 7.8 Hz,
1H), 7.54 (dd, J = 7.0, 4.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.32 – 7.20 (m, 1H), 6.93
(d, J = 7.9 Hz, 1H), 5.58 (d, J = 12.2 Hz, 1H), 4.70 (d, J = 112.0 Hz, 2H), 3.68 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 168.9, 156.8, 150.1, 145.9, 138.6, 138.0, 134.9, 131.2,
129.3, 128.8, 128.7, 127.2, 123.4, 117.1, 96.9, 54.7, 52.3. ESI+ calcd. for
C17H16N3O4S (M+H)+: 358.0856; Found: 358.0868.
Methyl
MeO2 C
N-{[2-(E)-(dimethoxyphosphoryl)vinyl]phenyl}-N-[(2-pyridyl)sulfonyl]N
SO2 Py
glycinate
OO
P
O
(15).
Dimethyl
vinylphosphonate
(36 µL,
0.3 mmol, 2.0 equiv) and 1-fluoro-2,4,6-trimethylpyridinium
triflate
(87 mg,
0.3 mmol,
2.0 equiv)
were
used.
Chromatography eluent: CH2Cl2-EtOAc 1:1. Pale yellow oil;
yield: 93%. H NMR (acetone-d6, 300 MHz) δ: 8.87 (dd, J = 4.7, 0.7 Hz, 1H), 8.27
1
(dd, J = 23.2, 17.9 Hz, 1H), 8.04 (td, J = 7.8, 1.7 Hz, 1H), 7.87 (dd, J = 7.8, 1.3 Hz,
1H), 7.78 – 7.73 (m, 1H), 7.71 (dd, J = 5.7, 4.8 Hz, 1H), 7.38 (dd, J = 11.2, 4.0 Hz,
1H), 7.29 (td, J = 7.7, 1.5 Hz, 1H), 7.03 (dd, J = 8.0, 1.1 Hz, 1H), 6.45 (dd, J = 18.6,
18.0 Hz, 1H), 4.78 (d, J = 117.9 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 2H), 3.68 (s, 3H).
13
C
NMR (acetone-d6, 75 MHz) δ 170.15, 157.44, 151.44, 146.28, 146.18, 139.65,
139.34, 136.81, 136.49, 131.63, 130.10, 130.08, 129.91, 128.55, 127.66, 123.74,
311
Experimental section
119.68, 115.94, 113.42, 55.40, 53.17, 53.10, 52.62. ESI+ calcd. for C18H22N2O7SP
(M+H)+: 441.0879; Found: 441.0877.
Methyl (E)-3-{5-chloro-2-[N-(methoxycarbonyl)methyl-N-(2-pyridyl)sulfonylamino]phenyl}acrylate (38). Methyl acrylate (67 µL, 0.75 mmol, 5.0 equiv) and 1MeO2C
fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
SO 2Py
N
CO2Me
2.0 equiv) were used. Chromatography eluent: n-hexaneEtOAc 2:1. Pale yellow solid; yield: 79%; mp = 111112 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.77 (d, J = 4.0
Cl
Hz, 1H), 7.86 (dd, J = 15.4, 6.3 Hz, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.55 –
7.48 (m, 1H), 7.30 – 7.23 (m, 2H), 6.31 (d, J = 16.1 Hz, 1H), 4.62 (d, J = 31.5 Hz,
2H), 3.79 (d, J = 0.8 Hz, 3H), 3.69 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ: 168.7, 166.2,
156.9, 150.3, 138.7, 137.9, 136.7, 136.4, 135.2, 132.4, 130.5, 127.0, 127.0, 122.8,
121.1, 54.16, 52.26, 51.74. ESI+ calcd. for C18H18N2O6SCl (M+H)+: 425.0568; Found:
425.0557.
Methyl
3-[(E)-2-(methoxycarbonyl)vinyl]-4-[N-(methoxycarbonyl)methyl-N-(2-
pyridyl)sulfonylamino]benzoate (39). Methyl acrylate (67 µL, 0.75 mmol, 5.0 equiv)
MeO 2C
N
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
SO 2Py
CO 2Me
0.3 mmol, 2.0 equiv) were used. Chromatography eluent:
n-hexane-EtOAc 3:1. Pale yellow solid; yield: 73%; mp =
CO2Me
136-139 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.76 (d, J =
4.2 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.99 – 7.87 (m, 2H), 7.82 (td, J = 7.7, 1.5 Hz,
1H), 7.71 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 6.8, 4.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H),
6.42 (d, J = 16.1 Hz, 1H), 4.65 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 3.66 (s, 3H). 13C
NMR (CDCl3, 75 MHz) δ: 168.6, 166.4, 165.5, 156.8, 150.3, 142.0, 139.1, 138.0,
135.0, 131.2, 131.0, 130.7, 128.5, 127.1, 122.8, 121.0, 54.0, 52.4, 52.3, 51.7. ESI+
calcd. for C20H21N2O8S (M+H)+: 449,1013; Found: 449.1024.
312
Chapter 6
Methyl
(E)-3-{4-methoxy-2-[N-(methoxycarbonyl)methyl-N-(2-pyridyl)sulfonyl-
amino]phenyl}acrylate (40). Methyl acrylate (67 µL, 0.75 mmol, 5.0 equiv) and 1MeO2C
N
fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
SO2 Py
CO 2Me
2.0 equiv) were used. Chromatography eluent: n-hexaneEtOAc 2:1. Pale yellow solid; yield: 67%; mp = 142-
MeO
143 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.75 (d, J = 4.4
Hz, 1H), 7.91 – 7.66 (m, 3H), 7.59 – 7.41 (m, 2H), 6.85 (dd, J = 6.6, 2.3 Hz, 2H), 6.17
(d, J = 16.0 Hz, 1H), 4.62 (d, J = 52.2 Hz, 2H), 3.73 (s, 3H), 3.68 (s, 3H), 3.67 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 168.8, 166.8, 161.2, 157.0, 150.2, 139.6, 139.4, 137.8,
128.0, 126.9, 126.7, 122.8, 117.4, 116.0, 115.7, 55.4, 54.3, 52.2, 51.4. ESI+ calcd. for
C19H21N2O7S (M+H)+: 421.1063; Found: 421.1052.
Methyl
(E)-3-{3-[N-(methoxycarbonyl)methyl-N-(2-pyridyl)sulfonylamino]-2-
naphthyl}acrylate (41). Methyl acrylate (67 µL, 0.75 mmol, 5.0 equiv) and 1-fluoro2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv)
MeO2 C
N
were used. Chromatography eluent: n-hexane-EtOAc 2:1;
SO2 Py
yellow solid; yield: 84%; mp = 158-159 ºC. 1H NMR (CDCl3,
300 MHz) δ: 8.79 (d, J = 3.9 Hz, 1H), 8.08 – 8.02 (m, 2H),
CO2 Me
7.80- 7.64 (m, 3H), 7.71 – 7.59 (m, 2H), 7.51 – 7.29 (m, 3H),
6.46 (d, J = 16.0 Hz, 1H), 4.74 (d, J = 53.1 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 3H).
13
C
NMR (CDCl3, 75 MHz) δ: 168.9, 166.8, 157.0, 150.4, 140.6, 137.9, 135.6, 133.8,
132.8, 132.1, 130.5, 128.2, 127.9, 127.7, 127.6, 127.5, 127.1, 123.0, 119.9, 54.6,
52.3, 51.7. ESI+ calcd. for C22H21N2O6S (M+H)+: 441.1114; Found: 441.1104.
Methyl
(E)-3-(4-bromo-2-[N-(methoxycarbonyl)methyl-N-(2-pyridyl)sulfonyl-
amino]phenyl}acrylate (42). Methyl acrylate (67 µL, 0.75 mmol, 5.0 equiv) and 1fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
2.0 equiv) were used. Chromatography eluent: nhexane-EtOAc 2:1. Pale yellow solid; yield: 67%. 1H
NMR (CDCl3, 300 MHz) δ: 8.99 – 8.64 (m, 1H), 7.98 –
7.81 (m, 2H), 7.81 – 7.72 (m, 1H), 7.62 – 7.48 (m, 1H), 7.48 – 7.43 (m, 2H), 6.41 –
313
Experimental section
6.21 (m, 1H), 4.63 (s, 2H), 3.79 (s, 3H), 3.71 (s, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
168.8, 166.6, 157.0, 150.5, 139.5, 139.2, 138.1, 134.3, 134.1, 132.7, 128.4, 127.3,
124.0, 123.1, 120.6, 54.4, 52.5, 51.9.
Butyl
(2E)-3-{2-[{2-[(1E)-3-butoxy-3-oxoprop-1-en-1-yl]benzyl}(pyridin-2-
ylsulfonyl)amino]phenyl}acrylate (53). Butyl acrylate (43 µL, 0.3 mmol, 2.0 equiv)
and 1-fluoro-2,4,6-trimethylpyridinium
triflate (87 mg,
0.3 mmol, 2.0 equiv) were used. Chromatography eluent:
n-hexane-EtOAc 9:1. Yellow oil; yield: 65%. 1H NMR
(CDCl3, 300 MHz) δ: 8.87 (d, J = 4.6 Hz, 1H), 7.86 (dt,
J = 1.7, 7.3 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.56-7.13
(m, 8H), 6.85 (dd, J = .6, 7.4 Hz, 1H), 5.98 (d, J = 16.1
Hz, 1H), 5.92 (d, J = 15.6 Hz, 1H), 5.42 (m, 1H), 4.80 (m, 1H), 4.16-4.09 (m, 4H),
3.52 (s, 3H), 1.70-1.60 (m, 4H), 1.48-1.37 (m, 4H), 1.01-0.93 (m, 6H).
13
C NMR
(CDCl3, 75 MHz) δ: 166.4, 166.1, 157.8, 150.4 (2C), 140.5, 139.5, 137.9 (2C), 137.1,
136.5, 134.5, 132.2, 130.5, 130.2, 130.1, 129.0, 128.7, 127.1, 126.8, 126.4, 123.2,
120.2 (2C), 64.2 (2C), 54.1, 30.8 (2C), 19.2 (2C), 13.8 (2C). ESI+ calcd. for
C33H38NO6S (M+H+): 576.2420; Found: 576.2427.
Butyl
(E)-3-(2-{[N-methyl-N-(2-pyridyl)sulfonylamino]methyl}phenyl)acrylate
(60). Butyl acrylate (24 µL, 0.165 mmol, 1.1 equiv) and 1fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
2.0 equiv) were used. Chromatography eluent: n-hexaneEtOAc 9:1. Colourless oil; yield: 81%. 1H NMR (CDCl3, 300
MHz) δ: 8.75(d, J = 4.0 Hz, 1H), 8.08 (d, J = 15.7 Hz, 1H),
8.00 (d, J = 7.8 Hz, 1H), 7.93 (dt, J = 1.3, 7.4 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.577.50 (m, 2H), 7.40 (dt, J = 1.3, 7.3 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 15.7
Hz, 1H), 4.61(s, 2H), 4.21 (m, 2H), 2.79 (s, 3H), 1.69 (m, 2H), 1.43 (m, 2H), 0.96 (m,
3H).
C NMR (CDCl3, 75 MHz) δ: 166.9, 157.0, 150.1, 140.9, 138.0, 134.8, 133.8,
13
130.3, 129.6, 128.3, 126.9, 126.7, 122.9, 120.9, 64.6, 52.0, 35.3, 30.7, 19.2, 13.8.
ESI+ calcd. for C20H25N2O4S (M+H+): 389.1535; Found: 389.1538.
314
Chapter 6
N-Methyl-2-[2-(E)-(phenylsulfonyl)vinyl]-N-[(2-pyridyl)sulfonyl]benzylamine (63).
Phenyl vinyl sulfone (50 mg, 0.3 mmol, 2.0 equiv) and 1fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
2.0 equiv) were used. Chromatography eluent: CH2Cl2EtOAc 20:1. Yellow oil; yield: 73%. 1H NMR (CDCl3, 300
MHz) δ: 8.76 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 15.2 Hz, 1H), 7.97 (ddd, J = 10.5, 9.2,
4.3 Hz, 4H), 7.71–7.22 (m, 6H), 6.80 (d, J = 15.2 Hz, 1H), 4.61 (s, 2H), 2.73 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 156.7, 150.1, 140.4, 139.1, 138.0, 135.3, 133.4, 131.8,
131.0, 130.1, 129.9, 129.3, 128.5, 127.8, 127.5, 126.7, 122.9, 52.3, 35.2. ESI+ calcd.
for C21H20N2O4S (M+H+): 428.0864; Found: 428.0868.
Phenyl
(E)-2-(2-{[N-methyl-N-(2-pyridyl)sulfonylamino]methyl}phenyl)ethenesulfonate (64). Phenyl vinyl sulfonate (52 mg, 0.3 mmol,
2.0 equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate
(87 mg,
0.3 mmol,
Chromatography eluent:
2.0 equiv)
were
used.
n-hexane-EtOAc 3:1. Pale
yellow oil; yield: 71%. H NMR (CDCl3, 300 MHz) δ: 8.67 (ddd, J = 4.7, 1.5, 1.0 Hz,
1
1H), 7.94–7.80 (m, 3H), 7.56–7.39 (m, 4H), 7.39–7.24 (m, 3H), 7.24 – 7.10 (m, 3H),
6.72 (d, J = 15.3 Hz, 1H), 4.44 (s, 2H), 2.66 (s, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
157.0, 150.1, 149.5, 142.8, 138.0, 135.8, 131.7, 130.9, 129.8, 129.7, 128.5, 127.3,
127.2, 126.7, 123.2, 122.8, 122.3, 51.8, 35.4. ESI+ calcd. for C21H20N2O5S2 (M+H+):
444.0814; Found: 444.0817.
Dimethyl
(E)-2-{2-[N-methyl-N-(2-pyridylsulfonyl)aminomethyl]phenyl}vinylphosphonate (65). Dimethyl vinylphosphonate (36 µL,
0.3 mmol,
2.0 equiv)
and
1-fluoro-2,4,6-trimethyl-
pyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv) were
used. Chromatography eluent: n-hexane-EtOAc 1:6. Pale
yellow oil; yield: 80%. 1H NMR (acetone-d6, 300 MHz) δ: 8.86–8.78 (m, 1H), 8.23–
8.11 (m, 2H), 8.11–8.03 (m, 1H), 7.81 (dt, J = 5.8, 2.8 Hz, 1H), 7.74 (ddd, J = 7.6,
4.7, 1.2 Hz, 1H), 6.43 (dd, J = 18.7, 17.4 Hz, 1H), 4.63 (s, 2H), 3.80 (s, 3H), 3.76 (s,
3H), 2.72 (s, 3H).
13
C NMR (acetone-d6, 75 MHz) δ 157.2, 151.1, 146.8, 146.7,
315
Experimental section
139.5, 135.7, 135.4, 135.3, 131.8, 131.8, 130.9, 129.6, 128.2, 127.8, 127.8, 123.9,
117.2, 114.7, 53.5, 53.0, 53.0, 35.2. ESI+ calcd. for C17H21N2O5PS (M+H+): 396.0909;
Found: 396.0912.
Butyl
(E)-3-(2-{2-[N-methyl-N-(2-pyridyl)sulfonylamino]ethyl}phenyl)acrylate
(74). Butyl acrylate (24 µL, 0.165 mmol, 1.1 equiv) and 1-fluoro2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv)
were used. Chromatography eluent: n-hexane-EtOAc 9:1. White
solid; yield: 87%; mp = 65-67 ºC. 1H NMR (CDCl3, 300 MHz) δ:
8.64 (cd, J = 0.9, 4.2 Hz, 1H), 7.98-7.89 (m, 2H), 7.86 (dt, J =
1.6, 7.8 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.44 (m, 1H), 7.30-7.23 (m, 3H), 6.36 (d,
J = 15.9 Hz, 1H), 4.20 (m, 2H), 3.44 (m, 2H), 3.03 (m, 2H), 2.94 (s, 3H), 1.68 (m, 2H),
1.42 (m, 2H), 0.94 (m, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 166.9, 157.4, 150.0, 141.2,
137.9, 137.8, 133.3, 130.8, 130.3, 127.3, 126.7, 126.4, 122.7, 120.7, 64.5, 52.3, 36.2,
32.6, 30.8, 19.2, 13.7. ESI+ calcd. for C21H27N2O4S (M+H+): 403.1692; Found:
403.1698.
Butyl
(2E)-3-(2-{3-[N-methyl-N-(2-pyridyl)sulfonylamino]propyl}phenyl)acrylate
(76). Butyl acrylate (43 µL, 0.3 mmol, 2.0 equiv) and 1-fluoro2,4,6-trimethylpyridinium triflate (130 mg, 0.45 mmol, 3.0 equiv)
were
used.
Chromatography
eluent:
hexane-EtOAc
9:1.
Colourless oil; yield: 78%. H NMR (CDCl3, 300 MHz) δ: 8.68
1
(dd, J=0.9, 4.7 Hz, 1H), 7.97-7.85 (m, 3H), 7.55 (m, 1H), 7.46
(m, 1H), 7.35-7.19 (m, 3H), 6.36 (d, J=15.9 Hz, 1H), 4.21 (m, 2H), 3.33 (m, 2H), 2.93
(s, 3H), 2.81 (m, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.43 (m, 2H), 0.94 (m, 3H).
13
C
NMR (CDCl3, 75 MHz) δ: 167.0, 157.2, 149.9, 141.7, 141.0, 137.8, 133.0, 130.2,
130.1, 126.7 (2C), 126.4, 122.8, 119.8, 64.5, 50.6, 35.4, 30.8, 30.3, 29.5, 19.2, 13.7.
ESI+ calcd. for C22H29N2O4S (M+H+): 417.1848; Found: 417.1845.
316
Chapter 6
Methyl (E)-3-(2-(2-(N-methylpyridine-2-sulfonamido)ethyl)phenyl)acrylate (78).
Methyl acrylate (14 µL, 0.165 mmol, 1.1 equiv) and 1-fluoro2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol, 2 equiv) were
used. Chromatography eluent: hexane-EtOAc 9:1. White solid;
yield: 86%; mp = 77-79 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.65
(d, J = 4.4 Hz, 1H), 7.99-7.91 (m, 2H), 7.86 (dt, J = 1.5, 7.6 Hz,
1H), 7.53 (d, J = 7.5 Hz, 1H), 7.44 (m, 1H), 7.30-7.21 (m, 3H), 6.34 (d, J = 15.8 Hz,
1H), 3.79 (s, 3H), 3.43 (m, 2H), 3.04 (m, 2H), 2.93 (s, 3H). 13C NMR (CDCl3, 75 MHz)
δ: 166.2, 157.4, 150.0, 141.6, 137.9, 137.8, 132.2, 130.8, 130.3, 127.3, 126.7, 126.4,
122.7, 119.8, 52.3, 51.7, 36.3, 32.6. ESI+ calcd. for C18H21N2O4S (M+H+): 361.1222;
Found: 361.1226.
(E)-3-{2-[2-N-Methyl-N-(2-pyridylsulfonylamino)ethyl]phenyl}acrylonitrile
(79).
Acrylonitrile (11 µL, 0.165 mmol, 1.1 equiv) and 1-fluoro-2,4,6-trimethylpyridinium
triflate (87 mg, 0.3 mmol, 2.0 equiv) were used. Chromatography
eluent: n-hexane-EtOAc 8:1. White solid; yield: 72 %; mp = 93-95
ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.68 (d, J=4.3 Hz, 1H), 7.95 (d,
J=7.7 Hz, 1H), 7.90 (dt, J=1.7, 7.4 Hz, 1H), 7.73 (d, J=16.3 Hz, 1H),
7.49-7.46 (m, 2H), 7.37 (t, J=7.4 Hz, 1H), 7.29-7.26 (m, 2H), 5.82 (d, J= 16.3 Hz, 1H),
3.44 (m, 2H), 3.02 (m, 2H), 2.93 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.0,
13
147.7, 138.0, 137.6, 132.6, 131.2, 130.9, 127.6, 126.6, 126.0, 122.7, 118.1, 98.4,
52.2, 36.3, 32.6. ESI+ calcd. for C17H18N3O2S (M+H+): 328.1120; Found: 328.1127.
N-Methyl-2-{[(E)-2-(phenylsulfonyl)vinyl]phenyl}-N-[(2-pyridyl)sulfonyl]ethanamine (80). Phenyl vinyl sulfone (28 mg, 0.165 mmol, 1.1
equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography eluent: n-hexaneEtOAc 1:1. White solid; yield: 83%; mp = 137-139 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.73 (d, J=4.4 Hz, 1H), 8.04-8.00 (m, 4H),
7.94 (t, J=6.6 Hz, 1H), 7.65-7.47 (m, 5H), 7.41-7.24 (m, 3H), 6.84 (d, J=15.2 Hz, 1H),
3.48 (m, 2H), 3.11 (m, 2H), 3.02 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.1,
13
140.5, 139.3, 138.4, 138.0, 133.4, 131.2 (2C), 131.1, 129.4 (2C), 129.3, 127.8 (2C),
317
Experimental section
127.5, 127.2, 126.5, 122.8, 52.4, 36.2, 32.5. ESI+ calcd. for C22H23N2O4S2 (M+H+):
443.1099; Found: 443.1095.
Phenyl
(E)-2-{2-[2-(N-methyl-N-(2-pyridylsulfonyl)amino)ethyl]phenyl}vinylsulfonate (81). Phenyl vinyl sulfonate (30 mg, 0.165 mmol, 1.1
equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography eluent: n-hexaneEtOAc 1:1. White solid; yield: 81%; mp = 197-199 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.59 (m, 1H), 7.88-7.78 (m, 2 H), 7.68 (dd,
J = 2.0, 15.3 Hz, 1H), 7.42-7.13 (m, 10 H), 6.70 (dd, J=2.3, 15.3 Hz, 1H), 3.25 (m,
2H), 2.86 (m, 2H), 2.76 (d, J=2.2 Hz, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.1,
13
149.6, 143.3, 138.6, 137.9, 131.7, 131.2, 130.6, 129.9 (2C), 127.6, 127.3, 127.1,
126.5, 122.7, 122.5
(2C), 122.4, 52.1, 36.1, 32.4. ESI+ calcd. for C22H23N2O5S2
(M+H+): 459.1048. Found: 459.1042.
Dimethyl
(E)-2-{2-[2-(N-methyl-N-(2-pyridylsulfonyl)amino)ethyl]phenyl}vinylphosphonate (82). Vinyl phosphonate (18 µL, 0.165 mmol,
1.1 equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87
mg, 0.3 mmol, 2.0 equiv) were used. Chromatography
eluent: n-hexane-EtOAc 1:3. Orange oil; yield: 69%.
