Antimicrobial activities of some novel thiazoles

Article abstract of DOI:10.1134/S1068162016040038

2-(4-Phenylthiazol-2(3H)-ylidene)-malononitrile was synthesized by treating 1-phenyl-2-thiocyanatoethanone with malononitrile. Reaction of 2-(4-phenylthiazol-2(3H)-ylidene)-malononitrile with hydrazine hydrate afforded 4-(4-phenylthiazol-2-yl)-1H-pyrazole

Full text of DOI:10.1134/S1068162016040038

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2016, Vol. 42, No. 4, pp. 428–433. © Pleiades Publishing, Ltd., 2016.
Antimicrobial Activities of Some Novel Thiazoles1
Saleh M. AlꢀMousawia, 2, Moustafa Sherief Moustafab, and Esmaeil AlꢀSalehb
aDepartment of Chemistry, Faculty of Science, University of Kuwait, Safat, 13060 Kuwait
bDepartment of Biological Sciences, Faculty of Science, University of Kuwait, Safat, 13060 Kuwait
Received December 25, 2015; in final form, February 2, 2016
Abstract—2ꢀ(4ꢀPhenylthiazolꢀ2(3
cyanatoethanone with malononitrile. Reaction of 2ꢀ(4ꢀphenylthiazolꢀ2(3
hydrazine hydrate afforded 4ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ1 ꢀpyrazoleꢀ3,5ꢀdiamine, reaction with benzylideneꢀ
malononitrile yielded 2ꢀ(5ꢀbenzylideneꢀ4ꢀphenylꢀ5 ꢀthiazolꢀ2ꢀylidene)ꢀmalononitrile, and coupling with
benzenediazonium chloride gave 2ꢀ(4ꢀphenylꢀ5ꢀphenylazoꢀ3 ꢀthiazolꢀ2ꢀylidene)ꢀmalononitrile. Diamiꢀ
nopyrazole reacted with enaminonitrile to yield the 3ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)pyrazolo[1,5ꢀa]pyrimidineꢀ
2,7ꢀdiamine. All synthesized compounds showed significant antimicrobial activities with MIC range of 5–
750 g/mL. The results demonstrated a correlation of the hydrophobicity of the compounds with their antiꢀ
microbial activity. The most potent antimicrobial compound was 2ꢀ(4ꢀphenylthiazolꢀ2(3 )ꢀylidene)ꢀmalꢀ
ononitrile.
H
)ꢀylidene)ꢀmalononitrile was synthesized by treating 1ꢀphenylꢀ2ꢀthioꢀ
H
)ꢀylidene)ꢀmalononitrile with
H
H
H
µ
H
Keywords: thiazoles, aminopyrazoles, antimicrobial activities
DOI: 10.1134/S1068162016040038
INTRODUCTION
nitrile
3,5ꢀdiamine
thiazolꢀ2ꢀylidene)ꢀmalononitrile (VII), and 2ꢀ(4ꢀ
phenylꢀ5ꢀphenylazoꢀ3Hꢀthiazolꢀ2ꢀylidene)ꢀmalonoꢀ
nitrile (VIII).
(
V
),
4
ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ
1Hꢀpyrazoleꢀ
(VI), 2ꢀ(5ꢀbenzylideneꢀ4ꢀphenylꢀ
5Hꢀ
In 1973, it has been reported [1] that arylhydrazone
of mesoxalic acid dinitrile (I) reacts with hydrazine
hydrate to yield 4ꢀ(aryldiazenyl)ꢀ1
Hꢀpyrazoleꢀ3,5ꢀ
diamine (II) (Scheme 1). The derivatives of comꢀ
pound (II) have attracted attention for their potential
as hair dyes [2, 3]. However, compound (II) and its
derivatives have several other useful properties that can
be exploited for commercial applications, e.g. the
antimicrobial activity [4–6].
Thiazoles are also biologically important moleꢀ
cules, their antimicrobial activities [7–9] and other
biological activities have been reported [10–13].
Despite numerous reports on thiazoles and their
derivatives, the biological activities of arylazocyanomꢀ
ethyl thiazole derivatives have not been investigated.
This was the objective of the present work. Also, the
emergence of antibiotic resistant pathogens necessiꢀ
tates the discovery of new antimicrobial agents to conꢀ
trol potential imminent health hazards.
