Copper-catalyzed cascade reaction of 4-iodopyrazole derivatives with amidines for the synthesis of pyrazolo[4,3-d]pyrimidine derivatives

Article abstract of DOI:10.1002/ejoc.201101454

An efficient copper-catalyzed cascade reaction of 4- iodopyrazolecarbaldehydes and 4-iodopyrazolecarboxamides with substituted amidines for the preparation of substituted pyrazolo[4,3-d]pyrimidines and pyrazolo[4,3-d]pyrimidin-7(6H)-ones, respectively, is

Full text of DOI:10.1002/ejoc.201101454

FULL PAPER
DOI: 10.1002/ejoc.201101454
Copper-Catalyzed Cascade Reaction of 4-Iodopyrazole Derivatives with
Amidines for the Synthesis of Pyrazolo[4,3-d]pyrimidine Derivatives[‡]
Maloy Nayak,[a] Neeraj Rastogi,[b] and Sanjay Batra*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Copper / C-N coupling
An efficient copper-catalyzed cascade reaction of 4-iodopyr-
azolo[4,3-d]pyrimidines and pyrazolo[4,3-d]pyrimidin-7(6H)-
azolecarbaldehydes and 4-iodopyrazolecarboxamides with ones, respectively, is described.
substituted amidines for the preparation of substituted pyr-
fully synthesized pyrazolo-fused benzodiazepines and
Introduction
benzoxazoazepines through copper-mediated C–N and C–
O cross-coupling cascade reactions of 4-iodopyrazolecarb-
aldehydes with 1,2-phenylenediamines and 2-aminophen-
ols, respectively.[5] However, interestingly, during the study
we discovered that only intramolecular C–N and C–O cou-
plings could be performed; the intermolecular version re-
sulted in failure. Continuing with an exploration of other
possibilities for C–N couplings, we reasoned that substi-
tuted amidines would also react with 4-iodopyrazolecarbal-
dehydes to afford substituted pyrazolo[4,3-d]pyrimidines
Research on pyrazole chemistry is currently in focus be-
cause of its potential application to a range of spheres in-
cluding agricultural, pharmaceutical, polymers, food, cos-
metics, and liquid crystals.[1] A recent review article by Fus-
tero et al.[1a] vividly describes the diverse synthetic routes
available to accomplish the synthesis of pyrazole and its
derivatives. A noticeable feature in the compilation is that,
although C–C coupling reactions at the 3, 4, or 5 positions
in pyrazole are widely reported, no C–N cross-coupling re-
actions are known for these positions. Indeed, C–N cou-
pling in pyrazoles is limited to Ullman type coupling involv-
ing the free NH of the pyrazole. An earlier review by
Stanetty et al. also noted the C–N coupling reaction in pyr-
azole only at the nitrogen atom of the ring.[2] Intrigued by
this observation, we initiated a project in which we focussed
on probing approaches that enable C–N cross-coupling re-
actions at the 4-position by employing substituted 4-iodo-
pyrazoles as the starting material. To this end, we have
achieved considerable success. For example, we have dem-
onstrated that amides derived from the Morita–Baylis–Hill-
man (MBH) adducts of 4-iodopyrazolecarbaldehyde un-
dergo copper-catalyzed intramolecular Goldberg-type C–N
coupling to afford substituted pyrazolo[4,3-b]pyridin-5-
ones, whereas the allylamines obtained from the MBH ad-
ducts undergo Ullman-type C–N coupling to afford substi-
tuted pyrazolo[4,3-b]pyridines.[3,4] In addition, we success-
[‡] CDRI Communication Number 8161
[a] Medicinal and Process Chemistry Division, CSIR-Central Drug
Research Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405 or +91-522-2623938
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
[b] Centre of Biomedical Magnetic Resonance, Sanjay Gandhi
Post-Graduate Institute of Medical Sciences Campus,
Raebareli Road, Lucknow 226014 UP, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101454.
Figure 1. Some of the biologically active compounds incorporating
the pyrazolo[4,3-d]pyrimidine core.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1360–1366

Synthesis of Pyrazolo[4,3-d]-pyrimidine Derivatives
through a cascade reaction involving initial Schiff base for- Table 1. Optimizing the reaction of 4-iodo-1,5-diphenyl-1H-pyr-
azole-3-carbaldehyde with acetamidine hydrochloride.[a]
mation followed by intramolecular Ullman type C–N cou-
pling reaction. It may be noted that Huang et al.[6] have
reported analogous coupling reactions with 2-halobenzal-
dehydes. Substituted pyrazolo[4,3-d]pyrimidines are of sig-
nificant pharmaceutical importance because they display a
variety of bioactivities including anticancer, PDE5 inhibi-
tion, antileishmanial, adenosine A3 receptor antagonist,
corticotropin-releasing factor (CRF-1) antagonist and can-
nabinoid receptor ligand binding (Figure 1).[7] For these
reasons, several elegant methods for the preparation of sub-
stituted pyrazolo[4,3-d]pyrimidines have been reported in
the literature, but, to the best of our knowledge, no route
involving copper-mediated cross-coupling reaction has been
developed. Towards this end, we have successfully ac-
complished the synthesis of substituted pyrazolo[4,3-d]pyr-
imidines from 4-iodopyrazole derivatives in a single step in
excellent yields. We present herein the results of this study.
