Synthesis of 4-hydrazinopyrazolo[3,4-d]pyrimidines and their reactions with carbonyl compounds

Article abstract of DOI:10.3184/174751912X13543818811749

Synthesis of a new 4-hydrazinopyrazolo[3,4-d]pyrimidine was achieved via heating (4,6-dithioxo-1H-pyrazolo[3,4-d] pyrimidin-3-yl)acetonitrile with hydrazine hydrate. Reactions of the latter product with thiophene-2-carbaldehyde and ethyl hydrazonoacetoacetate analogues afforded the corresponding hydrazone and pyrazole derivatives, respectively. Similarly, condensation of 2-[6-(benzylsulfanyl)-4-hydrazino-1H-pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile with thiophene-2-carbaldehyde and ethyl hydrazonoacetoacetate analogues gave the respective hydrazone and pyrazolone derivatives. Alkylation reactions of 2-[4,6-bis(benzylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile with arylamines gave the respective 4-(N-arylamino)-6-benzylsulfanylpyrazolo[3,4-d] pyrimidine derivatives.

Full text of DOI:10.3184/174751912X13543818811749

6
RESEARCH PAPER
JANUARY, 6–10
JOURNAL OF CHEMICAL RESEARCH 2013
Synthesis of 4-hydrazinopyrazolo[3,4-d]pyrimidines and their reactions
with carbonyl compounds
Mastoura M. Edreesa,b*
aDepartment of Organic Chemistry, National Organization for Drug Control and Research, PO Box 29, Cairo, Giza 12311, Egypt
bPresent address: King Khalid University, Faculty of Science, Department of Chemistry, PO Box 9004, ABHA, KSA
Synthesis of a new 4-hydrazinopyrazolo[3,4-d]pyrimidine was achieved via heating (4,6-dithioxo-1H-pyrazolo[3,4-d]
pyrimidin-3-yl)acetonitrile with hydrazine hydrate. Reactions of the latter product with thiophene-2-carbaldehyde
and ethyl hydrazonoacetoacetate analogues afforded the corresponding hydrazone and pyrazole derivatives, respect-
ively. Similarly, condensation of 2-[6-(benzylsulfanyl)-4-hydrazino-1H-pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile with
thiophene-2-carbaldehyde and ethyl hydrazonoacetoacetate analogues gave the respective hydrazone and pyrazo-
lone derivatives. Alkylation reactions of 2-[4,6-bis(benzylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile with
arylamines gave the respective 4-(N-arylamino)-6-benzylsulfanylpyrazolo[3,4-d]pyrimidine derivatives.
Keywords: 4-hydrazinopyrazolo[3,4-d]pyrimidines, 6-(benzylsulfanyl)-4-hydrazinopyrazolo[3,4-d]pyrimidines, 4,6-bis(benzyl-
sulfanyl)pyrazolo[3,4-d]pyrimidines
Cancer is part of a heterogeneous group of diseases character-
ised by uncontrolled growth of the malignant cell population.
The estimated worldwide incidences of different types of
cancers is around 10 million, roughly half of which occur in
developed countries.1–3 The development of resistance against
the existing anticancer drugs means the search continues for
new anticancer molecules.4 However, the options have become
narrower as it is more difficult to search for molecules that
can selectively inhibit the proliferation of abnormal cells only,
with the least or no effect on normal cells. Pyrazolopyrimi-
dines are of considerable chemical and pharmacological
importance as purine analogues. They have antitumour and
antileukaemic activities.5,6 Representative examples of pyrazo-
lopyrimidines such as, 4-dialkylaminopyrazolo[3,4-d] pyrimi-
dines A, 1,4-disubstituted pyrazolo[3,4-d] pyrimidines B
showed antitumour activity against adenocarcinoma 755 and
leukaemia 5178.7,8 Also, 7-phenyl-7H-pyrazolo[4,3-e][1,2,4]
triazolo[1,5-c]pyrimidine-2-thione C was found to be active
against Ehrlich ascites carcinoma (EAC) cell line as compared
to the standard drug, doxorubicin.9 (Fig. 1)
the basis of the above findings, I report here studies on the
synthesis of pyrazolo[3,4-d]pyrimidines in an extension to our
previous work.11,12
Results and discussion
The synthesis of novel pyrazolo[3,4-d]pyrimidine derivatives
having different substituent patterns as shown in Scheme 1.