RESULTS AND DISCUSSION
Chemistry
The synthesis of 2ꢀ(4ꢀphenylthiazolꢀ2(3H)ꢀ
ylidene)ꢀmalononitrile (
tion of aryl thiocyanate (III) with malononitrile (IV
V) was achieved by the reacꢀ
)
in the presence of piperidine as reported by Alꢀ
Mousawi et al. [17, 19]. Previously we have reported
the synthesis of compound (V) by mixing (III) and
malononitrile (IV) in the presence of chitozan as a hetꢀ
erogeneous ecofriendly catalyst but in the absence of a
solvent, with similar yields [20]. In none of these synꢀ
thetic attempts, 2ꢀ(2ꢀthiocyanatoethylidene)malonoꢀ
nitrile derivatives (IX) could be isolated as has been
claimed by Abdelrazik et al. [20].
Thiazole derivatives are prepared by treating
haloketones with cyanothioacetamide [14–16].
Recently, it has been reported that reaction of thiocyꢀ
anate (III) with malononitrile (IV) affords only 2ꢀ(4ꢀ
A new diaminopyrazole derivative (VI) was
obtained via the reaction of thiazole (
zine hydrate. Reaction of 2ꢀ(4ꢀphenylthiazolꢀ2(3
ylidene)malononitrile ( ) with benzylidenemalononiꢀ
trile in ethanolic piperidine solution afforded 2ꢀ(5ꢀ
benzylideneꢀ4ꢀphenylꢀ ꢀthiazolꢀ2ꢀylidene)ꢀmalonoꢀ
nitrile (VII). Coupling of 2ꢀ(4ꢀphenylthiazolꢀ2(3 )ꢀ
ylidene)malononitrile ( ) with benzenediazonium
chloride gave 2ꢀ(5ꢀphenylazoꢀ ꢀthiazolꢀ2ꢀylidene)ꢀ
malononitrile (VIII) in 85–90% yield (Scheme 2).
V
) with hydraꢀ
H)ꢀ
phenylthiazolꢀ2(3H)ꢀylidene)ꢀmalononitrile (V) [17–
V
19] that may have potential pharmacological properꢀ
ties. In this endeavor, we report facile synthesis and
antimicrobial activities of some interesting thiazoles
5H
H
including 2ꢀ(4ꢀphenylthiazolꢀ2(3H)ꢀylidene)malonoꢀ
V
1
3H
The article is published in the original.
Corresponding author: eꢀmail: salehalmousawi@hotmail.com.
2
428

ANTIMICROBIAL ACTIVITIES OF SOME NOVEL THIAZOLES
429
NH2
NH
Diaminopyrazole (VI) reacted with enaminonitrile
IX to yield the 3ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)pyraꢀ
zolo[1,5ꢀa]pyrimidineꢀ2,7ꢀdiamine ( ) (Scheme 3).
The 3ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)pyrazolo[1,5ꢀa]pyrimiꢀ
dineꢀ2,7ꢀdiamine ( ) was concluded to be the product
based on the results of Xꢀray crystallographic analyses
(CCDC 795153) (Fig. 1) [21].
Ar N N
H2N
H
CN
CN
NH NH
2
⋅ H O
(
)
2 2
Ar N N
X
EtOH/pip
N
X
(I
)
(II
)
Scheme 1. Synthesis of diaminopyrazole derivatives (II).
NC
Ph
CN
SCN
O
Fusion
CN
(IX)
Chetosan
+
CH2
Ph
Ph
CN
SCN
III
S
NH
CN
(
)
(IV
)
NC
(V)
+
–
EtOH
pip
Ph
CN
CN
EtOH
reflux
phN≡
NCl
NH NH ⋅ H O
2 2 2
Ph
N
PhN
N
Ph
Ph
Ph
S
S
NH
S
N
NH2
H2N
VI
NC
VIII
CN
NC
VII
CN
N N
H
(
)
(
)
(
)
Scheme 2. Synthesis of thiazoles derivatives (VI
–VIII).
Ph
Ph
N
N
S
N
N
DMF
Reflux 10 h
+
N
N
S
NH2
CN
NH2
H2N
H2N
N
NH
(VI
)
(IX)
(X)
Scheme 3. Synthesis of compound (X).
Antimicrobial Activity
activity of compound (V) against Bacillus spp., E. coli,
and P. aeruginosa was found to be more potent than
that of such antibiotics as cefotaxime and nitrofuranꢀ
toin (table). Compound (VI) was also more potent
against all gramꢀnegative bacteria when compared
The synthesized compounds were found to be
active against all tested microbial strains. However, the
potency of antimicrobial activity differed between the
compounds. The inhibitory effects of the synthesized
compounds were demonstrated by determination of
the minimal inhibitory concentration (MIC) values
with nitrofurantoin. Compounds (VI) and (VII
)
showed higher tendency to inhibit gramꢀpositive bacꢀ
and by the dose–response experiments. MICs for teria as compared with gramꢀnegative bacteria. Thus,
compounds ( VIII) are shown in the table.