1
H
NMR (CDCl3, 300 MHz) δ: 8.70 (d, J=4.6 Hz, 1H), 7.99 (d,
J=7.6 Hz, 1H), 7.95-7.83 (m, 2H), 7.57 (d, J=7.0 Hz, 1H), 7.50 (m, 1H), 7.40-7.25 (m,
3H), 6.23 (t, J= 17.4 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.49 (m, 2H), 3.09 (m, 2H),
2.99 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 156.2, 149.0, 145.4, 145.3, 136.9, 136.4,
13
132.8 (d, JC−P=22.5 Hz), 129.7, 129.4, 126.3, 125.5 (d, JC−P=3.8 Hz), 121.7, 113.5 (d,
JC−P=171.5 Hz), 51.6, 51.5, 51.3, 35.2, 31.5. ESI+: calcd for C18H24N2O5PS (M+H+):
411,1144. Found: 411,1148.
318
Chapter 6
Dibutyl
(E,E)-3,3'-(2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}-1,3-
phenylene)bisacrylate (83). Butyl acrylate (61 µL, 0.45 mmol, 3.0 equiv) and 1fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography
eluent: n-hexane-EtOAc 9:1. Yellow solid; yield:
84%. 1H NMR (CDCl3, 300 MHz) δ: 8.59 (d, J = 4.6
Hz, 1H), 7.97 (d, J = 15.7 Hz, 2H), 7.92 (d, J = 7.8
Hz, 1H), 7.82 (dt, J = 1.5, 7.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.37 (m, 1H), 7.23 (m,
1H), 6.27 (d, J = 15.7 Hz, 2H), 4.14 (m, 4H), 3.31 (m, 2H), 3.07 (m, 2H), 2.97 (s, 3H),
1.62 (m, 4H), 1.35 (m, 4H), 0.88 (m, 6H).
C NMR (CDCl3, 75 MHz) δ: 166.6 (2C),
13
157.6, 150.0 (2C), 141.4 (2C), 137.9, 136.4, 135.0 (2C), 128.5 (2C), 127.5, 126.4,
122.7, 121.9 (2C), 64.6, 51.4, 36.2, 30.7 (2C), 28.1, 19.2 (2C), 13.7 (2C). ESI+: calcd.
for C28H37N2O6S (M+H+): 529.2372; Found: 529.2375.
Dimethyl
(E,E)-3,3'-(2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}-1,3phenylene)bisacrylate (84). Methyl acrylate (41
Me
SO2Py
N
µL, 0.45 mmol, 3.0 equiv) and 1-fluoro-2,4,6trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0
MeO2C
CO2Me
equiv) were used. Chromatography eluent: nhexane-EtOAc 9:1. Yellow solid; yield: 89%; mp =
92-94 ºC. H NMR (CDCl3, 300 MHz) δ: 8.67 (d, J=4.2 Hz, 1H), 8.06 (d, J=15.8 Hz,
1
2H), 7.99 (d, J=7.9 Hz, 1H), 7.88 (dt, J=1.6, 7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 2H), 7.44
(m, 1H), 7.28 (m, 1H), 6.36 (d, J= 15.8 Hz, 2H), 3.82 (s, 6H), 3.38 (m, 2H), 3.15 (m,
2H), 3.02 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 166.9 (2C), 157.6, 150.0, 141.8 (2C),
13
137.9, 136.5, 135.0 (2C), 128.6 (2C), 127.5, 126.4, 122.7, 121.5 (2C), 51.8 (2C),
51.4, 36.3, 28.2. ESI+ calcd. for C22H25N2O6S (M+H+): 445.1433. Found: 445.1438.
319
Experimental section
2-{2,6-Bis[(E)-2-(phenylsulfonyl)vinyl]phenyl}-N-[methyl-N-(2-pyridyl)sulfonyl]ethanamine (85). Phenyl vinylsulfone (75 mg, 0.45
Me
SO2Py
N
mmol,
3.0
equiv)
and
1-fluoro-2,4,6-
trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0
PhO2S
SO2Ph
equiv) were used. Chromatography eluent: nhexane-EtOAc 1:1. White solid; yield: 79%; mp =
197-199 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.72 (d, J=4.5 Hz, 1H), 8.06-7.97 (m, 6H),
7.92 (dt, J=1.7, 7.8 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.92 (dt, J=1.0, 7.8 Hz, 1H), 7.637.45 (m, 8H), 7.24 (t, J= 7.8 Hz, 1H), 6.82 (d, J= 15.2 Hz, 2H), 3.36 (m, 2H), 3.18 (m,
2H), 3.05 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.3, 150.2, 140.2 (2C), 139.0 (2C),
13
138.1, 137.5, 133.6 (2C), 133.3 (2C), 131.4 (2C), 129.7 (2C), 129.5 (4C), 127.9 (4C),
127.8, 126.6, 122.9, 51.5, 36.2, 34.2.
Diphenyl
(E,E)-2,2'-(2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}-1,3Me
N
PhO3S
SO2Py
phenylene)divinylsulfonate
(86).
Phenyl
vinyl
sulfonate (83 mg, 0.45 mmol, 3.0 equiv) and 1-fluoroSO3Ph
2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
2.0 equiv) were used. Chromatography eluent: nhexane-EtOAc 1:1. White solid; yield: 85%; mp =
147-149 ºC. H NMR (CDCl3, 300 MHz) δ: 8.67 (cd, J=0.9, 4.7 Hz, 1H), 7.95 (td,
1
J=1.0, 7.8 Hz, 1H), 7.91-7.83 (m, 3H), 7.57 (dt, J=7.8 Hz, 2H), 7.46 (m, 1H), 7.427.36 (m, 5H), 7.31-7.26 (m, 6H), 6.85 (d, J= 15.2 Hz, 2H), 3.22 (m, 2H), 2.90 (m, 2H),
2.83 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 157.2, 150.0, 149.9 (2C), 143.0 (2C),
13
138.1, 137.7, 132.9 (2C), 130.1 (2C), 130.4 (4C), 128.1, 127.4 (2C), 126.6, 124.7
(2C), 122.7, 122.4 (4C), 51.3, 36.0, 28.0.
Methyl
(E,E)-3-(3-[(E)-2-(Phenylsulfonyl)vinyl]phenyl]-2-{2-[methyl(2-pyridylMe
N
SO2Py
sulfonyl)amino]ethyl}phenyl)acrylate (87). Phenyl
vinylsulfone (75 mg, 0.45 mmol, 3.0 equiv) and 1-
PhO2S
CO2Me
fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography
320
Chapter 6
eluent: n-hexane-EtOAc 1:1. White solid; yield: 80%; mp = 197-199 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.74 (d, J = 4.6 Hz, 1H), 8.11 (d, J = 6.9 Hz, 1H), 8.08-8.03 (m,
4H), 7.95 (dt, J = 1.4, 7.8 Hz, 1H), 7.64-7.48 (m, 5H), 7.30 (m, 1H), 6.86 (d, J = 15.1
Hz, 1H), 6.37 (d, J = 15.7 Hz, 1H), 3.84 (s, 3H), 3.43 (m, 2H), 3.20 (m, 2H), 3.08 (s,
3H).
C NMR (CDCl3, 75 MHz) δ: 166.8, 157.4, 150.1, 141.4, 139.5, 138.0, 137.0,
13
135.3, 133.5, 132.9, 131.0, 129.4 (2C), 129.3, 128.9, 127.9 (2C), 127.8, 127.6, 126.5,
122.8, 121.8, 51.9, 51.4, 36.2, 28.1. ESI+ calcd. for C26H27N2O6S2 (M+H+): 527.1311;
Found: 527.1318.
Methyl (E,E)-3-(3-[(E)-2-Cyanovinyl]-2-{2-[methyl(2-pyridylsulfonyl)amino]ethyl}phenyl)acrilatate (88). Acrylonitrile (30 µL, 0.45 mmol, 3 equiv) and 1-fluoro-2,4,6trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv)
were used. Chromatography eluent: n-hexane-EtOAc
4:1. White solid; yield: 36% (60% based in recovered
starting material); mp = 117-119 ºC. 1H NMR (CDCl3,
300 MHz) δ: 8.61 (d, J = 4.9 Hz, 1H), 7.96 (d, J = 15.8
Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.85 (dd, J = 1.5, 7.3 Hz, 1H), 7.53 (d, J = 7.8 Hz,
1H), 7.43-7.38 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 6.30 (d, J = 15.8 Hz, 1H), 5.76 (d, J =
16.3 Hz, 1H),3.75 (s, 3H), 3.33 (m, 2H), 3.10 (m, 2H), 2.93 (s, 3H).
13
C NMR (CDCl3,
75 MHz) δ: 166.8, 157.4, 150.0, 148.0, 141.3, 138.0, 136.2, 134.4, 129.3, 127.9,
127.8, 126.6, 122.7, 121.9, 117.7, 100.0, 51.9, 51.4, 36.3, 28.5. ESI+ calcd. for
C21H22N3O4S (M+H+): 412.1331. Found: 412.1338.
Butyl
(E)-3-(5-methyl-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
acrylate (105). Butyl acrylate (24 µL, 0.165 mmol, 1.1 equiv)
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
2.0 equiv) were used. Chromatography eluent: n-hexane-EtOAc
9:1. Colourless oil; yield: 75%. 1H NMR (CDCl3, 300 MHz)
δ: 8.66 (d, J=4.0 Hz, 1H), 7.95-7.84 (m, 3H), 7.45 (m, 1H), 7.37
(s, 1H), 7.16-7.12 (m, 2H), 6.36 (d, J=15.6 Hz, 1H), 4.20 (m,
2H), 3.41 (m, 2H), 3.01 (m, 2H), 2.95 (s, 3H), 2.32 (s, 3H), 1.68 (m, 2H), 1.42 (m, 2H),
0.96 (m, 3H).
C NMR (CDCl3, 75 MHz) δ: 167.0, 157.4, 150.0, 141.4, 137.8, 136.8,
13
321
Experimental section
134.8, 133.0, 131.2, 130.7, 127.2, 126.4, 122.7, 119.9, 64.5, 52.4, 36.2, 32.2, 30.8,
21.0, 19.2, 13.7. ESI+ calcd. for C22H29N2O4S (M+H+): 417.1848; Found: 417,1842.
Butyl
(E)-3-(5-chloro-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
acrylate (106). Butyl acrylate (24 µL, 0.165 mmol, 1.1 equiv)
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol,
2.0 equiv) were used. Chromatography eluent: n-hexane-EtOAc
9:1. Colourless oil; yield: 80%. 1H NMR (CDCl3, 300 MHz)
δ: 8.66 (d, J=3.8 Hz, 1H), 7.94-7.84 (m, 3H), 7.52 (d, J=1.9 Hz,
1H), 7.46 (dt, J=1.4, 4.5 Hz, 1H), 7.27 (m, 1H), 7.20 (d, J=8.9
Hz, 1H), 6.36 (d, J= 15.8 Hz, 1H), 4.20 (m, 2H), 3.43 (m, 2H), 3.02 (m, 2H), 2.93 (s,
3H), 1.68 (m, 2H), 1.42 (m, 2H), 0.95 (m, 3H).
C NMR (CDCl3, 75 MHz) δ: 166.5,
13
157.4, 150.0, 139.9, 137.9, 136.1, 135.0, 133.2, 132.2, 130.0, 1326.6, 126.5, 122.7,
121.6, 64.7, 52.1, 36.3, 32.1, 30.7, 19.2, 13.7. ESI+ calcd. for C21H26ClN2O4S (M+H+):
437.1302; Found: 437.1304.
Butyl
(E)-3-(4-methyl-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
Me
N
SO2Py
acrylate (107). Butyl acrylate (24 µL, 0.165 mmol, 1.1
equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
CO2Bu
0.3 mmol, 2.0 equiv) were used. Chromatography eluent: nhexane-EtOAc 9:1. Colourless oil; yield: 81%.
1
H NMR
(CDCl3, 300 MHz) δ: 8.66 (d, J=4.7 Hz, 1H), 7.99-7.85 (m,
Me
3H), 7.48-7.44 (m, 2H), 7.07-7.04 (m, 2H), 6.33 (d, J=15.9 Hz, 1H), 4.20 (m, 2H),
3.42 (m, 2H), 3.02 (m, 2H), 2.98 (s, 3H), 2.33 (s, 3H), 1.68 (m, 2H), 1.43 (m, 2H),
0.95 (m, 3H).
C NMR (CDCl3, 75 MHz) δ: 167.1, 157.4, 150.0, 141.1, 140.6, 137.9,
13
137.7, 131.5, 130.3, 128.2, 126.6, 126.4, 122.7, 119.2, 64.4, 52.4, 36.2, 32.6, 30.8,
21.3, 19.2, 13.7. ESI+ calcd. for C22H29N2O4S (M+H+): 417.1848; Found: 417.1846.
322
Chapter 6
Butyl
(E)-3-(4-chloro-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
acrylate (108). Butyl acrylate (24 µL, 0.165 mmol, 1.1 equiv)
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography eluent: nhexane-EtOAc 9:1. Colourless oil; yield: 84%.
1
H NMR
(CDCl3, 300 MHz) δ: 8.66 (d, J=4.6 Hz, 1H), 7.95-7.85 (m,
3H), 7.49-7.43 (m, 2H), 7.25-7.20 (m, 2H), 6.36 (d, J=15.8 Hz, 1H), 4.20 (m, 2H),
3.43 (m, 2H), 3.02 (m, 2H), 2.93 (s, 3H), 1.68 (m, 2H), 1.42 (m, 2H), 0.94 (m, 3H). 13C
NMR (CDCl3, 75 MHz) δ: 166.6, 157.3, 150.0, 140.0, 139.5, 137.9, 135.9, 131.8,
130.6, 128.0, 127.7, 126.3, 122.7, 120.8, 64.6, 52.0, 36.2, 32.5, 30.7, 19.2, 13.7. ESI+
calcd. for C21H26ClN2O4S (M+H+): 437.1302; Found: 437.1308.
Butyl
(E,E)-3-(3-{2-[methyl(2-pyridylsulfonyl)amino]ethyl}-2-naphthyl)acrylate
(109). Butyl acrylate (43 µL, 0.3 mmol, 2 equiv) and 1-fluoro2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv)
were used. Chromatography eluent: n-hexane-EtOAc 9:1.
Colourless oil; yield: 75%. 1H NMR (CDCl3, 300 MHz) δ: 8.65
(d, J = 3.9 Hz, 1H), 8.09-8.04 (m, 2H), 7.92 (d, J = 7.8 Hz,
1H), 7.86-7.74 (m, 3H), 7.70 (s, 1H), 7.50-7.39 (m, 2H), 6.50
(d, J = 15.5 Hz, 1H), 4.23 (m, 2H), 3.53 (m, 2H), 3.20 (m, 2H), 2.99 (s, 3H), 1.71 (m,
2H), 1.45 (m, 2H), 0.97 (m, 3H).
C NMR (CDCl3, 75 MHz) δ: 166.8 157.4, 150.0,
13
147.8, 137.8, 134.5, 134.1, 132.3, 131.9, 129.2, 128.1, 127.4, 127.2, 126.7, 126.4,
126.3, 122.6, 120.9, 64.6, 52.2, 36.3, 32.9, 30.8, 19.2, 13.8. ESI+ calcd. for
C25H28N2O4 (M+H+): 453.1848; Found: 453.1844.
Butyl (E)-3-(3-methoxy-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
acrylate (110). Butyl acrylate (43 µL, 0.3 mmol, 2.0 equiv)
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography eluent: nhexane-EtOAc 9:1. Colourless oil; yield: 86%. 1H NMR
(CDCl3, 300 MHz) δ:8.65 (d, J = 4.1 Hz, 1H), 8.00-7.92 (m,
2H), 7.86 (dt, J = 1.6, 7.5 Hz, 1H), 7.42 (m, 1H), 7.22-7.12 (m, 2H), 6.85 (d, J = 6.9
323
Experimental section
Hz, 1H), 6.33 (d, J = 15.8 Hz, 1H), 4.20 (m, 2H), 3.82 (s, 3H), 3.36 (m, 2H), 3.02 (m,
5H), 1.68 (m, 2H), 1.42 (m, 2H), 0.94 (m, 3H).
C NMR (CDCl3, 75 MHz) δ: 166.8,
13
157.9, 157.7, 149.9, 141.6, 137.8, 135.0, 127.7, 126.6, 126.3, 122.6, 121.0, 118.9,
111.5, 64.5, 55.7, 50.5, 35.9, 30.8, 24.8, 19.2, 13.7. ESI+ calcd. for C22H29N2O5S
(M+H+): 433.1797; Found: 433.1799.
Butyl
(E)-3-(3-methyl-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
acrylate (111). Butyl acrylate (43 µL, 0.3 mmol, 2.0 equiv)
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
mmol, 2.0 equiv) were used. Chromatography eluent: nhexane-EtOAc 9:1. Colourless oil; yield: 79%.
1
H NMR
(CDCl3, 300 MHz) δ: 8.64 (d, J=4.5 Hz, 1H), 7.99 (d, J=15.8
Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.87 (dt, J=1.5, 7.5 Hz, 1H), 7.44 (m, 1H), 7.39 (d,
J=7.3 Hz, 1H), 7.20-7.10 (m, 2H), 6.33 (d, J= 15.8 Hz, 1H), 4.19 (m, 2H), 3.34 (m,
2H), 3.08 (m, 2H), 3.03 (s, 3H), 2.40 (s, 3H), 1.68 (m, 2H), 1.40 (m, 2H), 0.95 (m, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 166.9, 157.5, 150.0, 142.1, 137.9, 137.7, 135.9, 133.8,
132.3, 127.0, 126.4, 124.7, 122.6, 120.0, 64.5, 50.8, 36.2, 30.8, 28.7, 19.9, 19.2,
13.7. ESI+ calcd. for C22H29N2O4S (M+H+): 417.1848; Found: 417.1844.
Butyl
(E)-3-(3-chloro-2-{2-[N-methyl-N-(2-pyridylsulfonyl)amino]ethyl}phenyl)
acrylate (112). Butyl acrylate (43 µL, 0.3 mmol, 2.0 equiv) and 1-fluoro-2,4,6trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv) were
used.
Chromatography
eluent:
n-hexane-EtOAc
9:1.
Colourless oil; yield: 77%. H NMR (CDCl3, 300 MHz) δ: 8.66
1
(d, J=4.5 Hz, 1H), 8.02-7.96 (m, 2H), 7.88 (dt, J=1.8, 7.6 Hz,
1H), 7.46-7.42 (m, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.18 (t, J=7.9 Hz, 1H), 6.34 (d, J=
15.7 Hz, 1H), 4.21 (m, 2H), 3.42 (m, 2H), 3.18 (m, 2H), 3.06 (s, 3H), 1.66 (m, 2H),
1.42 (m, 2H), 0.95 (m, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 166.4, 157.6, 150.0, 141.1,
137.9, 136.2, 135.5, 135.1, 130.8, 128.1, 126.4, 125.5, 122.7, 122.3, 64.7, 50.1, 36.1,
30.7, 29.1, 19.2, 13.8.
324
Chapter 6
6.2.6. General procedure for the Zn-promoted reductive N-desulfonylation:
A suspension of the corresponding olefinated adduct ( 0.1 mmol) and Zn powder (346
mg, 50 mmol) in a 1:1 mixture of THF and sat aq. NH4Cl solution (2 mL) was stirred
at room temperature until consumption of the starting material (TLC monitoring,
typically 24-72 h). The mixture was diluted with EtOAc (15 mL) and filtered over a pad
of Celite to remove the Zn. The filtrate was washed with brine (10 mL) and the
combined organic phase was dried (MgSO4) and concentrated to dryness. The
residue was purified by flash chromatography. Chromatography eluents will be
specified in each case.
Butyl (2-methylisoindol-1-yl)acetate (113). Chromatography eluent: n-hexaneEtOAc 9:1. White solid; yield: 73%; mp = 97-99 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 7.27-7.14 (m, 4H), 4.26 (d, J=12.9 Hz, 1H),
4.24-4.12 (m, 3H), 3.70 (d, J=12.9 Hz, 1H), 2.75-2.71 (m, 2H),
2.56 (s, 3H), 1.62 (m, 2H), 1.38 (m, 2H), 0.92 (m, 3H).
13
C NMR
(CDCl3, 75 MHz) δ: 172.1, 142.6, 139.3, 127.2, 126.9, 122.7 (2C), 67.1, 64.5, 60.5,
40.7, 39.7, 30.6, 19.1, 13.6. ESI+ calcd. for C15H22NO2 (M+H+): 248.1651; Found:
248.1656.
Butyl (2-methyl-1,2,3,4-tetrahydroisoquinol-1-yl)acetate (114). Chromatography
eluent: n-hexane-EtOAc 9:1. Yellow oil; yield: 78 %. 1H NMR
(CDCl3, 300 MHz) δ: 7.15-7.06 (m, 4H), 4.12 (m, 2H), 3.11 (m,
1H), 2.93 (m, 1H), 2.84-2.74 (m, 3H), 2.62-2.49 (m, 2H), 2.47 (s,
3H), 1.60 (m, 2H), 1.35 (m, 2H), 0.92 (m, 3H).
13
C NMR (CDCl3,
75 MHz) δ: 172.3, 137.8, 134.1, 129.0, 127.3, 126.3, 129.0, 64.4, 60.0, 46.3, 42.3,
41.0, 30.7, 25.1, 19.1, 13.7. ESI+ calcd. For C16H24NO2 (M+H+): 262.1807; Found:
262.1809.
325
Experimental section
6.2.7. Synthesis of indoles from N-(methoxycarbonyl)methyl-substituted
olefinated adducts: cyclization-deprotection-aromatization.
Typical
procedure:
methyl
3-[(methoxycarbonyl)methyl]-1H-indole-2-
carboxylate (45). (i) Cyclization: To a solution of compound 11 (153 mg, 0.39 mmol)
CO 2Me
CO 2Me
N
H
in THF (4 mL), cooled to 0 ºC under nitrogen atmosphere, was
slowly added a 1 M solution of LHMDS in THF (470 µL, 0.48
mmol, 1.2 equiv). The resulting solution was stirred at 0 ºC for 5
min before it was quenched with sat aq. solution of NH4Cl (5 mL).
The mixture was extracted with EtOAc (5 mL) and the organic phase was washed
with brine (5 ml), then dried (MgSO4) and concentrated to afford the corresponding N(2-pyridyl)sulfonyl indoline in high purity as a 1:1 mixture of diastereomers. (ii) Ndesulfonylation: The crude residue obtained in the previous step was dissolved in
MeOH (10 mL) and treated with magnesium turnings (189 mg, 7.8 mmol, 20 equiv).
