Microwave-assisted synthesis of substituted pyrazoles and pyrazolo [3,4-d]thiopyrimidines

Article abstract of DOI:10.1080/10426500500269646

Ethyl(ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile were synthesized from the reaction of malononitrile or ethylcyanoacetate with triethyl orthoformate or orthoacetate in N, N-dimethylacetamide under microwave irradiation. In a similar manner, substituted pyrazoles were synthesized from the reaction of ethyl (ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile with phenylhydrazine. These pyrazoles were converted to pyrazolo[3,4-d]thiopyrimidines upon treatment with arylisothiocyanate and thiourea under microwave irradiation. Copyright Taylor & Francis Group, LLC.

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Microwave-Assisted
Synthesis of Substituted
Pyrazoles and Pyrazolo [3, 4-
d]thiopyrimidines
Majid M. Heravi a , Navabeh Nami a , Nasim Seifi a ,
Hossein A. Oskooie a & Rahim Hekmatshoar a
a Department of Chemistry, Azzahra University,
Vanak, Tehran, Iran
Version of record first published: 01 Feb 2007.
To cite this article: Majid M. Heravi , Navabeh Nami , Nasim Seifi , Hossein A. Oskooie
& Rahim Hekmatshoar (2006): Microwave-Assisted Synthesis of Substituted Pyrazoles
and Pyrazolo [3, 4-d]thiopyrimidines, Phosphorus, Sulfur, and Silicon and the Related
Elements, 181:3, 591-599
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Phosphorus, Sulfur, and Silicon, 181:591–599, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500269646
Microwave-Assisted Synthesis of Substituted Pyrazoles
and Pyrazolo [3,4-d]thiopyrimidines
Majid M. Heravi
Navabeh Nami
Nasim Seifi
Hossein A. Oskooie
Rahim Hekmatshoar
Department of Chemistry, Azzahra University, Vanak, Tehran, Iran
Ethyl(ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile were syn-
thesized from the reaction of malononitrile or ethylcyanoacetate with triethyl ortho-
formate or orthoacetate in N, N-dimethylacetamide under microwave irradiation. In
a similar manner, substituted pyrazoles were synthesized from the reaction of ethyl
(ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile with phenylhy-
drazine. These pyrazoles were converted to pyrazolo[3,4-d]thiopyrimidines upon
treatment with arylisothiocyanate and thiourea under microwave irradiation.
Keywords Ethylcyanoacetate; malononitrile; pyrazolo[3,4-d]thiopyrimidine; triethyl
orthoacetate; triethyl orthoformate
Pyrazoles are a class of heterocyclic compounds that have many deriva-
tives with a wide range of interesting properties, such as antihyper-
glycemic, analgestic, anti-inflammatory, anti-pyretic, anti-bacterial, hy-
poglycemic, and sedative-hypnotic activity. In particular, aryl pyra-
zoles are important in medicinal and pesticide chemistry.2 Recently,
some arylpyrazole derivatives were reported to have nonnucleoside
HIV-1 reverse transcriptase inhibitory activity.3 The pyrazole moi-
ety is a core structure in a number of biologically active compounds,
such as pyrazolo[3,4-d]pyrimidine.4 The antitumor activty.5,6 of several
derivatives of the pyrazolo[3,4-d]pyrimidine system has prompted in-
vestigation of these compounds. The antitumor activity,5−6 of several
derivatives of the pyrazolo[3,4-d]pyrimidine system has prompted in-
vestigation of these compounds.
Received May 10, 2005; accepted May 10, 2005.
Address correspondence to Majid M. Heravi, Azzahra University, Department of
Chemistry, School of Sciences, Vanak, Tehran, Iran. E-mail: mmh1331@yahaoo.com
591

