Chemistry & Biology Interface, 2015, 5, 2, 157-165
RESEARCH PAPER
ISSN: 2249 –4820
CHEMISTRY & BIOLOGY INTERFACE
An official Journal of ISCB, Journal homepage; www.cbijournal.com
Domino C- and N-alkylation: Synthesis and structure analysis of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine derivatives
Krunalkumar Mehariya, Dilip Detroja, Anamik Shah*
National Facility for Drug Discovery Centre, Department of Chemistry, Saurashtra University, Rajkot-360005,
Gujarat (India)
E-mail: [email protected]
Received 3 April 2015; Accepted 29 April 2015
Abstract: In the present investigation, domino protocol for the synthesis of 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-d]pyrimidine derivatives (18 a-b) was realized via C- and N-alkylation of 3-methyl-1-phenyl1H-pyrazol-5-amine (15), corresponding primary amine (16) and formaldehyde (17). The compound was
characterized by spectroscopic techniques and confirmed by X-ray crystallographic studies.
Keywords: Domino, C-alkylation, N-alkylation, pyrazole
Introduction
Since last century, heterocyclic compounds
represent an importance class of biologically
and pharmaceutically active molecules.
Pyrazole ring containing natural products
natural sources, plants, animals, microbial and
marine molecules like skeleton consisting, for
example 4-methyl-1H-pyrazole-3-carboxylic
acid (1), 3-N-Nonylpyrazole (2), 1H-pyrazole3-carboxylic acid (3), (s)-3-pyrazolylalanine
(4), Difenamizole (5), Celecoxib (6), Phenazone
(7), Withsomnine (8a), 4’-Hydroxywithsomnine
(8b), 4’-Methoxywithsomnine (8c), Pyrazofurin
(9), Pyrazofurin B (10), Nostocine A (11),
Chemistry & Biology Interface
Formycin (12), Formycin B (13), oxyformycin
B (14) have therapeutic potentials[1-10].
Some of Pyrazole ring a wide range of
biological properties, such as antimicrobial11,
analgesic12, anti- inflammatory13, anticancer14
and antioxident15, Hepatitis C virus16. Pyrazole
derivatives were also found in natural
products17, as potential antivirals18, antifilarial19
etc. Hydrazones and corresponding hydrazides
derivatives of pyrazole-4-carboxylic acid groups
possess antimicrobial activity20. Since, they
contribute to the activities of many biologically
important compounds of pyrazole derivatives
having phenyl substituted were reported to
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possess high affinity and selectivity for HIV-1
reverse transcriptase inhibitor21.
O
Me
HN N
HO
N N
H
N
N
O
OH
C9H19
3
2
1
N
O
HO
Me
N
Me
Me
O
N
N
H
NH2
4
F
F
F
Me
HO
O
O
NH2
N
OH
NH
HO
HO
O
OH
N
OH
N
N Me
O
7
NH2
NH2
NH
O
N
OH
N
N
N
Me
N
11
10
9
8a, R=H;
8b, R=OH;
8c, R=OMe;
S
6
O
N
N
O
O
HO
Me
N N
5
R
N NH
O
OH
N
N
O
HO
12
N NH
OH
OH
NH2
N
NH
O
O
HO
OH
N NH
OH
13
HN
NH
O
O
HO
N NH
(1° or 2°) and the formaldehyde (CH2O) reaction
than same/other compound with the active
functional group (here, α CH-acidic compounds
in pyrazol skeleton) can tautomerization to the
enol form, after which it can attack the iminium
ion than involves in intramolecular bond
formation and generate complex molecule. I n
study of Domino reactions as processes of two
or more bond-forming during intramolecular
reactions under identical conditions often
proceed via highly reactive intermediates. In
fascinating way Domino reaction is built up
synthetic effectiveness and the development of
new chemical entities. It is allow the formation
of complexity into molecules with excellent
regioselectivity, starting from simple substrates
in a single transformation consisting of several
steps25-26.
In light of our work regarding the synthesis of
chromeno-pyrazoles in the presence of Zn[Lproline]2 catalyst27 and coumarinyl chalcone28
derivatives was achieved via microwaveassisted high-throughput method. Herein, we
prepared 5-benzyl-3-methyl-1-phenyl-4,5,6,7tetrahydro-1H- pyrazolo[3,4-d]pyrimidine via
domino one-pot protocol.