Entry
Catalyst
Ligand
Base
Solvent Yield [%][b]
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
0
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
62
65
78
46
68
0
54
56
58
42
46
10
11
12
Cu2O
CuCl
CuBr
Cs2CO3
Cs2CO3
Cs2CO3
Results and Discussion
The starting materials for the study were generated by
following reported procedures.[3–5] 4-Iodo-1,5-diphenyl-1H-
pyrazole-3-carbaldehyde and acetamidine hydrochloride
were selected as model substrates to optimize the reaction
conditions, including optimization of the copper source, li-
gands, base, and solvents under a nitrogen atmosphere. As
delineated in Table 1, four ligands were investigated at 90 °C
[a] Reagents and conditions: 4-iodo-1,5-diphenyl-1H-pyrazole-3-
carbaldehyde (1.0 mmol), acetamidine hydrochloride (1.2 mmol),
Cu-salt (0.1 mmol), ligand (0.2 mmol), base (3.0 mmol), solvent
(1.0 mL), 90 °C, 12 h. [b] Isolated yield after column chromatog-
raphy.
using 10 mol-% CuI as catalyst and 300 mol-% Cs2CO3 as tion between the formyl and the amino group is the initial
base in dimethyl sulfoxide (DMSO) (Table 1, entries 2–5); step, which is followed by cross coupling in the cascade cy-
it was found that l-proline (20 mol-%) displayed the best cle (Scheme 1).
activity.[8] No product was formed in the absence of ligand
We also attempted the cascade cyclization with ethyl 4-
(Table 1, entry 1). Other copper catalysts including Cu2O, iodo-1,5-diphenyl-1H-pyrazole-3-carboxylate and acet-
CuCl, CuBr showed weaker activity compared with CuI amidine hydrochloride for the synthesis of 5-methyl-2,3-di-
(Table 1, entries 10–12). The effect of solvent was also inves- phenyl-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one under sim-
tigated (Table 1, entries 4, 6, and 7), and DMSO was estab- ilar standard reaction conditions.[6] However, initial
lished as the best choice (entry 4); the reaction failed in tol- attempts did not yield the desired results. Ding et al. re-
uene (Table 1, entry 7). Of the three bases evaluated, ported the formation of quinazoline-4(3H)-ones under mild
Cs2CO3 proved to be the most effective (Table 1, entries 4, conditions by reaction of 2-haloarylcarboxamides with
8, and 9).
amidines.[9] Taking a cue from the report, we transformed
After successful optimization of the reaction conditions, 4-iodo-1,5-diphenyl-1H-pyrazole-3-carboxylate into 4-iodo-
the reaction between several 4-iodopyrazolecarbaldehydes N,1,5-triphenyl-1H-pyrazole-3-carboxamide, which was
and substituted amidine hydrochlorides were carried out in then reacted with acetamidine under the standardized con-
the presence of 10 mol-% CuI, 20 mol-% l-proline, and 300 ditions. The reaction was complete in the stipulated time
mol-% Cs2CO3 in DMSO at 90 °C under a nitrogen atmo- and, after purification, a solid product was isolated in 85%
sphere. As shown in Table 2, all the substrates examined af- yields. Unlike their observation, in our hands, the reaction
ford the required product in good yields. It was observed failed under ligand-free conditions. Spectroscopic analysis
that changes in the substitution at the pyrazole ring did not of the product led us to establish its structure as 5 (Table 3).
have any deleterious effect on the outcome. Of the three amid- This result contrasts with the outcome reported by Ding et
ines investigated, it was observed that acetamidine gave the al. who isolated the product carrying the N-phenyl group
products with relatively better yields, whereas the (pyridine- in major yields. The scope of the protocol was tested by
4-yl)acetamidine generated the desired products with including a p-methylphenyl-substituted substrate, which
slightly lower yields. Nevertheless, from the study it may be also reacted with acetamidine hydrochloride to afford the
inferred that the protocol is general and works efficiently required product in 84% yield (Table 3, entry 2). We did
with a wide range of substrates. As demonstrated pre- not observe the formation of any other product during the
viously,[5] we assume that, here too, the condensation reac- reaction.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Nayak, N. Rastogi, S. Batra
FULL PAPER
Table 2. Scope of reaction with substituted pyrazoles.[a]
Table 2. (continued)
[a] Reagents and conditions: 1 (1.0 mmol), 2 (1.2 mmol), CuI
(0.1 mmol), l-proline (0.2 mmol), Cs2CO3 (3.0 mmol), DMSO
(1.0 mL), 90 °C, 12 h. [b] Isolated yield after column chromatog-
raphy.
Scheme 1. Plausible mechanism for the synthesis of substituted pyr-
azolo[4,3-d]pyrimidines.