5-Amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile (1) was
reacted with carbon disulfide in pyridine to give (4,6-dithioxo-
1H-pyrazolo[3,4-d]pyrimidin-3-yl)acetonitrile (2).13 Reflux-
ing compound 2 with hydrazine hydrate in ethanol led to
displacement of the mercapto group at position 4 to give the
4-hydrazino derivative 3. The structure of compound 3 was
confirmed from its spectral and analytical data. Its IR spectrum
showed bands at (νmax/cm−1): 3483, 3320, 3300, 3112 (NH2,
3NH) and 2220 (CN) whilst its 1H NMR spectrum revealed a
pair of singlet signals at δ 4.55 and 8.23 assignable to NH2 and
azomethine groups, respectively. The mass spectrum of com-
pound 3 exhibited a molecular ion peak at m/z 221 and a base
peak at 190 (Scheme 1). The isomeric 6-hydrazino derivative 4
was excluded through NOE difference experiments. Thus irra-
diation of the CH2 protons in compound 3 at δ 3.79 enhanced
the NH signal of the hydrazino group at δ 8.23 while in the
6-hydrazino derivative 4 no such enhancement would be
possible. It has been reported previously14,18 that other pyrazolo
[3,4-d]pyrimdinedithiones react at C-4 regiospecifically. How-
ever, no supporting NOE evidence for this assignment was
provided.
The screening of these compounds against tumours in mice
does not reveal any antitumour activity, but they inhibit the
growth of Neurospora crassa. On the other hand, pyrazolo
[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines D were found to be
potent and selective A2A adenosine receptor antagonists.10 On
Refluxing of compound 3 with thiophene-2-carbaldehyde in
an equimolar ratio furnished the corresponding hydrazino
derivative 5. One the other hand, when a 2:1 molar ratio was
employed condensation of both hydrazine and active methy-
lene groups with thiophene-2-carbaldehyde occurred and gave
the corresponding acrylonitrile 6 (Scheme 2). The structures of
compounds 5 and 6 were elucidated based on the analytical
and spectral data. Thus, the IR spectrum of compound 5
showed bands at νmax 3212, 3118, 3111, 2217 cm−1 due to three
1
NH units and a CN group, respectively. Also, its H NMR
spectrum showed a pair of singlet signals at δ 3.35 and
8.56 ppm due to the methylene and azomethine protons,
respectively. In addition, cyclocondensation of compound 3
with ethyl 2-[2-(4-chlorophenyl)hydrazono]-3-oxobutanoate15
gave the corresponding pyrazolyl derivative 7 (Scheme 2). The
structural assignment of compound 7 was based upon spectral
data and elemental analyses. The 1H NMR spectrum exhibited
two singlet signals at δ 2.10, 3.21 attributed to methyl and
methylene groups, respectively (Scheme 2).
Fig. 1 Representative examples of pyrazolopyrimidines.
* Correspondent. E-mail: mmohamededrees@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2013
7
Scheme 1
Scheme 2
Alkylation of compound 3 with benzyl chloride gave the
corresponding benzylsulfanyl derivative 8 that was subse-
quently condensed with thiophene-2-carbaldehyde or ethyl
2-[2-(4-chlorophenyl)hydrazono]-3-oxobutanoate15 to give the
respective hydrazono and pyrazolyl derivatives 9 and 10,
respectively (Scheme 3).
