Studies with malononitrile derivatives: Synthesis and reactivity of 4-benzylpyrazole-3,5-diamine, 4-benzylisoxazole-3,5-diamine and thiazolidin-3-phenylpropanenitrile

Article abstract of DOI:10.3987/COM-07-11307

Benzylmalononitrile 6 reacts with hydrazines, and hydroxylamine hydrochloride to yield the 4-benzylpyrazole-3,5-diamines 7 and 4-benzylisoxazol- e-3,5-diamine 9, respectively. Pyrazole-3,5-diamines 7 could be readily reacted with α,β-unsaturated nitriles

Full text of DOI:10.3987/COM-07-11307

HETEROCYCLES, Vol. 75, No. 6, 2008
1371
HETEROCYCLES, Vol. 75, No. 6, 2008, pp. 1371 - 1383. © The Japan Institute of Heterocyclic Chemistry
Received, 16th December, 2007, Accepted, 8th February, 2008, Published online, 15th February, 2008. COM-07-11307
STUDIES WITH MALONONITRILE DERIVATIVES: SYNTHESIS AND
REACTIVITY OF 4-BENZYLPYRAZOLE-3,5-DIAMINE,
4-BENZYLISOXAZOLE-3,5-DIAMINE AND
THIAZOLIDIN-3-PHENYLPROPANENITRILE
Saleh Mohammed Al-Mousawi,* Moustafa Sherief Moustafa, and Mohamed
Hilmy Elnagdi
Department of Chemistry, Faculty of Science, University of Kuwait: P.O. Box
5969, Safat: 13060 Kuwait. E-mail: salehalmousawi@hotmail.com
Abstract – Benzylmalononitrile 6 reacts with hydrazines, and hydroxylamine
hydrochloride to yield the 4-benzylpyrazole-3,5-diamines 7 and 4-benzylisoxazol-
e-3,5-diamine 9, respectively. Pyrazole-3,5-diamines 7 could be readily reacted
with α,β-unsaturated nitriles to yield pyrazolo[1,5-a]pyrimidines 20. Benzylmalo-
nonitrile, also reacted with thioglycolic acid to yield tautomeric mixture of
2-(4-hydroxythiazol-2-yl)-3-phenylpropanenitrile 29 and 2-(4-oxothiazolidin-2-
yl)-3-phenylpropanenitrile 30 that coupled with benzene diazonium chloride to
yield 2-(4-oxo-5-(phenylhydrazono)-thiazolidin-2-ylidene)-3-phenylpropanenitri-
le 31.
INTRODUCTION
Since reported economical preparation of malononitrile,1 the chemistry of this unique molecule has
received considerable attention. It is now more than fourty years when one of us started investigations on
its potential utility for synthesis of functionally substituted heteroaromatics.2,3 Over this long period
Elnagdi et al. could develop synthetic approaches to a diversity of polyfunctional heteroaromatics
including
aminopyrans,4
thiopyrans,5
diaminopyrazoles,6
aminopyrazolo[1,5-a]pyrimidines,7
pyranopyrazoles,8 pyridines,9 quinolines10 and diversity of other heteroaromatics.11,12 It has been shown
that despite the reported formation of pyrazole-3,5-diamine 1 via reacting malononitrile with
hydrazines,13 the pyrazolylcarbonitrile 2 was the really formed product.14 In contrast, Elnagdi and