Finally, we examined a similar reaction between 4-iodo-
pyrazolecarbaldehyde and guanidine instead of amidines.
Accordingly,
4-iodo-1,5-diphenyl-1H-pyrazole-3-carbal-
dehyde was treated with guanidine hydrochloride under the
optimized reaction conditions (Scheme 2). Unfortunately,
under these conditions, the reaction resulted in a mixture
of products that could not be purified or characterized.
Scheme 2. Attempted reaction of 4-iodoprazolecarbaldehyde with
guanidine hydrochloride.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1360–1366

Synthesis of Pyrazolo[4,3-d]-pyrimidine Derivatives
(300 MHz, CDCl3): δ = 2.87 (s, 3 H, CH3), 7.38–7.50 (m, 10 H,
ArH), 9.45 (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
26.5, 124.9, 126.1, 127.9, 128.7, 129.0, 129.1, 129.5, 129.9, 130.4,
135.4, 138.7, 139.5, 140.3, 152.3, 162.1 ppm. MS (ESI+): m/z =
287.2 [M+ + 1]. HRMS (ESI+): calcd. for C18H15N4 [MH]+
287.1297; found 287.1294.
Table 3. Scope of reaction with 4-iodopyrazolecarboxamides and
amidine hydrochloride.
3-(4-Chlorophenyl)-5-methyl-2-phenyl-2H-pyrazolo[4,3-d]pyrimid-
ine: See Table 2, entry 1; yield 76 %; white solid (149 mg from
250 mg); m.p. 154–155 °C; Rf = 0.17 (hexanes/EtOAc, 80:20, v/v).
1H NMR (400 MHz, CDCl3): δ = 2.87 (s, 3 H, CH3), 7.38 (d, J =
8.5 Hz, 2 H, ArH), 7.45–7.49 (m, 7 H, ArH), 9.45 (s, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.5, 126.1, 126.3,
129.3, 129.7, 129.8, 131.1, 134.2, 135.3, 138.7, 140.0, 152.4,
162.3 ppm. MS (ESI+): m/z = 321.2 [M+ + 1]. HRMS (ESI+):
calcd. for C18H14ClN4 [MH]+ 321.0907; found 321.0911.
5-Methyl-3-(4-methylphenyl)-2-phenyl-2H-pyrazolo[4,3-d]pyrimid-
ine: See Table 2, entry 2; yield 77 %; white solid (149 mg from
250 mg); m.p. 174–175 °C; Rf = 0.17 (hexanes/EtOAc, 80:20, v/v).
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H, CH3), 2.86 (s, 3 H,
CH3), 7.20 (d, J = 7.9 Hz, 2 H, ArH), 7.40 (d, J = 8.0 Hz, 2 H,
ArH), 7.46 (s, 5 H, ArH), 9.43 (s, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.6, 26.6, 124.9, 126.1, 129.5, 129.7, 129.8,
135.6, 138.7, 139.2, 139.5, 140.4, 152.3, 161.9 ppm. MS (ESI+): m/z
= 301.3 [M+ + 1]; HRMS (DART): calcd. for C19H17N4 [MH]+
301.1453; found 301.1435.
[a] Reagents and conditions: 4 (1.0 mmol), 2 (1.2 mmol), CuI
(0.1 mmol), l-proline (0.2 mmol), Cs2CO3 (3.0 mmol), DMSO
(1.0 mL), 90 °C, 12 h. [b] Isolated yield after column chromatog-
raphy.
Conclusions
We have described a copper-mediated cascade protocol
for the facile syntheses of substituted pyrazolo[4,3-d]pyrim-
idines and pyrazolo[4,3-d]pyrimidin-7(6H)-ones from 4-
iodopyrazolecarbaldehydes and 4-iodopyrazolecarbox-
amides. The strategy is simple and efficient, and works with
a range of substrates. This study adds to the repertoire of
annulated-pyrazoles that can be generated through C–N
cross-coupling reactions of 4-iodopyrazole derivatives.
3-(4-Fluorophenyl)-5-methyl-2-phenyl-2H-pyrazolo[4,3-d]pyrimidine:
See Table 2, entry 3; yield 74%; yellow solid (143 mg from 250 mg);
1
m.p. 164–165 °C; Rf = 0.21 (hexanes/EtOAc, 80:20, v/v). H NMR
(400 MHz, CDCl3): δ = 2.86 (s, 3 H, CH3), 7.10 (t, J = 8.5 Hz, 2
H, ArH), 7.46–7.52 (m, 7 H, ArH), 9.45 (s, 1 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 26.5, 116.1, 116.4, 124.0, 126.1,
129.6, 129.7, 131.8, 131.9, 134.4, 138.7, 139.4, 140.1, 152.4, 161.9,
162.2 ppm. MS (ESI+): m/z = 305.0 [M+ + 1]. HRMS (ESI+):
calcd. for C18H14FN4 [MH]+ 305.1202; found 305.1196.