The mixture was sonicated for 10 min (TLC monitoring) before it was quenched with
sat aq. NH4Cl solution (5 mL). The mixture was extracted with EtOAc (5 mL) and the
organic phase was washed with brine (5 mL), then dried (MgSO4) and concentrated
to afford the free NH-indoline in high purity as a 1:1 mixture of diastereomers. (iii)
Aromatization: To a solution of the crude mixture of NH-indoline in CH2Cl2 (2.5 mL)
was added at room temperature DDQ (109.3 mg, 0.48 mmol, 1.2 equiv). The mixture
was stirred at room temperature for 5 min before the reaction was quenched with sat
aq. NaHCO3 solution (5 mL). The mixture was extracted with EtOAc (5 mL) and the
organic phase washed with brine (5 mL), then dried (MgSO4) and concentrated. The
residue was purified by a short column chromatography (n-hexane-EtOAc 6:1) to
afford the indole derivative 80 as a pale yellow solid. Overall yield (3 steps): 60 mg
(62%); mp = 127-128 ºC. 1H NMR (CDCl3, 300 MHz) δ: 9.15 (s, 1H), 7.65 (d, J = 8.1
326
Chapter 6
Hz, 1H), 7.32 (q, J = 8.4 Hz, 2H), 7.20 – 7.12 (m, 1H), 4.20 (s, 2H), 3.89 (s, 3H), 3.72
(s, 3H). 13C NMR (CDCl3, 75 MHz) δ: 171.9, 162.4, 135.9, 127.8, 125.7, 124.2, 120.6,
120.5, 115.8, 112.1, 52.1, 51.8, 30.5. EI+ calcd. for C13H13NO4 (M)+: 247.0845; Found:
247.0844.
Methyl 3-(cyanomethyl)-1H-indole-2-carboxylate (46). Chromatography eluent: nhexane-EtOAc 4:1. Pale yellow solid; yield: 28%.
1
H NMR
(CDCl3, 300 MHz) δ: 8.90 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.33
(d, J = 7.1 Hz, 1H), 7.19 (s, 1H), 4.18 (s, 2H), 3.93 (s, 3H).
13
C
NMR (CDCl3, 75 MHz) δ: 161.8, 135.8, 126.8, 126.6, 124.0, 121.6, 120.3, 117.6,
112.3, 111.2, 52.4, 13.7. EI+ calcd. for C12H10N2O2 (M)+: 214.0742; Found: 214.0732.
Methyl 3-methyl-1H-indole-2-carboxylate (47). Chromatography eluent: n-hexaneEtOAc 9:1. Pale yellow solid; yield: 63%; mp = 133-135 ºC. 1H
CO2 Me
N
H
NMR (CDCl3, 300 MHz) δ: 8.68 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H),
7.47 – 7.28 (m, 2H), 7.15 (td, J = 7.2, 0.6 Hz, 1H), 3.96 (d, J = 0.7
Hz, 3H), 2.62 (d, J = 0.6 Hz, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 163.0, 135.9, 128.5,
125.6, 123.2, 120.8, 120.4, 119.9, 111.6, 51.65, 9.89. EI+: calcd for C11H11NO2 (M)+:
189.079. Found: 189.0796.
Methyl
5-chloro-3-[(methoxycarbonyl)methyl]-1H-indole-2-carboxylate
CO2 Me
Cl
CO 2Me
N
H
(48).
Chromatography eluent: n-hexane-EtOAc 4:1. Pale yellow
solid; yield: 62%; mp = 148-149 ºC. 1H NMR (CDCl3, 300
MHz) δ: 9.11 (s, 1H), 7.58 (s, 1H), 7.21 (s, 2H), 4.12 (s, 2H),
3.89 (s, 3H), 3.74 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ:
171.7, 161.9, 134.1, 128.7, 126.4, 126.2, 125.4, 119.7, 115.1, 113.2, 52.2, 52.0, 30.2.
EI+: calcd for C13H12NO4Cl (M)+: 281,0455. Found: 281,0441.
Dimethyl
3-[(methoxycarbonyl)methyl]-1H-indole-2,5-dicarboxylate
CO 2Me
MeO2C
CO2 Me
N
H
(49).
Chromatography eluent: n-hexane-EtOAc 3:1. Pale
yellow solid; yield: 58%; mp = 162-164 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 9.35 (s, 1H), 8.39 (s, 1H), 7.94
327
Experimental section
(dd, J = 8.7, 1.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 4.19 (s, 2H), 3.93 (s, 3H), 3.88 (s,
3H), 3.73 (s, 3H).
C NMR (CDCl3, 75 MHz) δ: 171.7, 167.6, 161.9, 138.1, 127.4,
13
126.5, 125.7, 123.7, 122.8, 117.1, 111.8, 52.2, 52.0 (2C), 30.2. EI+: calcd for
C15H15NO6 (M)+: 305,0899. Found: 305,0903.
Methyl
6-methoxy-3-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate
(50).
Chromatography eluent: n-hexane-EtOAc 4:1. Pale yellow
solid; yield: 26%. 1H NMR (CDCl3, 300 MHz) δ: 8.78 (s,
1H), 7.50 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 8.7 Hz, 1.9, 1H),
6.76 (s, 1H), 4.14 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.70 (s, 3H).
13
C NMR (CDCl3,
75 MHz) δ: 171.9, 162.4, 159.4, 137.0, 123.2, 122.4, 121.6, 116.5, 112.3, 93.8, 55.6,
52.2, 51.8, 30.7. EI+: calcd for C14H15NO5 (M)+: 277.0950; Found: 277.0962.
328
Chapter 6
6.3. C−
−H di ortho-olefination of carbazoles
6.3.1. General methods
All the reactions were carried out in anhydrous solvents and under a nitrogen
atmosphere with exclusion of moisture from reagents, solvents and glassware using
standard techniques. Melting points were taken in open-end capillary tubes. NMR
spectra were recorded at 25 ºC using a 300 MHz spectrometer [300 MHz (1H), 75
MHz (13C)], unless otherwise specified. Chemical shifts (δ) are represented in parts
per million, referenced to residual protons in the NMR solvent [CDCl3 (unless
otherwise specified): 1H NMR δ = 7.26 ppm (singlet);
13
C NMR δ = 77.16 ppm
(triplet)]. Data are reported as follows: chemical shift, multiplicity, coupling constant
(J, in Hz) and integration. All
13
C NMR spectra were obtained with complete proton
decoupling. MS spectra were recorded on a VG AutoSpec mass spectrometer.
Reactions were monitored by thin-layer chromatography carried out on 0.25 mm
silica gel plates (230-400 mesh). Flash column chromatography was performed using
230-400 mesh ultra-pure silica gel. All commercially available compounds were used
as provided without further purification.
6.3.2. Synthesis of the starting carbazoles and derivatives
6.3.2.1. N-Protection of commercially available carbazoles and derivatives
Typical procedure: synthesis of N-(2-pyridyl)sulfonyl-9H-carbazole (2). To a
suspension of NaH (1.2 equiv, 103 mg, 7.17 mmol) in THF (60 mL) at 0 ºC, the 9Hcarbazole (1.0 g, 5.98 mmol) was added portion wise. The mixture was stirred at 0 ºC
for 5 min before 2-pyridylsulfonyl chloride221(1.3 equiv, 2.68 g, 7.77
mmol) was added drop wise. The solution was allowed to reach
N
S
N
O
O
room temperature and it was stirred overnight. The mixture was
diluted with ethyl acetate and washed with a saturated aqueous
solution of ammonium chloride. The aqueous phase was then
221
García Rubia, A.; Urones, B.; Gómez Arrayás, R.; Carretero, J. C. Angew. Chem. Int. Ed. 2011,
50, 10927.
329
Experimental section
extracted three times with ethyl acetate. The combined organic phase was washed
with brine, dried over MgSO4 and concentrated under reduced pressure. The residue
was purified by column chromatography (n-hexane-EtOAc 6:1) affording 5 as a pale
yellow solid; yield: 1.7 g (92%); mp = 126-127 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.43
(d, J=4.7, 1H), 8.32 (d, J=8.3, 2H), 8.05 (d, J=7.9, 1H), 7.92 (d, J=7.6, 2H), 7.79 (td,
J=7.7, 1.6, 1H), 7.52 – 7.42 (m, 2H), 7.41 – 7.31 (m, 3H).
13
C NMR (CDCl3, 75 MHz)
δ: 155.6, 150.4, 138.8, 138.0, 127.6, 127.5, 126.3, 124.0, 122.2, 120.0, 115.3. EI+:
calcd for C17H12N2O2S (M)+: 308,0619. Found: 308,0615.
N-(2-p-Toluene)sulfonyl-9H-carbazole (5). Following the typical procedure but
using the commercially available p-toluenesulfonyl chloride (1.5
equiv), compound 4 was obtained after column chromatography (nN
S
O
hexane-EtOAc 20:1) as a pale grey solid; yield: 87%; mp = 134 ºC.
O
1
H NMR (CDCl3, 300 MHz) δ: 8.34 (d, J=8.3, 2H), 7.98 – 7.83 (m,
2H), 7.70 (d, J=8.0, 2H), 7.60 – 7.43 (m, 2H), 7.41 – 7.31 (m, 2H),
7.09 (d, J=8.0, 2H), 2.25 (s, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
145.0, 138.5, 135.2, 129.8, 127.5, 126.6, 126.5, 124.0, 120.1, 115.3, 21.6. FB+: calcd
for C19H15NO2S (M)+: 321,0824. Found: 321,0836.
N-(tert-Butyl)-9H-carbazole-9-carboxylate (7) was prepared according to literature
procedure.222 Colourless oil. 1H NMR (CDCl3, 300 MHz) δ: 8.31 (d,
J=8.3, 1H), 7.99 (d, J=7.4, 1H), 7.47 (ddd, J=8.5, 7.3, 1.5, 1H), 7.35
N
O
222
O
(td, J=7.4, 1.1, 1H), 1.77 (s, 5H).
V. Diep, J. J. Dannenberg, R. W. Franck, J. Org. Chem. 2003, 68, 7907.
330
Chapter 6
2,3,4,9-Tetrahydro-N-(2-pyridyl)sulfonyl-1H-carbazole (15). Following the typical
procedure, 2,3,4,9-tetrahydro-1H-carbazole was protected with 2pyridylsulfonyl chloride. After column chromatography (n-hexaneN
SO2 Py
EtOAc 8:1), the titled compound was obtained as a yellow solid;
yield: 92%; mp = 137-138 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.51 (d,
J=5.9, 1H), 8.12 (d, J=8.7, 1H), 7.99 (d, J=7.9, 1H), 7.76 (td, J=7.8, 1.7, 1H), 7.39 –
7.28 (m, 2H), 7.22 (ddd, J=6.4, 4.1, 1.8, 2H), 3.19 (s, 2H), 2.59 (s, 2H), 1.91 (d,
J=5.8, 4H), 1.83 (d, J=4.5, 2H).
C NMR (CDCl3, 75 MHz) δ: 156.0, 150.3, 1378.0,
13
136.6, 136.0, 130.4, 127.3, 123.7, 123.3, 121.8, 118.2, 117.9, 114.2, 24.4, 23.2, 22.1,
21.1. FB+: calcd for C17H16N2O2S (M)+: 312,0932. Found: 312,0928.
3-Bromo-N-(2-pyridyl)sulfonyl carbazole (17). Following the typical procedure, 3bromo-9H-carbazole223
was
protected
with
2-pyridylsulfonyl
chloride. After column chromatography (n-hexane-EtOAc 10:1),
the titled compound was obtained as a white solid; yield: 89%; mp
= 212–213 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.44 (d, J=4.7, 1H),
8.28 (d, J=8.3, 1H), 8.22 (d, J=8.8, 1H), 8.10 – 7.99 (m, 2H), 7.91 – 7.77 (m, 2H),
7.57 (dd, J=8.9, 2.1, 1H), 7.53 – 7.44 (m, 1H), 7.43 – 7.31 (m, 2H).
13
C NMR (CDCl3,
75 MHz) δ: 155.5, 150.5, 139.1, 138.1, 137.7, 130.2, 128.2, 128.1, 127.8, 125.1,
124.3, 122.9, 122.3, 120.2, 117.4, 117.0, 115.4. ESI+: calcd for C17H12N2O2SBr
(M+H)+: 386,9797. Found: 386,9801.
N-(2-Pyridyl)sulfonyl-1,2,3,4-tetrahydroquinoline
procedure,
(31).
1,2,3,4-tetrahydroquinoline
Following
was
the
protected
typical
with
2-
pyridylsulfonyl chloride. After column chromatography (n-hexaneEtOAc 8:1), the titled compound was obtained as a white solid; yield:
91%. H NMR (CDCl3, 300 MHz) δ: 8.66 (d, J = 3.0 Hz, 1H), 8.05 – 7.96 (m, 1H), 7.90
1
(td, J = 7.7, 1.7 Hz, 1H), 7.46 (ddd, J = 7.3, 4.9, 1.4 Hz, 1H), 7.21 – 6.96 (m, 4H),
4.56 (s, 2H), 3.66 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.9 Hz, 3H).
223
Midya, A.; Xie, Z.; Yang, J.-X.; Chen, Z.-K.; Blackwood, D. J.; Wang, J.; Adams, S.; Ping Loh, K.
Chem. Commun., 2010,46, 2091.
331
Experimental section
N-(2-Pyridyl)sulfonyl-10H-phenoxazine (33). Following the typical procedure,
phenoxazine was protected with 2-pyridylsulfonyl chloride. After
column chromatography (n-hexane-EtOAc 5:1), the titled compound
was obtained as a pale yellow solid; yield: 83%. 1H NMR (CDCl3,
300 MHz) δ: 8.50 (d, J = 3.9 Hz, 1H), 7.80 – 7.55 (m, 3H), 7.48 –
7.32 (m, 2H), 7.23 – 7.05 (m, 4H), 6.82 (dd, J = 7.2, 2.1 Hz, 2H).
N-(2-Pyridyl)sulfonyl indoline (35). Following the typical procedure, indoline was
protected with 2-pyridylsulfonyl chloride. After column chromatography
(n-hexane-EtOAc 8:1), the titled compound was obtained as a white
N
SO 2Py
solid; yield: 93%; mp = 126-127 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.61
(ddd, J=4.7, 1.6, 0.8, 1H), 7.97 (dt, J=7.9, 1.0, 1H), 7.83 (td, J=7.8,
1.7, 1H), 7.53 – 7.41 (m, 1H), 7.42 (ddd, J=7.6, 4.7, 1.2, 1H), 7.14 – 7.05 (m, 2H),
6.98 – 6.89 (m, 1H), 4.33 (t, J=8.5, 2H), 3.05 (t, J=8.5, 2H).
13
C NMR (CDCl3, 75
MHz) δ: 156.5, 150.3, 141.7, 137.8, 132.1, 127.6, 127.0, 125.2, 123.8, 123.2, 114.6,
51.5, 28.2. FB+: calcd for C13H12N2O2S (M)+: 260,0619. Found: 260,0621.
332
Chapter 6
6.3.2.2. Oxidative
cyclization
of
N-(2-pyridyl)sulfonyl
2-aminobiphenyl
derivatives
Typical procedure: synthesis of 3-methoxy-N-(2-pyridyl)sulfonyl-9H-carbazole
OMe
(18). To a solution of 2-amino-3'-methoxybiphenyl224 (370 mg,
1.86 mmol, 1.0 equiv), in pyridine (9 mL, 0.2 M), cooled at 0 ºC
under
N
SO2 Py
nitrogen
atmosphere,
was
added
chloride (495 mg, 2.78 mmol, 1.5 equiv).
2-pyridylsulfonyl
225
The resulting
mixture was stirred at room temperature for 12 h before it was poured into water. The
mixture was extracted with CH2Cl2 (3 times) and the combined organic phase was
dried over MgSO4 and concentrated in vacuo. The residue was crystallized in a
mixture
of
n-hexane-CH2Cl2
to
give
the
N-(2-pyridyl)sulfonyl-2-amino-3’-
methoxybiphenyl.
To a solution of N-(2-pyridyl)sulfonyl 2-amino-3'-methoxybiphenyl (400 mg, 1.17
mmol, 1.0 equiv) in 1,1,1,3,3,3-hexafluoropropan-2-ol (6 mL, 0.05 M) was added
PhI(OAc)2 (454 mg, 1.41 mmol, 1.2 equiv) at room temperature.226 The reaction
mixture was stirred for 12 h at room temperature before it was concentrated under
reduced pressure. The residue was purified by column chromatography (n-hexaneCH2Cl2 1:1) to afford the titled product as a white solid; yield: 146 mg (37%); mp =
224
The corresponding 2-aminobiphenyl derivatives were prepared via Suzuki coupling between 2-
bromoanilines and arylboronic acids following a reported procedure: Cho, S. H.; Yoon, J.; Chang, S.
J. Am. Chem. Soc. 2011, 133, 5996.
225
For the synthesis of analogous N-(2-p-toluene)sulfonyl-2-aminobiaryls, see: Youn, S. W.; Bihn, J.
H.; Kim, B. S. Org. Lett., 2011, 13, 3738.
226
For the oxidative cyclization of analogous N-(2-p-toluene)sulfonyl-2-aminobiaryls, see: Antonchick,
A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem. Int. Ed. 2011, 50, 8605.
333
Experimental section
171-172 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.41 (d, J=4.0, 1H), 8.29 (d, J=8.4, 1H),
8.21 (d, J=9.1, 1H), 7.99 (d, J=7.9, 1H), 7.85 (d, J=7.7, 1H), 7.75 (td, J=7.8, 1.7, 1H),
7.45 (t, J=7.2, 1H), 7.39 – 7.28 (m, 3H), 7.05 (dd, J=9.1, 2.6, 1H), 3.88 (s, 3H). 13C
NMR (CDCl3, 75 MHz) δ: 157.0, 155.5, 150.3, 139.4, 137.9, 133.0, 127.6, 127.5,
127.3, 126.4, 123.9, 122.2, 120.0, 116.3, 115.5, 115.3, 103.3, 55.9. FB+: calcd for
C18H14N2O3S (M)+: 338,0725. Found: 338,0723..
2-Chloro-N-(2-pyridyl)sulfonyl-9H-carbazole (19). Chromatography: n-hexaneCH2Cl2 3:1. White solid; yield: 50%; mp =165-166 ºC. 1H NMR
Cl
N
(CDCl3, 500 MHz) δ: 8.47 (ddd, J=4.6, 1.6, 0.8, 1H), 8.35 (d,
J=1.9, 1H), 8.27 (d, J=8.3, 1H), 8.10 (d, J=7.9, 1H), 7.89 (d,
SO2Py
J=7.7, 1H), 7.88 – 7.85 (m, 1H), 7.83 (d, J=8.4, 1H), 7.47 (ddd,
J=8.5, 7.4, 1.3, 1H), 7.43 – 7.38 (m, 1H), 7.36 (ddd, J=8.3, 6.5, 1.4, 2H). 13C NMR
(CDCl3, 125 MHz) δ: 155.5, 150.6, 139.4, 139.0, 138.2, 133.2, 127.9, 127.7, 125.4,
124.8, 124.6, 124.3, 122.3, 120.7, 120.0, 115.7, 115.3. FB+: calcd for C17H11N2O2SCl
(M)+: 342,0230. Found: 342,0231.
1-Fluoro-N-(2-pyridyl)sulfonyl-9H-carbazole
(20). Chromatography:
n-hexane-
CH2Cl2 1:1. White solid; yield: 49%; mp =134-135 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.44 – 8.38 (m, 1H), 8.35 (d, J=8.5, 1H), 8.10
F
N
SO2 Py
(ddt, J=7.9, 1.8, 1.0, 1H), 7.87 – 7.74 (m, 2H), 7.59 (dd, J=7.7, 1.0,
1H), 7.42 (ddd, J=8.6, 7.3, 1.3, 1H), 7.35 – 7.30 (m, 1H), 7.30 – 7.23
(m, 1H), 7.19 – 7.08 (m, 1H), 6.96 (ddd, J=12.2, 8.1, 1.0, 1H). 13C NMR (CDCl3, 75
MHz) δ: 156.5, 156.4, 151.8, 150.2, 148.5, 140.6, 137.9, 130.4, 130.3, 128.2, 127.4,
125.6, 125.6, 125.4, 124.8, 124.7, 124.0, 122.7, 122.6, 120.0, 116.4, 115.7, 115.7,
114.6, 114.3. FB+: calcd for C17H11N2O2SF (M)+: 326,0525. Found: 326,0523.
N-(2-Pyridyl)sulfonyl-5H-benzo[b]carbazole
(21).
Chromatography:
n-hexane-
CH2Cl2 1:1. White solid; yield: 68%; mp = 170-171 ºC. 1H NMR
(CDCl3, 300 MHz) δ: 8.98 (dd, J=8.7, 1.1, 1H), 8.28 (d, J=8.2,
N
SO2Py
334
1H), 8.14 (ddd, J=4.8, 1.6, 1.0, 1H), 7.92 (d, J=8.7, 1H), 7.86 –
7.78 (m, 2H), 7.76 – 7.71 (m, 1H), 7.63 (ddd, J=8.5, 6.9, 1.4,
Chapter 6
1H), 7.57 – 7.51 (m, 1H), 7.51 – 7.37 (m, 3H), 7.35 – 7.29 (m, 1H), 7.14 (ddd, J=7.1,
4.7, 1.5, 1H). 13C NMR (CDCl3, 75 MHz) δ: 153.7, 149.4, 141.2, 137.1, 137.1, 134.2,
129.4, 128.5, 127.5, 127.1, 127.0, 126.7, 126.2, 125.9, 125.8, 125.4, 122.5, 119.4,
119.1, 117.4. FB+: calcd for C21H14N2O2S (M)+: 358,0776. Found: 358,0787.
6.3.3. C−
−H alkenylation reaction
Synthesis of butyl (E)-3-[N-(2-pyridyl)sulfonyl-9H-carbazol-1-yl]acrylate (3). A
screw-capped test tube was charged with the carbazole
derivative 2 (46.2 mg, 0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015
mmol, 10 mol%) and Ce(SO4)2 (96.6 mg, 0.3 mmol, 2.0
equiv). The mixture was placed under nitrogen atmosphere
before DCE (1.5 mL) and n-butyl acrylate (43 µL, 0.3 mmol, 2.0 equiv) were
successively added. The mixture was heated to 110 ºC for 18 h, and then it was
allowed to reach room temperature, diluted with EtOAc (10 mL) and filtered through a
pad of Celite. The filtrate was concentrated under reduced pressure and the residue
was purified by flash chromatography (n-hexane-EtOAc 6:1) to afford 6 as a pale
yellow solid; yield: 16.8 mg (26%); mp = 151-152 ºC. 1H NMR (CDCl3, 300 MHz) δ:
8.39 (d, J = 15.9 Hz, 1H), 8.34 (d, J = 3.9 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.89 –
7.81 (m, 2H), 7.80 – 7.70 (m, 2H), 7.67 (d, J = 6.5 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.36
– 7.27 (m, 2H), 6.46 (d, J = 15.8 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 1.72 (tt, J = 8.4, 6.4
Hz, 2H), 1.55 – 1.40 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
167.3, 154.8, 149.9, 143.8, 140.9, 139.4, 137.7, 130.1, 128.0, 127.7, 127.4, 127.1,
126.3, 125.4, 125.2, 123.0, 121.1, 119.8, 118.7, 117.9, 64.5, 31.0, 19.4, 13.9.