Their structures were established on the basis of elemental
analysis and spectral data.16 The IR spectrum of compound 10
showed a new absorption band at νmax 1650 cm−1 characteristic
for a carbonyl group, and the 1H NMR spectrum showed three
singlet signals at δ 2.30, 3.15 and 4.31 chracteristic for CH3,
CH2 and SCH2 groups, respectively. The mass spectrum dis-
played a molecular ion peak at m/z 515 correspoding to the
molecular formula C24H18ClN9OS.
respectively (Scheme 4). The analytical and spectral data
were in good agreement with the proposed structures. NOE
measurements revealed that irradiation of the NH proton
at position 4 led to enhancement of the signal from the methy-
lene protons of the CH2CN group which is in accordance
with nucleophile substitution occurring at position 4, not at
position 6.
Conclusion
A simple and efficient method for the synthesis of novel
4,6-disubstituted pyrazolo[3,4-d]pyrimidine derivatives has
been described.
On the other hand, compound 2 was reacted with two
equivalents of benzyl chloride17 to give the di(benzylsulfanyl)
derivative 11. Nucleophilic substitution reactions of 4,6-diben-
zylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl-acetonitrile
(11) with different primary and secondary amines such as
2-aminobenzothiazole, 4-chloroaniline, 5-amino-1,3,4-thiadi-
azole-2-thione, 4-amino-5-methyl-4H-1,2,4-triazole-3-thione,
morpholine, and piperdine gave a single product in each case
which was confirmed on the basis of their spectral data as
the 4-amino-1H-pyrazolo[3,4-d]pyrimidines 12a–d, 13 and 14
Experimental
All melting points are uncorrected. IR spectra were recorded for (KBr)
discs on a Pye Unicam SP-1000 spectrophotometer. 1H NMR, spectra
were measured on a Varian EM 390–200 MHz in DMSO-d6 as solvent
and using TMS as internal standard, and chemical shifts are expressed
as δ ppm. Mass spectra were recorded on a Shimadzu GCMS-QP1000
EX mass spectrometer at 70 eV. Analytical data were recorded at
the Micro analytical Center, Cairo University, Giza, Egypt. 2-(4,6-
dithioxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl)aceto-
nitrile (2) was prepared as previously reported.13

8
JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 3
Scheme 4

JOURNAL OF CHEMICAL RESEARCH 2013
9
2-(4-Hydrazino-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyri-
midin-3-yl)acetonitrile (3): A mixture of hydrazine hydrate (0.5 g,
0.01 mol) and compound 2 (2.23 g, 0.01mol) in ethanol (20 mL) was
heated under reflux for 15 minutes. After the reaction was complete
the precipitated product was collected by filtration, and crystallised
from ethanol to afford the hydrazino derivative as orange crystals,
yield (1.63 g, 74%), m.p. 206–208 °C. IR (KBr) νmax 3483, 3320,
4.31 (s, 2H, CH2), 7.13–7.64 (m, 8H, ArH), 8.12 (s, 1H, CH=N), 11.20
(s, 1H, NH), 12.54 (s, 1H, NH), MS m/z (%) 405.5 (M+, 30), 309 (20),
280 (12), 189 (80), 117 (13), 88 (8). Anal. Calcd for C19H15N7S2
(405.50): C, 56.28; H, 3.73; N, 24.18. Found: C, 56.54; H, 3.46; N,
24.26%.
2-{6-(Benzylsulfanyl)-4[4-(2-(4-chlorophenyl)hydrazono)-3-
methyl-5-oxo-4,5-dihydropyrazol-1-yl]-6-thioxo-6,7-dihydro-1H-pyr-
azolo[3,4-d]pyrimidin-3-yl}acetonitrile (10): A mixture of compound
8 (3.11 g, 0.01 mol), and ethyl 2-[2-(4-chlorophenyl)hydrazono]-3-
oxobutanoate (2.68 g, 0.01 mol) in ethanol (20 mL) and 2 drops of
piperidine was heated under reflux for 3 h. After cooling the mixture
was poured into cold water and neutralised with HCl. The precipitate
was filtered off, dried and crystallised from ethanol to give a brown
solid, yield (3.6 g, 69%), m.p. 258 °C. IR (KBr) νmax 3205, 3117
1
3300, 3112 (NH2, 3NH), 2220 (CN) cm−1; H NMR δ 3.79 (s, 2H,
CH2), 4.55 (s, 2H, NH2), 8.23 (s, 1H, NH), 9.32 (br.s, 1H, NH), 12.34
(s, 1H, NH), MS m/z (%) 221 (M+, 8), 190 (90), 117 (33), 88 (25).