Experimental Section
5-Methyl-1,3-diphenyl-1H-pyrazolo[4,3-d]pyrimidine: See Table 2,
entry 4; yield 79%; white solid (151 mg from 250 mg); m.p. 142–
143 °C; Rf = 0.47 (hexanes/EtOAc, 80:20, v/v). 1H NMR
(400 MHz, CDCl3): δ = 2.95 (s, 3 H, CH3), 7.41–7.45 (m, 2 H,
ArH), 7.54 (t, J = 7.5 Hz, 2 H, ArH), 7.60 (t, J = 7.6 Hz, 2 H,
ArH), 7.80 (d, J = 7.9 Hz, 2 H, ArH), 8.59 (d, J = 7.8 Hz, 2 H,
ArH), 9.30 (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
26.1, 121.9, 127.47, 127.52, 128.9, 129.1, 129.8, 130.1, 131.4, 139.5,
General: Melting points are uncorrected and were determined in
capillary tubes with a Precision melting point apparatus containing
silicon oil. IR spectra were recorded with a Perkin–Elmer RX I
FTIR spectrophotometer. 1H and 13C NMR spectra were recorded
either with a Bruker DPX-200, a Bruker Avance DRX-300 or a
Bruker-400 MHz FT spectrometer, using TMS as internal standard
(chemical shifts: δ values). The MS (EI) were recorded with a
MICROMASS Quadro-II LCMS system. HRMS (EI) spectra were
recorded with an Agilent 6520 Q-TOF, LC-MS/MS mass spectrom-
eter.
141.9, 144.3, 145.5, 162.0 ppm. MS (ESI+): m/z = 287.3 [M+
+
1]. HRMS (DART): calcd. for C18H15N4 [MH]+ 287.1297; found
287.1295.
Typical Procedure; Synthesis of 5-Methyl-2,3-diphenyl-2H-pyr-
azolo[4,3-d]pyrimidine: To a solution of 4-iodo-1,5-diphenyl-1H-
pyrazole-3-carbaldehyde (250 mg, 0.67 mmol) and acetamidine hy-
drochloride (75 mg, 0.80 mmol) in DMSO (4 mL), Cs2CO3
(652 mg, 2.00 mmol), CuI (13 mg, 0.067 mmol), and l-proline
(15 mg, 0.134 mmol) were added and the reaction mixture was
heated at 90 °C for 12 h under a nitrogen atmosphere. Thereafter,
water (50 mL) and ethyl acetate (25 mL) were added and the reac-
tion mass was pass through a Celite bed and the layers were sepa-
rated. The aqueous layer was further extracted with ethyl acetate
(2ϫ20 mL) and the collected organic layer was washed with brine,
dried with anhydrous Na2SO4, and concentrated under vacuum.
Column chromatography (ethyl acetate/hexanes, 1:5) of the crude
product over silica gel furnished pure 5-methyl-2,3-diphenyl-2H-
pyrazolo[4,3-d]pyrimidine as a white solid (149 mg, 78%).
3-(4-Chlorophenyl)-5-methyl-1-phenyl-1H-pyrazolo[4,3-d]pyrimid-
ine: See Table 2, entry 5; yield 78 %; white solid (153 mg from
250 mg); m.p. 198–188 °C; Rf = 0.46 (hexanes/EtOAc, 80:20, v/v).
1H NMR (400 MHz, CDCl3): δ = 2.95 (s, 3 H, CH3), 7.44 (t, J =
7.2 Hz, 1 H, ArH), 7.50 (d, J = 8.5 Hz, 2 H, ArH), 7.61 (t, J =
7.8 Hz, 2 H, ArH), 7.79 (d, J = 7.9 Hz, 2 H, ArH), 8.57 (d, J =
8.5 Hz, 2 H, ArH), 9.31 (s, 1 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 26.1, 121.9, 127.7, 128.7, 129.2, 129.9, 130.2, 135.0,
139.4, 142.1, 145.3, 147.2, 162.2 ppm. MS (ESI+): m/z = 321.2 [M+
+ 1]. HRMS (DART): calcd. for C18H14ClN4 [MH]+ 321.0907;
found 321.0864.
5-Methyl-3-(4-methylphenyl)-1-phenyl-1H-pyrazolo[4,3-d]pyrimid-
ine: See Table 2, entry 6; yield 79%; white solid (153 mg from
250 mg); m.p. 144–145 °C; Rf = 0.48 (hexanes/EtOAc, 80:20, v/v).
5-Methyl-2,3-diphenyl-2H-pyrazolo[4,3-d]pyrimidine: See Table 1; 1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 2.95 (s, 3 H,
1
m.p. 155–156 °C; Rf = 0.26 (hexanes/EtOAc, 80:20, v/v). H NMR
CH3), 7.35 (d, J = 7.9 Hz, 2 H, ArH), 7.42 (t, J = 7.4 Hz, 1 H,
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M. Nayak, N. Rastogi, S. Batra
ArH), 7.60 (t, J = 7.8 Hz, 2 H, ArH), 7.80 (d, J = 7.9 Hz, 2 H, 3-(4-Chlorophenyl)-1-phenyl-5-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyr-
FULL PAPER
ArH), 8.48 (d, J = 8.0 Hz, 2 H, ArH), 9.30 (s, 1 H, ArH) ppm. 13
NMR (100 MHz, CDCl3): δ = 21.7, 26.1, 121.8, 127.4, 128.5, 129.7,
C
imidine: See Table 2, entry 13; yield 67%; white solid (157 mg from
250 mg); m.p. 239–240 °C; Rf = 0.26 (hexanes/EtOAc, 70:30, v/v).