Typical procedure for di-ortho-olefination: synthesis of (E,E)-dibutyl 3,3'-[N-(2pyridyl)sulfonyl-9H-carbazole-1,8-diyl]diacrylate
(4). A screw-capped test tube was charged with the
carbazole derivative 2 (46.2 mg, 0.15 mmol),
Pd(OAc)2 (3.4 mg, 0.015 mmol, 10 mol%) and 1fluoro-2,4,6-trimethylpyridinium triflate (130.2 mg,
0.45 mmol, 3.0 equiv). The mixture was placed under nitrogen atmosphere before
335
Experimental section
DCE (1.5 mL) and n-butyl acrylate (86 µL, 0.6 mmol, 4.0 equiv) were successively
added. The mixture was heated to 110 ºC for 18 h, and then it was allowed to reach
room temperature, diluted with EtOAc (10 mL) and filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure and the residue was purified by
flash chromatography (CH2Cl2-EtOAc 40:1) to afford 7 as a pale yellow solid; yield:
53.8 mg (64%); mp = 175-177 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.48 (d, J=16.0, 2H),
8.22 (dd, J=4.7, 1.6, 1H), 7.69 (d, J=7.8, 2H), 7.61 (d, J=7.5, 2H), 7.57 – 7.50 (m,
1H), 7.43 – 7.29 (m, 3H), 7.24 – 7.20 (m, 1H), 6.55 (d, J=16.0, 2H), 4.27 (t, J=6.7,
4H), 1.82 – 1.69 (m, 4H), 1.49 (q, J=7.5, 4H), 1.00 (t, J=7.4, 6H). 13C NMR (CDCl3, 75
MHz) δ: 167.0, 152.8, 149.2, 141.8, 141.5, 137.1, 131.8, 128.2, 127.2, 126.8, 126.3,
123.3, 121.0, 118.7, 64.6, 31.0, 19.3, 13.9. ESI+: calcd for C31H33N2O6S (M+H)+:
561,2053. Found: 561,2071.
336
Chapter 6
1,8-Bis[(E)-2-(phenylsulfonyl)vinyl]-
N-(2-pyridyl)sulfonyl-9H-carbazole
(8).
Following the typical procedure, carbazole 2 (46.2
mg, 0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol),
phenyl vinyl sulfone (101.0 mg, 0.6 mmol, 4.0 equiv)
N
PhO 2S
SO 2Py
SO2Ph
and 1-fluoro-2,4,6-trimethylpyridinium triflate (130.2
mg,
0.45
mmol,
3.0
equiv)
were
used.
Chromatography eluent: CH2Cl2-EtOAc 20:1. Pale yellow solid; yield: 64%; mp = 253254 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.43 (d, J = 15.4 Hz, 2H), 8.23 (d, J = 3.3 Hz,
1H), 8.08 (d, J = 6.9 Hz, 4H), 7.69 (d, J = 7.5 Hz, 2H), 7.67 – 7.50 (m, 10H), 7.42 –
7.30 (m, 2H), 6.95 (d, J = 15.3 Hz, 2H).
13
C NMR (acetone-d6, 125 MHz) δ: 153.2,
150.3, 142.6, 142.4, 140.6, 138.8, 134.2, 132.7, 130.2, 128.9, 128.7, 128.6, 128.4,
128.3, 128.0, 127.8, 126.8, 124.2, 123.2. ESI+: calcd for C33H25N2O6S3 (M+H)+:
641,0869. Found: 641,0847.
(E,E)-1,1'-[N-(2-Pyridyl)sulfonyl-9H-carbazole-1,8-diyl]bis(pent-1-en-3-one)
(9).
Following the typical procedure, carbazole 2 (46.2 mg,
0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), ethyl vinyl
EtOC
N
SO2Py
ketone (60 µL, 0.6 mmol, 4.0 equiv) and 1-fluoro-2,4,6COEt
trimethylpyridinium triflate (130.2 mg, 0.45 mmol, 3.0
equiv) were used. Chromatography eluent: CH2Cl2-EtOAc 20:1; yellow solid; yield:
80%; mp = 142-143 ºC; 1H NMR (CDCl3, 300 MHz) δ: 8.29 (d, J=16.3, 2H), 8.08 (d,
J=3.4, 1H), 7.64 (d, J=7.7, 2H), 7.53 (dd, J=7.5, 1.1, 2H), 7.44 (t, J=7.7, 1H), 7.30 (t,
J=7.4, 2H), 7.21 – 7.11 (m, 2H), 6.73 (dd, J=16.4, 1.2, 2H), 2.85 (qd, J=7.3, 1.2, 4H),
1.17 (td, J=7.3, 1.3, 6H).13C NMR (CDCl3, 75 MHz) δ: 201.88, 152.41, 149.28,
141.67, 139.92, 137.16, 131.93, 128.41, 127.36, 127.09, 126.93, 126.18, 123.35,
121.15, 32.96, 8.36. ESI+: calcd for C27H25N2O4S (M+H)+: 473,1529. Found:
473,1538.
337
Experimental section
1,8-Bis[(E)-4-nitrostyryl]-N-(2-pyridyl)sulfonyl-9H-carbazole (10). Following the
typical procedure, carbazole 2 (46.2 mg, 0.15
mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), 4N
nitrostyrene (78 µL, 0.6 mmol, 4.0 equiv) and 1-
SO 2Py
fluoro-2,4,6-trimethylpyridinium triflate (130.2 mg,
0.45 mmol, 3.0 equiv) were used. Chromatography
O 2N
NO2
eluent: n-hexane-CH2Cl2 1:2; yellow solid; yield:
80%; mp = 235-236 ºC. H NMR (DMSO-d6, 300 MHz) δ: 8.46 (d, J = 3.8 Hz, 1H),
1
8.28 (d, J = 8.8 Hz, 4H), 8.03 (d, J = 16.3 Hz, 2H), 7.93 (dd, J = 7.7, 1.6 Hz, 4H), 7.84
– 7.73 (m, 5H), 7.62 – 7.45 (m, 6H).
C NMR (DMSO-d6, 125 MHz) δ: 153.0, 149.7,
13
146.4, 144.1, 140.3, 138.5, 131.2, 130.4, 128.9, 128.4, 127.4, 126.9, 126.5, 125.3,
124.1, 123.3, 120.5. ESI+: calcd for C33H23N2O4S (M+H)+: 603,1332. Found:
603,1351.
1,8-Bis[(E)-4-(trifluoromethyl)styryl]-N-(2-pyridyl)sulfonyl-9H-carbazole
(11).
Following the typical procedure, carbazole 2 (46.2
mg, 0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol),
4-(trifluoromethyl)styrene (89 µL, 0.6 mmol, 4.0
N
SO 2Py
equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate
(130.2 mg, 0.45 mmol, 3.0 equiv) were used.
F 3C
CF3
Chromatography
eluent:
n-hexane-CH2Cl2
1:3.
1
Yellow solid; yield: 91%; mp = 217-218 ºC. H NMR
(CDCl3, 500 MHz) δ: 8.23 (dt, J=4.7, 0.9, 1H), 8.07 (d, J=16.3, 2H), 7.78 – 7.73 (m,
6H), 7.66 (d, J=8.0, 4H), 7.53 (dd, J=7.5, 1.1, 2H), 7.44 (td, J=7.8, 1.7, 1H), 7.40 –
7.31 (m, 3H), 7.28 – 7.20 (m, 3H). 13C NMR (CDCl3, 125 MHz) δ: 153.0, 149.1, 141.1,
141.0, 136.8, 132.1, 130.2, 129.5, 129.3, 128.9, 127.2, 127.1, 127.0, 126.8, 125.7,
125.7, 125.6, 125.6, 125.4, 124.8, 123.5, 123.2, 119.2. ESI+: calcd for C35H23N2O2F6S
(M+H)+: 649,1378. Found: 649, 1399.
338
Chapter 6
(E,E)-Dibutyl
3,3'-[3-methoxy-N-(2-pyridyl)sulfonyl-9H-carbazole-1,8-diyl]diacrylate (24). Following the typical procedure,
OMe
nBuO2C
carbazole 18 (50.7 mg, 0.15 mmol), Pd(OAc)2 (3.4
mg, 0.015 mmol), n-butyl acrylate (86 µL, 0.6
N
SO 2Py
mmol,
CO2nBu
4.0
equiv)
and
1-fluoro-2,4,6-
trimethylpyridinium triflate (130.2 mg, 0.45 mmol,
3.0 equiv) were used. Chromatography eluent: CH2Cl2-EtOAc 100:1. Yellow solid;
yield: 48%; mp = 145-146ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.45 (dd, J=16.0, 5.3, 2H),
8.19 (d, J=5.1, 1H), 7.67 (d, J=7.8, 1H), 7.59 – 7.45 (m, 2H), 7.33 (t, J=7.7, 1H), 7.28
– 7.17 (m, 3H), 7.07 (d, J=2.5, 1H), 6.54 (dd, J=16.0, 5.4, 2H), 4.28 (t, J=6.7, 4H),
3.88 (s, 3H), 1.76 (p, J=6.9, 4H), 1.49 (q, J=7.4, 4H), 1.00 (t, J=7.3, 6H).
13
C NMR
(CDCl3, 75 MHz) δ: 167.1, 167.0, 158.7, 152.6, 149.2, 142.3, 141.7, 141.6, 137.0,
135.5, 133.2, 132.1, 129.1, 128.4, 127.1, 126.8, 126.4, 123.5, 120.9, 118.9, 118.7,
111.8, 106.2, 64.7, 64.7, 56.0, 31.0, 19.4, 13.9O ESI+: calcd for C32H35N2O7S (M+H)+:
591,2140. Found: 591,2143.
(E,E)-Dibutyl
3,3'-[3-bromo-N-(2-pyridyl)sulfonyl-9H-carbazole-1,8-diyl]diBr
acrylate (25). Following the typical procedure,
carbazole 17 (58.1 mg, 0.15 mmol), Pd(OAc)2 (3.4
nBuO2C
mg, 0.015 mmol), n-butyl acrylate (86 µL, 0.6
N
SO 2Py
mmol,
CO2nBu
4.0
equiv)
and
1-fluoro-2,4,6-
trimethylpyridinium triflate (130.2 mg, 0.45 mmol,
3.0 equiv) were used. Chromatography eluent: CH2Cl2; pale yellow solid; yield: 59%;
mp = 163-165 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.40 (dd, J=16.0, 5.7, 2H), 8.26 (d,
J=4.4, 1H), 7.76 (dd, J=15.9, 1.9, 2H), 7.71 – 7.64 (m, 1H), 7.63 – 7.53 (m, 2H), 7.45
– 7.27 (m, 3H), 6.52 (d, J=16.0, 2H), 4.26 (t, J=6.7, 4H), 1.90 – 1.62 (m, 4H), 1.56 –
1.38 (m, 4H), 0.99 (t, J=7.3, 6H).
13
C NMR (CDCl3, 75 MHz) δ: 166.9, 166.6, 153.0,
149.4, 141.7, 141.5, 140.6, 140.5, 137.4, 133.4, 130.6, 129.8, 128.9, 128.2, 127.5,
127.0, 127.0, 123.7, 123.0, 121.1, 120.4, 119.8, 119.1, 64.7, 64.7, 30.9, 30.9, 19.3,
13.9. ESI+: calcd for C31H32N2O6SBr (M+H)+: 639,1158. Found: 639,1148.
339
Experimental section
(E,E)-Dibutyl
3,3'-[2-chloro-N-(2-pyridyl)sulfonyl-9H-carbazole-1,8-diyl]diacrylate (26). Following the typical procedure,
carbazole 19 (51.4 mg, 0.15 mmol), Pd(OAc)2
Cl
nBuO2 C
N
SO 2Py
(3.4 mg, 0.015 mmol), n-butyl acrylate (86 µL,
0.6
CO2nBu
mmol,
4.0
trimethylpyridinium
equiv)
and
1-fluoro-2,4,6-
triflate (130.2 mg, 0.45
mmol, 3.0 equiv) were used. Chromatography eluent: CH2Cl2. Yellow oil; yield: 58%.
This compound could not be completely purified from minor alkenylated side
products. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (d, J=15.9, 1H), 8.36 (ddd, J=4.6, 1.8,
1.0, 1H), 8.05 (d, J=16.4, 1H), 7.65 (d, J=7.8, 3H), 7.61 – 7.50 (m, 2H), 7.49 – 7.40
(m, 1H), 7.38 – 7.35 (m, 1H), 7.34 – 7.28 (m, 1H), 6.49 (d, J=15.9, 1H), 6.41 (d,
J=16.4, 1H), 4.19 (dt, J=13.8, 6.7, 4H), 1.83 – 1.62 (m, 4H), 1.56 – 1.37 (m, 4H), 0.98
(td, J=7.3, 2.6, 6H).
C NMR (CDCl3, 75 MHz) δ: 167.0, 166.3, 154.3, 149.5, 142.3,
13
142.0, 141.3, 140.2, 137.5, 133.4, 130.8, 129.9, 128.2, 127.9, 127.5, 127.3, 126.6,
126.4, 124.9, 123.2, 121.0, 120.3, 119.0, 64.7, 64.6, 30.9, 30.8, 19.4, 19.3, 13.9,
13.9. ESI+: calcd for C31H32N2O6SCl (M+H)+: 595,1664. Found: 595,1627.
(E)-Butyl
3-[8-fluoro-N-(2-pyridyl)sulfonyl-9H-carbazol-1-yl]acrylate
(27).
Following the typical procedure, carbazole 20 (48.9 mg,
0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), n-butyl
F
acrylate (43 µL, 0.3 mmol, 2.0 equiv) and 1-fluoro-2,4,6-
N
SO2Py
CO2nBu
trimethylpyridinium triflate (86.8 mg, 0.3 mmol, 2.0 equiv)
were used. Chromatography eluent: n-hexane-CH2Cl2
1:10. Pale yellow solid; yield: 66%; mp = 158-159 ºC. 1H NMR (CDCl3, 300 MHz) δ:
9.00 (d, J=15.8, 1H), 8.71 (dt, J=5.2, 1.2, 1H), 8.17 – 8.08 (m, 1H), 7.92 (td, J=7.8,
1.7, 1H), 7.85 (dd, J=7.6, 1.3, 1H), 7.74 (dd, J=7.9, 1.4, 1H), 7.61 (dd, J=7.7, 1.1,
1H), 7.51 (ddd, J=7.6, 4.7, 1.2, 1H), 7.42 (t, J=7.7, 1H), 7.30 (dt, J=8.0, 4.0, 1H), 7.08
(ddd, J=11.1, 8.2, 1.0, 1H), 6.52 (d, J=15.8, 1H), 4.19 (t, J=6.7, 2H), 1.65 (dq, J=8.5,
6.7, 2H), 1.51 – 1.33 (m, 2H), 0.94 (t, J=7.4, 3H). 13C NMR (CDCl3, 75 MHz) δ: 167.2,
155.9, 155.9, 153.8, 150.5, 150.0, 143.1, 140.1, 137.8, 132.0, 132.0, 130.0, 129.9,
128.8, 128.6, 127.6, 126.9, 126.9, 126.6, 126.5, 125.8, 123.3, 123.3, 121.5, 118.0,
340
Chapter 6
115.9, 115.8, 115.0, 114.7, 64.4, 30.9, 19.3, 13.9. ESI+: calcd for C24H22N2O4FS
(M+H)+:453,1278. Found: 453,1284.
(E)-Butyl
3-{N-(2-pyridyl)sulfonyl-5H-benzo[b]carbazol-4-yl}acrylate
(28).
Following the typical procedure, carbazole 21 (53.8
mg, 0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), nbutyl acrylate (43 µL, 0.3 mmol, 2.0 equiv) and 1N
fluoro-2,4,6-trimethylpyridinium triflate (86.8 mg, 0.3
SO 2Py
CO2nBu
mmol, 2.0 equiv) were used. Chromatography eluent:
CH2Cl2. Brown solid; yield: 64%; mp = 160-162 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.87
(d, J=8.6, 1H), 8.56 (d, J=16.0, 1H), 8.06 (ddd, J=4.7, 1.8, 0.9, 1H), 7.87 (dd, J=8.2,
1.5, 1H), 7.78 – 7.74 (m, 1H), 7.69 (dt, J=8.6, 1.4, 2H), 7.66 – 7.61 (m, 1H), 7.61 –
7.57 (m, 1H), 7.54 (ddd, J=8.2, 6.9, 1.2, 1H), 7.43 – 7.38 (m, 1H), 7.37 – 7.30 (m,
1H), 7.12 (ddd, J=7.7, 4.7, 1.1, 1H), 7.00 (dt, J=7.9, 1.0, 1H), 6.63 (d, J=16.0, 1H),
4.29 (t, J=6.7, 2H), 1.86 – 1.70 (m, 2H), 1.59 – 1.43 (m, 2H), 1.01 (t, J=7.4, 3H). 13C
NMR (CDCl3, 75 MHz) δ: 167.2, 152.1, 148.9, 142.2, 138.8, 136.6, 133.8, 132.8,
128.4, 128.3, 128.2, 128.2, 127.0, 126.8, 126.7, 126.5, 126.4, 126.3, 125.4, 123.2,
120.7, 118.3, 117.1, 64.6, 31.0, 19.4, 14.0. ESI+: calcd for C28H25N2O4S
(M+H)+:485,1529. Found: 485,1530.
(E)-Butyl
3-N-(2-pyridyl)sulfonyl-2,3,4,9-tetrahydro-1H-carbazol-8-yl]acrylate
(29). Following the typical procedure, carbazole 15 (46.8
mg, 0.15 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), n-butyl
acrylate (86 µL, 0.6 mmol, 4.0 equiv) and PhI(OAc)2
N
SO 2Py
(144.9
CO2nBu
mg,
0.45
mmol,
3.0
equiv)
were
used.
Chromatography eluent: n-hexane-EtOAc 6:1. Yellow
solid; yield: 84%; mp = 104-105 ºC. 1H NMR (CDCl3, 300 MHz) δ: 8.57 (ddd, J=4.7,
1.7, 0.8, 1H), 8.37 (d, J=15.6, 1H), 7.90 (dt, J=8.0, 1.1, 1H), 7.87 – 7.80 (m, 1H), 7.48
– 7.37 (m, 2H), 7.31 (dd, J=7.6, 1.4, 1H), 7.28 – 7.20 (m, 1H), 6.30 (d, J=15.7, 1H),
4.22 (t, J=6.7, 2H), 3.21 – 3.05 (m, 2H), 2.68 – 2.40 (m, 2H), 1.99 – 1.76 (m, 4H),
1.77 – 1.64 (m, 2H), 1.58 – 1.37 (m, 2H), 0.97 (t, J=7.3, 3H). 13C NMR (CDCl3, 75
MHz) δ: 167.3, 155.9, 150.0, 145.1, 139.6, 138.0, 136.4, 133.5, 127.4, 124.6, 124.5,
341
Experimental section
124.4, 122.6, 120.7, 119.5, 117.7, 64.4, 31.0, 25.7, 23.6, 22.1, 21.3, 19.3, 13.9. ESI+:
calcd for C24H27N2O4S (M+H)+:439,1692. Found: 439,1695.
(E)-Butyl 3-[N-(2-pyridyl)sulfonyl)indolin-7-yl]acrylate (38). Following the typical
procedure, indoline 35 (39.0 mg, 0.15 mmol), Pd(OAc)2 (3.4
mg, 0.015 mmol), n-butyl acrylate (43 µL, 0.3 mmol, 2.0
nBuO2 C
1
N
SO 2Py
equiv) and 1-fluoro-2,4,6-trimethylpyridinium triflate (86.8
mg, 0.3 mmol, 2.0 equiv) were used. Chromatography
eluent: CH2Cl2. Yellow solid; yield: 80%; mp = 107-108 ºC.
H NMR (CDCl3, 300 MHz) δ: 8.63 (d, J=4.6, 1H), 8.14 (d, J=16.1, 1H), 7.75 (t, J=7.7,
1H), 7.61 (d, J=7.9, 1H), 7.52 – 7.40 (m, 2H), 7.18 – 7.02 (m, 2H), 6.40 (d, J=16.1,
1H), 4.29 (t, J=7.5, 2H), 4.21 (t, J=6.7, 2H), 2.55 (t, J=7.3, 2H), 1.70 (p, J=6.9, 2H),
1.45 (h, J=7.4, 2H), 0.96 (t, J=7.3, 3H). 13C NMR (CDCl3, 75 MHz) δ: 167.1, 156.2,
150.2, 142.0, 141.6, 137.9, 137.8, 128.0, 127.2, 126.8, 126.0, 125.6, 123.5, 118.1,
64.5, 53.4, 30.9, 29.4, 19.3, 13.9. ESI+: calcd for C20H23N2O4S (M+H)+:387,1373.
Found: 387,1354.
6.3.4. Zn-promoted reductive N-desulfonylation
Typical
procedure:
synthesis
of
(E,E)-dibutyl
3,3'-(9H-carbazole-1,8-
diyl)diacrylate (39). A suspension of diolefinated
adduct 4 (56,1 mg, 0.1 mmol) and activated Zn
powder (327 mg, 5 mmol, 50 equiv) in a 1:1
N
H
nBuO 2C
CO2 nBu
mixture of THF and sat aq. NH4Cl solution (5 mL)
was stirred at room temperature until consumption
of the starting material (TLC monitoring). The mixture was diluted with EtOAc (15 mL)
and filtered over a pad of celite to remove the Zn. The filtrate was washed with a
saturated aqueous solution of ammonium chloride (10 mL) and brine (10 mL). The
combined organic phase was dried (MgSO4) and concentrated to dryness. The
residue was purified by flash chromatography (n-hexane-EtOAc 3:1) to afford 39 as a
yellow oil; yield: 39 mg (93%). 1H NMR (CDCl3, 300 MHz) δ: 8.95 (s, 1H), 8.12 (d,
J=15.9, 2H), 8.04 (d, J=7.7, 2H), 7.63 (d, J=7.5, 2H), 7.25 – 7.19 (m, 2H), 6.56 (d,
342
Chapter 6
J=15.9, 2H), 4.21 (t, J=6.8, 4H), 1.74 – 1.60 (m, 4H), 1.39 (dtd, J=16.6, 8.6, 8.0, 5.5,
4H), 0.91 (t, J=7.3, 6H).
