α,β-Unsaturated Diazoketones: Synthesis and
Applications in Organic Chemistry
synthesis
applications
2015. 04. 09
Liang, H. M.
中科院上海有机化学研究所
Content
 Introduction and Background
 Preparation of α,β-unsaturated Diazoketones
 Applications of α,β-unsaturated Diazoketones
 Conclusion
α-Diazocarbonyl compound
 α-Diazocanbonyl compounds have a long history of useful applications in organic
chemistry. They are easily prepared from accessible precursors and can be introduced
to undergo a wide variety of chemical transformations under very mild conditions.
 The first reported synthesis of an α-diazocanbonyl compound dates back to the work
done by Curtius[1] in 1883.
Curtius, T. Ber. Dtsch.chem.Ges. 1883, 16, 2230
 The Wolff rearrangement[2] -diazocarbonyl compounds were noticed.
Wolff, L. Justus Liebigs Ann.chenm. 1902, 325, 129
α-Diazocarbonyl compound
Two general protocols to prepare diazocarbonyl compound
 The acylation of diazomethane developed by Arndt et al in 1927.
 The important technique of diazo transfer was
developed by Regitz
Arndt, F. Ber. Dtsch. Chem. Ges. B Ser. 1927, 60, 1367
Regitz, M.; Menz, F. Justus Liebigs Ann. Chem. 1970, 739, 174
α-Diazocarbonyl compound
An interesting and different method to prepare diazoketones done by Aller
O
O
N
(H3C)3C
NH2
N2
(H3C)3C
Cl
75%
51%
O
O
N
ClH2C
N2
ClH2C
NH2
Cl
86%
79%
O
O
N
N2
NH2
Cl
82%
61%
O
O
N
N2
NH2
Cl
64%
75%
Allen, E.; Molina, P.; Lorenzo, A. Synlett. 2000 ,526
α-Diazocarbonyl compound
Now many new synthetic methodologies have appeared
Using the α-diazocanbonyl compound(Figure 1).
O
R1
R2
 Wollf rearrangement
O
R3
R2
R1
 Cyclopropanation
X
R3
X=S, N, O, P
 Ylide formation
Yli
R3
R1
Cyclopropanation
R
3X
de
Fo
rm
ati
on
O
R2
R1
 C-H insertion
N2
 1,3-Dipolar cycloaddition
O
R1
 Dimerization
C-H
R2
I
Nu
nt
H
me
Nu
e
g
ran
ea
r
f
olf
W
H
C-
R3
O
R2
n
rtio
nse
Dim
eri
za
tio
n
O
R2
R1
X=Y
H CR3
1,3-Dippolar
Cycloaddition
R1
R2
O
O X
R1
Y
R2
Figure 1
Preparation of α,β-unsaturated Diazoketones
1955 Buco study
1936 Grundman
first attempts
1974 Gupta modification
1970 Regitz
Deformlative
Dizao Transfer
1990 Danheiser
Detrifluoroacetylating
diazo transfer
1976 Chapman
Br-protected
double bond
2000 Aller
Iminophosphorane
reagent
Figure 2. Timeline scale of the methods to prepare α,β-unsaturated α’-diazoketones
2010 Burtoloso
Diazophosphonate
reagents
Preparation of α,β-unsaturated Diazoketones
Different diazocanbonyl compounds can now be prepared by using the
diazomethane acylation and diazo transfer protocols.
Preparation of α,β-unsaturated diazoketones by the diazomethane acylation
furnishes poor yields[5](scheme 1).
Grundmann, C. Justus Liebigs Ann. Chem.
1936, 524, 36
Wotiz, J. H.; Buco, S, N. J. Org. Chem.
1955, 20, 210
Scheme 1. Preparation of α,β-unsaturated diazoketones
Preparation of α,β-unsaturated Diazoketones
Several ways to form the unsaturated diazoketone.