1H NMR (400 MHz, CDCl3): δ = 7.49–7.56 (m, 3 H, ArH), 7.64
129.8, 130.1, 139.1, 139.6, 141.8, 144.5, 145.5, 161.9 ppm. MS
(ESI+): m/z = 301.3 [M+ + 1]. HRMS (ESI+): calcd. for C19H17N4 (s, 2 H, ArH), 7.82 (s, 2 H, ArH), 8.43 (s, 2 H, ArH), 8.63 (d, J =
[MH]+ 301.1453; found 301.1430.
6.6 Hz, 2 H, ArH), 8.82 (s, 2 H, ArH), 9.47 (s, 1 H, ArH) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 122.1, 122.3, 128.1, 128.7, 129.3,
129.6, 130.3, 130.5, 135.5, 142.4, 145.1, 150.7, 157.0 ppm. MS
(ESI+): m/z = 384.1 [M+ + 1]. HRMS (ESI+): calcd. for
C22H15ClN5 [MH]+ 384.1016; found 384.1019.
2,5-Dimethyl-3-(4-methylphenyl)-2H-pyrazolo[4,3-d]pyrimidine: See
Table 2, entry 7; yield 70%; yellow solid (128 mg from 250 mg);
1
m.p. 164–165 °C; Rf = 0.12 (hexanes/EtOAc, 70:30, v/v). H NMR
(400 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 2.81 (s, 3 H, CH3), 4.26
(s, 3 H, NCH3), 7.38 (d, J = 7.8 Hz, 2 H, ArH), 7.56 (d, J = 7.8 Hz,
2 H, ArH), 9.32 (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.6, 26.4, 40.1, 124.8, 129.8, 130.0, 136.0, 137.7, 139.5, 139.7,
151.1, 161.5 ppm. MS (ESI+): m/z = 239.3 [M+ + 1]. HRMS
(ESI+): calcd. for C14H15N4 [MH]+ 239.1297; found 239.1300.
3-(4-Methylphenyl)-1-phenyl-5-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyr-
imidine: See Table 2, entry 14; yield 68%; white solid (159 mg from
250 mg); m.p. 220–221 °C; Rf = 0.24 (hexanes/EtOAc, 70:30, v/v).
1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 7.40 (d, J =
7.7 Hz, 2 H, ArH), 7.47 (t, J = 7.4 Hz, 1 H, ArH), 7.63 (t, J =
7.6 Hz, 2 H, ArH), 7.85 (d, J = 7.8 Hz, 2 H, ArH), 8.46 (d, J =
4.6 Hz, 2 H, ArH), 8.57 (d, J = 7.8 Hz, 2 H, ArH), 8.82 (s, 2 H,
ArH), 9.47 (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.7, 122.0, 122.3, 127.5, 127.9, 128.2, 129.8, 130.2, 130.4, 139.3,
139.6, 142.2, 145.4, 145.7, 150.7, 156.7 ppm. MS (ESI+): m/z =
364.3 [M+ + 1]. HRMS (ESI+): calcd. for C23H18N5 [MH]+
364.1562; found 364.1561.
2,5-Dimethyl-2H-pyrazolo[4,3-d]pyrimidine: See Table 2, entry 8;
yield 78%; yellow oil (122 mg from 250 mg); Rf = 0.21 (hexanes/
EtOAc, 50:50, v/v). 1H NMR (300 MHz, CDCl3): δ = 2.69 (s, 3 H,
CH3), 4.19 (s, 3 H, NCH3), 7.99 (s, 1 H, ArH), 9.19 (s, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.9, 40.9, 124.1,
136.9, 139.9, 150.4, 159.7 ppm. MS (ESI+): m/z = 149.2 [M+ + 1].
HRMS (ESI): calcd. for C7H9N4 [MH]+ 149.0827; found 149.0830.
2-Methyl-3-(4-methylphenyl)-5-(pyridin-4-yl)-2H-pyrazolo[4,3-d]pyr-
imidine: See Table 2, entry 15; yield 64%; white solid (148 mg from
250 mg); m.p. 200–201 °C; Rf = 0.13 (hexanes/EtOAc, 60:40, v/v).