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M. M. Heravi et al.
Organic synthesis under microwave irradiation is presently under
extensive examinations.7−10 The relatively low cost of modern domes-
tic microwave ovens makes them readily available to academic and
industrial chemists, and the use of such unconventional reaction con-
ditions reveals several features such as a short reaction time compared
to conventional heating, reduction of the usual thermal degradation,
and better selectivity.1−13 An attractive synthetic methodology is the
possibility of performing reactions in solvent-free conditions or on solid
inorganic supports.
Indeed, in several cases, a solid-state organic reaction occurs more
efficiently and more selectively than does its solution counterpart, be-
cause molecules in a crystal are arranged tightly and regularly.14−18
Mineral oxides are very efficient MW absorbents.17
This results in a very rapid and homogeneous heating and conse-
quently, reactions in solid supports under microwaves show strange
MW effects.18
In continuation of our interest to perform organic reactions under
microwave irradiation19 and the synthesis of heterocyclic systems,20
here we wish to report the synthesis of pyrazoles and pyrazolo[3,4-
d]thiopyrimidines.
First we investigated the addition of ethylcyanoacetate to triethyl
orthoformate or orthoacetate under microwave irradiation. The reac-
tions were simply conducted by mixing ethylcyanoacetate with triethyl
orthoformate or orthoacetate, silica gel, and N,N-dimethylacetamide in
a beaker and placing the beaker in a microwave oven for a short period
of time. The progress of the reaction was monitored by TLC using ethyl
acetate and n-hexane (1:9). Ethyl(ethoxymethylene)cyanoacetate 1a21
and ethyl α-cyano-β-ethoxycrotonat 1c22 were prepared, respectively.
In a similar manner, the reaction of malononitrile with triethyl or-
thoformate or orthoacetate in N,N-dimethylacetamide on the surface of
silica gel gave ethoxymethylene malononitrile 1b23 and ethoxyethyli-
dene malononitrile 1d,24 respectively.
The reaction of 1a–d with phenylhydrazine under microwave irra-
diation in a solventless system gave 3-amino-4-carbethoxy-2-phenyl-
pyrazole 2a,21 3-amino-4-cyano-5-methyl-2-phenylpyrazole 2b,25,26
3-amino-4-carbethoxy-5-methyl-2-phenylpyrazole 2c,27 and 3-amino-4-
cyano-5-methyl-2-phenylpyrazole 2d,25,26 respectively (Scheme 1).
The reaction of phenylisothiocyanate and 4-nitrophenylisothiocya-
nate with 2b and 2d under microwave irradiation gave 4-imino-
1,5-diphenylpyrazolo[3,4-d]pyrimidine-6(7H)-thione 3a,28 4-imino-
3-methyl-1,5-diphenylpyrazolo[3,4-d]pyrimidine-6(7H)-thione 3b, 4-
imino-3-methyl-l-phenyl-5-(4-nitrophenyl) pyrazolo[3,4-d]pyrimidine-
6(7H)-thione 3c, and 4-imino-l-phenyl-5-(4-nitrophenyl) pyrazolo[3,

Microwave-Assisted Synthesis
593
SCHEME 1
4-d]pyrimidine 6(7H)-thione 3d. The reaction of 2a–2d with thiourea
under microwave irradiation gave 1- phenyl pyrazolo[3,4-d]pyrimidin-
4(5H)-one-6(7H)-thione 4a, 4-amino-l-phenyl pyrazolo[3,4-d]pyrimidin-
6(7H)-thione 4b, 3-methyl-l-phenylpyrazolo[3,4-d]pyrimidin-4(5H)-
one-6(7H)-thione 4c, and 4-amino-3-methyl-l-phenylpyrazolo[3,4-
d]pyrimidin-4(5H)-one-6(7H)-thione 4d respectively (Scheme 2).
EXPERIMENTAL
The melting points were obtained using an electrothermal IA 9100 dig-
ital melting point apparatus. The IR spectra were recorded on a Bruker
(400–4000 cm−1) spectrometer. 1HNMR spectra were recorded on a 300
MHz spectrometer using TMS as internal standard. Mass spectrometric
measurements were made on an Agilent Technologies 6890 N Network
GC system. The microwave oven used was LG MOD MC-838 WR.
Synthesis of 1a–d
General Procedure
Malononitrile or ethylcyanoacetate (0.1 mmol) and triethyl or-
thoformate or orthoacetate (0.1 mmol), silica gel (1 g), and N,N-
dimethylacetamide (1 mL) were thoroughly mixed in a beaker using

594
M. M. Heravi et al.
SCHEME 2
a spatula. The beaker was placed in a microwave oven for a specified
time. The progress of the reaction was monitored by TLC using ethyl ac-
etate and n-hexane (1:9). The mixture was extracted with ethanol. The
solvent was evaporated and the crude product was passed through a
columm of silica gel using ethyl acetate and n-hexane (1:9), giving 1a–d.
Ethyl(ethoxymethylene)cyanoacetate 1a
Irradiation time was 10 min (900 W), m.p. = 52◦C (Lit.2152–53◦C), yield
55%.
Ethoxymethylene Malononitrile 1b
Irradiation time was 5 min (720 W), m.p. = 66–67◦C (Lit.23 65–68◦C),
yield 95%.
Ethyl α-Cyano-β-ethoxycrotonate 1c
Irradiation time was 10 min (900 W), m.p. = 74◦C (Lit.27C), yield 60%.
Ethoxyethylidene Malononitrile 1d
Irradiation time was 4 min (900 W), m.p. = 87◦C (Lit,24 90◦C), yield
89%.