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HETEROCYCLES, Vol. 75, No. 6, 2008
Abdulla2 have shown that 2-arylhydrazonomesoxalonitrile 3 which is prepared via coupling malononitrile
with aromatic diazonium salts, reacts with hydrazines to yield 4-arylazopyrazole-3,5-diamine 4 that has in
recent years deserved several patents due to its observed potential antibacterial and anticancer activities
(Scheme 1).15,16 Moreover, a patent in 2005 has also claimed these compounds as potential hair dyes.17 In
the light of this, we were again attracted to synthesis of the diaminopyrazoles. Although Elguero et al.18
and Soto et al.19 have sometime ago reported the synthesis of 4-substituted pyrazole-3,5-diamines via
reacting alkylmalononitrile with hydrazines and reported some of their chemistry, the chemistry of these
pyrazole derivatives did not attract further attention perhaps as monoalkyl malononitriles are not readily
accessible. A recent paper,20 however, has reported that mixing aldehydes or ketones with malononitrile
and reducing the most likely formed arylidenemalononitrile 5 with sodium borohydride affords
arylmethylenemalononitrile 6 (Scheme 1). This synthesis appeared in our eyes an easy way to
monosubstituted malononitriles that can subsequently be utilized for the synthesis of a variety of
heteroaromatics by adopting our established synthetic methodologies.
RESULTS AND DISCUSSIONS
Mixing benzaldehyde, malononitrile and NaBH4 in isopropanol has afforded 6 in 85 % yield. Compound
6 reacted smoothly with hydrazine hydrate and with phenylhydrazine to yield the pyrazole-3,5-diamines
7a and 7b respectively. On the other hand, reacting 6 with hydroxylamine hydrochloride in ethanolic
solution containing sodium acetate resulted in the formation of amidooxime 8. This could be successfully
cyclized into the isoxazole-3,5-diamine 9 in 66 % yield upon refluxing in N,N-dimethylformamide
containing a few drops of piperidine (Scheme 2).
Clearly initially nitrogen lone pair in hydrazine and hydroxylamine adds to the electrophilic activated
nitrile. In case of reaction with hydrazine intermediately formed amidrazone could not be isolated
yielding the aromatic diaminopyrazole. Aromatisity is deriving force for cyclization. Incase of reaction
with hydroxyl amine the reaction stopped at amidoxime as energy in cyclization step is higher than that
with hydrazine. Only upon reflux in DMF energy barrier for cyclization could be overcomed. Elguero et
al.18 and Soto et al.19 had in the past conducted a similar work and the formed 3,5-diaminoisoxazole was
sole 3,5-diaminoisoxazole. Recently trials to synthesize 4-arylazoisoxazole-3,5-diamines have failed,
where the reaction of 2-arylhydrazonomesoxalonitrile 3 and hydroxylamine resulted only in the formation
of amidooxime 10 which on attempted cyclization afforded 1,2,3-triazole 1121 (Scheme 2). We obtained
13C NMR data very close to those reported by Elguero et al.18 and Soto et al.19 For example, in our hands
the diaminopyrazole 7 revealed C-4 at δ = 87.79 ppm for 7a and at δ = 90.25 ppm for 7b, which are the
expected positions for pyrazole C-4 shielded by two amino functions.

HETEROCYCLES, Vol. 75, No. 6, 2008
1373
NH2
N
H2N
R
N
CN
CN
R-NHNH2
1
H2C
NH2
NC
N
NC
ArN NCl
R
N
2
NH2
Ar
N
N
CN
R-NHNH2
ArNHN
N
H2N
R
N
CN
4
3
CN
CN
CH
CN
NaBH4
PhCHO
H2C
Ph
CN
i-PrOH
Ph
CN
CN
6
5
Scheme 1
13
Elguero's reported C-4 at δ = 89.9 ppm. The C NMR of isoxazole 9 revealed a pattern very close to
those of the pyrazolediamine 7a for C-4, benzyl protons, C-3 and C-5 which appeared at δ = 142, δ = 164
ppm and δ = 166 ppm respectively. These are somewhat lower field than that for pyrazoles which is in
accordance with increased deshielding of these carbons on replacing the nitrogen by an oxygen.
Ph
NH2
R-NHNH2
3
4
5
N
2
H2N
R
N
1
CN
CH
CN
7
a, R= H
b, R= Ph
Ph
OH
N
Ph
NH2
NH2
6
EtOH
Ph
DMF
CH
.
NH2OH HCl
pipreidine
heat
N
CN
H2N
O
8
9
NC
NH2
OH
N
N
N
N
CN
CN
.
NH2
Ar
NH2OH
HCl
H
Ar-NH-N
11
N
N
C
NaOAc
EtOH
Ar
CN
NH2
N
ArN
3
10
N
H2N
O
11A
Scheme 2

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HETEROCYCLES, Vol. 75, No. 6, 2008
When refluxed in acetic anhydride, compound 7a afforded a diacetyl derivative for which structure 12
could be assigned based on 1H NMR that revealed only one low field NH signal and amide signals at δ =
9.84 ppm and δ = 10.04 ppm. Refluxing this diacetyl derivative with N,N-dimethylformamide dimethyl
acetal (DMFDMA) afforded 13 via condensation of the amino function with the reagent and subsequent
deacylation (cf. Scheme 3).
O
Me
Ph
NMe2
Ph
N
HN
NH
Ac2O
DMFDMA
7a
NH
HN
HN
N
N
Me
Me
O
O
12
13
Scheme 3
Elnagdi et al.22 have reported that the addition of benzylidenemalononitrile 14 to 3(5H-1H)pyrazoleamine
15 afforded the 7-aminopyrazolo[1,5-a]pyrimidines 16, not as previously stated the 5-aminoisomer 17
based on HMBC-N15 NMR (Scheme 4).
Ph
R1
NH2
R1
N
CN
N
N
R2
R2
N
H
N
NH2
16
15
NH2
R1
N
CN
CN
Ph
CN
C
N
R2
N
Ph
17
14
Ph
Ph
N
N
N
4
CN
N
H2N
N
NH2
18
Scheme 4
Although Soto et al.19 have reported that, the reaction of arylidenemalononitrile 14 with 4 affords 18, no
convening evidence for an observed regio orientation has been offered (Scheme 4). In this investigation
we have found that reacting 7a with 14 affords a mixture of two products 19 and 20 of molecular masses
342 and 340 respectively. It is most likely that compound 19 of molecular weight (342) was autooxidised
on long standing at room temperature into the other product 20 of molecular formula (340). Accordingly,