1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H, CH3), 4.36 (s, 3 H,
NCH3), 7.45 (d, J = 8.0 Hz, 2 H, ArH), 7.69 (d, J = 8.1 Hz, 2 H,
ArH), 8.36 (dd, J1 = 1.4, J2 = 4.6 Hz, 2 H, ArH), 8.73 (d, J =
6.0 Hz, 2 H, ArH), 9.50 (s, 1 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.7, 25.9, 40.5, 122.3, 129.8, 130.1, 140.0, 140.5,
142.7, 147.9, 150.4, 163.0 ppm. MS (ESI+): m/z = 302.2 [M+ + 1].
HRMS (ESI+): calcd. for C18H16N5 [MH]+ 302.1406; found
302.1407.
2,3-Diphenyl-5-(pyridin-4-yl)-2H-pyrazolo[4,3-d]pyrimidine:
See
Table 2, entry 9); yield 68%; white solid (159 mg from 250 mg);
1
m.p. 203–204 °C; Rf = 0.13 (hexanes/EtOAc, 70:30, v/v). H NMR
(400 MHz, CDCl3): δ = 7.44–7.48 (m, 3 H, ArH), 7.51–7.52 (m, 5
H, ArH), 7.61–7.63 (m, 2 H, ArH), 8.41 (d, J = 5.1 Hz, 2 H, ArH),
8.77 (d, J = 4.6 Hz, 2 H, ArH), 9.62 (s, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 122.4, 126.2, 129.0, 129.4, 129.7, 129.9,
130.0, 140.2, 145.7, 147.7, 150.6, 152.6, 158.2 ppm. MS (ESI+):
m/z = 350.2 [M+ + 1]. HRMS (ESI+): calcd. for C22H16N5 [MH]+
350.1406; found 350.1428.
3-(4-Chlorophenyl)-2-phenyl-5-(pyridin-4-yl)-2H-pyrazolo[4,3-d]pyr-
imidine: See Table 2, entry 10; yield 65%; white solid (152 mg from
250 mg); m.p. 167–168 °C; Rf = 0.14 (hexanes/EtOAc, 70:30, v/v).
1H NMR (400 MHz, CDCl3): δ = 7.44 (d, J = 8.5 Hz, 2 H, ArH),
7.52 (s, 5 H, ArH), 7.57 (d, J = 8.5 Hz, 2 H, ArH), 8.40 (d, J =
5.5 Hz, 2 H, ArH), 8.78 (d, J = 4.0 Hz, 2 H, ArH), 9.62 (s, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 122.4, 126.1, 128.0,
129.4, 129.9, 130.1, 131.1, 135.7, 139.4, 140.0, 145.6, 147.3, 150.5,
152.7, 156.9 ppm. MS (ESI+): m/z = 384.2 [M+ + 1]. HRMS
(ESI+): calcd. for C22H15ClN5 [MH]+ 384.1016; found 384.1033.
5-Cyclopropyl-2,3-diphenyl-2H-pyrazolo[4,3-d]pyrimidine: See
Table 2, entry 16; yield 71%; white solid (148 mg from 250 mg);
1
m.p. 160–161 °C; Rf = 0.48 (hexanes/EtOAc, 80:20, v/v). H NMR
(400 MHz, CDCl3): δ = 1.04–1.09 (m, 2 H, CH2), 1.11–1.15 (m, 2
H, CH2), 2.35–2.42 (m, 1 H, CH), 7.27–7.34 (m, 4 H, ArH), 7.36–
7.40 (m, 4 H, ArH), 7.51–7.54 (m, 2 H, ArH), 9.38 (s, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.3, 12.0, 18.9,
126.1, 128.7, 128.9, 129.5, 129.9, 130.8, 134.8, 139.3, 152.4,
166.0 ppm. MS (ESI+): m/z = 313.3 [M+ + 1]. HRMS (ESI+):
calcd. for C20H17N4 [MH]+ 313.1453; found 313.1464.
3-(4-Methylphenyl)-2-phenyl-5-(pyridin-4-yl)-2H-pyrazolo[4,3-d]pyr-
imidine: See Table 2, entry 11; yield 66%; white solid (154 mg from
250 mg); m.p. 200–201 °C; Rf = 0.14 (hexanes/EtOAc, 70:30, v/v).
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 7.26 (d, J =
7.8 Hz, 2 H, ArH), 7.51–7.54 (m, 7 H, ArH), 8.40 (d, J = 5.4 Hz,
2 H, ArH), 8.76 (d, J = 3.8 Hz, 2 H, ArH), 9.60 (s, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.6, 122.3, 124.7, 126.1, 129.6,
129.7, 129.8, 139.4, 140.3, 145.7, 150.5, 152.5, 156.5 ppm. MS
(ESI+): m/z = 364.3 [M+ + 1]. HRMS (ESI+): calcd. for C23H18N5
[MH]+ 364.1562; found 364.1561.
3-(4-Chlorophenyl)-5-cyclopropyl-1-phenyl-1H-pyrazolo[4,3-d]pyr-
imidine: See Table 2, entry 17; yield 70%; white solid (148 mg from
250 mg); m.p. 155–156 °C; Rf = 0.63 (hexanes/EtOAc, 80:20, v/v).