OH
14
Figure 1
In view of the diverse pharmacological profile
of condensed pyrazoles, we have synthesized
a 4,5,6,7-tetrahydro-1H-pyrazol derivative
utilizing
3-methyl-1-phenyl-1H-pyrazol5-amine, benzyl amine and formaldehyde
in ethanol at room-temperature with their
subsequent ring closure by C-alkylation and Scheme 1 Preparation of 5-benzyl-3-methyl-1N-alkylation to afford the title compound. The phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]
alkylation reaction has long been a very useful pyrimidine
stage for the development of such techniques. Me
R
NH
A wide range of reactions have been reported
Me
N
NH
N
O
Ethanol
by C-alkylation and N-alkylation in indole and
N
+
N
+
rt
H
H
N
pyrrole produced by regiooselective synthesis
N
R
H
17
in heterocyclic chemistry22.
16
15
2
2
In an attempt to begin an experimentally
convenient approach to preparative C-alkylation
and N-alkylation via an intramolecular Mannich
type cyclization23-44and Domino reaction
(Scheme-1). Mannich reaction is one of the most
important for C-C bond and C-N bond formation
during reactions in organic synthesis. The
mechanism of the Mannich reaction starts with
the formation of an iminium ion from the amine
Chemistry & Biology Interface
R= H, 4-OCH3
18 a,b
Scheme 1
Experimental
All chemicals were of analytical grade and used
as received. The progress of the reaction was
monitored by TLC.The IR was recorded on
Shimadzu FTIR-8400 spectrometer (KBr Pellet
method, 400–4000 cm-1). Melting point was
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Chemistry & Biology Interface, 2015, 5, 2, 157-165
recorded by open capillary method. Reactions
were monitored by thin layer chromatography
technique using silica gel-G plates of 0.5
mm thickness and spots were observed using
iodine and UV. Mass spectra were recorded on
Shimadzu GC-MS-QP-2010 model using direct
injection probe technique. 1H NMR spectra
were recorded on Brukeravance400 MHz
spectrometer determined in DMSO-d6.
General Synthesis of 18(a-b)
The preparation of the compounds 18(a-b)
were carried out with 3-methyl-1-phenyl-1Hpyrazol-5-amine (1.0 mmol, 1.0 equiv) (15),
corresponding primary amine (1.0 mmol, 1.0
equiv) (16) and formaldehyde (2.0 mmol, 2.0
equiv) (17) in ethanolic solution, which was
allowed to stir for 4 h at rt. After completion of
reaction as indicated by TLC, the solvent was
removed by filtration to leave the crude product
which was again recrystallized with ethanol
to get pure compound. Crystallization of the
products from ethanol by slow evaporation
afforded the crystals of the products 18(a-b)
suitable for X-ray crystallographic analyses.
mp ˚C; MS: m/z 334; IR (KBr): ν = 3220 (NH),
1600, 1595, 1555, 1534, 1050; 1H NMR (400
MHz, DMSO-d6): δ 3.50 (4H, m, 2×CH2), 3.73
(3H, s, OCH3), 3.82˗3.83 (2H, d, J = 5.60 Hz,
CH2), 5.98 (1H, s, NH), 6.88˗6.90 (2H, d, J =
8.28 Hz, 2×ArH), 7.18˗7.21(1H, s, J = 7.28 Hz,
ArH), 7.26˗7.29 (2H, d, J = 8.24 Hz, 2×ArH),
7.39˗7.43 (2H, t, J = 7.60 Hz, 2×ArH), 7.71˗7.73
(2H, d, J = 7.8 Hz, 2×ArH); 13C NMR (100
MHz, DMSO-d6):12.11, 55.48, 63.19, 98.93,
113.54, 120.11, 124.78, 128.91, 129.90, 130.69,
139.49, 142.68, 144.95,158.28.
X-ray Structure Determination
The crystals of 18(a-b) were mounted by Loctite
Super Glue and mounted on fibers for data
collection. All measurements were made on a
Rigaku SCX mini diffractometer using graphite
monochromated Mo-Kα radiation. The crystalto-detector distance was 52.00 mm. Details
of crystal data and structure refinement for all
structures have been provided in Table 1. The
data were corrected for Lorentz and polarization
effects. An empirical absorption correction was
applied which resulted in transmission factors
ranging from 0.594 to 0.970 for crystal structure
5 - b e n z y l - 3 - m e t h y l - 1 - p h e n y l - 4 , 5 , 6 , 7 - 18a and 0.462 to 0.976 for crystal structure
tetrahydro-1H-pyrazolo[3,4-d]pyrimidine 18b. The data were corrected for Lorentz and
(18a): White solid; Yield 90%; mp 144-146 polarization effects. The structure was solved
˚C; MS: m/z 304; IR (KBr): ν = 3200 (NH), by direct methods29 and expanded using Fourier
1599, 1589, 1560, 1529; 1H NMR (400 MHz, techniques.