HETEROCYCLES, Vol. 75, No. 6, 2008
1375
it was assumed that these products are the 2,7-diamino-3-benzyl-5-phenyl-4,5-dihydropyrazolo[1,5-
a]pyrimidine-6-carbonitrile 19 and the 2,7-diamino-3-benzyl-5-phenylpyrazolo[1,5-a]pyrimidine-6-
carbonitrile 20 (Scheme 5).
Ph
H
Ph
H
Ph
Ph
5
N
N
3a
3
4
- H2
reflux
EtOH
6
CN
CN
7
N
N
2
H2N
H2N
7a
N
N
1
NH2
NH2
20
19
7a
14
NH2
5
H
Ph
N
3
3a
4
CN
6
7
N
H2N
2
7a
N
Ph
1
H
21
Scheme 5
15
15
To provide a conclusive evidence for these structure assignments, N NMR and N HMBC of 20 were
15
run and inspected. N NMR of 20 revealed six nitrogen signals at δ = 272, 236, 225, 186, 80, 52 ppm
respectively. The signals at δ = 80 and δ = 52 ppm were attributed to the aminofunctions at C-2 and C-7
respectively. The aminofunction at δ = 52 ppm revealed a crosspeak peak at δ = 225 ppm for N-7a. It was
thus concluded that the product of molecular formula (340) is compound 20. If it was the 5-amino isomer
formed via 21, this amino function should have a cross peak with N-4 at δ = 272.23
Treatment of 7a with sodium nitrite in the presence of hydrochloric acid afforded a diazonium salt that
easily coupled with malononitrile to yield 2,7-diamino-3-benzylpyrazolo[5,1-c][1,2,4]triazine-6-
carbonitrile 22 (Scheme 6). Reacting 7a with ethyl acetoacetate afforded a product of condensation via
water and ethanol elimination. This can be formulated as 23 or its isomeric form 24. Structure 23 was
readily established based on NOE difference experiment which indicated that NH and CH3 protons are
sterically proximal. Thus irradiating NH signal at δ = 12.09 ppm enhanced CH3 signal at δ = 2.31 ppm
and vise versa. Compound 7a was reacted with 1-chloro-1-(2-phenylhydrazono)propan-2-one 25 in
ethanolic triethylamine to yield a mixture of two products 26 and 27 of molecular formula C19H18N6
(330.39) and C28H26N8O (490.22). The one of two products corresponds to the reaction of 7a with one
molecule of 25, via hydrochloric acid and water elimination and the other formed from condensation of
7a with two molecules of 25, with elimination of two molecules of hydrochloric acid and one molecule of
water. These were assigned to structures 26 and 27 respectively, however, we could not get an accurate
elemental ' N ' analysis as for compound 27. Structure 28 for the monocondensation product was excluded

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HETEROCYCLES, Vol. 75, No. 6, 2008
based on NOE that revealed special proximity of NH proton and aryl protons as in the case with 23
(Scheme 6).
Ph
N
i) NaNO2 / HCl
ii) CH2(CN)2
N
CN
N
EtOH
NaOAc
H2N
N
NH2
22
Me
H
N
Ph
O
O
N
H2N
N
O
Me
OEt
7a
23
- H2O, - EtOH
O
H
N
Ph
N
H2N
N
Me
24
O
Ph
Ph
Cl
N
N
Me
Me
Me
N
N
N
HN
H2N
O
N
N
N
N
NHPh
NHPh
25
NHPh
N
NHPh
26
Me
27
EtOH, Et3N
H
Ph
N
N
NPh
N
H2N
N
Me
28
Scheme 6
Benzylmalononitrile 6 could be also used for the synthesis of thiazolidin-4-ones via reaction of 6 with
thioglycolic acid utilizing a procedure similar to that reported originally by Elnagdi et al.11 for converting
malononitrile into 2-(4-hydroxythiazol-2-yl)-3-phenylpropanenitrile. Thus refluxing 6 with thioglycolic
acid in acetic acid afforded a product of addition and water elimination. The 1H NMR, 13C NMR and IR
indicated that this product is a mixture of two of the tautomeric products 29 and 30. IR revealed two
signals corresponding to OH and CO groups and in 13C-NMR an amide carbonyl carbon appeared at δ =
175.69 ppm. As indicated in (Scheme 7) initially sulphur lone pair adds to alectron deficient cyanocarbon.
Formed adduct again cyclized via addition of formed amino group to carboxylic acid group and
subsequent cyclization. These tautomeric products were coupled readily with benzene diazonium chloride
to yield 31 (Scheme 7).