C NMR (CDCl3, 75 MHz) δ: 167.3, 139.6, 138.5, 125.0,
13
124.5, 122.5, 120.5, 119.1, 118.3, 64.9, 30.8, 19.4, 13.6. ESI+: calcd for C26H30NO4
(M+H)+:420,2169. Found: 420,2187.
(E)-Butyl 3-(indolin-7-yl)acrylate (41). Chromatography eluent: n-hexane- CH2Cl2
1:2. Dark yellow solid; yield: 63 %; mp = 61-62 ºC. 1H NMR (CDCl3, 300
N
H
CO2 nBu
MHz) δ: 7.70 (d, J=16.0, 1H), 7.16 (d, J=7.9, 1H), 7.09 (d, J=7.1, 1H),
6.69 (t, J=7.5, 1H), 6.28 (d, J=16.0, 1H), 4.48 (s, 1H), 4.19 (t, J=6.7,
2H), 3.62 (t, J=8.5, 2H), 3.05 (t, J=8.4, 2H), 1.68 (dt, J=14.3, 6.8, 2H),
1.43 (h, J=7.4, 2H), 0.96 (t, J=7.3, 3H).
C NMR (CDCl3, 75 MHz) δ:
13
167.6, 150.9, 141.5, 130.8, 127.0, 126.3, 119.0, 116.7, 116.3, 64.3, 47.1, 30.9, 29.4,
19.3, 13.8. FB+: calcd for C15H19NO2 (M)+: 245,1416. Found: 245,1418.
6.3.5. Mg-promoted reductive N-desulfonylation
Typical
procedure:
synthesis
of
dimethyl
3,3'-(9H-carbazole-1,8-
diyl)dipropanoate (40). The diolefinated adduct 2
(0.1 mmol) was dissolved in MeOH (5 mL) and
treated with magnesium turnings (51 mg, 2 mmol, 20
N
H
MeO 2C
CO2 Me
equiv).
The
temperature
mixture
until
was
sonicated
consumption
of
the
at
room
starting
material (TLC monitoring, 2h), then diluted with EtOAc (10 mL) and filtered (celite) to
remove excess of Mg. The filtrate was washed with sat. aq NH4Cl (10 mL) and brine
(10 mL). The combined organic phase was dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash chromatography (n-hexane-EtOAc 3:1) to afford 40
as a yellow solid; yield: 22 mg (75%); mp = 136-138 ºC. 1H NMR (CDCl3, 300 MHz) δ:
9.32 (s, 1H), 7.94 (d, J=7.6, 2H), 7.27 – 7.11 (m, 4H), 3.69 (s, 6H), 3.31 (t, J=7.1,
4H), 2.85 (t, J=7.1, 4H).
C NMR (CDCl3, 75 MHz) δ: 174.8, 138.8, 125.7, 123.9,
13
123.4, 119.6, 118.8, 52.0, 34.6, 26.6. FB+: calcd for C20H21NO4 (M)+: 339,1471.
Found: 339,1472.
343
Experimental section
1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]quinolin-4-one (42).227 The crude product was
purified by trituration in a mixture of ether and hexane, obtaining a pale
yellow solid; yield: 43 mg (99%); mp = 80-81 ºC
N
H NMR (CDCl3, 500
MHz) δ: 7.07 (d, J=7.4, 1H), 6.99 (m, 1H), 6.92 (t, J=7.4, 1H), 4.08 (t,
O
13
1
J=8.4, 2H), 3.19 (t, J=8.4, 2H), 2.97 (t, J=7.8, 2H), 2.68 (t, J=7.8, 2H).
C NMR (CDCl3, 125 MHz) δ: 167.8, 141.4, 129.1, 125.5, 123.4, 123.4, 120.4, 45.3,
31.8, 27.9, 24.6. ESI+: calcd for C11H11NO (M)+:173,0841. Found: 173,0842.
6.3.6. Oxidative aromatization
Pyrrolo[3,2,1-ij]quinolin-4-one
(43).228
To
a
solution
of
1,2,5,6-
tetrahydropyrrolo[3,2,1-ij]quinolin-4-one (38,4 mg, 0.22 mmol) in DCE
(1.5 mL) at room temperature was added DDQ (149.8 mg, 0.66 mmol,
N
3.0 equiv). The mixture was heated at 80 ºC overnight before it was
O
allowed to reach room temperature and quenched with sat aq. NaHCO3
solution (5 mL). The mixture was extracted with EtOAc (5 mL) and the organic phase
washed with brine (5 mL), then dried (MgSO4) and concentrated. The residue was
purified by column chromatography (n-hexane-CH2Cl2 1:1) to afford the indole
derivative as a light brown solid; yield: 26,4 mg (71%); mp = 110-112 ºC [mplit(8) = 113
ºC]. 1H NMR (CDCl3, 300 MHz) δ: 7.96 (d, J=3.6, 1H), 7.91 – 7.81 (m, 2H), 7.61 (d,
J=7.6, 1H), 7.43 (t, J=7.6, 1H), 6.90 (d, J=3.6, 1H), 6.72 (d, J=9.5, 1H).
13
C NMR
(CDCl3, 75 MHz) δ: 159.4, 139.0, 132.6, 127.9, 125.5, 124.4, 124.2, 123.8, 117.2,
110.9. ESI+: calcd for C11H7NO (M)+:169,0528. Found: 169,0526.
227
Yin, L.; Lucas, S.; Maurer, F.; Kazmaier, U.; Hu, Q.; Hartmann, R. W. J. Med. Chem. 2012, 55,
6629.
228
McNab, H.; Nelson, D. J.; Rozgowska, E. J. Synthesis, 2009, 13, 2171.
344
Chapter 6
6.4. Aerobic copper-catalyzed ortho-halogenation of anilines
6.4.1. General methods
The corresponding starting materials were synthetized using oven-dried
glassware under a nitrogen atmosphere containing a teflon-coated stirrer bar and dry
septum. All halogenation reactions were performed at ambient O¬2 pressure in ovendried 20 mL vessel containing a teflon-coated stirrer bar and dry septum. All reactions
were monitored by GC using n-hexadecane as an internal standard. Response
factors of the products with regard to n-hexadecane were obtained experimentally by
analyzing known quantities of the substances. GC analyses were carried out using an
HP-5 capillary column (Phenyl Methyl Siloxane 30 m x 320 x 0.25, 100/2.3-30-300/3)
and a time program beginning with 2 min at 60 ºC followed by 30 ºC/min ramp. to 300
ºC, then 3 min at this temperature. Flash column chromatography was performed
using 230-400 mesh ultra-pure silica gel. NMR spectra were obtained on Bruker AC300 or on Bruker AMX-500 systems using acetone-d6 as solvent, with proton and
carbon resonances at 300/500 MHz and 75/125 MHz, respectively. Mass spectral
data were acquired on a VG AutoSpec mass spectrometer.
Solvents were purified by standard procedures prior to use. Copper salts were
dried in vacuo at 60 ºC prior to use. O2 was supplied with a purity of 99.99%. All other
compounds are commercially available and were used without further purification.
All oxidation reactions involving sodium hypochlorite were carried with rapid
continuous magnetic stirring in Erlenmeyer flasks open to the atmosphere. Sodium
hypochlorite was commercial “ultra” laundry bleach containing a stated concentration
of 6% NaOCl.
Hydrochloric acid (ca. 1 M) containing 25 wt % of calcium chloride was prepared
by dissolving 125 g of anhydrous calcium chloride in 350 mL of water and cooling to
room temperature. Once the solution had cooled, 42 mL of concentrated hydrochloric
acid was added and the solution was diluted to 500 mL with water.
345
Experimental section
6.4.2. Typical procedure for the N-sulfonylation of anilines.
Synthesis of N-phenylpyridine-2-sulfonamide (1).229 To a solution of aniline
(364 µL, 4.00 mmol, 1.00 equiv) in THF (40 mL), pyridine
(388 µL, 4.80 mmol, 1.20 equiv) and 2-pyridylsulfonyl chloride
(852 mg, 4.80 mmol, 1.20 equiv) were successively added
dropwise at 0 ºC and under N2 atmosphere. The mixture was warmed to room
temperature and stirred overnight. During this time, a gradual formation of a
precipitate was observed. The resulting mixture was then suction filtered through a 6cm fritted glass funnel (coarse) into a round-bottomed flask, and the filter cake was
rinsed with THF (3 x 10 mL). To the resulting filtrate and the washes, water (20 mL)
was added and the THF was removed by evaporation at reduced pressure, yielding a
suspension of a white solid in the aqueous medium. This solid was collected by
filtration, washed sequentially with toluene (2 x 5 mL) and diethyl ether (2 x 5 mL).
Then it was transferred to a round-bottomed flask, and dried at 1.0 mmHg to provide
1 as a white powder; yield: 862 mg (92%); mp = 170-172 ºC. The analytical data
(NMR, HRMS analysis) matched those reported in the literature for N-phenylpyridine2-sulfonamide [CAS: 103863-00-9]. 1H NMR (acetone-d6, 300 MHz) δ: 9.19 (s, 1H),
8.69 (dd, J = 3.6, 1.2, 1H), 8.06 – 7.98 (m, 1H), 7.98 – 7.91 (m, 1H), 7.59 (ddd, J =
7.2, 4.8, 1.5, 1H), 7.33 – 7.14 (m, 4H), 7.03 (t, J = 7.2 Hz, 1H). ESI+ calcd. for
C11H11N2O2S (M+H)+: 235.0535; Found: 235.0537.
N-(4-Methoxyphenyl)pyridine-2-sulfonamide (2). Compound 2 was prepared
following the typical procedure from 4-methoxyaniline (493 mg, 4.00 mmol) to give 2
as a white solid; yield: 951 mg (90%); mp = 167-168 ºC.
1
H NMR (acetone-d6, 300 MHz) δ: 8.93 (s, 1H), 8.71
(ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.98 (td, J = 7.7, 1.7 Hz,
1H), 7.86 (dt, J = 7.9, 1.1 Hz, 1H), 7.58 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.15 (d, J =
9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 3.70 (s, 3H). 13C NMR (acetone-d6, 75 MHz) δ:
229
García-Rubia, A.; Urones, B.; Gómez Arrayás, R.; Carretero, J. C. Angew. Chem. Int. Ed. 2011,
50, 10927.
346
Chapter 6
158.3, 158.1, 150.8, 139.0, 130.8, 127.7, 125.5, 123.5, 114.9, 55.6. ESI+ calcd. for
C12H13N2O3S (M+H)+: 265.0641; Found: 265.0649.
N-(p-Tolyl)pyridine-2-sulfonamide (9) Compound 9 was prepared following the
typical procedure from p-toluidine (440 µL, 4.00 mmol) to
give 9 as a white solid; yield: 934 mg (94%); mp = 196197 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.04 (s, 1H), 8.69
(ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.00 (td, J = 7.7, 1.7 Hz, 1H), 7.92 (dt, J = 7.8, 1.1 Hz,
1H), 7.58 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.08 – 6.98 (m,
2H), 2.20 (s, 3H).
C NMR (acetone-d6, 75 MHz) δ: 158.1, 150.9, 139.0, 135.9,
13
135.0, 130.3, 127.8, 123.5, 122.6, 20.7. ESI+ calcd. for C12H13N2O2S (M+H)+:
249.0692; Found: 249.0691.
N-(4-Iodophenyl)pyridine-2-sulfonamide
(10).
Compound
10
was
prepared
following the typical procedure from 4-iodoaniline (876 mg,
4.00 mmol) to give 10 as a white solid; yield: 1.28 g (89%); mp
= 193-194 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.34 (s, 1H),
8.69 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.05 (td, J = 7.6, 1.7 Hz, 1H), 7.98 (ddd, J = 7.9,
1.5, 0.9 Hz, 1H), 7.67 – 7.55 (m, 3H), 7.12 (d, J = 8.7 Hz, 2H). 13C NMR (acetone-d6,
75 MHz) δ: 157.8, 151.0, 139.2, 138.8, 128.1, 123.7, 123.6, 123.5, 88.3. ESI+ calcd.
for C11H10N2O2SI (M+H)+: 360.9502; Found: 360.9492.
N-(4-Bromophenyl)pyridine-2-sulfonamide (11). Compound 11 was prepared
following the typical procedure from 4-bromoaniline (688 mg,
4.00 mmol) to give 11 as a white solid; yield: 1.09 g (87%);
mp = 192-193 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.34 (s,
1H), 8.69 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.04 (td, J = 7.6, 1.7 Hz, 1H), 7.98 (dt, J =
7.9, 1.2 Hz, 1H), 7.61 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.25 (d,
J = 8.8 Hz, 2H). 13C NMR (acetone-d6, 75 MHz) δ: 157.8, 151.0, 139.2, 138.2, 138.1,
132.8, 128.1, 123.6, 123.6, 123.5, 117.7. ESI+ calcd. for C11H10N2O2SBr (M+H)+:
312.9640; Found: 312.9645.
347
Experimental section
N-(4-Chlorophenyl)pyridine-2-sulfonamide (12). Compound 12 was prepared
following the typical procedure from 4-chloroaniline (510 mg,
4.00 mmol) to give 12 as a white solid; yield: 817 mg (76%);
mp = 182-184 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.33
(s, 1H), 8.69 (dd, J = 4.5, 1.0 Hz, 1H), 8.10 – 8.00 (m, 1H), 8.00 – 7.94 (m, 1H), 7.61
(ddd, J = 7.3, 4.7, 1.4 Hz, 1H), 7.37 – 7.20 (m, 4H).
13
C NMR (acetone-d6, 75 MHz)
δ: 157.8, 151.0, 139.2, 137.6, 130.1, 129.8, 128.1, 123.5, 123.4, 123.4. ESI+ calcd.
for C11H10N2O2SCl (M+H)+: 269.0146; Found: 269.0155.
N-(4-Fluorophenyl)pyridine-2-sulfonamide (13). Compound 13 was prepared
following the typical procedure from 4-fluoroaniline (379 µL,
4.00 mmol) to give 13 as a white solid; yield: 797 mg (79%);
mp = 156-157 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.21 (s,
1H), 8.70 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.02 (td, J = 7.7, 1.7 Hz, 1H), 7.92 (dt, J =
7.9, 1.1 Hz, 1H), 7.60 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.36 – 7.22 (m, 2H), 7.01 (t, J =
8.8 Hz, 2H).
C NMR (acetone-d6, 75 MHz) δ: 160.9 (d, JC-F = 242.0 Hz), 157.9,
13
150.9, 139.1, 134.7 (d, JC-F = 2.7 Hz), 127.9, 124.8 (d, JC-F = 8.3 Hz), 123.5, 116.4 (d,
JC-F = 22.8 Hz).
19
F NMR (acetone-d6, 282 MHz) δ: 57.8. ESI+ calcd. for
C11H10N2O2FS (M+H)+: 253.0441; Found: 253.0437.
N-[4-(Trifluoromethyl)phenyl]pyridine-2-sulfonamide
prepared
following
the
(3).
typical
Compound
procedure
3
from
was
4-
(trifluoromethyl)aniline (502 µL, 4.00 mmol) to give 3 as a
white solid; yield: 919 mg (76%) mp = 179-180 ºC. 1H NMR
(acetone-d6, 300 MHz) δ: 9.69 (s, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.07 (d, J = 3.4 Hz,
2H), 7.72 – 7.46 (m, 5H).
13
C NMR (acetone-d6, 75 MHz) δ : 157.7, 151.1, 142.6,
139.4, 128.9 (q, JC-F = 270.7 Hz), 128.3, 127.1 (q, JC-F = 3.8 Hz), 126.0 (q, JC-F = 32.5
Hz), 123.5, 120.52.
19
F NMR (acetone-d6, 282 MHz) δ: 114.9. ESI+ calcd. for
C12H10N2O2F3S (M+H)+: 303.0409; Found: 303.0413.
348
Chapter 6
Methyl 4-[N-(2-pyridyl)sulfonylamino]benzoate (14). Compound 14 was prepared
following
the
typical
procedure
from
methyl
4-
aminobenzoate (605 mg, 4.00 mmol) to give 14 as a
white solid; yield: 748 mg (64%); mp = 222-224 ºC. The
analytical data (NMR, GC-MS analysis) matched those
reported in the literature for methyl 4-[N-(2-pyridyl)sulfonylamino]benzoate [CAS:
1352965-44-6]. 1H NMR (acetone-d6, 300 MHz) δ: 9.66 (s, 1H), 8.68 (d, J = 4.6 Hz,
1H), 8.07 (d, J = 3.5 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.70 – 7.52 (m, 1H), 7.41 (d, J
= 8.7 Hz, 2H), 3.82 (s, 3H).
N-(3-Fluorophenyl)pyridine-2-sulfonamide (15). Compound 15 was prepared
following
the
typical
procedure
from
3-isopropylaniline
(384 µL, 4.00 mmol) to give 15 as a white solid; yield: 837 mg
(83%); mp = 164-165 ºC. 1H NMR (acetone-d6, 500 MHz) δ:
9.53 (s, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.06 (td, J = 7.6, 1.7 Hz, 1H), 8.03 (dt, J = 7.9,
1.3 Hz, 1H), 7.63 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.26 (td, J = 8.3, 6.6 Hz, 1H), 7.16 –
7.07 (m, 2H), 6.80 (td, J = 8.5, 2.2 Hz, 1H). 13C NMR (acetone-d6, 125 MHz) δ: 163.7
(d, JC-F = 243.4 Hz), 157.7, 151.0, 140.6 (d, JC-F = 10.6 Hz), 139.3, 131.4 (d, JC-F = 9.5
Hz), 128.2, 123.5, 116.9 (d, JC-F = 3.0 Hz), 111.5 (d, JC-F = 21.3 Hz), 108.1 (d, JC-F =
25.8 Hz). 19F NMR (acetone-d6, 471 MHz) δ: -113.3. EI+ calcd. for C11H9N2O2FS (M)+:
252.0369; Found: 252.0359.
N-(3-Isopropylphenyl)pyridine-2-sulfonamide (16). Compound 16 was prepared
following the typical procedure from 3-isopropylaniline (541 mg, 4.00 mmol) to give
16 as a white solid; yield: 884 mg (80%); mp = 185-186 ºC.
1
H NMR (acetone-d6, 500 MHz) δ: 9.11 (s, 1H), 8.70 (ddd, J
= 4.8, 1.8, 0.9 Hz, 1H), 8.01 (td, J = 7.7, 1.7 Hz, 1H), 7.95
(dt, J = 7.9, 1.1 Hz, 1H), 7.59 (ddd, J = 7.6, 4.7, 1.3 Hz, 1H), 7.16 – 7.09 (m, 2H),
7.07 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 6.93 (dt, J = 7.6, 1.5 Hz, 1H), 2.78 (h, J = 6.9 Hz,
1H), 1.13 (d, J = 6.9 Hz, 6H). 13C NMR (acetone-d6, 125 MHz) δ: 158.1, 150.9, 150.6,
139.0, 138.5, 129.7, 127.8, 123.6, 123.4, 120.0, 119.5, 34.6, 24.1. EI+ calcd. for
C14H16N2O2S (M)+: 276.0932; Found: 276.0940.
349
Experimental section
N-[3-(Trifluoromethyl)phenyl]pyridine-2-sulfonamide (17). Compound 17 was
prepared following the typical procedure from 3-(trifluoromethyl)aniline (575 µL,
4.00 mmol) to give 17 as a white solid; yield: 883 mg (73%);
mp = 190-191 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 9.57
(s, 1H), 8.70 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 8.11 – 8.05 (m,
1H), 8.05 – 8.00 (m, 1H), 7.68 – 7.61 (m, 2H), 7.61 – 7.55 (m, 1H), 7.49 (t, J = 8.0 Hz,
1H), 7.39 (dt, J = 7.6, 0.8 Hz, 1H).
13
C NMR (acetone-d6, 75 MHz) δ: 157.7, 151.1,
139.7, 139.4, 131.6 (q, JC-F = 32.3 Hz), 131.0, 128.2, 124.9, 124.9 (q, JC-F = 271.7
Hz), 123.4, 121.6 (q, JC-F = 3.9 Hz), 117.8 (q, JC-F = 4.0 Hz).
19
F NMR (acetone-d6,
471 MHz) δ: -63.4. EI calcd. for C12H9N2O2F3S (M+H) : 302.0337; Found: 302.0324.
+
+
N-(3-Chloro-4-iodophenyl)pyridine-2-sulfonamide
(18).
Compound
18
was
prepared following the typical procedure from 3-chloro-4-iodoaniline (1.01 g,
4.00 mmol) to give 18 as a white solid; yield: 1.10 g (70%);
mp = 205-206 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 9.54 (s,
1H), 8.70 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 8.08 (td, J = 7.6, 1.7
Hz, 1H), 8.03 (dt, J = 7.8, 1.1 Hz, 1H) 7.79 (d, J = 8.6 Hz, 1H), 7.64 (ddd, J = 7.5, 4.7,
1.3 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.7, 2.5 Hz, 1H).
13
C NMR
(acetone-d6, 125 MHz) δ: 157.6, 151.1, 141.5, 140.6, 139.4, 139.2, 128.3, 123.4,
121.6, 121.2, 91.6. EI+ calcd. for C11H8N2O2SClI (M)+: 393.9040; Found: 393.9031.
N-(4-Bromo-3-chlorophenyl)pyridine-2-sulfonamide (19). Compound 19 was
prepared following the typical procedure from 4-bromo-3-chloroaniline (826 mg,
4.00 mmol) to give 19 as a white solid; yield: 1.15 g (83%);
mp = 195-197 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 9.54 (s,
1H), 8.70 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 8.08 (td, J = 7.6, 1.7
Hz, 1H), 8.03 (dt, J = 7.8, 1.1 Hz, 1H), 7.64 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.59 (d, J
= 8.7 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 8.7, 2.6 Hz, 1H).
13
C NMR
(acetone-d6, 125 MHz) δ: 157.6, 151.1, 139.6, 139.4, 135.0, 134.9, 128.3, 123.4,
122.7, 121.3, 117.2. EI+ calcd. for C11H8N2O2SBrCl (M)+: 345.9178; Found: 345.9162.
350
Chapter 6
N-(3,4-Dichlorophenyl)pyridine-2-sulfonamide (20). Compound 20 was prepared
following the typical procedure from 3,4-dichloroaniline (648 mg, 4.00 mmol) to give
19 as a white solid; yield: 1.03 g (85%); mp = 183-184 ºC.
1
H NMR (acetone-d6, 500 MHz) δ: 9.54 (s, 1H), 8.70 (ddd, J
= 4.7, 1.7, 0.9 Hz, 1H), 8.08 (td, J = 7.6, 1.7 Hz, 1H), 8.03 (dt,
J = 7.8, 1.1 Hz, 1H), 7.65 (ddd, J = 7.6, 4.7, 1.3 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H),
7.44 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.8, 2.5 Hz, 1H).