DMSO-d6):1H NMR (400 MHz, DMSO-d6): δ
2.02 (3H, s, CH3), 3.54 (2H, s, CH2), 3.63 (2H, The non-hydrogen atoms were refined
s, CH2), 3.84˗3.85 (2H, d, J = 5.76 Hz, CH2), anisotropically. Hydrogen atoms were refined
6.00˗6.01 (1H, d, J = 5.08 Hz, NH), 7.18˗7.20 using the riding model. The final cycle of full(2H, d, J = 7.20 Hz, 2×ArH), 7.22˗7.26 (2H, d, matrix least-squares refinement on F2 was based
J = 15 Hz, 2×ArH), 7.27˗7.39 (2H, m,2×ArH), on 7392 for crystal structure 18a and 7949
7.43˗7.46(2H, d, J = 11.6 Hz, 2×ArH), 7.48˗7.51 for crystal structure 18b observed reflections
(2H, d, J = 9.92 Hz, 2 × ArH); 13C NMR (100 and 415 for crystal structure 18a and 451 for
MHz, DMSO-d6):12.13, 63.29, 98.90, 120.12, crystal structure 18b variable parameters and
122.55, 124.81, 126.51, 126.78, 126.91, 127.08, converged. Neutral atom scattering factors were
128.50, 138.94, 139.48, 141.99, 145.64, 149.20. taken from Cromer and Waber30. Anomalous
5-(4-methoxybenzyl)-3-methyl-1-phenyl- dispersion effects were included in Fcalc31, the
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d] values for Δf′ and Δf″ were those of Creagh and
pyrimidine (18b): White solid; Yield 95%; McAuley32. The values for the mass attenuation
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coefficients are those of Creagh and Hubbell33.
All calculations were performed using the
Crystal structure crystallographic software
package except for refinement, which was
performed using SHELXL-9734.Fig. 1 and Fig.
3 are represents the ORTEP35.
Results and Discussion
The crystals of 18(a-b) crystallize in triclinic
space group, P-1 (#2). The bond distances
and bond angles in all the compounds are in
excellent agreement with the expected values
for the corresponding dimensions. In molecule
of 18a (Fig. 3) benzyl amine ring and 18b (Fig.
6) 4-methoxy benzyl amine ring present into the
pyrazole skeleton.
Table 1 Summary of crystal data and structure refinement parameters for compounds (18 a-b)
18a18b
CCDC Deposition Number CCDC1059157
CCDC 1059157
Empirical FormulaC19H20N4C22H20N4
Formula Weight304.39334.42
Crystal Color, Habit
colorless, block
colorless, chunk
Crystal Dimensions, mm
0.790 × 0.400 × 0.400
0.790 × 0.400 × 0.310
Crystal Systemtriclinictriclinic
Lattice TypePrimitivePrimitive
Lattice Parameters
a = 9.423(2) Å
a = 10.177(4) Å
b = 13.664(3) Å
b = 13.073(5) Å
c = 14.656(3) Å
c = 14.494(5) Å
α = 110.922(4)°
α = 92.04(2)°
β = 95.792(4)°
β = 109.20(3) °
γ= 107.324(4)°
γ = 101.64(1) °
V = 1636.6(5) Å3 V = 1773(2) Å3
Space GroupP-1 (#2)P-1 (#2)
Z value44
Dcalc1.235 g/cm31.253 g/cm3
F(000)648.00712.00
-1
-1
µ(MoKα)
0.756 cm 0.800 cm
ω oscillation Range -120.0 - 60.0°
-120.0 - 60.0°
Exposure Rate 10.0 sec/°
10.0 sec/°
Detector Position52.00 mm52.00 mm
2θmax
55.0°
55.0°
No. of Reflections Measured
Total: 16284
Total: 17275
Unique: 7392Unique: 7949
Rint0.05850.0884
0.1434
R1 (I>2.00σ(I))
R (All reflections)
0.2019
0.4220
0.4210
WR2 (All reflections)
0.46, -0.40 0.64, -0.38
Largest diff. peak and hole, e. Å-3
Goodness of Fit 1.0481.213