HETEROCYCLES, Vol. 75, No. 6, 2008
1377
In conclusion the recently obtainable benzylmalononitrile is an interesting precursor to diaminoazoles,
substituted thiazolidinones and products similar to these reported here which are expected to have
potential biological activity of these unique diaminoazoles.
CN
CN
CN
NH2
H2C CO2H
Ph
Ph
Ph
N
NH
HSCH2CO2H
AcOH
6
S
S
OH
O
S
- H2O
30
29
CN
Ph
NH
PhN NCl
S
O
N
NH
Ph
31
Scheme 7
EXPERIMENTAL
All melting points are uncorrected and were determined with Sanyo (Gallaenkamp) instrument. Infrared
spectra were recorded in KBr and were determined on a Perkin-Elmer 2000 FT–IR system.1H NMR
spectra were determined on a Bruker DPX at 400 MHz and 13C NMR were determined on Bruker DPX at
600 MHz spectrometer in CDCl3 or DMSO-d6 as solvent and TMS as internal standard; chemical shifts
are reported in δ (ppm). Mass spectra were measured on VG Autospec Q MS 30 and MS 9 (AEI)
spectrometers, with EI 70 EV. Elemental analyses were measured by means of LEOCHNS-932 Elemental
Analyzer.
Synthesis of compound 2-Benzyl-malononitrile 6
A solution of malononitrile (0.66 g, 0.01 mol) and benzaldehyde (1.00 mL, 0.01 mol) in i-PrOH (5 mL)
o
was cooled to 0 C. Sodium borohydride (0.756 g, 0.02 mol) was added and the reaction mixture was
stirred (followed by TIC test using EtOAc : petroleum ether 1 : 1 until completion). If any intermediate
was present or aldehyde is remaining, more sodium borohydride (up to 0.6 equivalent) was added. The
reaction was carefully quenched with ice-H2O and 1M HCl solution, extracted with CH2Cl2, filtered, and
concentrated. The crude product was recrystallized from 60-80 traction was used as petroleum ether to
give colorless crystals; yield 85 %; mp 88-90 ºC. Anal. Calcd for C10H8N2 (156.19): C, 76.90; H, 5.16;
1
N, 17.94. Found: C, 76.88; H, 5.16; N, 18.13. IR (KBr): υmax = 2257 (CN), 2189 (CN); H NMR (400
MHz, CDCl3): δ, ppm = 3.31 (d, 2H, CH2, J = 8 Hz), 3.93 (t, 1H, CH, J = 8 Hz), 7.34-7.46 (m, 5H,

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HETEROCYCLES, Vol. 75, No. 6, 2008
Ar-H); 13C NMR (600 MHz, DMSO-d6): δ, ppm = 133.40, 129.73, 129.61, 129.24, 112.72, 37.03, 25.43.
MS: m/z (%) 156 (M+, 30), 91 (100), 65 (20).
General procedures for preparation of compounds (7a and 7b)
Equimolecular amounts of 6a,b (0.01 mol) and hydrazine hydrate (0.5 g, 0.01 mol) or phenylhydrazine
(1.08 g, 0.01 mol) in EtOH (20 mL) were refluxed for 5-10 h (monitored by TLC using EtOAc:
petroleum ether 1 : 1). The reaction mixture was cooled and poured onto ice-water. The solid, so formed,
was collected by filtration and recrystallized from EtOH.
4-Benzyl-1H-pyrazole-3,5-diamine (7a)
White product; yield 80 %; mp 149-150 ºC. Anal. Calcd for C10H12N4 (188.10): C, 63.81; H, 6.43; N,
29.76. Found: C, 63.77; H, 6.43; N, 29.62. IR (KBr): υmax = 3416, 3311 (NH2), 3369, 3193 (NH2), 3138
1
(NH); H NMR (400 MHz, DMSO-d6): δ, ppm = 3.50 (s, 2H, CH2), 4.26 (br, 4H, amino-H, D2O
exchangeable, 7.12-7.23 (m, 5H, Ar-H), 9.91 (br, 1H, NH, D2O exchangeable); 13C NMR (600 MHz,
DMSO-d6): δ, ppm = 143.53, 129.30, 129.20, 126.22, 86.7, 80.20, 27.94. MS: m/z (%) 188 (M+, 100),
172 (25), 145 (30), 130 (15), 111 (80), 91 (15), 77 (10).
4-Benzyl-1-phenyl-1H-pyrazole-3,5-diamine (7b)
Brown product; yield 75 %; mp 133-135 ºC. Anal. Calcd for C16H16N4 (264.33): C, 72.70; H, 6.10; N,
1
21.20. Found: C, 72.57; H, 6.10; N, 21.31. IR (KBr): υmax = 3422, 3265 (NH2), 3335, 3157 (NH2); H
NMR (400 MHz, CDCl3): δ, ppm = 3.62 (s, 2H, CH2), 4.54 (br, 2H, NH2, D2O exchangeable), 5.01 (br,
2H, NH2, D2O exchangeable, 7.09-7.56 (m, 10H, Ar-H); 13C NMR (600 MHz, DMSO-d6): δ, ppm =
154.15, 143.89, 141.88, 140.21, 128.73, 128.19, 127.94, 125.36, 123.69, 120.87, 90.25, 26.78. MS: m/z
(%) 264 (M+, 100), 246 (30), 221 (15), 187 (70), 155 (10), 19 (90), 77 (40).
Synthesis of 3-cyano-N'-hydroxy-4-phenylbutanamidine (8)
A mixture of 6a (1.56 g, 0.01 mol), hydroxylamine hydrochloride (0.69 g, 0.01 mol), and sodium acetate
(1.5 g) in EtOH (20 mL) was refluxed for 4 h. After cooling the mixture was poured onto ice-water. The
solid, so formed, was collected by filtration and recrystallized from petroleum ether to give white crystals;
yield 90 %; mp. 160-162 ºC Anal. Calcd for C10H11N3O (189.22): C, 63.48; H, 5.86; N, 22.21. Found: C,
1
63.44; H, 5.80; N, 22.39. IR (KBr): υmax = 3446 (OH), 3352, 3195 (NH2), 2256 (CN); H NMR (400
MHz, DMSO-d6): δ, ppm = 3.21 (d, 2H, CH2, J = 8 Hz), 3.62 (t, 1H, CH, J = 8 Hz), 5.87 (br, 2H, NH2,
D2O exchangeable), 7.24-7.33 (m, 5H, Ar-H), 9.42 (br, 1H, OH, D2O exchangeable); 13C NMR (600
MHz, DMSO-d6): δ, ppm = 148.75, 138.03, 130.14, 129.52, 127.97, 119.73, 36.76, 36.54. MS: m/z (%)
189 (M+, 25), 130 (30), 91 (100).
Synthesis of 4-benzylisoxazole-3,5-diamine (9)
A mixture of compound 8 (1.89 g, 0.01 mol), and N,N-dimethylformamide (DMF) (10 mL) was treated
with a few drops of piperidine. The reaction mixture was refluxed for 6-8 h. (monitored by TLC using