Compound ( ) showed the MIC ranging between
5–15 μg/mL for the yeast Candida albicans, gramꢀ
V–
compounds (V) and (VII) exhibited higher tendency to
inhibit gramꢀpositive bacteria (compounds), while
compound (VI) demonstrated higher inhibitory
V
positive, and gramꢀnegative bacterial strains. The potentials against gramꢀnegative bacteria. The aptiꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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2016

430
SALEH M. ALꢀMOUSAWI et al.
S(1)
N(3)
C(18)
C(15)
C(21)
C(10)
C(9)
C(13)
C(22)
C(20)
C(12)
C(14)
C(8)
N(2)
N(4)
C(11)
C(17)
C(16)
C(19)
N(6)
N(5)
N(7)
Fig. 1. Plot of the Xꢀray crystallographic data of 3ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)pyrazolo[1,5ꢀ
a]pyrimidineꢀ2,7ꢀdiamine (X).
tude of chemical compounds and antibiotics to nounced linear relationship between bacterial growth
restrain the growth of specific bacterial groups has
been reported previously by Saene et al. [22]. Though,
E. coli, S. enterica, and P. aeruginosa are gramꢀnegative
and concentration was demonstrated by the hydroꢀ
philic compounds ( ) and (VI) (Fig. 2, curve ). This
may be due to their higher solubility in aqueous media
implicating their faster transport through the bacterial
V
1
bacteria associated with Gamma Proteobacteria [23]
and are expected to possess common genetic backꢀ
ground implying similar behavior [24], the tested
strains showed different responce towards the syntheꢀ
sized compounds. Similarly, though methicillinꢀresisꢀ
tant Staphylococcus aureus (MRSA) and Bacillus are
gramꢀpositive bacteria, MRSA strains show generally
higher resistance to the tested compounds as comꢀ
pared to Bacillus strains. In addition, all synthesized
compounds demonstrated antifungal activity that was
cell wall. Conversely, compounds (VII) and (VIII
)
with their higher hydrophobic character showed a
nonꢀlinear correlation between bacterial growth and
their concentration (Fig. 3, curve
1). An initial
increase in the concentration of these compounds in
the culture media resulted in an insignificant inhibiꢀ
tory effect. However, an addition of these compounds
at a higher concentration resulted in instant inhibition
of the bacterial growth (Fig. 3, curve 1). The hydroꢀ
phobicity of compounds (VII) and (VIII) could hinder
the most potent for compounds (V) and (VII). The
antimicrobial efficacy of the newly synthesized comꢀ
pounds was confirmed by comparison of their antimiꢀ
crobial activity with that of well known antibiotics,
such as cefotaxime, nitrofurantoin, penicillin, and
piperacillin. The choice of these four antibiotics for
comparison was based on the higher frequency of their
usage in Kuwait and on the ability of these antibiotics
to inhibit gramꢀpositive and gramꢀnegative bacteria.
their transport through bacterial cell wall leading to
modest antibacterial activity (Fig. 3, curve 1). Howꢀ
ever, an exposure of the tested bacteria to higher conꢀ
centrations of compounds (VII) and (VIII) may
induce alteration in pharmacodynamics and antimiꢀ
crobial activity by binding to the cell wall receptors
enhancing their toxicity for the microorganism. For
example, an addition of compound (VIII) (0–
450
μg/mL) in the culture media of P. aeruginosa
The doseꢀresponse studies showed that the inhibiꢀ
tory effects were proportional to the amount of the
resulted in an initial insignificant decrease in bacterial
compound added in the microbial culture. A proꢀ growth followed by a significant inhibition at the
Antimicrobial activity of compounds (V–VIII) and the reference compounds
MIC,
VIII
50–70
90–100 200–250
Nil
= 50) 12.5 15–30 200–250 400–500
= 25) 12.5 15–30 250–500 625–750
= 20) 5–15 25–50 5–10 50–400
µg/mL
Microorganism
(number of strains)
(
V
)
(
VI
)
(
VII
)
(
)
Cefo Nf
P
Pip
Bacillus spp. (
MRSA ( = 20)
E. coli = 20)
P. aeruginosa
S. enteric
C. albicans
n
= 10) 5–10 25–30
45–50
10
30
30
60
5
5
1
1
5
Gramꢀpositive bacteria
n
5–10 25–30
15
130
130
130
–
10
30
30
5
(
n
12.5 15–30 250–625
130
10
5
Gramꢀ negative bacteria
Yeast
(n
(
n
(
n
–
–
–
MRSA, methicillinꢀresistant Staphylococcus aureus; MIC, minimum inhibitory concentration; Cefo, Cefotaxime; Nf, Nitrofurantoin;
P, Penicillin; Pip, Piperacillin.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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ANTIMICROBIAL ACTIVITIES OF SOME NOVEL THIAZOLES
431
Optical density, a. u.