1H NMR (400 MHz, CDCl3): δ = 1.13–1.17 (m, 2 H, CH2), 1.24–
1.28 (m, 2 H, CH2), 2.46–2.53 (m, 1 H, CH), 7.42 (t, J = 7.4 Hz, 1
H, ArH), 7.49 (d, J = 8.6 Hz, 2 H, ArH), 7.59 (t, J = 7.9 Hz, 2 H,
ArH), 7.78 (d, J = 7.7 Hz, 2 H, ArH), 8.56 (d, J = 8.6 Hz, 2 H,
ArH), 9.24 (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
11.1, 18.5, 121.8, 127.6, 128.6, 129.1, 130.1, 134.9, 139.5, 142.1,
142.9, 145.3, 166.4 ppm. MS (ESI+): m/z = 347.2 [M+ + 1]. HRMS
(ESI+): calcd. for C20H16ClN4 [MH]+ 347.1063; found 347.1150.
1,3-Diphenyl-5-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine: See
Table 2, entry 12; yield 69%; white solid (161 mg from 250 mg);
1
m.p. 186–187 °C; Rf = 0.25 (hexanes/EtOAc, 70:30, v/v). H NMR
5-Cyclopropyl-3-(4-methylphenyl)-1-phenyl-1H-pyrazolo[4,3-d]pyr-
(400 MHz, CDCl3): δ = 7.47–7.49 (m, 2 H, ArH), 7.57–7.63 (m, 4 imidine: See Table 2, entry 18; yield 72%; white solid (151 mg from
H, ArH), 7.84 (d, J = 7.0 Hz, 2 H, ArH), 8.46 (s, 2 H, ArH), 8.68
(d, J = 6.8 Hz, 2 H, ArH), 8.81 (s, 2 H, ArH), 9.46 (s, 1 H,
250 mg); m.p. 160–161 °C; Rf = 0.65 (hexanes/EtOAc, 80:20, v/v).
1H NMR (400 MHz, CDCl3): δ = 1.11–1.16 (m, 2 H, CH2), 1.25–
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 122.0, 122.3, 127.6, 1.28 (m, 2 H, CH2), 2.44 (s, 3 H, CH3), 2.48–2.53 (m, 1 H, CH),
128.0, 129.0, 129.5, 130.2, 130.4, 131.0, 139.3, 142.3, 145.2, 150.7,
156.8 ppm. MS (ESI+): m/z = 350.3 [M+ + 1]. HRMS (DART):
calcd. for C22H16N5 [MH]+ 350.1406; found 350.1408.
7.34 (d, J = 7.9 Hz, 2 H, ArH), 7.40 (t, J = 7.3 Hz, 1 H, ArH),
7.58 (t, J = 7.7 Hz, 2 H, ArH), 7.79 (d, J = 8.2 Hz, 2 H, ArH),
8.49 (d, J = 7.9 Hz, 2 H, ArH), 9.23 (s, 1 H, ArH) ppm. 13C NMR
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1360–1366

Synthesis of Pyrazolo[4,3-d]-pyrimidine Derivatives
(100 MHz, CDCl3): δ = 11.0, 18.4, 21.7, 121.7, 127.3, 128.7, 129.6,
130.0, 139.0, 139.7, 141.8, 144.2, 145.6, 166.1 ppm. MS (ESI+):
m/z = 327.3 [M+ + 1]. HRMS (ESI+): calcd. for C21H19N4 [MH]+
327.1610; found 327.1634.
= 303.3 [M+ + 1]. HRMS (ESI+): calcd. for C18H15N4O [MH]+
303.1246; found 303.1248.
5-Methyl-3-(4-methylphenyl)-2-phenyl-2,6-dihydro-7H-pyrazolo-
[4,3-d]pyrimidin-7-one: See Table 3, entry 2; yield 84%; white solid
(139 mg from 250 mg); m.p. Ͼ250 °C; Rf = 0.27 (hexanes/EtOAc,
Synthesis of 4-Iodo-N,1,5-triphenyl-1H-pyrazole-3-carboxamide
(Typical Procedure): To a stirred solution of 4-iodo-1,5-diphenyl-
1H-pyrazole-3-carboxylic acid (250 mg, 0.64 mmol) and aniline
(0.07 mL, 0.77 mmol) in anhydrous CH2Cl2 (10 mL) was added N-
methylmorpholine (NMM; 0.084 mL, 0.77 mmol) and the mixture
was cooled to –10 °C in an ice/salt bath. Thereafter N-ethyl-NЈ-[3-
(dimethylamino)propyl]carbodiimide (EDC; 148 mg, 0.77 mmol)
was added to the reaction mixture over 10 min, which was stirred
for another 2 h. Upon completion, the reaction mixture was
quenched with water (50 mL) and extracted with CH2Cl2
(3ϫ20 mL). The combined organic layers were washed with brine,
dried with Na2SO4, and concentrated in vacuo. Column
chromatography of the crude product over silica gel (ethyl acetate/
hexanes, 1:20) furnished 4-iodo-N,1,5-triphenyl-1H-pyrazole-3-
carboxamide as a white solid (247 mg, 83%).