Microwave-Assisted Synthesis
595
Synthesis of Pyrazoles
General Procedure
la–d (0.1 mmol), phenylhydrazine (0.1 mmol), silica gel (1 g), and N,
N-dimethylacetamide(1 mL) were a thoroughly mixed in a beaker using
a spatula. The beaker was placed in a microwave oven for a specified
time. The progress of the reaction was monitored by TLC using ethyl
acetate and n-hexane (1:9). The mixture was extracted with ethanol.
The solvent was evaporated and the crude product was purified by re-
crystallization from an appropriate solvent, giving 2a–d.
3-Amino-4-carbethoxy-2-phenylpyrazole 2a
Irradiation time was 9 min (900 W), m.p. = 99◦C from ethanol/water
(50:50), (Lit.21 99–101◦C), yield 60%.
3-Amino-4-cyano-2-phenylpyrazole 2b
Irradiation time was 9 min (900 W), m.p. = 130◦C from ethanol/water
(50:50), (Lit.25,26 130◦C), yield 92%.
3-Amino-4-carbethoxy-5-methyl-2-phenylpyrazole 2c
Irradiation time was 9 min (900 W), m.p. = 215◦C from ethanol/water
(50:50), (Lit.27 215◦C), yield 62%.
3-Amino-4-cyano-5-methyl-2-phenylpyrazole 2d
Irradiation time was 9 min (900 W), m.p. = 125◦C from ethanol/water
(50:50), (Lit.25,26 125◦C), yield 83%.
Synthesis of Pyrazolo[3,4-d]thiopyrimidines
General Procedure
An appropriate pyrazole (0.1 mmol) was thoroughly mixed
with phenylisothiocyanate, 4-nitrophenyl isothiocyanate, or thiourea
(0.1 mmol), in a beaker using a spatula. The beaker was placed in a
microwave oven for a specified time. The progress of the reaction was
monitored by TLC using ethyl acetate and n-hexane (1:9). The crude
product was crystallized from an appropriate solvent.

596
M. M. Heravi et al.
4-Imino-1,5-diphenyl pyrazolo[3,4-d]pyrimidine-
6(7H)-thione 3a
Irradiation time was 8 min (900 W), m.p. = 227◦C from ethanol (Lit.28
227◦C), yield 82%.
4-Imino-3-methyl-1,5-diphenyl Pyrazolo[3,4-d]pyrimidine-
6(7H)-thione 3b
Irradiation time was 8 min (900 W), m.p. = 260◦C from ethanol, yield
65%. 1HNMR: δ (d6-DMSO), 2.41 (s, 3H, CH3), 7.13 (s, 1H, NH), 7.32 (m,
10H, Ar-H), 9.35 (br, 1H, NH). IR (KBr) (vmax, cm−1): 3362 (NH, str),
3246 (NH, str), 3062 (Ar-H, str), 2998 (alkyl-H, str), 1627 (C S, str),
1584 (C N, str), 1544 (C C, str), 1436 (C C, str), 1374, 1329, 1205,
1147, 1072, 750, 687. MS, m/z; M+, 333.
4-Imino-3-methyl-1-phenyl-5-(4-nitrophenyl)pyrazolo[3,4-
d]pyrimidine-6(7H)-thione 3c
Irradiation time was 7 min (2 × 5 min, 400 W), m.p. = 192◦C from
methanol, yield 75%. 1HNMR: δ (d6-DMSO), 2.46 (s, 3H, CH3), 7.04 (s,
1H, NH), 7.22 (m, 5H, Ar-H), 8.14 (d, J = 7, 2H, Ar-H), 8.51 (d, J = 7, 2H,
Ar-H), 10.21 (br, 1H, NH). IR (KBr) (vmax, cm−1): 3421 (NH, str), 3310
(NH, str), 3050 (Ar-H, str), 2980 (alkyl-H, str), 1617 (C S, str), 1587
(C N, str), 1553 (C C, str), 1504 (C C, str), 1462 (N O, str), 1434,
1329, 1249, 1181, 1112, 1087, 962, 850, 750, 690. MS, m/z; M+, 378.
4-Imino-1-phenyl-5-(4-nitrophenyl)pyrazolo[3,4-d]pyrimidine-
6(7H)-thione 3d
Irradiation time was 10 min (900 W), m.p. = 189◦C from methanol,
yield 65%. 1HNMR: δ (d6-DMSO), 7.15 (s, 1H, NH), 7.31 (m, 5H, Ar-H),
8.11 (s, 1H, CH), 8.22 (d, J = 7, 2H, Ar-H), 8.58 (d, J = 7, 2H, Ar-H),
10.48 (br, 1H, NH). IR (KBr) (υmax, cm−1): 3391 (NH, str), 3230 (NH,
str), 3035 (Ar-H st), 1622 (C S, str), 1590 (C N, str), 1509 (C C, str),
1437 (N O, str), 1315, 1111, 1010, 855, 764, 692. MS, m/z; M+, 364.
1-Phenylpyrazolo[3,4-d]pyrimidin-4(5H)-one-6(7H)-thione 4a
Irradiation time was 10 min (2 × 5 min, 300 W), m.p. = 200◦C from
1
methanol, yield 65%. HNMR: δ (CDCl3), 7.39(s, 1H, CH), 7.52 (m,
3H, Ar-H), 8.15 (m, 2H, Ar-H), 8.22 (s, 1H, NH), 10.88 (s, 1H, NH), IR
(KBr) (υmax, cm−1): 3430 (NH, str), 3321 (NH, str), 3052 (Ar-H, st), 1660