0.14
Optical density, a. u.
0.14
0.12
0.10
0.08
0.12
0.10
0.08
1
0.06
0.06
2
1
2
0.04
0.04
4
3
3
0.02
0.02
4
0
100
200
300
400 500
Concentration,
600
µg/mL
0
5
10
15
20
25
Concentration,
30
µ
35
g/mL
Fig. 3. Dose–response curves for 2ꢀ(5ꢀbenzylideneꢀ4ꢀ
phenylꢀ5 ꢀthiazolꢀ2ꢀylidene)ꢀmalononitrile (VII) and
2ꢀ(4ꢀphenylꢀ5ꢀphenylazoꢀ3 ꢀthiazolꢀ2ꢀylidene)ꢀmalꢀ
ononitrile (VIII) with MRSA and P. aeruginosa. 1, comꢀ
pound (VIII) against P. aeruginosa , compound (VIII
against MRSA; , compound (VII) against P. aeruginosa
, compound (VII) against MRSA.
Fig. 2. Dose–response curves for 2ꢀ(4ꢀphenylthiazolꢀ
2(3 )ꢀylidene)ꢀmalononitrile ( ) and 4ꢀ(4ꢀphenylthiaꢀ
zolꢀ2ꢀyl)ꢀ1 ꢀpyrazoleꢀ3,5ꢀdiamine (VI) with MRSA and
P. aeruginosa. 1, compound ( ) against P. aeruginosa
compound (VI) against P. aeruginosa , compound (VI
against MRSA; , compound ( ) against MRSA.
H
H
V
H
H
V
;
2
)
,
;
2
)
;
;
3
3
4
V
4
higher concentration of 450 to 500
μ
g/mL (Fig. 3, out until starting materials were completely conꢀ
). Similar results were shown for MRSA (Fig. 3, sumed.
).
curve
curve
2
3
Phenylthiazolꢀ2(3
H
)ꢀylidene)malononitrile (V).
ꢀthiocyanatoketone (III
Method a: A solution of
α
)
In conclusion, some of the synthetic products, in
particular compound ( ), showed higher broadꢀspecꢀ
(1.77 g, 0.01 mol) and malononitrile (IV) (0.66 g,
0.01 mol) in ethanol (15 mL) containing piperidine
V
trum antibacterial and antifungal activities against
tested microorganisms causing common hospital
(
20 μL) was stirred at reflux for 3–4 h. The solid mateꢀ
rial was produced by pouring the reaction mixture into
ice water and subsequent separation by filtration.
Crystallization in DMF yielded green crystals in 82%
infections. Compound (V) was found to be the most
potent antimicrobial agent followed by compounds (VI
)
and (VII), while the lowest activity was observed for
compound (VIII). These compounds may be potenꢀ
tially useful drugs that can be explored further for their
antimicrobial activity.
yield. Method b: An equimolar mixture of αꢀthiocyꢀ
anatoketone (III) and malononitrile (IV) with chitoꢀ
san (15%) was heated for 15 min without any solvent.
The reaction mixture was cooled and dissolved in ethꢀ
anol. The solid material thus obtained was collected by
filtration and crystallized from DMF to give green
EXPERIMENTAL
crystals. Yield 93%; mp 275–276°C; IR: 3147 (NH),
2210 (CN), 2175 (CN); 1H NMR (400 MHz): 7.33 (s,
1H, CH), 7.45–7.49 (m, 3H, ArꢀH), 7.71–7.72 (m,
2H, ArꢀH), 13.23 (br, 1H, NH, D2O exchangeable);
13C NMR: 172.27, 143.70, 130.01, 129.12(2C),
128.92, 127.51 (2C), 127.64 117.75, 105.93 (2CN).