 Br-protected double bond(scheme2[6])
Scheme 2. Synthesis of Unsaturated Diazoketones by Chapman and Rosenquist
Rosenquist, N. R.; Chapman, O, L. J. Org. Chem. 1976, 6.733
 Deformylative dizao transfer(scheme3[7])
Scheme 2. Synthesis of Unsaturated Diazoketones by Regitz and Gupta
Regitz, M.; Menz, F.; Liedhegener, A. Justus Liebigs Ann. Chem. 1970, 739, 174
Harmon, R. E.; Gupta, S. K. Synthesis. 1974, 577
Preparation of α,β-unsaturated Diazoketones
O
Mechanism：
H
H
R
ON Tos
N N
O
H
(p)-Tos-N3
N
Tos
O
O
R
O
H
N2
O
R
product
O
H
O
O
 Detrifluoroacetylating diazo transfer
N2
85%
Ph
N2
66%
O
O
N2
N2
74-86%
84%
O
N2
N2
O
Danheiser, R. L.; Park, S. Z. J. Org. Chem. 1990, 55, 1959
48%
87%
Burtoloso group works
Two types of Horner-Wadsworth-Emmons(HWE) reagents 1 and 2
O
O
 Complete E selectivity
and no epimerization in
the γ-position
R=H, 91%
R=Cl, 83%
N2 R=NO2, 84%
R=OMe, 50%
R
N2
N2
O
78%
N2
O
O
74%
67%
O
O
O
BocNH
N2
O
 High stereoselectivity
for reagent 1
80%
N2
N2
N2
N
Boc
H
76% total
61% Z
Z:E 8:2
CH3
87% total
78% Z
Z:E 9:1
4
81%
O
N2
O
O
N2
NHTs
66% total
40% Z
Z:E 6:4
NH
Boc
N
Boc
N2
74% total
67% Z
Z:E 9:1
NHTs
73% total
73% Z
Z:E 10:0
Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011. 76 289
Applications of α,β-unsaturated Diazoketones
First application example of α,β-Unsaturated Diazoketones
Triazolindione
Cyclopentenone synthesis
Regtiz, M.; Theis, W. Tetrahedron Lett. 1981, 22, 2535
Benzannulation reaction
Ceccherelli, P.; Wenkert, E. A. J. Org. Chem. 1990, 55, 311
Danheiser, R. L. Miler, R. F. J . Am. Chem. Soc. 1990. 112. 3093
Applications of α,β-unsaturated Diazoketones
Tandem Wittig/Nazarov cyclization
O
O
O
Ph
Ph
Ph
Et
Yield: 95%
Z/E: 12/1
O
Ph
Et
Yield: 71%
Z/E: 24/1
O
Cl
Yield: 87%
Z/E: 15/1
Proposed stererochemical
Modle
Cao, P.; Sun, X. L.; Tang, Y. Org. Lett. 2009, 11, 3048
Yield: 91%
Z/E: 9/1
Ph
Yield: 71%
Z/E: 24/1
Et
Application used in the synthesis of nitrogen heterocycles
Synthesis of Dihydropyridones
Fang, F. G.; Prato, M. Danishefsky, S. J. Tetrahedron Lett. 1989, 30, 3625
Application used in the synthesis of nitrogen heterocycles
2,5-Disubstituted Pyrrolidinones
But the Stereoselectivity is not good
Clark, J. S.; Hodgson, P. B.; Street, L. J. J. Chem. Soc., Pekin Trans. 1 2001, 3312
Application used in the synthesis of nitrogen heterocycles
Cis-2,5-Disubstituted Pyrrolidinones
Single cis isomer
Rossrt, I. G.; Dias, R. M. P.; Burtoloso, A. C .B. J. Org. Chem. 2014, 79, 6748
Application used in the synthesis of nitrogen heterocycles
Total synthesis of the alkaloid preussin
Rossrt, I. G.; Dias, R. M. P.; Burtoloso, A. C .B. J. Org. Chem. 2014, 79, 6748
Application used in the synthesis of nitrogen heterocycles
Synthesis of Dihydropyridin-3-ones
Prepare highly functionlized piperidine
in just two steps from Z-unsaturated
diazoketones
Rosset, I. G.; Burtoloso, A. C. B. J. Org.Chem. 2013, 76, 9464
Conclusion
 The chemistry of α,β-unsaturated diazokeones has proven to be very promising
 The combination of three important functions( a double bond, a ketone and a
diazo) in the same mlolecule makes these compound very useful to synthesis many
important moleculaes
 Many transformations still desirve investigation from these substrates