13
C NMR (acetone-d6,
125 MHz) δ: 157.6, 151.1, 139.4, 139.0, 132.9, 131.7, 128.3, 127.9, 123.4, 122.9,
121.3. EI+ calcd. for C11H8N2O2SCl2 (M)+: 301.9684; Found: 301.9689.
4-Methyl-N-phenylbenzenesulfonamide (4). Compound 4 was prepared following
NHTs
the typical procedure from aniline (364 µL, 4.00 mmol) and 4methylbenzenesulfonyl chloride (915 mg, 4.80 mmol, 1.2 equiv) to
give 4 as a white solid; yield: 752 mg (76%); mp = 96-97 ºC. The
analytical data (NMR, GC-MS analysis) matched those reported in the literature for 4methyl-N-phenylbenzenesulfonamide
[CAS: 68-34-8].
1
H NMR
(acetone-d6,
300 MHz) δ: 8.90 (s, 1H), 7.67 (d, J=8.3, 2H), 7.31 (d, J=7.9, 2H), 7.26 – 7.16 (m,
4H), 7.13 – 7.00 (m, 1H), 2.35 (s, 3H).
13
C NMR (CDCl3, 75 MHz) δ: 144.0, 136.7,
136.2, 129.8, 129.4, 127.4, 125.4, 121.6, 21.6.
N-Methyl-N-phenylpyridine-2-sulfonamide (8). Compound 8 was prepared from Nmethylaniline (433 µL, 4.00 mmol), according to the already
described protocol by our group,229 to give 8 as a white solid; yield:
844 mg (85%); mp = 100-102 ºC. The analytical data (NMR, HRMS
analysis) matched those reported in the literature for N-methyl-Nphenylpyridine-2-sulfonamide [CAS: 1352965-24-2]. 1H NMR (acetone-d6, 300 MHz)
δ: 8.78 (dd, J = 4.7, 0.8 Hz, 1H), 8.01 (td, J = 7.8, 1.7 Hz, 1H), 7.74 (d, J = 7.8 Hz,
1H), 7.66 (ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 7.36 – 7.15 (m, 5H), 3.48 (s, 3H). EI+ calcd.
for C12H12N2O2S (M)+: 248.0619; Found: 248.0630.
351
Experimental section
3.1.1.
Typical procedure for the synthesis of N-(pyrimidiyl)sulfonyl of
anilines
Synthesis of N-(4-chloro-2-fluorophenyl)pyrimidine-2-sulfonamide (21-Cl). A
solution
of
2-mercaptopyrimidine
(0.561 g,
5 mmol,
1.00 equiv) in a mixture of CH2Cl2 (25 mL) and a 1 M
solution of HCl having 25 wt % of CaCl2 (25 mL) was stirred
in a 125-mL Erlenmeyer flask for 10 min at −30 to −25 °C
(internal temperature, maintained by intermittent cooling with a dry ice-acetone bath).
Then calcium chloride 6-hydrate (19 g) was dissolved in sodium hypochlorite (6%
solution, 0.74 M, 24 mL, 18 mmol, 3.3 equiv), and the resulting clear solution was
added
dropwise
with
very
rapid
stirring
to
the
original
solution
of
2-
mercaptopyrimidine while maintaining the internal temperature at −30 to −25 °C. The
resulting mixture was stirred for 15 min at −30 to −25 °C (internal temperature) before
it was diluted with of ice/water (25 mL) and transferred to a separatory funnel (precooled with ice water). The organic phase was rapidly separated and collected in a
clean 125-mL Erlenmeyer flask cooled in a dry ice-acetone bath. 2-Chloro-4fluoroaniline (1.49 mL, 12.5 mmol, 2.5 equiv) was added with stirring, whereupon the
mixture became a white suspension. The flask was moved to an ice-water bath and
the suspension was stirred for 30 min at 0 °C. To th e resulting suspension was added
1 M phosphoric acid and the organic phase was successively washed with water and
brine. The combined organic phase was dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash chromatography (n-hexaneEtOAc 2:1) to afford 21-Cl as a pale yellow solid; yield: 2.87 g (80%); mp = 139140 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 8.99 (d, J = 4.8 Hz, 2H), 8.89 (s, 1H), 7.77
(t, J = 4.8 Hz, 1H), 7.66 (dd, J = 9.0, 5.6 Hz, 1H), 7.29 (dd, J = 8.4, 2.9 Hz, 1H), 7.13
(ddd, J = 9.0, 8.0, 2.9 Hz, 1H). 13C NMR (acetone-d6, 75 MHz) δ: 166.5, 161.1 (d, JC-F
= 246.7 Hz), 159.7, 131.7, 130.8 (d, JC-F = 10.7 Hz), 129.2 (d, JC-F = 8.9 Hz), 124.9,
117.6 (d JC-F = 26.2 Hz), 115.5 (d, JC-F = 22.4 Hz). 19F NMR (acetone-d6, 282 MHz) δ:
61.9. EI+ calcd. for C10H7N3O2FSCl (M)+: 286.9932; Found: 286.9924.
352
Chapter 6
N-(2-Bromo-4-methylphenyl)pyrimidine-2-sulfonamide (22). Compound 22 was
prepared following the typical procedure from 2-bromo-4methylaniline (1.55 mL, 12.5 mmol), to give 22 as a white
solid; yield: 3.03 g (74%); mp = 127-129 ºC.
1
H NMR
(acetone-d6, 500 MHz) δ: 8.98 (d, J = 4.9 Hz, 2H), 7.75 (t, J
= 4.9 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 1.9, 0.8 Hz, 1H), 7.14 (ddd, J =
8.3, 2.0, 0.8 Hz, 1H), 2.28 (s, 3H).
C NMR (acetone-d6, 125 MHz) δ: 166.5, 159.7,
13
138.7, 134.0, 133.6, 129.8, 127.0, 124.8, 119.2, 20.4. EI+ calcd. for C11H10N3O2SBr
(M)+: 326.9677; Found: 326.9682.
N-(4-Fluorophenyl)pyrimidine-2-sulfonamide (21). Compound 21 was prepared
following the typical procedure from 4-fluoroaniline (1.18 mL, 12.5 mmol), to give 21
as a white solid solid; yield: 1.72 g (54%); mp = 145-147 ºC.
1
H NMR (acetone-d6, 300 MHz) δ: 9.32 (s, 1H), 8.97 (d, J =
4.9 Hz, 2H), 7.72 (t, J = 4.9 Hz, 1H), 7.38 (dd, J = 9.2 Hz, 4.8,
2H), 7.16 – 6.87 (m, 2H).
C NMR (acetone-d6, 75 MHz) δ: 166.3, 160.7 (d, JC-F =
13
241.9 Hz), 159.7, 134.7 (d, JC-F = 2.9 Hz), 124.8, 124.7, 116.4 (d, JC-F = 22.9 Hz).
19
F NMR (acetone-d6, 282 MHz) δ: 57.8. EI+ calcd. for C10H8N3O2FS (M)+: 253.0321;
Found: 253.0314.
N-(p-Tolyl)pyrimidine-2-sulfonamide (23). Compound 23 was prepared following
the typical procedure from p-toluidine (1.38 mL, 12.5 mmol),
to give 23 as a white solid; yield: 2.54 g (82%); mp = 134135 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 9.23 (s, 1H),
8.96 (d, J = 4.8 Hz, 2H), 7.70 (t, J = 4.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.05 (d, J =
8.1 Hz, 2H), 2.22 (s, 3H).
13
C NMR (acetone-d6, 125 MHz) δ: 166.4, 159.6, 135.9,
135.0, 130.3, 124.6, 122.5, 20.7. EI+ calcd. for C11H11N3O2S (M)+: 249.0572; Found:
249.0569.
353
Experimental section
3.1.2.
Synthesis of N-phenyl-2-pyridinecarboxamide (7).
Compound 7 was synthetized in a 10.0 mmol-scale following the literature
procedure,230 to give 7 as a pale yellow solid; yield: 1.05 g (53%);
mp = 76-77 ºC. The analytical data (NMR, HRMS analysis)
matched those reported in the literature for N-phenyl-2pyridinecarboxamide [CAS: 10354-53-7]. 1H NMR (acetone-d6, 300 MHz) δ: 10.23 (s,
1H), 8.68 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 8.25 (dt, J=7.9, 1.1 Hz, 1H), 8.05 (td, J =
7.7, 1.7 Hz, 1H), 7.94 (dd, J = 8.6, 1.1 Hz, 2H), 7.63 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H),
7.44 – 7.34 (m, 2H), 7.21 – 7.09 (m, 1H). EI+ calcd. for C12H10N2O (M)+: 198.0793;
Found: 198.0794.
6.4.3. General procedures for the copper-catalyzed ortho-halogenation
6.4.3.1. METHOD A: ortho-Chlorination using 1,1,2,2-tetracloroethane as
chlorine source
An oven-dried, nitrogen-flushed 20 mL vessel was charged with the corresponding N(2-pyridyl)sulfonyl aniline (1-3) (0.20 mmol) and copper(II) chloride (5.38 mg,
0.04 mmol, 20 mol%). The reaction vessel was sealed with a Teflon lined cap, then
evacuated and flushed with oxygen three times. Under the atmosphere of oxygen,
Cl2CHCHCl2 (1 mL) and the internal standard n-hexadecane (50 µL) were added via
syringe. After stirring the reaction mixture at 130 °C for 24 h, it was diluted with 5 mL
of CH2Cl2 and filtered through a pad of Celite. The filtrate was washed twice with
brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The
residue was purified by column chromatography (SiO2, n-hexane-ethyl acetate 5:1),
yielding the corresponding ortho-chlorinated product.
N-(2-Chlorophenyl)pyridine-2-sulfonamide (1-Cl). Compound 1-Cl was prepared
following Method A from N-phenylpyridine-2-sulfonamide 1
(46.9 mg, 0.20 mmol), to give 1-Cl as a white solid; yield: 41.9 mg
(78%); mp = 105-106 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 8.70
230
Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255.
354
Chapter 6
(ddd, J = 4.6, 1.7, 1.0 Hz, 1H), 8.59 (s, 1H), 8.05 (tt, J = 7.8, 1.6 Hz, 1H), 8.00 – 7.90
(m, 1H), 7.69 – 7.59 (m, 2H), 7.38 (dd, J = 7.9, 1.5 Hz, 1H), 7.28 (ddd, J = 8.1, 7.4,
1.5 Hz, 1H), 7.20 – 7.12 (m, 1H).
C NMR (acetone-d6, 75 MHz) δ: 158.2, 151.0,
13
139.2, 135.0, 130.5, 128.5, 128.2, 127.9, 127.5, 125.9, 123.2. ESI+ calcd. for
C11H10N2O2SCl (M+H)+: 269.0146; Found: 269.0144.
N-(2-Chloro-4-methoxyphenyl)pyridine-2-sulfonamide (2-Cl). Compound 2-Cl was
prepared following Method A from N-(4-methoxyphenyl)pyridine-2-sulfonamide 2
(52.9 mg, 0.20 mmol) to give 2-Cl as a white solid; yield:
56.1 mg (94%); mp = 131-132 ºC. 1H NMR (acetone-d6,
500 MHz) δ: 8.72 (ddd, J = 4.7, 1.9, 0.9 Hz, 1H), 8.53 (s,
1H), 8.03 (td, J = 7.8, 1.7 Hz, 1H), 7.86 (dt, J = 7.9, 1.0 Hz, 1H), 7.65 (ddd, J = 7.6,
4.7, 1.2 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 2.9 Hz, 1H), 6.86 (dd, J = 8.9,
2.9 Hz, 1H), 3.79 (s, 3H).
C NMR (acetone-d6, 125 MHz) δ: 159.5, 158.5, 151.0,
13
139.1, 131.3, 129.6, 128.0, 127.4, 123.2, 115.5, 114.2, 56.1. EI+ calcd. for
C12H11N2O3SCl (M)+: 298.0179; Found: 298.0173.
N-(2-Chloro-4-(trifluoromethyl)phenyl)pyridine-2-sulfonamide (3-Cl). Compound
3-Cl was prepared following Method A from N-[4-(trifluoromethyl)phenyl]pyridine-2sulfonamide 3 (60.5 mg, 0.20 mmol) to give 3-Cl as a white
solid; yield: 60.0 mg (89%); mp = 109-110 ºC. 1H NMR
(acetone-d6, 500 MHz) δ: 9.01 (s, 1H), 8.71 (ddd, J = 4.7,
1.7, 0.9 Hz, 1H), 8.12 (td, J = 7.7, 1.7 Hz, 1H), 8.05 (dt, J = 7.9, 1.1 Hz, 1H), 7.97 (dd,
J = 8.7, 1.0 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.69 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H),
7.67 – 7.64 (m, 1H). 13C NMR (acetone-d6, 125 MHz) δ: 158.0, 151.2, 139.6, 139.1,
128.6, 127.9 (q, JC-F = 33.4 Hz), 127.6 (q, JC-F = 32.5 Hz), 126.9, 125.6 (q, JC-F = 3.7
Hz), 124.6, 124.4 (q, JC-F = 271.4 Hz), 123.2.
+
19
F NMR (acetone-d6, 282 MHz) δ:
+
114.5. EI calcd. for C12H8N2F3O2SCl (M) : 335.9947; Found: 335.9945.
355
Experimental section
6.4.3.2. METHOD B: ortho-Chlorination using NCS as a source of chlorine
An oven-dried, nitrogen-flushed 20 mL vessel was charged with the corresponding Nprotected aniline (1-20) (0.20 mmol, 1.00 equiv), NCS (32.0 mg, 0.24 mmol,
1.2 equiv) and CuCl2 (2.69 mg, 0.02 mmol, 10 mol%). The reaction vessel was
sealed with a Teflon lined cap, then evacuated and flushed with oxygen three times.
Under the atmosphere of oxygen, MeCN (1 mL) and the internal standard nhexadecane (50 µL) were added via syringe. The resulting mixture was stirred at
100 °C for 4-8 h, depending on the reactivity of th e substrate (indicated for each
case). After the reaction was complete, the volatiles were removed in vacuo and the
residue was purified by column chromatography (n-hexane-EtOAc 5:1), yielding the
corresponding chlorinated products.
N-(2-Chlorophenyl)pyridine-2-sulfonamide (1-Cl). Compound 1-Cl was prepared
following Method B (reaction time: 4 h) from N-phenylpyridine-2sulfonamide 1 (46.9 mg, 0.20 mmol), to give 1-Cl as a white solid;
yield: 51.0 mg (95%); mp = 105-106 ºC. For the analytical data
(NMR, HRMS analysis) see compound 1-Cl described in Method A.
N-(4-Chlorophenyl)-4-methylbenzenesulfonamide (4-Cl). Compound 4-Cl was
NHTs
prepared following Method B (reaction time: 4 h) from 4-methylN-phenylbenzenesulfonamide 4 (49.5 mg, 0.20 mmol) to give 4-
Cl
Cl as a white solid; yield: 55.0 mg (97%). 1H NMR (acetone-d6,
500 MHz) δ: 9.06 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.27 (d, J
= 9.0 Hz, 2H), 7.22 (d, J = 9.1 Hz, 2H), 2.35 (s, 3H). 13C NMR (acetone-d6, 125 MHz)
δ: 144.6, 137.8, 137.7, 130.5, 130.1, 129.9, 128.0, 123.0, 21.36.
N-(2,6-dichlorophenyl)acetamide (5-Cl). Compound 5-Cl was detected when Nphenylacetamide 5 (27.0 mg, 0.20 mmol) was used following
Method B (reaction time: 4 h). MS: m/z (%) = 203 (100), 205(64),
207 (13), 204 (9), 206 (5).
356
Chapter 6
N-(4-Chlorophenyl)-2-pyridinecarboxamide (7-Cl). Compound 7-Cl was prepared
following Method B (reaction time: 4 h) from N-phenyl-2pyridinecarboxamide 7 (39.6 mg, 0.20 mmol) to give 7-Cl as
a white solid; yield: 32.0 mg (69%). 1H NMR (acetone-d6,
300 MHz) δ: 10.34 (s, 1H), 8.68 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 8.24 (dt, J = 7.8, 1.1
Hz, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.64 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.41 (d, J = 8.9
Hz, 2H).
C NMR (acetone-d6, 75 MHz) δ: 163.1, 150.7, 149.2, 138.9, 138.4, 129.6,
13
129.1, 127.7, 123.1, 122.2.
N-Methyl-N-(4-chlorophenyl)pyridine-2-sulfonamide (8-Cl). Compound 8-Cl was
prepared
following
Method
B
(reaction
time:
4
h;
chromatography eluents: n-hexane-EtOAc 5:1) from N-methylN-phenylpyridine-2-sulfonamide 8 (49.7 mg, 0.20 mmol) to
give 8-Cl as a white solid; yield: 51.0 mg (90%). 1H NMR
(acetone-d6, 300 MHz) δ: 8.77 (ddd, J = 4.6, 1.7, 0.9 Hz, 1H), 8.04 (td, J = 7.8, 1.7
Hz, 1H), 7.79 (dt, J = 7.8, 1.1 Hz, 1H), 7.67 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.37 –
7.26 (m, 4H), 3.46 (s, 3H).
13
C NMR (acetone-d6, 75 MHz) δ: 157.7, 151.0, 141.6,
139.2, 132.9, 129.7, 129.2, 128.1, 123.9, 40.0.
N-(2-Chloro-4-methoxyphenyl)pyridine-2-sulfonamide (2-Cl). Compound 2-Cl was
prepared following Method B (reaction time: 4 h) from N-(4-methoxyphenyl)pyridine2-sulfonamide 2 (52.9 mg, 0.20 mmol) to give 2-Cl as a
white solid; yield: 53.1 mg (89%). For the analytical data
(NMR, HRMS analysis), see compound 2-Cl in Method A.
N-(2-Chloro-4-methylphenyl)pyridine-2-sulfonamide (9-Cl). Compound 9-Cl was
prepared following Method B (reaction time: 4 h) from N-(p-tolyl)pyridine-2sulfonamide 9 (49.7 mg, 0.20 mmol) to give 9-Cl as a white
solid; yield: 44.0 mg (78%); mp = 128-129 ºC.
1
H NMR
(acetone-d6, 300 MHz) δ: 8.74 – 8.67 (m, 1H), 8.53 (s, 1H),
8.04 (td, J = 7.7, 1.8 Hz, 1H), 7.91 (dt, J = 7.6, 1.1 Hz, 1H), 7.64 (ddd, J = 7.4, 4.6,
1.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.0
357
Experimental section
Hz, 1H), 2.26 (s, 3H).
C NMR (acetone-d6, 125 MHz) δ: 158.3, 151.0, 139.1, 138.1,
13
132.2, 130.7, 129.1, 128.5, 128.0, 126.6, 123.2, 20.5. EI+ calcd. for C12H11N2O2SCl
(M)+: 282.0230; Found: 282.0233.
N-(2-Chloro-4-iodophenyl)pyridine-2-sulfonamide (10-Cl). Compound 10-Cl was
NHSO2Py
prepared following Method B (reaction time: 4 h); from N-(4iodophenyl)pyridine-2-sulfonamide 10 (72.0 mg, 0.20 mmol) to
I
Cl
give 10-Cl as a white solid; yield: 46.0 mg (58%); mp = 102-
103 ºC. H NMR (acetone-d6, 500 MHz) δ: 8.79 (s, 1H), 8.70 (ddd, J = 4.6, 1.8, 0.9
1
Hz, 1H), 8.07 (td, J = 7.8, 1.7 Hz, 1H), 7.97 (dt, J = 7.9, 1.0 Hz, 1H), 7.74 (d, J = 2.0
Hz, 1H), 7.70 – 7.63 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H).
13
C NMR (acetone-d6,
125 MHz) δ: 158.0, 151.0, 139.3, 138.5, 137.6, 135.3, 129.0, 128.3, 127.6, 123.2,
89.6. EI+ calcd. for C11H8N2O2SClI (M)+: 393.9040; Found: 393.9048.
N-(4-Bromo-2-chlorophenyl)pyridine-2-sulfonamide (11-Cl). Compound 11-Cl
was prepared following Method B (reaction time: 4 h) from N(4-bromophenyl)pyridine-2-sulfonamide
11
(62.6 mg,
0.20 mmol) to give 11-Cl as a white solid; yield: 42.0 mg
(61%); mp = 163-165 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 8.76 (s, 1H), 8.71 (d, J =
3.6 Hz, 1H), 8.09 (tt, J = 7.5, 1.7 Hz, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.73 – 7.60 (m,
1H), 7.65 – 7.56 (m, 2H), 7.49 (dt, J = 8.7, 2.0 Hz, 1H).
13
C NMR (acetone-d6,
125 MHz) δ: 158.1, 151.1, 139.4, 134.7, 132.8, 131.6, 129.3, 128.3, 127.7, 123.2,
119.1. EI+ calcd. for C11H8N2O2SClBr (M)+: 345.9178; Found: 345.9169.
N-(2,4-dichlorophenyl)pyridine-2-sulfonamide (12-Cl). Compound 12-Cl was
prepared following Method B (reaction time: 4 h) from N-(4chlorophenyl)pyridine-2-sulfonamide
12
(53.7 mg,
0.20 mmol) to give 12-Cl as a white solid; yield: 46.0 mg
(76%); mp = 110-111 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 8.79 (s, 1H), 8.70 (ddd,
J = 4.7, 1.7, 0.9 Hz, 1H), 8.08 (td, J = 7.8, 1.7 Hz, 1H), 7.96 (dt, J = 7.8, 1.0 Hz, 1H),
7.70 – 7.64 (m, 2H), 7.47 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H). 13C NMR
358
Chapter 6
(acetone-d6, 125 MHz) δ: 158.1, 151.1, 139.4, 134.3, 131.8, 130.0, 129.2, 128.7,
128.3, 127.5, 123.2. EI+ calcd. for C11H8N2O2SCl2 (M)+: 301.9684; Found: 301.9681.
N-(2-Chloro-4-fluorophenyl)pyridine-2-sulfonamide (13-Cl). Compound 13-Cl was
prepared following Method B (reaction time: 4 h) from N-(4fluorophenyl)pyridine-2-sulfonamide 13 (50.5 mg, 0.20 mmol)
to give 13-Cl as a white solid; yield: 46.0 mg (80%); mp = 9798 ºC. H NMR (acetone-d6, 500 MHz) δ: 8.75 – 8.68 (m, 2H), 8.06 (td, J = 7.8, 1.7
1
Hz, 1H), 7.91 (dd, J = 7.9, 2.5 Hz, 1H), 7.70 – 7.59 (m, 2H), 7.25 (dt, J = 8.4, 2.7 Hz,
1H), 7.13 (ddt, J = 9.0, 7.9, 2.7 Hz, 1H). 13C NMR (acetone-d6, 125 MHz) δ: 161.1 (d,
JC-F = 161.1 Hz), 158.31 (s), 151.0, 139.3, 131.6 (d, JC-F =3.4 Hz), 130.5 (d, JC-F =
10.9 Hz), 129.1 (d, JC-F = 9.2 Hz), 128.2, 123.1, 117.5 (d, JC-F = 26.2 Hz), 115.5 (d, J
= 22.4 Hz). 19F NMR (acetone-d6, 471 MHz) δ: -115.7. EI+ calcd. for C11H8N2O2FSCl
(M)+: 285.9979; Found: 285.9991.