General
Melting points reported are uncorrected and were
determined with a Sanyo (Gallaenkamp) instrument.
Infrared spectra in KBr pellets were recorded using a
FT–IR 6300 (Jasco) instrument, absorption bands are
reported as νmax, cm–1. 1H and 13C NMR spectra were
determined using a Bruker DPX instrument at
400 MHz or 600 MHz for 1H NMR and 100 MHz for
13C NMR and DMSOꢀd6 solutions with TMS as interꢀ
MS:
m/z
(%) 225 (M+, 100), 180 (20), 134 (45), 108
(10), 102 (15), 89 (15), 77 (10). Calcd. for C12H7N3S
(225.27): C, 63.98; H, 3.13; N, 18.65; S, 14.23.
Found: C, 63.94; H, 3.31; N; 18.45; S, 13.92.
4ꢀ(4ꢀPhenylthiazolꢀ2ꢀyl)ꢀ1
(VI). An equimolar mixture of compound (
H
ꢀpyrazoleꢀ3,5ꢀdiamine
nal standards. Chemical shifts (δ) are reported in ppm.
V) and hyꢀ
Mass spectra and accurate mass measurements were
made using a GCMS DFS (Thermo) spectrometer
with the EI (70 EV) mode. Xꢀray crystallographic
structure determinations were performed using Rapid II
(Rigaku) and X8 Prospector (Bruker) single crystal Xꢀray
diffractometers. All Xꢀray crystal structure data can be
obtained free of charge from the Cambridge Crystalloꢀ
graphic Data Centre via www.ccdc.cam.ac.uk. All reacꢀ
tions were monitored using TLC using ethyl acetateꢀ
petroleum ether (1 : 1, v/v) as an eluent and carried
drazine monohydrate in DMF (10 mL) was stirred at
reflux for 20 h. The mixture was cooled and poured inꢀ
to ice water. The solid product collected by filtration
was crystallized from DMF to give light yellow crystals.
Yield 78%; mp 322–323°C; IR: 3372, 3256 (NH2),
1
3176, 3112 (NH2), 3132 (NH); H NMR (400 MHz):
5.39 (br, 4H, 2NH2, D2O exchangeable), 7.31–7.46 (m,
3H, ArꢀH), 7.75 (s, 1H, CH), 7.96–7.98 (m, 2H, ArꢀH),
10.73 (br, 1H, NH, D2O exchangeable); 13C NMR:
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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2016

432
SALEH M. ALꢀMOUSAWI et al.
166.29, 162.08, 152.30 (2C), 134.31, 128.69 (2C),
127.69, 125.89 (2C), 107.48, 87.97. MS: (%) 257
(M+, 100), 226 (10), 200 (5), 134 (35), 128 (10), 134.31, 128.75 (2C), 127.72, 125.90 (2C), 109.66, 89.99,
90 (10). Calcd. for C12H11N5S (257.31): C, 56.01; H,
4.31; N, 27.22; S, 12.41. Found: C, 55.80; H, 4.41; N; 154 (5), 134 (30), 102 (5), 89(5), 77 (5). Calcd. for
8.01 (m, 2H, ArꢀHs), 8.07 (d, 1H,
NMR: 160.59, 156.98, 152.22, 149.36, 147.14, 146.94,
J
= 6.0, CH); 13C
m/z
88.59. MS: m/z
(%) 308 (M+, 100), 268 (30), 175 (5),
26.88; S, 11.99.
C15H12N6S (308.36): C, 58.43; H, 3.92; N, 27.25;
S, 10.40. Found: C, 58.33; H, 3.79; N; 27.20; S, 10.37.
2ꢀ(5ꢀBenzylideneꢀ4ꢀphenylthiazolꢀ2(5H)ꢀylidene)malꢀ
ononitrile (VII). An equimolar mixture of compound
) and benzylidenemalononitrile in EtOH (20 mL)
and piperidine (1 mL) was stirred under reflux for 3 h.