HETEROCYCLES, Vol. 75, No. 6, 2008
1379
EtOAc : petroleum ether 1 : 1), cooled and then poured onto ice-water. The solid, so formed, was
collected by filtration and recrystallized from petroleum ether to give colorless crystals; yield 66 %; mp
70-72 ºC. Anal. Calcd for C10H11N3O (189.22): C, 63.48; H, 5.86; N, 22.21. Found: C, 63.60; H, 5.87; N,
22.19. IR (KBr): υmax = 3367, 3301 (NH2), 3343, 3184 (NH2); 1H NMR (400 MHz, DMSO-d6): δ, ppm =
3.47 (s, 2H, CH2), 4.98 (br, 2H, NH2, D2O exchangeable), 6.07 (br, 2H, NH2, D2O exchangeable),
13
7.14-7.31 (m, 5H, Ar-H); C NMR (600 MHz, DMSO-d6): δ, ppm = 166.36, 164.86, 142.18, 135.19,
131.25, 129.27, 81.07, 26.41. MS: m/z (%) 189 (M+, 25), 155 (10), 130 (15), 117 (25), 91 (100), 65 (15).
Synthesis of N-(1-acetyl-5-amino-4-benzyl-1H-pyrazol-3-yl)acetamide (12)
A mixture of compound 7a (1.88 g, 0.01 mol) and acetic anhydride (20 ml) was refluxed for 2 h. The
reaction mixture was evaporated under reduced pressure in vacuum yielding a crude product. The crude
product formed was recrystallized from petroleum ether to give a white product; yield 80 %; mp 197-199
ºC. Anal. Calcd for C14H16N4O2 (272.31): C, 61.75; H, 5.92; N, 20.57. Found: C, 61.64; H, 5.93; N, 20.42.
1
IR (KBr): υmax = 3263 (NH), 3062 (NH), 3028 (NH), 1742 (CO), 1675 (CO); H NMR (400 MHz,
DMSO-d6): δ, ppm = 1.88 (s, 3H, CH3), 1.98 (s, 3H, CH3), 3.61 (s, 2H, CH2), 7.05-7.24 (m, 5H, Ar-H),
9.84 (br, 1H, NH, D2O exchangeable), 10.04 (br, 2H, NH, D2O exchangeable); 13C NMR (600 MHz,
DMSO-d6): δ, ppm = 170.16, 170.10, 148.37, 139.64, 136.58, 129.08, 129.02, 126.82, 116.15, 29.20,
23.48, 23.39. MS: m/z (%) 272 (M+, 100), 229 (85), 186 (45), 127 (35), 90 (25).
Synthesis of N-(4-benzyl-5-((dimethylamino)methyleneamino)-1H-pyrazol-3-yl)acetamide (13)
A mixture of compound 12 (2.72 g, 0.01 mol) and N,N-dimethylformamide dimethyl acetal (DMFDMA)
(1.19 g, 0.01 mol) in xylene (20 mL) ) was refluxed for 6 h. The reaction mixture was evaporated under
reduced pressure in vacuum yielding a crude product, which was recrystallized from toluene to give a
faint yellow product; yield 60 %; mp 148-150 ºC. Anal. Calcd for C15H19N5O (285.35): C, 63.14; H, 6.71;
1
N, 24.54. Found: C, 62.94; H, 6.60; N, 24.72. IR (KBr): υmax = 3263 (NH), 3295 (NH), 3062 (NH); H
NMR (400 MHz, DMSO-d6): δ, ppm = 1.62 (s, 3H, CH3), 2.86 (s, 3H, CH3), 2.91 (s, 3H, CH3), 3.60 (s,
2H, CH2), 7.05-7.21 (m, 5H, Ar-H), 7.76 (s, 1H, CH), 9.47 (br, 1H, NH, D2O exchangeable), 11.6 (br, 1H,
NH, D2O exchangeable); 13C NMR (600 MHz, DMSO-d6): δ, ppm = 170.39, 155.25, 142.73, 141.35,
129.07, 129.00, 126.45, 102.05, 79.88, 39.53, 34.57, 23.46. MS: m/z (%) 285 (M+, 100), 272 (30), 225
(30), 187 (30), 172 (30), 91 (40), 77 (10).
Synthesis of compounds (19 and 20)
Equimolecular amounts of 7a (1.88 g, 0.01 mol) and benzylidenemalononitrile (1.54 g, 0.01 mol) in
EtOH (20 mL) were refluxed for 5-7 h (monitored by TLC using EtOAc : petroleum ether 1 : 1). The
reaction mixture was evaporated under reduced pressure in vacuum yielding a crude product. This crude
product contains two compounds which were separated by a long column chromatography using a
mixture of petroleum ether and EtOAc (1:1) as an eluent. Compound 19 was separated at Rf = 0.54, while