N-(2-Chloro-4-(trifluoromethyl)phenyl)pyridine-2-sulfonamide (3-Cl). Compound
3-Cl was prepared following Method B (reaction time: 4 h)
from N-[4-(trifluoromethyl)phenyl]pyridine-2-sulfonamide 3
(60.5 mg, 0.20 mmol) to give 3-Cl as a white solid; yield:
54.0 mg (80%). For the analytical data (NMR, HRMS analysis) see compound 3-Cl in
Method A.
Methyl 3-chloro-4-(pyridine-2-sulfonamido)benzoate (14-Cl). Compound 14-Cl
was prepared following Method B (reaction time: 4 h)
from methyl 4-[N-(2-pyridyl)sulfonylamino]benzoate 14
(58.5 mg, 0.20 mmol) to give 14-Cl as a white solid;
yield: 56.0 mg (86%); mp = 129-130 ºC.
1
H NMR
(acetone-d6, 500 MHz) δ: 8.94 (s, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.10 (td, J = 7.7, 1.7
Hz, 1H), 8.05 (dt, J = 7.9, 1.1 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 8.6, 1.8
Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.67 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 3.86 (s, 3H).
13
C NMR (acetone-d6, 125 MHz) δ: 165.6, 157.8, 151.1, 139.5, 139.5, 131.3, 129.5,
359
Experimental section
128.5, 128.3, 126.0, 123.4, 123.3, 52.6. EI+ calcd. for C13H11N2O4SCl (M)+: 326.0128;
Found: 326.0116.
N-(2-chloro-3-fluorophenyl)pyridine-2-sulfonamide (15-Cl). Compound 15-Cl was
prepared following Method B (reaction time: 8 h) from N-(3fluorophenyl)pyridine-2-sulfonamide 15 (50.5 mg, 0.20 mmol)
to give 15-Cl as a white solid; yield: 45.0 mg (78%); mp = 114116 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 8.81 (s, 1H), 8.72
(ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 8.10 (td, J = 7.7, 1.7 Hz, 1H), 8.03 (dt, J = 7.9, 1.1 Hz,
1H), 7.68 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.55 (dd, J = 10.4, 3.0 Hz, 1H), 7.43 (dd, J =
8.9, 5.7 Hz, 1H), 6.97 (ddd, J = 8.9, 7.9, 3.0 Hz, 1H).
13
C NMR (acetone-d6,
125 MHz) δ: 162.1 (d, JC-F = 244.3 Hz), 157.9, 151.1, 139.5, 136.6 (d, JC-F = 11.3 Hz),
131.6 (d, JC-F = 9.4 Hz), 128.4, 123.2, 122.2 (d, JC-F = 3.5 Hz), 113.9 (d, JC-F = 23.3
Hz), 112.0 (d, JC-F = 27.6 Hz).
19
F NMR (acetone-d6, 471 MHz) δ: -114.4. EI+ calcd.
for C11H8N2O2FSCl (M)+: 285.9979; Found: 285.9989.
N-(2-chloro-5-isopropylphenyl)pyridine-2-sulfonamide (16-Cl). Compound 16-Cl
iPr
NHSO2Py
was prepared following Method B (reaction time: 8 h) from
N-(3-isopropylphenyl)pyridine-2-sulfonamide 16 (55.3 mg,
Cl
0.20 mmol) to give 16-Cl as a white solid; yield: 32.0 mg
(52%); mp = 136-137 ºC. This compound could not be completely purified from
presumably minor chlorinated side products. 1H NMR (acetone-d6, 500 MHz) δ: 8.72
(ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 8.57 (s, 1H), 8.11 – 8.02 (m, 1H), 7.96 (dt, J = 7.8, 1.0
Hz, 1H), 7.65 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.3
Hz, 1H), 7.04 (dd, J = 8.3, 2.1 Hz, 1H), 2.78 (s, 1H), 1.16 (d, J = 6.9 Hz, 6H).
13
C NMR (acetone-d6, 125 MHz) δ: 158.2, 151.0, 149.5, 139.2, 134.7, 130.2, 128.1,
125.7, 125.2, 124.0, 123.4, 34.3, 24.0. EI+ calcd. for C14H15N2O2SCl (M)+: 310.0543;
Found: 310.0536.
360
Chapter 6
N-(2-chloro-3-(trifluoromethyl)phenyl)pyridine-2-sulfonamide and N-(2-chloro-5(trifluoromethyl)phenyl)pyridine-2-sulfonamide
(17-Cl).
Following
Method
B
(reaction time: 8 h) from N-[3(trifluoromethyl)phenyl]pyridine-2sulfonamide
17
0.20 mmol)
a
(60.4 mg,
mixture
of
regioisomers 17-Cl was obtained in a 1:1 ratio, as a white solid; yield: 39.0 mg (58%).
1
H NMR (acetone-d6, 300 MHz) δ: 9.02 (s, 1H), 8.85 – 8.52 (m, 1H), 8.31 – 7.91 (m,
3H), 7.87 – 7.58 (m, 2H), 7.58 – 7.36 (m, 1H). MS: m/z (%)
N-(2,3-dichloro-4-iodophenyl)pyridine-2-sulfonamide (18-Cl). Compound 18-Cl
was prepared following Method B (reaction time: 8 h) from N-
Cl
Cl
NHSO2Py
(3-chloro-4-iodophenyl)pyridine-2-sulfonamide 18 (78.9 mg,
0.20 mmol) to give 18-Cl as a white solid; yield: 50.0 mg
I
(58%); mp = 152-154 ºC. 1H NMR (acetone-d6, 500 MHz) δ:
9.73 (s, 1H), 9.49 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.88 (td, J = 7.7, 1.7 Hz, 1H), 8.79
(dt, J = 7.9, 1.1 Hz, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.47 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H),
8.26 (d, J = 8.7 Hz, 1H).
C NMR (acetone-d6, 125 MHz) δ: 158.0, 151.1, 139.5,
13
139.1, 137.5, 137.4, 128.4, 126.3, 125.0, 123.2, 94.4. EI+ calcd. for C11H7N2O2SCl2I
(M)+: 427.8650; Found: 427.8645.
N-(4-Bromo-2,3-dichlorophenyl)pyridine-2-sulfonamide (19-Cl). Compound 19-Cl
was prepared following Method B (reaction time: 8 h) from N-
Cl
Cl
NHSO2Py
(4-bromo-3-chlorophenyl)pyridine-2-sulfonamide
19
(69.5 mg, 0.20 mmol) to give 19-Cl as a white solid; yield:
Br
46.0 mg (60%); mp = 144-145 ºC.
1
H NMR (acetone-d6,
500 MHz) δ:9.00 (s, 1H), 8.70 (ddd, J = 4.5, 1.6, 0.8 Hz, 1H), 8.09 (td, J = 7.8, 1.7 Hz,
1H), 8.00 (dt, J = 7.8, 1.0 Hz, 1H), 7.80 – 7.66 (m, 2H), 7.63 (d, J = 8.9 Hz, 1H).
13
C NMR (acetone-d6, 125 MHz) δ: 158.0, 151.1, 139.5, 136.6, 133.8, 132.7, 128.4,
128.0, 125.0, 123.2, 119.9. EI+ calcd. for C11H7N2O2SCl2Br (M)+: 379.8789; Found:
379.8797.
361
Experimental section
N-(2,3,4-Trichlorophenyl)pyridine-2-sulfonamide (20-Cl). Compound 20-Cl was
prepared following Method B
(reaction time: 8 h) from N-
(3,4-dichlorophenyl)pyridine-2-sulfonamide
20
(78.9 mg,
0.20 mmol) to give 20-Cl as a white solid; yield: 55.0 mg
(64%); mp = 131-132 ºC. 1H NMR (acetone-d6, 300 MHz) δ:
8.97 (s, 1H), 8.70 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 8.10 (td, J = 7.8, 1.7 Hz, 1H), 7.99
(dt, J = 7.9, 1.1 Hz, 1H), 7.75 – 7.61 (m, 2H), 7.55 (td, J = 9.0 Hz, 1H).
13
C NMR
(acetone-d6, 125 MHz) δ: 158.0, 151.1, 139.5, 135.9, 132.0, 131.5, 130.8, 129.4,
128.4, 124.8, 123.2. EI+ calcd. for C11H7N2O2SCl3 (M)+: 335.9294; Found: 335.9305.
6.4.3.3. METHOD C: ortho-Bromination using NBS as a source of bromine
Method C is analogous to the previous NCS-chlorination (Method B), but using NBS
as brominating agent and a range of reaction time of 8-16 h, depending on the
reactivity of the substrate. The following amounts were used: N-(2-pyridyl)sulfonyl
aniline 2-3, 9-15, or 20 (0.20 mmol), NBS (42.7 mg, 0.24 mmol, 1.20 equiv), CuBr2
(4.47 mg, 0.02 mmol, 10 mol%), n-hexadecane (50 µL) and MeCN (1.00 mL). After
the reaction was complete, the volatiles were removed in vacuo and the residue was
purified by column chromatography (n-hexane-EtOAc 5:1), yielding the corresponding
N-(2-bromophenyl)pyridine-2-sulfonamides.
N-(2-Bromo-4-methoxyphenyl)pyridine-2-sulfonamide (2-Br). Compound 2-Br
was prepared following Method C (reaction time 16 h) from
N-(4-methoxyphenyl)pyridine-2-sulfonamide
2
(52.9 mg,
0.20 mmol), copper(II) bromide (8.94 mg, 0.04 mmol,
20 mol%) and DMF (1.00 mL) at 150 ºC, to give 2-Br as a white solid; yield: 60.3 mg
(88%); mp = 136-137 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 8.71 (ddd, J = 4.6, 1.7,
0.8 Hz, 1H), 8.38 (s, 1H), 8.10 – 7.94 (m, 1H), 7.86 (dt, J = 7.9, 1.0 Hz, 1H), 7.64
(ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.40 (dd, J = 8.9, 1.0 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H),
6.90 (ddd, J = 8.9, 2.8, 1.0 Hz, 1H), 3.79 (s, 3H).
C NMR (acetone-d6, 75 MHz) δ:
13
159.5, 158.6, 151.0, 139.1, 129.5, 128.9, 127.9, 123.2, 121.5, 118.7, 114.8, 56.1. EI+
calcd. for C12H11N2O3SBr (M)+: 341.9674; Found: 341.9675.
362
Chapter 6
N-(2-Bromo-4-methylphenyl)pyridine-2-sulfonamide (9-Br). Compound 9-Br was
prepared following Method C (reaction time: 8 h) from N-(ptolyl)pyridine-2-sulfonamide 9 (49.7 mg, 0.10 mmol) to give
9-Br as a white solid; yield: 35.0 mg (71%); mp = 120121 ºC. H NMR (acetone-d6, 500 MHz) δ: 8.71 (dd, J = 3.8, 1.0 Hz, 1H), 8.36 (s,
1
1H), 8.04 (td, J = 7.8, 1.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.1 Hz, 1H), 7.65 (ddd, J = 7.6,
4.7, 1.2 Hz, 1H), 7.44 (dd, J = 8.2, 3.4 Hz, 1H), 7.37 (s, 1H), 7.13 (dd, J = 8.3, 2.0 Hz,
1H), 2.27 (s, 3H).
C NMR (acetone-d6, 125 MHz) δ: 158.3, 151.0, 139.2, 138.5,
13
134.0, 133.6, 129.8, 128.1, 126.7, 123.3, 119.0, 20.40. EI+ calcd. for C12H11N2O2SBr
(M)+: 325.9725; Found: 325.9738.
N-(2-Bromo-4-iodophenyl)pyridine-2-sulfonamide (10-Br). Compound 10-Br was
prepared following Method C (reaction time: 8 h) from N-(4iodophenyl)pyridine-2-sulfonamide 10 (72.0 mg, 0.20 mmol) to
give 10-Br as a white solid; yield: 50.0 mg (57%); mp = 111112 ºC. H NMR (acetone-d6, 500 MHz) δ: 8.70 (ddd, J = 4.7, 1.6, 0.8, 1H), 8.56 (s,
1
1H), 8.13 – 8.03 (m, 1H), 8.01 – 7.94 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.75 – 7.62
(m, 2H), 7.45 (d, J = 8.6 Hz, 1H).
C NMR (acetone-d6, 125 MHz) δ: 158.1, 151.1,
13
141.5, 139.4, 138.3, 136.7, 128.3, 127.8, 123.24, 119.4, 100.9, 90.1. EI+ calcd. for
C11H8N2O2SBrI (M)+: 437.8535; Found: 437.8553.
N-(2,4-Dibromophenyl)pyridine-2-sulfonamide (11-Br). Compound 11-Br was
prepared following Method C (reaction time: 8 h) from N-(4-bromophenyl)pyridine-2sulfonamide 11 (62.6 mg, 0.2 mmol) to give 11-Br as a white
solid; yield: 67.0 mg (85%); mp = 101-102 ºC.
1
H NMR
(acetone-d6, 500 MHz) δ: 8.71 (ddd, J = 4.7, 1.6, 0.9 Hz,
1H), 8.59 (s, 1H), 8.08 (td, J = 7.8, 1.7 Hz, 1H), 7.96 (dt, J = 7.9, 1.0 Hz, 1H), 7.75 (d,
J = 2.2 Hz, 1H), 7.67 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.53
(dd, J = 8.7, 2.3 Hz, 1H).
13
C NMR (acetone-d6, 75 MHz) δ: 158.1, 151.1, 139.4,
136.0, 135.8, 132.2, 128.3, 127.9, 123.2, 119.5, 119.5. EI+ calcd. for C11H8N2O2SBr2
(M)+: 389.8673; Found: 389.8684.
363
Experimental section
N-(2-Bromo-4-chlorophenyl)pyridine-2-sulfonamide (12-Br). Compound 12-Br
was
prepared
following
Method
C
(reaction
time:
chlorophenyl)pyridine-2-sulfonamide
8 h)
12
from
(53.7 mg,
N-(40.20
mmol) to give 12-Br as a white solid; yield: 31.0 mg (45%);
mp = 103-104 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 8.71
(ddd, J = 4.7, 1.6, 0.8 Hz, 1H), 8.60 (s, 1H), 8.08 (td, J = 7.8, 1.7 Hz, 1H), 7.96 (dt, J
= 7.8, 1.0 Hz, 1H), 7.68 (d, J = 1.1 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 2.4
Hz, 1H), 7.40 (dd, J = 8.7, 2.4 Hz, 1H).
C NMR (acetone-d6, 75 MHz) δ: 158.1,
13
151.1, 139.4, 135.6, 133.1, 132.1, 129.2, 128.3, 127.7, 123.2, 119.4. EI+ calcd. for
C11H8N2O2SClBr (M)+: 345.9178; Found: 345.9180.
N-(2-Bromo-4-fluorophenyl)pyridine-2-sulfonamide (13-Br). Compound 13-Br
was prepared following Method C (reaction time: 8 h) from N(4-fluorophenyl)pyridine-2-sulfonamide
13
(50.5 mg,
0.20 mmol) to give 13-Br as a white solid; yield: 52.0 mg
(79%); mp = 111-112 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 8.71 (ddd, J = 4.7, 1.8,
1.0 Hz, 1H), 8.58 (s, 1H), 8.06 (td, J = 7.8, 1.7 Hz, 1H), 7.92 (dd, J = 7.9, 1.1 Hz, 1H),
7.67 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 7.62 (dd, J = 9.0, 5.5 Hz, 1H), 7.41 (dd, J = 8.2,
2.9 Hz, 1H), 7.17 (ddd, J = 9.1, 8.0, 2.9 Hz, 1H).
C NMR (acetone-d6, 125 MHz) δ:
13
161.1 (d, JC-F = 248.2 Hz), 158.3, 151.1, 139.3, 133.0 (d, JC-F = 3.3 Hz), 129.2 (d, JC-F
= 8.9 Hz), 128.2, 123.2, 120.6 (d, JC-F = 25.8 Hz), 120.5, 116.0 (d, JC-F = 22.4 Hz).
19
F NMR (acetone-d6, 471 MHz) δ: -115.6. EI+ calcd. for C11H8N2O2FSBr (M)+:
329.9474; Found: 329.9463.
N-(2-Bromo-4-(trifluoromethyl)phenyl)pyridine-2-sulfonamide (3-Br). Compound
3-Br was prepared following Method C (reaction time: 8 h)
from N-(4-(trifluoromethyl)phenyl)pyridine-2-sulfonamide 3
(60.5 mg, 0.20 mmol) to give 3-Br as a white solid; yield:
71.0 mg (83%); mp = 88-89 ºC. 1H NMR (acetone-d6, 500 MHz) δ: 8.78 (s, 1H), 8.74
– 8.69 (m, 1H), 8.12 (td, J = 7.8, 1.7 Hz, 1H), 8.05 (dd, J = 7.9, 1.3 Hz, 1H), 7.94 (d, J
= 8.6 Hz, 1H), 7.92 (s, 1H), 7.73 – 7.67 (m, 2H).
C NMR (acetone-d6, 125 MHz) δ:
13
157.9, 151.2, 140.4, 139.6, 130.8 (q, JC-F = 3.8 Hz), 128.6, 128.4 (q, JC-F = 33.4 Hz),
364
Chapter 6
126.3 (q, JC-F = 3.8 Hz), 124.9, 124.2 (q, JC-F = 271.5 Hz), 123.3, 117.0.
+
19
F NMR
+
(acetone-d6, 471 MHz) δ: -62.9. EI calcd. for C12H8N2O2F3SBr (M) : 379.9442;
Found: 379.9423.
Methyl 3-bromo-4-(pyridine-2-sulfonamido)benzoate (14-Br). Compound 14-Br
was prepared following Method C (reaction time: 8 h)
from methyl 4-[N-(2-pyridyl)sulfonylamino]benzoate 14
(58.5 mg, 0.20 mmol) to give 14-Br as a white solid;
yield: 64.0 mg (86%); mp = 145-146 ºC.
1
H NMR
(acetone-d6, 500 MHz) δ: 8.70 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.67 (s, 1H), 8.14 –
8.08 (m, 2H), 8.05 (dt, J = 7.9, 1.1 Hz, 1H), 7.93 (dd, J = 8.6, 1.9 Hz, 1H), 7.84 (d, J =
8.6 Hz, 1H), 7.68 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 3.87 (s, 3H).
13
C NMR (acetone-d6,
75 MHz) δ: 165.4, 157.8, 151.2, 140.7, 139.5, 134.7, 130.2, 128.8, 128.5, 123.7,
123.4, 116.2, 52.6. EI+ calcd. for C13H11N2O4SBr (M)+: 369.9623; Found: 369.9638.
N-(2-Bromo-3-fluorophenyl)pyridine-2-sulfonamide (15-Br). Compound 15-Br
was prepared following Method C (reaction time: 16 h) from N(3-fluorophenyl)pyridine-2-sulfonamide
15
(50.5 mg,
0.20 mmol) to give 15-Br as a white solid; yield: 42.0 mg
(64%). This compound could not be completely purified from
presumably minor brominated side products. 1H NMR (acetone-d6, 500 MHz) δ: 9.59
(s, 1H), 8.70 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.13 – 8.06 (m, 1H), 8.06 – 8.02 (m, 1H),
7.65 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.52 (dd, J = 8.7, 7.9 Hz, 1H), 7.27 (dd, J = 10.6,
2.5 Hz, 1H), 7.09 (ddd, J = 8.8, 2.5, 1.0 Hz, 1H).
C NMR (acetone-d6, 125 MHz) δ:
13
159.7 (d, JC-F = 244.7 Hz), 157.6, 140.2 (d, JC-F = 9.7 Hz), 139.4, 137.0, 128.5, 128.3,
123.5, 118.3 (d, JC-F = 3.3 Hz), 113.3 (d, JC-F = 27.9 Hz), 109.2 (d, JC-F = 26.6 Hz),
103.5 (d, JC-F = 20.9 Hz).
19
F NMR (acetone-d6, 471 MHz) δ: -107.3. EI+ calcd. for
C11H8N2O2FSBr (M)+: 329.9474; Found: 329.9472.
365
Experimental section
N-(2-Bromo-3,4-dichlorophenyl)pyridine-2-sulfonamide (20-Br). Compound 20-Br
was prepared following Method C (reaction time: 16 h) from
Br
Cl
N-(3,4-dichlorophenyl)pyridine-2-sulfonamide 20 (60.6 mg,
NHSO2Py
0.20 mmol) to give 20-Br as a white solid; yield: 46.0 mg
(60%); mp = 176-178 ºC. 1H NMR (acetone-d6, 500 MHz) δ:
Cl
8.76 (s, 1H), 8.70 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 8.09 (td, J = 7.8, 1.7 Hz, 1H), 7.99
(dd, J = 7.8, 1.0 Hz, 1H), 7.73 – 7.65 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H).
13
C NMR
(acetone-d6, 125 MHz) δ: 158.1, 151.1, 139.5, 137.7, 133.9, 130.6, 130.1, 128.4,
125.1, 123.2, 120.76. ESI+ calcd. for C11H7N2O2SCl2Br (M)+: 379.8789; Found:
379.8788.
6.4.3.4. Method D: ortho-iodination using NIS as a source of iodine.
Method D is analogous to NCS-chlorination (Method B), but using NIS as iodine
source and Cu(OAc)2 instead of CuCl2 (reaction time: 24 h). The following amounts
were used: N-(2-pyridyl)sulfonyl aniline (3, 14) (0.20 mmol), NIS (54.0 mg,
0.24 mmol, 1.20 equiv), Cu(OAc)2 (7.27 mg, 0.04 mmol, 20 mol%), n-hexadecane
(50 µL) and MeCN (1.00 mL). After the reaction was complete, the volatiles were
removed in vacuo and the residue was purified by column chromatography (nhexane-EtOAc
5:1),
yielding
the
corresponding
N-(2-iodophenyl)pyridine-2-
sulfonamides.
N-(2-Iodo-4-(trifluoromethyl)phenyl)pyridine-2-sulfonamide (3-I). Compound 3-I
was prepared following Method D from N-[4-(trifluoromethyl)phenyl]pyridine-2sulfonamide 3 (60.5 mg, 0.20 mmol) to give 3-I as a white
solid; yield: 52.0 mg (60%); mp = 100-102 ºC. 1H NMR
(acetone-d6, 500 MHz) δ: 8.72 (ddd, J = 4.5, 1.6, 0.9 Hz,
1H), 8.52 (s, 1H), 8.17 – 8.08 (m, 2H), 8.07 – 8.00 (m, 1H), 7.87 – 7.80 (m, 1H), 7.75
– 7.66 (m, 2H).