Anal. Calcd for C7H7N7S (221.24): C, 38.00; H, 3.19; N, 44.32. Found:
C, 37.89; H, 3.27; N, 44.14%.
2-{4-[2-(2-Thienylmethylene)hydrazino]-6-thioxo-6,7-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-3-yl}acetonitrile (5): A mixture of com-
pound 3 (2.21 g, 0.01 mol) and thiophene-2-carbaldehyde (1.12 mL,
0.01 mmol) in N,N-dimethylformamide (20 mL) was stirred at room
temperature for 12 h. When the reaction was complete, the solution
was evaporated under reduced pressure and the precipitate was fil-
tered off, dried and crystallised from ethanol to give yellow crystals,
yield (2.5 g, 79%), m.p. 215 °C. IR (KBr) νmax 3212, 3118, 3111(3NH),
2217 (CN) cm−1; 1H NMR δ 3.35 (s, 2H, CH2), 7.32–8.06 (m, 4H, 3H-
thienyl+NH), 8.56 (s, 1H, CH), 9.84 (s, 1H, NH), 10.02 (s, 1H, NH),
MS m/z (%) 315 (M+, 5), 219 (11), 190 (80), 117 (20), 88 (15). Anal.
Calcd for C12H9N7S2 (315.38): C, 45.70; H, 2.88; N, 31.09. Found: C,
45.91; H, 2.64; N, 31.31%.
1
(2NH), 2220 (CN), 1650 (C=O) cm−1, H NMR δ 2.30 (s, 3H, CH3),
3.15 (s, 2H, CH2), 4.31 (s, 2H, CH2), 7.06–7.94 (m, 9H, ArH), 8.54 (s,
1H, NH), 9.96 (s, 1H, NH), MS m/z (%) 517 (M++2, 12), 515 (M+, 26),
375 (14), 280 (21), 189 (80), 117 (15), 88 (19). Anal. Calcd for
C24H18ClN9OS (515.98): C, 55.87; H, 3.52; N, 24.43. Found: C, 55.91;
H, 3.43; N, 24.62%.
2-[4,6-Bis(benzylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]
acetonitrile (11): To a stirred solution of compound 2 (2.23 g,
0.01 mol) in ethanol (20 mL) was added sodium hydroxide (15 mL,
1M) at room temperature, then the reaction mixture was treated
with benzyl chloride (2.51 mL, 0.02 mol) drop wise with stirring. The
reaction mixture was stirred for 2 h and then refluxed for 3h. The solid
product obtained was filtered off, washed with water, dried and cryst-
allised from ethanol to give the desired product as yellow crystals,
yield (3.2 g, 79%), m.p. 206–208 °C. IR (KBr) νmax 3125 (NH), 2218
(CN) cm−1; 1H NMR δ 3.24 (m, 4H, CH2), 4.31 (s, 4H, SCH2), 7.13–
7.89 (m, 10H, ArH), 12.54 (s,1H, NH), MS m/z (%) 403 (M+, 15), 312
(20), 189 (67), 117 (22), 88 (13). Anal. Calcd for C21H17N5S2 (403.52):
C, 62.51; H, 4.25; N, 17.36. Found: C, 62.71; H, 4.34; N, 17.52%.