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HETEROCYCLES, Vol. 75, No. 6, 2008
compound 20 was separated at Rf = 0.32.
2,7-Diamino-3-benzyl-5-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile (19)
The solid, so formed after evaporation of the eluent, was recrystallized from petroleum ether to give a
faint brown product; yield 35 %; mp 179-180 ºC. Anal. Calcd for C20H18N6 (342.40): C, 70.16; H, 5.30; N,
24.54. Found: C, 70.07; H, 5.33; N, 24.13. IR (KBr): υmax = 3440, 3332 (NH2), 3381, 3329 (NH2), 3203
1
(NH), 2172 (CN); H NMR (400 MHz, DMSO-d6): δ, ppm = 3.56 (s, 2H, CH2), 5.02-5.11 (br, 3H, CH,
NH2, D2O exchangeable), 6.43 (br, 2H, NH2, D2O exchangeable), 7.13 (br, 1H, NH, D2O exchangeable),
13
7.20-7.34 (m, 10H, Ar-H); C NMR (600 MHz, DMSO-d6): δ, ppm = 158.35, 148.68, 145.17, 144.24,
141.98, 129.23, 128.93, 128.85, 128.30, 126.84, 126.41, 121.89, 88.19, 55.12, 54.01, 26.75. MS: m/z (%)
342 (M+, 80), 264 (35), 186 (40), 111 (80), 91 (100).
2,7-Diamino-3-benzyl-5-phenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (20)
The solid, so formed after evaporation of the eluent, was recrystallized from petroleum ether (60-80) to
give a faint yellow product; yield 55 %; mp 214-216 ºC. Anal. Calcd for C20H16N6 (340.14): C, 70.57; H,
4.74; N, 24.69. Found: C, 70.33; H, 4.73; N, 24.40. IR (KBr): υmax = 3443, 3352 (NH2), 3417, 3300
(NH2), 2212 (CN); 1H NMR (400 MHz, DMSO-d6): δ, ppm = 3.89 (s, 2H, CH2), 5.78 (br, 2H, NH2, D2O
13
exchangeable), 7.11-7.79 (m, 10H, Ar-H), 8.13 (br, 2H, NH2, D2O exchangeable); C NMR (600 MHz,
DMSO-d6): δ, ppm = 161.08, 158.56, 149.71, 146.50, 142.06, 138.88, 131.03, 130.29, 129.48, 129.23,
129.18, 126.71, 118.34, 96.45, 70.93, 27.44. MS: m/z (%) 340 (M+, 100), 324 (15), 297 (30), 263 (80),
195 (10), 153 (10), 127 (10), 104 (20), 77 (10).
Synthesis of 4,7-diamino-8-benzylpyrazolo[5,1-c][1,2,4]triazine-3-carbonitrile (22)
A solution of malononitrile (0.66 g, 0.01 mol) in EtOH (50 mL) was treated with sodium acetate (5 g).
The diazonium salt was then added gradually, with stirring, to the mixture. These diazonium salts was
prepared from compound 7a (1.88 g, 0.01 mol) dissolved in acetic acid (5 mL), concentrated
hydrochloric acid (2.5 mL), and sodium nitrite (0.69 g, 0.01 mol) according to the standard literature
procedures. After complete addition of the diazonium salt, the reaction mixture was kept at rt for 1 h. The
resulting solid product was filtered. The solid, so formed, was collected by filtration and recrystallized
from EtOH to give a yellow product; yield 80 %; mp 237-239 ºC. Anal. Calcd for C13H11N7 (265.28): C,
58.86; H, 4.18; N, 36.96. Found: C, 58.91; H, 4.14; N, 37.08. IR (KBr): υmax = 3314, 3162 (NH2), 3235,
3159 (NH), 2225 (CN); 1H NMR (400 MHz, DMSO-d6): δ, ppm = 4.21 (s, 2H, CH2), 7.17-7.32 (m, 7H,
Ar-H, NH2, D2O exchangeable), 9.28 (br, 1H, NH2, D2O exchangeable); 13C NMR (600 MHz,
DMSO-d6): δ, ppm = 146.06, 145.61, 143.15, 140.21, 128.41, 128.36, 126.11, 115.99, 112.46, 104.30,
28.20. MS: m/z (%) 265 (M+, 40), 250 (60), 222 (30), 170 (20), 129 (30), 84 (100), 66 (20).
Synthesis of compound 2-amino-3-benzyl-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one (23)
Equimolecular amounts of 7a (1.88 g, 0.01 mol) and EtOAc (1.30 g, 0.01 mol) in ethanol (20 mL) were