Microwave-Assisted Synthesis
597
(C O, str), 1618 (C N, str), 1549 (C C, str), 1461, 1372, 1279, 1200,
1128, 946, 913, 784, 753, 701, 603. MS, m/z; M+, 244.
4-Amino-1-phenylpyrazolo[3,4-d]pyrimidine-6(7H)-thione 4b
Irradiation time was 7 min (900 W), m.p. = 215◦C from methanol, yield
80%. 1HNMR: δ (d6-DMSO), 7.18(s, 1H, CH), 7.47 (m, 3H, Ar-H), 7.99
(m, 2H, Ar-H), 8.63 (s, 2H, NH2), 9.84 (s, 1H, NH), IR (KBr) (υmax, cm−1):
3408 (NH, str), 3312 (NH2, str), 3035 (Ar-H, str), 1625 (C N, str), 1588
(C C, str), 1543 (C C, str), 1498 (C C, str), 1440, 1296, 1161, 1019,
936, 806, 760. MS, m/z; M+, 243.
3-Methyl-1-phenylpyrazolo[3,4-d]pyrimidin-4(5H)-one-6(7H)-
thione 4c
Irradiation time was 7 min (900 W), m.p. = 217◦C from methanol, yield
53%. 1HNMR: δ (d6-DMSO), 2.23 (s, 3H, CH3), 7.49 (m, 3H, Ar-H), 8.01
(m, 2H, Ar-H), 8.18 (br, 1H, NH), 12.61 (br, 1H, NH). IR (KBr) (υmax
,
cm−1): 3458 (NH, str), 3257 (NH, str), 3050 (Ar-H, CH, str), 2981
(alkyl-H, str), 1656 (C O, str), 1546 (C N, str), 1461 (C C, str), 1438,
1380, 1141, 1103, 1050, 1006, 659, 559, 446. MS, m/z; M+, 258.
4-Amino-3-methyl-1-phenylpyrazolo[3,4-d]pyrimidine-6(7H)-
thione 4d
Irradiation time was 7 min (900 W), m.p. > 300◦C from methanol, yield
87%. 1HNMR: δ (d6-DMSO), 2.11 (s, 3H, CH3), 7.52 (m, 3H, Ar-H), 7.98
(m, 2H, Ar-H), 8.05 (s, 2H, NH2)−8.45 (br, 1H, NH). IR (KBr) (υmax
,
cm−1): 3352 (NH, str), 3127 (NH, str), 3045 (Ar-H, str), 2991 (alkyl-H,
str), 1689 (C O, str), 1636 (C N, str), 1524 (C C, str), 1473 (C C, str),
1380, 1298, 1197, 943, 777, 690.
CAUTION
Although we did not have any accident, the use of a microwave oven in
an efficient hood is highly recommended.
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