The reaction mixture was cooled and poured into iceꢀ
water giving a solid which was collected by filtration
and crystallized from EtOH to give the product as faint
(V
Antimicrobial Activity
Antimicrobial activity of the synthesized comꢀ
pounds was assessed using gramꢀpositive bacteria
Bacillus spp. and methicillinꢀresistant Staphylococꢀ
(
cus aureus (MRSA)), gramꢀnegative bacteria (E. coli
,
yellow crystals. Yield 77%; mp 280–282°C; IR: 22.7
(CN), 2179 (CN); 1H NMR (600 MHz): 5.84 (s, 1H,
CH), 7.15–7.42 (m, 10H, ArꢀH); 13C NMR: 169.07,
141.21, 140.04, 131.24, 130.57, 129.69, 129.21 (2C),
128.91 (2C), 128.45 (2C), 128.21, 127.94, 127.61
(2C), 124.62, 122.00, 117.17. MS: m/z (%) 313 (M+,
80), 285 (10), 235 (90), 225 (100), 178 (10), 134 (60),
98 (20). Calcd. for C19H11N3S (313.38): C, 72.82; H,
3.54; N, 13.41; S, 10.23. Found: C, 12.94; H, 3.32; N;
13.31; S, 10.19.
Pseudomonas aeruginosa, and Salmonella enterica),
and yeast (Candida albicans). Microdilution method
was used as reported by James and Jean [25]. Briefly,
the synthesized compounds at different concentraꢀ
tions in DMSO were added to shaked cultures of test
strains (10 strains of Bacillus spp.; MRSA, E. coli, and
C. albicans 20 strains each, 25 strains of S. enterica, and
50 strains of P. aeruginosa). Optical density (λ600 nm) of
the microbial cultures was measured in sterile 96 well
plates using the LD400 (Beckman Coulter, USA)
reader in the presence or absence (controls) of the
2ꢀ(4ꢀPhenylꢀ5ꢀphenylazoꢀ3Hꢀthiazolꢀ2ꢀylidene)maꢀ
lononitrile (VIII). A cold solution of benzenediazoniꢀ
um chloride (0.01 mol) was added to a solution of soꢀ
dium nitrite (0.7 g in 10 mL H2O) and a solution of
aniline hydrochloride (0.93 g, 0.01 mol of aniline and
concentrated HC1, 5 mL) with stirring at room temꢀ
perature. The resulting solution was then added to a
experimental compounds at 37°C. The minimum
inhibitory concentrations (MIC) of the compounds
were calculated. For comparative studies, effect of
antibiotics (cefotaxime, nitrofurantoin, penicillin,
and piperacillin) on the growth of test microorganisms
was examined and the results were used to determine
MIC. In addition, the doseꢀresponse curves were built
using the aforementioned method. All test microorꢀ
ganisms were isolated from medical samples collected
from hospitals in Kuwait. The strains were identified
by sequencing of the 16S [26] and 18S rRNA genes
[27]. All experiments were conducted in triplicates.
cold solution of compound (V) (2.25 g, 0.01 mol) in
ethanol (50 mL) containing sodium acetate (2 g). The
reaction mixtures was stirred for 1 h and filtered. The
solid products were crystallized from EtOH to give red
crystals. Yield 85%; mp 198–200°C; IR: 3180 (NH),
2216 (2CN); 1H NMR (400 MHz): 5.03 (br, 1H, NH,
D2O exchangeable), 7.25–7.60 (m, 8H, ArꢀH), 8.22–
8.24 (m, 2H, ArꢀH); 13C NMR: 175.46, 147.29, 138.67,
131.79, 131.47, 130.73 (2C), 130.70 (2C), 129.59
(2C), 128.63 (2C), 127.05, 118.96, 117.71, 115.70
ACKNOWLEDGMENTS
The authors are grateful Dr. Bivin Thomas for
graphical assistance and to Kuwait University
Research Administration for the financial support of
project no. SC12/13. Analytical facilities were proꢀ
vided by the GFS projects no. GS 01/01, GS 01/03,
GS 01/05, GS 02/10, and GS 03/08 and are greatly
appreciated.
(2CN). MS:
m/z
(%) 329 (M+, 100), 301 (20), 237
(15), 225 (25), 153 (5), 103 (20), 92 (25), 77 (65).
Anal. calcd. for C18H11N5S (329.38): C, 65.64; H,
3.37; N, 21.26; S, 9.73. Found: C, 65.49; H, 3.51; N,
21.15; S, 9.39.
3ꢀ(4ꢀPhenylthiazolꢀ2ꢀyl)pyrazolo[1,5ꢀa]pyrimidineꢀ
2,7ꢀdiamine (X). A mixture of (VI) (2.57 g, 0.01 mol) and
3ꢀ(piperidinꢀ1ꢀyl)acrylonitrile (IX) (1.36 g, 0.01 mol)
in DMF (10 mL) was stirred at reflux for 10 h. The reꢀ
action mixture was cooled and poured into ice water
giving a solid which was collected by filtration and
crystallized from DMF to give the product as yellow
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