HETEROCYCLES, Vol. 75, No. 6, 2008
1381
refluxed for 5-10 h (monitored by TLC using EtOAc : petroleum ether 1 : 1). The reaction mixture was
cooled and poured onto ice-water. The solid, so formed, was collected by filtration and crystallized from
EtOH, to give a white crystals, yield 85 %; mp 255-256 ºC. Anal. Calcd for C14H14N4O (254.29): C,
66.13; H, 5.55; N, 22.03. Found: C, 66.33; H, 5.55; N, 21.98. IR (KBr): υmax = 3338, 3266 (NH2), 3173
1
(NH), 1681 (CO); H NMR (400 MHz, DMSO-d6): δ, ppm = 2.31 (s, 3H, CH3), 3.94 (s, 2H, CH2), 5.56
(br, 2H, NH2, D2O exchangeable, 7.16-7.30 (m, 5H, Ar-H), 7.68 (s, 1H, CH), 12.09 (br, 1H, NH, D2O
exchangeable); 13C NMR (600 MHz, DMSO-d6): δ, ppm = 156.76, 150.78, 143.55, 141.21, 139.26,
128.75, 128.62, 126.44, 101.70, 95.22, 27.88, 19.08. MS: m/z (%) 254 (M+, 15), 239 (100), 211 (20), 162
(50), 128 (15), 91 (25).
Synthesis of compounds (26 and 27)
Equimolecular amounts of 7a (1.88 g, 0.01 mol) and 25 (1.96 g, 0.01 mol) in EtOH (20 mL) was treated
with a few drops of Et3N. and the whole mixture was refluxed for 5-7 h (monitored by TLC using EtOAc:
petroleum ether 1 : 1). The reaction mixture was evaporated under reduced pressure in vacuum yielding a
crude product. The crude was washed with petroleum ether to extract the compound 27 as a red product.
The residue was crystallized from toluene to yield compound 26 as a red product also.
1-(7-Benzyl-2-methyl-3H-imidazo[1,2-b]pyrazol-3-ylidene)-2-phenylhydrazine (26)
Compound 26 was formed in 55 % yield; mp166-168 ºC. Anal. Calcd for C19H18N6 (330.39): C, 69.07; H,
1
5.49; N, 25.44. Found: C, 68.87; H, 5.70; N, 25.65. IR (KBr): υmax = 3328, 3292 (NH2), 3228 (NH); H
NMR (400 MHz, DMSO-d6): δ, ppm = 2.50 (s, 3H, CH3), 3.82 (s, 2H, CH2), 5.67 (br, 2H, NH2 D2O
exchangeable), 6.95-7.36 (m, 10H, Ar-H), 10.06 (br, 1H, NH, D2O exchangeable); 13C NMR (600 MHz,
DMSO-d6): δ, ppm = 166.54, 160.11, 152.25, 142.67, 139.99, 131.50, 129.49, 128.31, 128.19, 125.99,
122.02, 113.57, 96.93, 26.69, 14.78. MS: m/z (%) 330 (M+, 25), 274 (95), 236 (20), 278 (70), 160 (40),
147 (25), 105 (45), 77 (60).
N-(7-Benzyl-2-methyl-3-(2-phenylhydrazono)-3H-imidazo[1,2-b]pyrazol-6-yl)-2-oxo-N'-(phenyl-
amino)propanamidine (27)
Compound 27 was formed in 35 % yield; mp 181-183 ºC. Anal. Calcd for C28H26N8O (490.57): C, 68.55;
H, 5.34; N, 22.84. Found: C, 68.76; H, 5.52; N, 20.43. IR (KBr): υmax = 3436 (NH), 3336 (NH), 3252
(NH), 1654 (CO); 1H NMR (400 MHz, CDCl3): δ, ppm = 2.60 (s, 3H, CH3), 4.05 (s, 2H, CH2), 6.70-7.40
(m, 16H, Ar-H, NH, D2O exchangeable), 9.11 (br, 1H, NH, D2O exchangeable), 9.71 (br, 1H, NH D2O
exchangeable); MS: m/z (%) 490 (M+, 15), 474 (25), 434 (20), 398 (30), 274 (100), 178 (30), 77 (70).
Synthesis of 2-(4-hydroxythiazol-2-yl)-3-phenylpropanenitrile (29) and 2-(4-oxothiazolidin-2-
ylidene)-3-phenylpropanenitrile (30)
Equimolecular amounts of 6a (1.56 g, 0.01 mol) and thioglycolic acid (0.92 g, 0.01 mol) in acetic acid
(20 mL) were refluxed for 5 h. The reaction mixture was cooled and poured onto ice-water. The solid, so