3-(2-Thienyl)-2-{4-[2-(2-thienylmethylene)hydrazino]-6-thioxo-6,7-
dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl}acetonitrile (6): A mixture
of the hydrazine derivative 3 (2.21 g, 0.01 mol) and the thiophene-
2-carbaldehyde (2.24 mL, 0.02 mol) in N,N-dimethylformamide
(20 mL) was heated under reflux for 3 h. When the reaction was
complete, the solution was evaporated under reduced pressure and the
precipitate was filtered off, dried and crystallised from ethanol to give
orange crystals, yield (2.7 g, 66%), m.p. 170 °C. IR (KBr) νmax 3205,
1
3110, 3100 (3NH), 2210 (CN) cm−1; H NMR δ 7.00–7.85 (m, 6H,
6H-thienyl)), 8.10 (s, 1H, CH=), 8.21 (s,1H, NH), 8.23 (s,1H, NH),
8.25 (s,1H, CH=N), 12.01 (s,1H, NH), MS m/z (%) 409 (M+, 20), 313
(2), 217 (23), 188 (67), 115 (10), 86 (10). Anal. Calcd for C17H11N7S3
(409.51): C, 49.86; H, 2.71; N, 23.94. Found: C, 49.62; H, 2.95; N,
24.05%.
2-[4-(Arylamino)-6-(benzylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-
3-yl]acetonitriles (12a–d); general procedure
A mixture of compound 11 (4.03 g, 0.01 mol) and 2-amine derivatives
( 0.01 mol) in ethanol (20 mL) was heated at reflux for 3 h. The reac-
tion mixture was evaporated and the precipitate was filtered off, dried
and crystallised from ethanol to give 12a–d.
2-{4-[4-(2-(4-Chlorophenyl)hydrazono)-3-methyl-5-oxo-4,5-dihy-
dropyrazol-1-yl]-6-thioxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-
3-yl}acetonitrile (7): A mixture of compound 3 (2.21 g, 0.01 mol), in
ethanol (20 mL) with 2 drops of piperidine and ethyl 2-[2-(4-chloro-
phenyl)hydrazono]-3-oxobutanoate (2.39 g, 0.01 mol) was heated
under reflux for 3 h. The reaction mixture was poured into cold water,
then, neutralised with dil. HCl. The precipitate was collected by
filtration, washed with water, filtered off, dried and crystallised from
ethanol as reddish-brown crystals, yield (3.5 g, 82%), m.p. 240 °C. IR
(KBr) νmax 3205, 3250, 3110 (3NH), 2215 (CN), 1657 (C=O) cm−1; 1H
NMR δ 2.10 (s, 3H, CH3), 3.21 (s, 2H, CH2), 7.10–7.25 (d, J = 8 Hz,
2H, ArH), 7.31–7.52 (d, J = 8 Hz, 2H, ArH), 8.10 (s, 1H, NH), 11.01
(s, 1H, NH), 12.01 (s, 1H, NH). MS m/z (%) 427 (M++2, 5), 425 (M+,
17), 285 (11), 190 (59), 117 (4), 88 (6). Anal. Calcd for C17H12ClN9OS
(425.85): C, 47.95; H, 2.84; N, 29.60. Found: C, 47.78; H, 2.67; N,
29.46%.
2-[6-(Benzylsulfanyl)-4-hydrazono-1H-pyrazolo[3,4-d]pyrimidin-
3-yl]acetonitrile (8): Sodium hydroxide (15 mL, 1M) was added to a
stirred solution of compound 3 (2.21 g, 0.01 mol), in ethanol (20 mL)
at room temperature then the reaction mixture was treated with benzyl
chloride (1.26 mL, 0.01 mol) dropwise with stirring. The reaction
mixture was stirred for 4 h, then the solid product was collected by
filtration, washed with water, dried and crystallised from ethanol to
give the desired product as a brown solid, yield (2.4 g, 77%), m.p.
190–192 °C. IR (KBr) νmax 3345, 3205, 3115 (NH), 2218 (CN) cm−1;
1H NMR δ 3.37 (s, 2H, CH2), 4.99 (s, 2H, CH2), 5.69 (s, 2H, NH2),
7.16–7.77 (m, 5H, ArH), 8.18 (s, 1H, NH), 9.85 (s, 1H, NH). MS m/z
(%) 311 (M+, 40), 280 (9), 189 (75), 117 (41), 88 (20). Anal. Calcd for
C14H13N7S (311.36), C, 54.00; H, 4.21; N, 31.49. Found: C, 54.24; H,
4.42; N, 31.68%.