1
50:50, v/v); IR (KBr): ν
= 1689 (CONH), 3400 (NH) cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 2.36 (s, 3 H, CH3), 2.57 (s, 3 H,
NCH3), 7.18 (d, J = 7.9 Hz, 2 H, ArH), 7.32 (d, J = 8.0 Hz, 2 H,
ArH), 7.40–7.45 (m, 5 H, ArH), 11.65 (s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.5, 22.2, 125.1, 126.0, 128.9, 129.2, 129.6,
129.8, 132.1, 135.7, 136.3, 137.1, 139.1, 140.1, 152.4, 160.1 ppm.
MS (ESI+): m/z = 317.3 [M+ + 1]. HRMS (ESI+): calcd. for
C19H17N4O [MH]+ 317.1402; found 317.1406.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds.
Acknowledgments
One of the authors (M. N.) gratefully acknowledges financial help
in the form of a fellowship from the Council of Scientific and In-
dustrial Research (CSIR), New Delhi. The authors acknowledge
the SAIF Division for recording the spectroscopic and analytical
data.
4-Iodo-N,1,5-triphenyl-1H-pyrazole-3-carboxamide: M.p. 187–
188 °C; R = 0.28 (hexanes/EtOAc, 80:20, v/v); IR (KBr): ν
=
˜
f
max
1683 (CONH), 3381 (NH) cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.13 (t, J = 7.1 Hz, 1 H, ArH), 7.26–7.29 (m, 4 H, ArH), 7.34–7.40
(m, 8 H, ArH), 7.74 (d, J = 8.2 Hz, 2 H, ArH), 8.86 (s, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 63.2, 120.0, 124.4,
125.3, 128.8, 129.2, 129.7, 130.7, 138.0, 139.5, 144.9, 147.4,
159.1 ppm. MS (ESI+): m/z = 466.0 [M+ + 1]. HRMS (ESI+):
calcd. for C22H17IN3O [MH]+ 466.0416; found 466.0430.
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4-Iodo-5-(4-methylphenyl)-N,1-diphenyl-1H-pyrazole-3-carbox-
amide: Yield 82%; white solid (243 mg from 250 mg); m.p. 214–
215 °C; R = 0.26 (hexanes/EtOAc, 80:20, v/v). IR (KBr): ν
=
˜
f
max
1667 (CONH), 3435 (NH) cm–1. 1H NMR (300 MHz, CDCl3): δ =
2.38 (s, 3 H, CH3), 7.10–7.18 (m, 5 H, ArH), 7.24–7.27 (m, 2 H,
ArH), 7.34–7.38 (m, 5 H, ArH), 7.73 (d, J = 7.7 Hz, 2 H, ArH),
8.85 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6,
63.1, 120.0, 124.4, 125.3, 128.6, 129.2, 129.5, 130.6, 138.0, 139.6,
139.8, 147.5, 159.1 ppm. MS (ESI+): m/z = 480.1 [M+ + 1]. HRMS
(ESI+): calcd. for C23H19IN3O [MH]+ 480.0573; found 480.0570.
Synthesis of 5-Methyl-2,3-diphenyl-2,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one (Typical Procedure): To a solution of 4-iodo-
N,1,5-triphenyl-1H-pyrazole-3-carboxamide (250 mg, 0.54 mmol)
and acetamidine hydrochloride (61 mg, 0.65 mmol) in DMSO
(4 mL), Cs2CO3 (527 mg, 1.62 mmol), CuI (10 mg, 0.054 mmol),
and l-proline (12 mg, 0.108 mmol) were added and the reaction
mixture was heated at 90 °C for 12 h under a nitrogen atmosphere.
Thereafter, water (50 mL) and ethyl acetate (25 mL) were added
and the reaction mass was pass through a Celite bed. The layers
were separated and the aqueous layer was further extracted with
ethyl acetate (2ϫ20 mL). The collected organic layer was washed
with brine, dried with anhydrous Na2SO4 and concentrated under
vacuum. Column chromatography of the crude product over silica
gel (ethyl acetate/hexanes, 1:1) furnished pure 5-methyl-2,3-di-
phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one as a white
solid (138 mg, 85%).
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one: See Table 3, entry 1); m.p. Ͼ250 °C; Rf = 0.25 (hexanes/
EtOAc, 50:50, v/v); IR (KBr): ν
= 1687 (CONH), 3374
˜
max
1
(NH) cm–1. H NMR (300 MHz, CDCl3): δ = 2.58 (s, 3 H, CH3),
7.35–7.41 (m, 10 H, ArH), 11.72 (s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.1, 126.0, 128.0, 128.8, 129.0, 129.2,
129.9, 135.7, 136.1, 137.0, 139.9, 152.7, 159.9 ppm. MS (ESI+): m/z
Eur. J. Org. Chem. 2012, 1360–1366
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1365

M. Nayak, N. Rastogi, S. Batra
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Received: October 6, 2011
Published Online: January 10, 2012
1366
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1360–1366