13
C NMR (acetone-d6, 125 MHz) δ: 158.0, 151.2, 143.3, 139.6, 137.2
(q, JC-F = 4.0 Hz), 128.8 (q, JC-F = 32.9 Hz), 128.5, 127.1 (q, JC-F = 3.7 Hz), 124.7,
124.0 (q, JC-F = 271.7 Hz), 123.3, 93.5.
19
F NMR (acetone-d6, 471 MHz) δ: -62.9. EI+
calcd. for C12H8N2O2F3SI (M)+: 427.9303; Found: 427.9318.
366
Chapter 6
Methyl 3-iodo-4-(pyridine-2-sulfonamido)benzoate (14-I). Compound 14-I was
prepared following Method D from methyl 4-[N-(2-pyridyl)sulfonylamino]benzoate 14
(58.5 mg, 0.20 mmol), yielding 14-I as a white solid;
yield: 42.0 mg (50%); mp = 155-156 ºC.
1
H NMR
(acetone-d6, 500 MHz) δ: 8.71 (ddd, J = 4.7, 1.7, 0.9 Hz,
1H), 8.40 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.10 (td, J = 7.8, 1.7 Hz, 1H), 8.05 – 8.01
(m, 1H), 7.95 (dd, J = 8.5, 2.0 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.69 (ddd, J = 7.6,
4.7, 1.2 Hz, 1H), 3.86 (s, 3H).
13
C NMR (acetone-d6, 75 MHz) δ: 165.3, 157.8, 151.2,
143.6, 141.4, 139.5, 131.0, 129.2, 128.5, 123.6, 123.4, 92.6, 52.6. EI+ calcd. for
C13H11N2O4SI (M)+: 417.9484; Found: 417.9500.
6.4.3.5. Method E: N-(2-pyrimidyl)sulfonyl-directed copper-catalyzed orthoclorination.
Method E is analogous to the NCS-chlorination of N-(2-pyridyl)sulfonyl anilines
(Method B), but switching to N-(pyrimidyl)sulfonyl aniline as substrate and with a
reaction time of 16 h. The following amounts were used: N-(pyrimidil)sulfonyl aniline
(21, 21-Cl, 22-23) (0.20 mmol), CuCl2 (8.1 mg, 0.06 mmol, 30 mol%), n-hexadecane
(50 µL). The solvent used [MeCN or DMF (1.00 mL)], the temperature (130 ºC or
150 ºC) and the exact amount of NCS would be specified in each case. After the
reaction was complete, the volatiles were removed in vacuo and the residue was
purified by column chromatography (n-hexane-EtOAc 2:1), yielding the corresponding
N-(2-chlorophenyl)pyrimidine-2-sulfonamides.
N-(2,6-dichloro-4-fluorophenyl)pyrimidine-2-sulfonamide (21-Cl2). Compound 21Cl2 was prepared following Method E from N-(4-chloro-2fluorophenyl)pyrimidine-2-sulfonamide 21-Cl (65.6 mg, 0.20
mmol) and NCS (32.0 mg, 0.24 mmol, 1.2 equiv), in MeCN at
130 ºC, to give 21-Cl2 as a white solid; yield: 56.6 mg (78%);
mp = 187-188 ºC. 1H NMR (acetone-d6, 300 MHz) δ: 9.00 (d, J = 4.8 Hz, 2H), 7.77 (t,
J = 4.9 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H).
C NMR (acetone-d6, 125 MHz) δ: 167.1,
13
161.6 (d, JC-F = 252.1 Hz), 159.5, 138.0 (d, JC-F = 12.4 Hz), 129.8 (d, JC-F = 4.3 Hz),
367
Experimental section
124.7, 117.2 (d, JC-F = 25.7 Hz).
19
F NMR (acetone-d6, 282 MHz) δ: 66.3. EI+ calcd.
for C10H6N3O2FCSCl2 (M)+: 320.9542; Found: 320.9527.
N-(2-Bromo-6-chloro-4-methylphenyl)pyrimidine-2-sulfonamide
(22-Cl).
Com-
pound 22-Cl was prepared following Method E from N-(2bromo-4-methylphenyl)pyrimidine-2-sulfonamide
22
(65.6 mg, 0.20 mmol) and NCS (32.0 mg, 0.24 mmol,
1.2 equiv), in DMF at 150 ºC, to give 22-Cl as a white solid;
yield: 58.0 mg (80%); mp = 198-200 ºC. 1H NMR (acetone-d6, 500 MHz) δ:9.89 (s,
1H), 8.99 (d, J = 4.8 Hz, 2H), 7.75 (t, J = 4.9 Hz, 1H), 7.45 (d, J = 1.1 Hz, 1H), 7.30
(dd, J = 1.8, 0.8 Hz, 1H), 2.33 (s, 3H).
13
C NMR (acetone-d6, 125 MHz) δ: 178.9,
167.2, 159.4, 142.1, 136.3, 133.4, 131.3, 130.7, 126.9, 124.6, 20.4. EI+ calcd. for
C11H9N3O2SClBr (M)+: 360.9287; Found: 360.9304.
N-(2,6-dichloro-4-fluorophenyl)pyrimidine-2-sulfonamide (21-Cl2). Compound 20Cl2
was
prepared
following
Method
fluorophenyl)pyrimidine-2-sulfonamide
E
21
from
N-(4-
(50.6 mg,
0.20 mmol) and NCS (64.1 mg, 0.48 mmol, 2.4 equiv), in
DMF at 150 ºC, to give 21-Cl2 as a white solid; yield: 37.4 mg
(58%); mp = 187-188 ºC. The analytical data (NMR and HRMS analysis) matched
those described for compound 21-Cl.
N-(2,6-Dichloro-4-methylphenyl)pyrimidine-2-sulfonamide (23-Cl2). Compound
23-Cl2 was prepared following Method E from N-(ptolyl)pyrimidine-2-sulfonamide 23 (49.9 mg, 0.20 mmol) and
NCS (64.1 mg, 0.48 mmol, 2.4 equiv), in MeCN at 130 ºC,
to give 23-Cl2 as a pale yellow oil; yield: 58.0 mg (85%).
1
H NMR (acetone-d6, 500 MHz) δ: 8.99 (d, J = 4.8 Hz, 2H), 7.75 (t, J = 4.8 Hz, 1H),
7.27 (s, 2H), 2.33 (s, 3H).
13
C NMR (acetone-d6, 125 MHz) δ: 167.2, 159.4, 141.7,
136.5, 130.1, 129.9, 124.5, 20.6. EI+ calcd. for C11H9N3O2SCl2 (M)+: 316.9793; Found:
316.9803.
368
Chapter 6
6.4.4. Typical procedure for the Mg-promoted N-desulfonylation
Synthesis of 2-chloroaniline (24). To a solution of N-(2-chlorophenyl)pyridine-2sulfonamide 1-Cl (53.5 mg, 0.2 mmol, 1.00 equiv) in dry MeOH (10 mL)
was added magnesium (turnings, 48.6 mg, 2.00 mmol, 10 equiv). The
reaction mixture was sonicated at room temperature until complete
conversion of the starting material (TLC monitoring). Equal volumes of diethyl ether
and saturated aq. NH4Cl were added, and the organic phase was separated. The
aqueous phase was extracted with diethyl ether (2 x 10 mL) and the combined
organic phases were dried (MgSO4) and concentrated to dryness to give pure 24 as
colourless oil; yield: 22.0 mg (85%). The analytical data (NMR, GC-MS analysis) are
in agreement with those of the commercial available 2-chloroaniline [CAS: 95-51-2].
2,6-Dichloro-4-fluoraniline
(25).
N-(2,6-Dichloro-4-fluorophenyl)pyrimidine-2-
sulfonamide 21-Cl2 (64.4 mg, 0.20 mmol) was deprotected following
the above described typical procedure for Mg-promoted Ndesulfonylation to give 25 as a white solid; yield: 28.1 mg (78%); mp
= 50-52 ºC. The analytical data (NMR, GC-MS analysis) are in
agreement with those of the commercial available 2,6-dichloro-4-fluoraniline [CAS:
344-19-4].
369
Experimental section
6.4.5. Typical procedure for the synthesis of 2-substitued NH-indoles from
ortho-bromo-substituted
N-(2-pyridil)sulfonyl
anilines:
Sonogahira
coupling/cyclization/deprotection.
a) Sonogashira coupling-cyclization: Synthesis of 2-phenyl-5-(trifluoromethyl)N-(2-pyridyl)sulfonyl indole (26). An oven-dried, nitrogen-flushed 20 mL vessel was
charged with sulfonamide 3-Br (76.2 mg, 0.20 mmol, 1.00 equiv), Pd(PPh3)4
(23.1 mg, 0.02 mmol, 10 mol%) and CuI (7.6 mg, 0.04 mmol,
20 mol%). The reaction vessel was then evacuated and
flushed with nitrogen three times. Under nitrogen atmosphere,
p-xylene
(2 mL),
ethynylbenzene
(26.3 µL,
0.24 mmol,
1.20 equiv) and triethylamine (55.8 µL, 0.4 mmol, 2.00 equiv) were added via syringe.
The resulting mixture was stirred at 110 °C for 16 h before the volatiles were removed
in vacuo. The residue was purified by column chromatography (n-hexane-EtOAc
10:1), to give indole 26 as a white solid; yield: 77.2 mg (96%); mp = 118-122 ºC.
1
H NMR (acetone-d6, 500 MHz) δ: 8.57 (ddd, J = 4.5, 1.7, 0.9 Hz, 1H), 8.42 – 8.33
(m, 1H), 8.04 (td, J = 7.8, 1.7 Hz, 1H), 7.98 (dd, J = 1.7, 0.8 Hz, 1H), 7.80 (dt, J = 7.9,
1.0 Hz, 1H), 7.72 – 7.62 (m, 2H), 7.50 – 7.42 (m, 3H), 7.42 – 7.35 (m, 2H), 6.85 (s,
1H).
C NMR (acetone-d6, 125 MHz) δ: 156.3, 151.3, 145.1, 140.8, 139.5, 132.6,
13
131.4, 130.7, 129.7, 129.3, 128.3, 126.5 (d, JC-F = 32.1), 125.7 (q, JC-F = 271.2 Hz)
123.4, 121.8 (q, JC-F = 3.6 Hz), 119.1 (q, JC-F = 4.1 Hz), 117.3, 112.5.
19
F NMR
(acetone-d6, 471 MHz) δ: -61.7. EI calcd. for C20H13N2O2SF3 (M) : 402.0650; Found:
+
402.0658.
370
+
Chapter 6
b) Deprotection: synthesis of 2-phenyl-5-(trifluoromethyl)-1H-indole (27). The
indole 26 (80.4 mg, 0.20 mmol, 1.00 equiv) was deprotected
following the above described typical procedure for Mgpromoted N-desulfonylation to give indole 27 as a white solid;
yield: 43 mg (81%); mp = 132-135 ºC. The analytical data
(NMR, HRMS analysis) matched those reported in the literature for 2-phenyl-5(trifluoromethyl)-1H-indole [CAS: 491601-38-8]. 1H NMR (acetone-d6, 300 MHz) δ:
7.95 (s, 1H), 7.90 (dd, J = 8.2, 1.0 Hz, 2H), 7.60 (dd, J = 8.7, 0.9 Hz, 1H), 7.54 – 7.45
(m, 2H), 7.43 – 7.33 (m, 3H), 7.07 (d, J = 1.1 Hz, 1H). 13C NMR (acetone-d6, 75 MHz)
δ: 141.2, 139.8, 132.8, 129.9, 129.6, 129.0, 126.7 (q, JC-F = 126.3 Hz), 122.4 (q, JC-F =
31.4 Hz), 119.0 (q, JC-F = 3.6 Hz), 118.7 (q, JC-F = 4.4 Hz), 112.6, 100.7. EI+ calcd. for
C15H10NF3 (M)+: 261.0765; Found: 261.0778.
6.4.6. Intramolecular isotopic kinetic effect
a) Synthesis of deuterated aniline derivative 29.
Following the literature procedure, 1.00 g (5.82 mmol) of 2-bromoaniline was
treated with several portions of MeOD to give 2-bromoaniline-d2 (amino group
exchange). The 2-bromoaniline-d2 was the added to 2.0 g (0.03 mmol) of zinc dust in
20 mL of 10% NaOD in D2O and the slurry heated under reflux for 72 h, after which
time the 2-deuteroaniline-d3 was isolated as a colorless oil, after filtration, extraction
and drying.
Following the typical procedure for N-sulfonyation, pyridine (388 µL, 4.80 mmol,
1.20 equiv) and 2-pyridylsulfonyl chloride (852 mg, 4.80 mmol, 1.20 equiv) were
successively added dropwise at 0 ºC to a solution of 2-deuteroaniline (376 mg,
371
Experimental section
4.00 mmol, 1.00 equiv) in THF (40 mL), under N2 atmosphere. The mixture was
warmed to room temperature and stirred overnight. During this time, a gradual
formation of a precipitate was observed. The resulting mixture was then suction
filtered through a 6-cm fritted glass funnel (coarse) into a round-bottomed flask, and
the filter cake was rinsed with THF (3 x 10 mL). To the resulting filtrate and the
washes, water (20 mL) was added and the THF was removed by evaporation at
reduced pressure, yielding a suspension of a white solid in the aqueous medium.
This solid was collected by filtration, washed sequentially with toluene (2 x 5 mL) and
diethyl ether (2 x 5 mL). Then it was transferred to a round-bottomed flask, and dried
at 1.0 mmHg to provide 29 as a white powder; yield: 800 mg (85%). 1H NMR
(acetone-d6, 300 MHz) δ: 9.23 (s, 1H), 8.68 (dt, J = 4.7, 1.3 Hz, 1H), 8.10 – 7.92 (m,
2H), 7.58 (ddd, J = 7.2, 4.8, 1.6 Hz, 1H), 7.37 – 7.16 (m, 3H), 7.11 – 6.98 (m, 1H).
13
C NMR (acetone-d6, 75 MHz) δ: 158.0, 150.9, 139.1, 138.6, 129.8, 129.7, 127.9,
125.2, 123.5, 121.9, 121.8.
b) Determining the intramolecular isotopic kinetic effect
D
NHSO2Py
CuCl2 (10 mol%)
NCS (1.2 equiv)
H
O2 (1 atm), MeCN
100 ºC, 4 h
H
D
NHSO2Py
Cl
NHSO2Py
+
Cl
1:1
An oven-dried, nitrogen-flushed 20 mL vessel was charged with the corresponding Nprotected aniline (29) (0.20 mmol, 1.00 equiv), NCS (32.0 mg, 0.24 mmol, 1.2 equiv)
and CuCl2 (2.69 mg, 0.02 mmol, 10 mol%). The reaction vessel was sealed with a
Teflon lined cap, then evacuated and flushed with oxygen three times. Under the
atmosphere of oxygen, MeCN (1 mL) and the internal standard n-hexadecane (50 µL)
were added via syringe. The resulting mixture was stirred at 100 °C for 1 h. After the
reaction was complete, the volatiles were removed in vacuo and the residue was
purified by column chromatography (n-hexane-EtOAc 5:1), yielding a mixture of
29(H)-Cl and 29(D)-Cl in a ratio 1:1.
372
Chapter 6
6.4.7. Regioselectivity in the ortho-chlorination process.
In order to ensure the correct regio-position of the new halogen-carbon bond, a
series of para-substituted anilines bearing a chlorine in the ortho- or meta-position
were N-protected with (2-pyridyl)sulfonyl chloride. Thus, 2-chloro-4-iodoaniline, 2chloro-4-fluoraniline and methyl 4-amino-3-chlorobenzoate were derivatized to the
corresponding protected substrates 30, 31 and 32, respectively (vide infra). The NMR
spectra recorded for the corresponding N-(2-pyridyl)sulfonyl anilines matched those
reported for the Cu-catalyzed ortho-chlorinated products.
For the non-comercially available ortho-chloro anilines, the meta-regioisomer
was N-protected with (2-pyridyl)sulfonyl chloride. This is the case for 3-chloro-4methoxyaniline (substrate 33), 3-chloro-4-iodoaniline (18), 4-bromo-3-chloroaniline
(19) and 3,4-dichloroaniline (20). The NMR spectra recorded for the corresponding N(2-pyridyl)sulfonyl anilines did not match those reported for the Cu-catalyzed orthochlorinated products. Anilines 18, 19 and 20 have been already described because
they were used as starting materials. The corresponding 1H NMR spectra of both
regioisomers, ortho- and meta-, can be compared in NMR spectra appendix.
N-(2-Chloro-4-iodophenyl)pyridine-2-sulfonamide
(30).
Compound
30
was
prepared following the typical procedure for the N-sulfonylation
NHSO2Py
of anilines from 2-chloro-4-iodoaniline (1.01 g, 4.00 mmol) to
give 30 as a white solid; yield: 1.28 g (81%); mp = 102-103 ºC.
I
Cl
The analytical data (NMR, HRMS analysis) matched those
obtained for the ortho-chlorinated product 10-Cl. The NMR spectra did not match
those reported for the meta-chlorinated product 18. 1H NMR (acetone-d6, 500 MHz)
δ: 8.75 (s, 1H), 8.70 (ddd, J = 4.6, 1.8, 0.9 Hz, 1H), 8.08 (td, J=7.8, 1.7, 1H), 7.97 (dt,
J=7.9, 1.1, 1H), 7.75 (d, J=2.0, 1H), 7.71 – 7.62 (m, 2H), 7.47 (d, J=8.6, 1H). EI+
calcd. for C11H8N2O2SClI (M)+: 393.9040; Found: 393.9022.
373
Experimental section
N-(2-Chloro-4-fluorophenyl)pyridine-2-sulfonamide
(31). Compound 31 was
prepared following the typical procedure for the N-sulfonylation of anilines from 2chloro-4-fluoroaniline (0.448 mL, 4.00 mmol) to give 31 as a
white solid; yield: 0.91 g (79%); mp = 97-98 ºC. The analytical
data (NMR, HRMS analysis) matched those obtained for the
ortho-chlorinated product 13-Cl. 1H NMR (acetone-d6, 500 MHz) δ: 8.79 – 8.66 (m,
2H), 8.06 (td, J=7.8, 1.7, 1H), 7.91 (dt, J=7.9, 1.0, 1H), 7.72 – 7.60 (m, 2H), 7.25 (dd,
J=8.4, 2.9, 1H), 7.13 (ddd, J=9.1, 8.0, 2.9, 1H). EI+ calcd. for C11H8N2O2FSCl (M)+:
285.9972; Found: 285.9991.
Methyl 3-chloro-4-(pyridine-2-sulfonamido)benzoate (32). Compound 32 was
prepared following the typical procedure for the Nsulfonylation
of
anilines
from
methyl
4-amino-3-
chlorobenzoate (724 mg, 4.00 mmol) to give 32 as a
white solid; yield: 1.07 g (82%); mp = 127-128 ºC. The analytical data (NMR, HRMS
analysis) matched those obtained for the ortho-chlorinated product 14-Cl. 1H NMR
(acetone-d6, 500 MHz) δ: 8.94 (s, 1H), 8.70 (ddd, J=4.7, 1.7, 1.0, 1H), 8.12 (td, J =
7.7, 1.7 Hz, 1H), 8.04 (dt, J = 7.9, 1.1 Hz, 1H), 7.95 (d, J=1.9, 1H), 7.89 (dd, J = 8.6,
1.8 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.68 (ddd, J=7.5, 4.7, 1.2, 1H), 3.87 (s, 3H). EI+
calcd. for C13H11N2O4SCl (M)+: 326.0125; Found: 326.0116.
N-(3-chloro-4-methoxyphenyl)pyridine-2-sulfonamide (33). Compound 33 was
prepared following the typical procedure for the Nsulfonylation of anilines from 3-chloro-4-methoxyaniline
(630 mg, 4.00 mmol) to give 33 as a white solid; yield:
1.06 g (89%); mp = 208-209 ºC. The NMR spectra did not
match those obtained for the ortho-chlorinated product 2-Cl. 1H NMR (acetone-d6,
500 MHz) δ: 9.11 (s, 1H), 8.72 (ddd, J=4.7, 1.7, 0.9, 1H), 8.23 – 7.97 (m, 1H), 7.91
(dt, J=7.8, 1.0, 1H), 7.62 (ddd, J=7.7, 4.7, 1.1, 1H), 7.31 (d, J=2.6, 1H), 7.17 (dd,
J=8.9, 2.6, 1H), 6.98 (d, J=8.9, 1H), 3.82 (s, 3H).
13
C NMR (acetone-d6, 125 MHz) δ:
157.9, 153.6, 151.0, 139.2, 131.6, 128.0, 125.3, 123.5, 123.3, 122.6, 113.5, 56.6. EI+
calcd. for C12H11N2O3SCl (M)+: 298.0179; Found: 298.0173.
374
Appendix I
Publications
375
376
To date, the results reported in this Thesis have been disclosed in the following top
peer-reviewed journals:
1.
PdII-Catalyzed C−H Functionalization of Indoles and Pyrroles Assisted by
the Removable N-(2-Pyridyl)sulfonyl Group: C(2)−Alkenylation and
Dehydrogenative Homocoupling.
García-Rubia, A.; Urones, B.; Gómez Arrayás, R.; Carretero, J. C.
Chem. Eur. J. 2010, 16, 9676 - 9685.
2.
Coordinating Sulfonyl Substrates
Phosphorus, Sulfur and Silicon.
in
Metal-Catalyzed
Reactions.
Hernández, J.; García-Rubia, A.; Urones, B.; Gómez Arrayás, R.;
Carretero, J. C.
Phosphorus, Sulfur and Silicon 2011, 186, 1019 - 1031.
3.
PdII-Catalyzed C-H Olefination of N-(2-Pyridyl)sulfonyl Anilines and
Arylalkylamines.
García-Rubia, A.; Urones, B.; Gómez Arrayás, R.; Carretero, J. C.
Angew. Chem. Int. Ed. 2011, 50, 10927-10931 (Featured as VIP).
4.
PdII-Catalyzed C−H Olefination of N-(2-Pyridyl)sulfonyl Carbazoles.
Urones, B.; Gómez Arrayás, R.; Carretero, J. C.
Org. Lett. 2013, 15, 1120-1123.
5.
Aerobic Copper-Catalyzed ortho-Halogenation of Anilines.
Urones, B.; Rodríguez, N.; Gómez Arrayás, R.; Carretero, J. C.
Manuscript accepted in JACS (with major revisions) 2013.
377