2-[6-(Benzylsulfanyl)-4-(benzothiazol-2-yl-amino)-1H-pyr-
azolo[3,4-d]pyrimidin-3-yl]acetonitrile (12a): Yellow crystals, yield
(2.8 g, 65%), m.p. 170 °C. IR (KBr) νmax 3145, 3114 (2NH), 2220
(CN) cm−1; 1H NMR δ 3.36 (s, 2H, CH2), 4.31 (s, 2H, CH2), 7.21–8.01
(m, 9H, ArH), 9.56 (s, 1H, NH), 12.54 (s, 1H, NH), MS m/z (%) 429
(M+, 10), 295 (12), 190 (60), 117 (9), 88 (15). Anal. Calcd for
C21H15N7S2 (429.52): C, 58.72; H, 3.52; N, 22.83. Found: C, 58.54; H,
3.72; N, 22.61%.
2-[6-(Benzylsulfanyl)-4-(4-chlorophenylamino)-1H-pyrazolo[3,4-d]
pyrimidin-3-yl]acetonitrile (12b): Dark orange crystals. Yield (3.1 g,
76%), m.p. 160 °C. IR (KBr) νmax 3145, 3118 (2NH), 2220 (CN) cm−1;
1H NMR δ 3.35 (s, 2H, CH2), 3.62 (s, 2H, CH2), 7.53–7.80 (m, 9H,
ArH), 8.10 (s, 1H, NH), 12.23 (s, 1H, NH), MS m/z (%) 408 (M++2,
10), 406 (M+, 34), 295 (35), 280 (31), 190 (75), 117 (15), 88 (18).
Anal. Calcd for C20H15ClN6S (406.89): C, 59.04; H, 3.72; N, 20.65.
Found: C, 59.24; H, 3.46; N, 20.81%.
2-[6-(Benzylsulfanyl)-4-(5-mercapto-1,3,4-thiadiazol-2-ylamino)-
1H-pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile (12c): Reddish-brown
solid, yield (2.9 g, 70%), m.p. 154 °C. IR (KBr) νmax 3145, 3113 (NH),
2219(CN) cm−1; 1H NMR δ 3.56 (s, 2H, CH2), 4.31 (s, 2H, CH2), 7.21–
7.61 (m, 5H, ArH), 9.56 (s, 1H, NH), 12.54 (s, 1H, NH), 12.92 (s, 1H,
NH), MS m/z (%) 412 (M+, 41), 295 (32), 280 (15), 190 (68), 117 (7),
88 (15). Anal. Calcd for C16H12N8S3 (412.52): C, 46.59; H, 2.93; N,
27.16. Found: C, 46.31; H, 3.02; N, 27.25%.
2-[6-(Benzylsulfanyl)-4-(3-mercapto-5-methyl-4H-1,2,4-triazol-4-
ylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile (12d): Redish
brown solid, yield (3.1 g, 76%), m.p. 167 °C. IR (KBr) νmax 3250,
1
3145, 3131 (3NH), 2222 (CN) cm−1; H NMR δ 2.45 (s, 3H, CH3),
3.26 (s, 2H, CH2), 3.31 (s, 2H, CH2), 7.09–7.52 (m, 5H, ArH), 8.35 (s,
1H, NH), 10.81(s, 1H, NH), 12.81 (s, 1H, NH), MS m/z (%) 409 (M+,
30), 295 (21), 280 (12), 190 (78), 117 (14), 88 (9). Anal. Calcd for
C17H15N9S2 (409.49): C, 49.86; H, 3.69; N, 30.78. Found: C, 49.64; H,
3.81; N, 30.49%.