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Table 2 Bond Lengths (Å)
Bond distances (Å) 18a
Bond distances (Å) 18b
C1-C21.373(5)C1-C21.366(8)
C20-C211.383(6)C14-C151.346(6)
N1-N21.379(5)N1-N21.375(5)
N5-N61.383(4)N5-N61.378(6)
N3-C301.454(5)N3-C101.445(6)
N7-C121.451(5)N7-C301.460(5)
N4-C311.464(5)N4-C111.496(6)
N8-C131.471(6)N8-C301.473(6)
C26-C281.492(6)C7-C121.479(6)
C7-C101.498(5)C27-C321.498(8)
N3-H30.860N3-H30.860
N7-H70.860N7-H70.860
C10-H10A0.960C12-H12A0.960
C28-H28A0.960C32-H32A0.960
O1-C171.360(7)
O2-C371.355(7)
O1-C201.397(7)
O2-C401.421(9)
Table 3 Bond angles (°)
Bond angles (°) 18a
Bond angles (Å) 18b
N2-N1-C20118.3(3)N2-N1-C1118.4(4)
N6-N5-C1119.0(3)N6-N5-C21118.6(4)
N6-N5-C9110.6(3)N2-N1-C9110.6(4)
N2-N1-C38110.2(3)N6-N5-C29110.7(4)
N3-C30-N4112.6(4)N3-C10-N4113.6(4)
N7-C12-N8112.70(4)N7-C30-N8114.2(4)
C17-O1-C20119.4(5)
C37-O2-C40118.7(5)
Table 2 and Table 3 give the list of Bond Lengths
and Bond Angles of non-hydrogen atoms
respectively. The bond lengths and bond angles
are in excellent conformity with the standard
values. The crystal structure 18a 1.379(5)Å
for N1-N2, 1.383(4) Å for N5-N6 and crystal
structure 18b 1.375(5)Å for N1-N2, 1.378(6)Å
for N5-N6 is near to that of a typical Aromatic
N=N bond (1.35 Å).
(1.47 Å). The crystal structure 18b 1.397(7)Å
for O1-C20 and 1.421(9)Å is O2-C40 is near to
that of a typical C-O bond (1.43 Å).The crystal
structure 18a 0.860Å for N3-H3, N7-H7 and
the crystal structure 18b 0.860Å for N3-H3,
N7-H7 is near to that of a typical secondary
amine N-H bond (0.99Å). The crystal structure
18a 0.960Å for C10-H10A, C28-H28A and The
crystal structure 18b 0.960Å for C12-H12A,
C32-H32A is near to that of a typical alkyl –
CH3 group of C-H bond (1.09 Å).
The crystal structure 18a 1.454(5)Å for N3-C30,
1.451(5) Å for N7-C12 and crystal structure
18b 1.445(6)Å for N3-C10, 1.460(5)Å for N7- The bond length of crystal structure 18a of
C30 is near to that of a typical alkyl C-N bond 118.3(3)° for N2-N1-C20, 119.0(3)° for N6Chemistry & Biology Interface
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N5-C1, and crystal structure 18b 118.4(4)° Fig. 3 represents the ORTEP of only one
for N2-N1-C1, 118.6(4)° for N6-N5-C21 is molecule (18a) with ball and stick drawn at
near to that of a typical C-N-C bond angle 50% probability.
(120°, sp2 hybridized atoms, pyrazol ring of
N=N bond directly attached with aromatic
benzene ring Carbon atom). The bond angle of
crystal structure 18a 112.6(4)° for N3-C30-N4,
112.70(4)° for N7-C12-N8 and crystal structure
18b 113.6(4)° for N3-C10-N4, 114.2(4)° for
N7-C30-N8 is near to that of a typical C-N-C
bond angle(120°, sp2 hybridized atoms).The
bond angle of crystal structure 18b 119.4(5)°
for C17-O1-C20, 118.7(5)° for C37-O2-C40 is
near to that of a typical C-O-C bond angle(120°,
sp2 hybridized atoms).
Fig. 4 Packing diagram of the molecules (18a)
Fig. 2 represents the ORTEP of the molecule when viewed down the a* axis. The dashed
(18a) with thermal ellipsoids drawn at 50% lines represent the hydrogen bonds
probability.