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HETEROCYCLES, Vol. 75, No. 6, 2008
formed, was collected by filtration and recrystallized from EtOH, to give a brown product; yield 75 %;
mp 180-182 ºC. Anal. Calcd for C12H10N2OS (230.05): C, 62.59; H, 4.38; N, 12.16; S, 13.92. Found: C,
62.38; H, 4.59; N, 12.19; S, 13.84. The mixture of two tautomers give IR (KBr): υmax = 3443 (OH), 3174
(NH), 2244 (CN), 2202 (CN), 1720 (CO); 1H NMR (400 MHz, DMSO-d6): δ, ppm = 3.08 (d, 2H, CH2, J
= 8 Hz), 3.45 (s, 2H, CH2), 3.91 (s, 2H, CH2), 4.69 (t, 1H, CH, , J = 8 Hz), 7.26-7.41 (m, 11H, Ar-H, CH),
9.29 (br, 1H, OH, D2O exchangeable), 11.85 (br, 1H, NH, D2O exchangeable); 13C NMR (600 MHz,
DMSO-d6): δ, ppm = 175.69, 175.18, 154.34, 139.32, 138.02, 129.98, 129.63, 129.19, 128.04, 127.87,
127.70, 120.48, 120.44, 81.81, 57.47, 45.23, 35.75, 34.41, 34.35, 32.33. MS: m/z (%) 230 (M+, 70), 196
(10), 161 (45), 129 (20), 101 (100), 83 (85), 73 (40).
Synthesis of 2-[4-oxo-5-(phenylhydrazono)-thiazolidin-2-ylidene]-3-phenylpropionitrile (31)
A solution of a mixture of two of the tautomiric products 29 and 30 (2.30 g, 0.01 mol) in EtOH (50 mL)
was treated with sodium acetate (5 g). Benzenediazonium chloride was then added gradually, with stirring,
to the mixture; the diazonium salt was prepared from aniline (0.93 g, 0.01 mol), concentrated
hydrochloric acid (2.5 mL) according to standard literature procedures, and sodium nitrite (0.69 g, 0.01
mol). After complete addition of the diazonium salt, the reaction mixture was kept at rt for 1 h. The solid,
so formed, was collected by filtration and recrystallized from EtOH, to give red product; yield 80 %; mp
236-237 ºC. Anal. Calcd for C18H14N4OS (334.4): C, 64.65; H, 4.22; N, 16.75; S, 9.59. Found: C, 64.65;
1
H, 4.36; N, 16.88; S, 9.44. IR (KBr): υmax = 3272 (NH), 3237 (NH), 2205 (CN), 1710 (CO); H NMR
(400 MHz, DMSO-d6): δ, ppm = 3.81 (s, 2H, CH2), 7.01-7.43 (m, 11H, Ar-H, NH, D2O exchangeable),
8.18 (br, 1H, NH, D2O exchangeable); 13C NMR (600 MHz, DMSO-d6): δ, ppm = 165.45, 133.12, 129.97,
129.84, 129.74, 128.68, 128.50, 126.50, 123.49, 118.50, 117.51, 114.39, 114.30, 35.11. MS: m/z (%) 234
(M+, 90), 207 (25), 181 (15), 90 (100).
ACKNOWLEDGEMENTS
The authors are grateful to Kuwait University, Research Administration for financial support through
project No. SC05/07 and for SAF facilities projects GS01/01; GS03/01.
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