2-[6-(Benzylsulfanyl)-4-(morpholino-1-yl)-1H-pyrazolo[3,4-d]
pyrimidin-3-yl]acetonitrile (13): A mixture of compound 11 (4.03 g,
0.01 mol) and morpholine (0.89 mL, 0.01 mol) in ethanol (30 mL)
2-[6-(Benzylsulfanyl)-4-(2-(2-thienylmethylene)hydrazino]-1H-
pyrazolo[3,4-d]pyrimidin-3-yl]acetonitrile (9): A mixture of the
compound 8 (3.11 g, 0.01 mol) and thiophene-2-aldehyde (1.2 mL,
0.01 mol) in N,N-dimethylformamide (20 mL) was stirred at room
temperature for 12 h and then evaporated under reduced pressure. The
precipitate was filtered off, dried and crystallised from ethanol to give
a redish brown solid, yield (3.2 g, 79%), m.p. 172 °C. IR (KBr) νmax
1
3205, 3120 (2NH), 2216 (CN) cm−1; H NMR δ 3.15 (s, 2H, CH2),

10 JOURNAL OF CHEMICAL RESEARCH 2013
was heated under reflux for 3 h. After cooling it was poured into cold
water and acidified with HCl. The precipitate was collected by filtra-
tion, dried and crystallised from ethanol to give orange solid, yield
(3.3 g, 90%), m.p. 154 °C. IR (KBr) νmax 3129 (NH), 2221(CN) cm−1;
1H NMR δ 3.41 (s, 2H, CH2), 3.74–3.78 (m, 4H, CH2), 3.81–3.88 (m,
4H, CH2), 4.51 (s, 2H, CH2), 7.47–8.10 (m, 5H, ArH), 12.35 (s, 1H,
NH), MS m/z (%) 366 (M+, 20), 280 (16), 190 (70), 117 (6), 88 (10).
Anal. Calcd for C18H18N6OS (366.44): C, 59.00; H, 4.95; N, 22.93.
Found: C, 59.21; H, 5.12; N, 23.12%.
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2-[6-(Benzylsulfanyl)-4-(piperidin-1-yl)-1H-pyrazolo[3,4-d]
pyrimidin-3-yl]acetonitrile (14): A mixture of compound 11 (4.03 g,
0.01 mol) and piperidine (0.85 mL, 0.01 mol) in ethanol (30 mL) was
heated at reflux for 3 h, and then poured onto cold water and acidified
with HCl. The precipitate was collected by filtration, dried and cryst-
allised from ethanol to give orange crystals, yield (3.1 g, 85%),
10 P.G. Baraldi, B. Cacciari, G. Spalluto, M. Bergonzoni and S.E. Dionisotti,
J. Med. Chem., 1998, 41, 2126.
11 M.M. Edrees, T.A. Farghaly, F.A.A. El-Hag and M.M. Abdalla, Eur. J.
Med. Chem., 2010, 45, 5702.
12 S.R. Gerrard, M.M. Edrees, I. Bouamaied, K.R. Fox and T. Brown, Org.
Biomol. Chem., 2010, 8, 5087.
13 L.S. Vartanyan, Y.E. Rashba and A.I. Kazachenko, Kim-Farm. Zh., 1982,
16, 655.
1
m.p. 140 °C. IR (KBr) νmax 3116 (NH), 2219 (CN) cm−1; H NMR
δ 1.42–2.1 (m, 6H, CH2), 3.15 (s, 2H, CH2), 3.81–3.83 (t, J = 7 Hz,
4H, CH2), 4.31 (s, 2H, CH2), 7.13–7.64 (m, 5H, ArH), 12.54 (s, 1H,
NH), MS m/z (%) 364 (M+, 19), 280 (51), 190 (87), 117 (5), 88 (21).
Anal. Calcd for C19H20N6S (364.47): C, 62.61; H, 5.53; N, 23.06.
Found: C, 62.85; H, 5.61; N, 23.13%.
14 A.I. Diaa, M.E. Amira and E.A. Elham, Arkivoc, 2009, vii, 12.
15 H.K. Fan, S. Chantrapromma, M. Padaki, A. Radhika and A.M. Isloor, Acta
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34, 153.
17 B.C. Avasthik, A. Sharon and P.R. Maulik, Acta Crystallogr., 2003, 59,
494.
Received 26 July 2012; accepted 17 November 2012
Paper 1201432 doi: 10.3184/174751912X13543818811749
Published online: 15 January 2013
18 A.I. Diaa, M.E. Amira and E.A. Elham, Arkivoc, 2009, vii, 12.