Table 4 Possible hydrogen bonds
18a18b
Donor H
Acceptor D...A
Donor H
Acceptor
N3
H3
N8
3.048(5)
N7
H7
N4
N7
H7
N4
3.005(5)
N3
H3
N8
D-H H...A D-H...A
D-H H...A D-H...A
0.86 2.60
113.55 0.85 2.50
113.45
0.86 2.58
111.63
0.88 2.55
111.60
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D...A
3.045(5)
3.025(5)
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The D–H and H–A distances are essentially
standard values and are not derived from
the experiment. The structure exhibits in
crystal structure 18a and 18b both inter and
intramolecular hydrogen bonds of the type
C–H…N and N–H….C. These hydrogen bonds
link the molecules into chains and help in
stabilizing the crystal structure. The observed
hydrogen bonds are listed in Table 4.
Fig. 5 represents the ORTEP of the molecule
(18b) with thermal ellipsoids drawn at 50%
probability.
Fig. 7 Packing diagram of the molecules (18b)
when viewed down the a* axis. The dashed
lines represent the hydrogen bonds
Fig. 6 represents the ORTEP of only one
molecule (18b) with ball and stick drawn at
50% probability.
Table 5 Torsion Angles (°)
(Those having bond angles > 160 or < 20 degrees are excluded.)
18a18b
atom1atom2atom3atom4 angle
atom1atom2 atom3atom4 angle
C11N8C12N7-66.9(4) C11N4C10N3-65.2(4)
C29N4 C30N3 -67.3(4)
C31N8 C30N7 -64.5(4)
C12N8 C13C14-167.2(3)
C10N4 C13C14-173.6(3)
C30N4 C31C32-172.7(3)
C30N8 C33C34-176.1(4)
O1
C17
C18
C19
-179.8(5)
O2
C37
C38
C39
-179.7(5)
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However, intermolecular hydrogen bonds for
crystal structure 18a N3-H3-N8, N7-H7-N4 and
crystal structure 18b N7-H7-N4, N3-H3-N8
this order is likely the cause of the apparent
short H…H contacts involving the 5-amino
pyrazole skeleton. The pyrazol skeleton of
crystal structure 18a [N1/C26/C27/C38/N2],
[N5/C7/C8/C9/N6] and crystal structure 18b
[N1/C7/C8/C9/ N2] and [N5/C27/C28/C29/N6]
is planar because of aromatic ring.
In supporting information Crystallographic data
in tables of crystal data and figure for crystal
of
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]
pyrimidine derivatives (18 a-b) of the number
of CCDC 1059157 for 18a and CCDC
1059157 for 18b, contain the supplementary
crystallographic data for this paper. These
data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
A study of the torsion angles, asymmetric
parameters and least-squares plane calculations
reveals that the six membered ring of pyrimidine
of crystal structure 18a [C38/N3/C30/N4/C29/
C27], [C9/N7/C12/N8/C11/C8] and crystal
structure 18b [C9/N3/C10/N4/C11/C8], [C29/
N7/C30/N8/C31/C28] in the structure adopts a
flattened boat conformation with the atoms. The
torsion angle of crystal structure 18a between
the [C11/N8/C12/N7] is -66.9(4), [C29/N4/
C30/N3] is -67.3(4) and crystal structure 18b
between[C11/N4/C10/N3] is -65.2(4) and [C30/
N8/C31/N7] is -64.5(4) are showing that the
two groups are staggered in six membered ring.
Conclusions
The torsion angle between the phenyl carbon
atoms and alkyl carbon atom of crystal structure
18a [C30/N4/C31/C32] is -172.7(3), [C12/N8/
C13/C14] is -167.2(3) and crystal structure 18b
[C10/N4/C13/C14] is -173.6(3), [C30/N8/C33/
C34] is -176.1(4) this shows that the benzene
ring with alkyl carbon atom is not coplanar this
shows that the benzene ring with alkyl carbon
atom is not coplanar.
In conclusion, we have achieved a convenient
and efficient domino protocol for the synthesis
of 4,5,6,7-tetrahydro-1H-pyrazolo derivatives
via Domino C- and N-alkylation and an
intramolecular Mannich type cyclization
reaction. The compound, 5-benzyl-3-methyl-1phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]
pyrimidine (18a) and 5-(4-methoxybenzyl)3-methyl-1-phenyl-4,5,6,7-tetrahydro1H-pyrazolo[3,4-d]pyrimidine (18b) were
synthesized and characterized by 1H NMR,
13
C-NMR, mass spectrometry, FTIR and
confirmed by X-ray crystallographic studies.
Acknowledgments
The authors would like to express their thanks
to National Facility for Drug Discovery
Complex, Department of Chemistry, Saurashtra
University, Rajkot for the Laboratory Facility
and UGC, Major Research Project for financial
assistance under the project 41-256/2012(SR).
In crystal structure 18b the spatial arrangement References
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2935
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