Synthesis and antimicrobial study of linked heterocyclics containing pyrazole-pyrimidine-thiazolidin-4-one

Article abstract of DOI:10.1248/cpb.58.1622

A new series of linked heterocyclics, 3-[4-(4-chlorophenyl)-6-(3,5- dimethyl-1-phenyl-1H-4-pyrazolyl)-2-pyrimidinyl]-2-(aryl/heteryl)-1, 3-thiazolan-4-ones (6a - j), has been synthesized by the one-pot cyclo-condensation of 4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4- pyrazolyl)-2-pyrimidinamine (5), aryl/heteroaryl aldehyde and thioglycolic acid. The structures of the synthesized compounds have been confirmed via IR, ¹H-NMR, ¹³C-NMR, MS and elemental analyses. Further, all the newly synthesized compounds 6a - j have been assayed for their antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi. The compounds containing moieties like 4-nitrophenyl (6c), 3-nitrophenyl (6d), 4-dimethylaminophenyl (6g), 2-furyl (6i) and 1,3-benzodioxole (6j), at 2-position of thiazolidin-4-one ring exhibited good inhibitory activity against all the tested organisms.

Full text of DOI:10.1248/cpb.58.1622

1622
Regular Article
Chem. Pharm. Bull. 58(12) 1622—1626 (2010)
Vol. 58, No. 12
Synthesis and Antimicrobial Study of Linked Heterocyclics Containing
Pyrazole-pyrimidine-thiazolidin-4-one
b
Cherkupally SANJEEVA REDDY, ,a Macherla VANI DEVI,a Malladi SUNITHA,a and Adki NAGARAJ
*
a Department of Chemistry, Kakatiya University; Warangal–506 009, India: and b Department of Pharmaceutical
Chemistry, Telangana University; Nizamabad–503 322, India.
Received August 18, 2010; accepted September 13, 2010; published online September 24, 2010
A new series of linked heterocyclics, 3-[4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(aryl/heteryl)-1,3-thiazolan-4-ones (6a—j), has been synthesized by the one-pot cyclo-condensa-
tion of 4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-pyrimidinamine (5), aryl/heteroaryl alde-
1
hyde and thioglycolic acid. The structures of the synthesized compounds have been confirmed via IR, H-NMR,
13C-NMR, MS and elemental analyses. Further, all the newly synthesized compounds 6a—j have been assayed for
their antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi. The compounds con-
taining moieties like 4-nitrophenyl (6c), 3-nitrophenyl (6d), 4-dimethylaminophenyl (6g), 2-furyl (6i) and 1,3-ben-
zodioxole (6j), at 2-position of thiazolidin-4-one ring exhibited good inhibitory activity against all the tested
organisms.
Key words thiazolidin-4-one; pyrimidine; antimicrobial activity
Pyrimidines have a unique place and have contributed sig- 2-pyrimidinyl]-2-(aryl/heteryl)-1,3-thiazolan-4-ones.
nificantly to biological and medicinal fields.1) Pyrimidine
ring systems containing substituted six membered ring ex- Results and Discussion
hibit anticancer and herbicidal activities.2,3) In recent years
Synthesis The compound 1 on cyclo-condensation with
pyrimidine derivatives have received significant attention phenyl hydrazine in ethanol at reflux for 3 h gave the 3,5-di-
owing to their diverse range of biological properties, particu- methyl-1-phenyl-1H-pyrazole (2) in 90% yield. Formylation
larly, antitubercular4) and calcium channel blockers.5) 3- of 2 with N,N-dimethylformamide (DMF) in phosphorous
Azido-3-deoxythymidine (AZT),6) a pyrimidine derivative, oxychloride, at reflux for 1 h, gave the 3,5-dimethyl-1-
has been found to be a potent antiviral agent against human phenyl-1H-4-pyrazolecarb-aldehyde (3) in 86% yield. The
immunodeficiency virus (HIV) type 1 in vitro, and has found compound 3 on Claisen condensation with 4-chloroacetophe-
to decrease mortality and opportunistic infections in patients none in ethanol, in the presence of 60% aq. KOH, at room
with AIDS. Similarly, there has been a considerable interest temperature for 6 h, afforded the (E)-1-(4-chlorophenyl)-3-
in the chemistry of thiazolidin-4-one ring system, which is a (3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-propen-1-one (4)
core structure in various synthetic pharmaceuticals display- in 72% yield. The cyclo-condensation of 4 with guanidine
ing a broad spectrum of biological activities.7) Thiazolidin-4- hydrochloride, in the presence of aq. NaOH, in ethanol at re-
one ring also occurs in nature; thus actithiazic acid isolated flux for 6 h, afforded the 4-(4-chlorophenyl)-6-(3,5-dimethyl-
from Streptomyces strains exhibits highly specific in vitro ac- 1-phenyl-1H-4-pyrazolyl)-2-pyrimidinamine (5) in 75%
tivity against Mycobacterium tuberculosis.8) Thiazolidin- yield. Further, the one-pot cyclo-condensation of 5 with
4-one derivatives are also known to exhibit diverse bioactiv- aryl/heteroaryl aldehyde and thioglycolic acid, in the pres-
ities such as anti-convulsant,9) antidiarrheal,10) anti-platelet ence of ZnCl2 in toluene at reflux temperature for 5 h, pro-
activating factor,11) anti-histaminic,12) anti-diabetic,13) cyclo- duced 3-[4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-
oxygenase (COX) inhibitory,14) Ca2ϩ-channel blocker,15) pyrazolyl)-2-pyrimidinyl]-2-(aryl/heteroaryl)-1,3-thiazolan-
platelet activating factor (PAF) antagonist,16) cardioprotec- 4-ones (6a—j) in good yield (Chart 1, Table 1). Chemical
tive,17) anti-ischemic,18) anti-cancer,19) tumor necrosis factor- structures of all the newly prepared compounds were con-
1
a antagonist20) and nematicidal activities,21) On the other firmed by their elemental analyses, IR, H-NMR, 13C-NMR
hand, pyrazole and their derivatives exhibit significant bio- and MS spectral data.
logical activities such as antidepressant,22) inhibitors of pro-
In the IR spectra of compounds 6a—j, disappearance of
tein kinases,23) antiagreegating,24) antiarthritic25) and cerebro- amine (NH2) absorption in the region 3390—3250 cmϪ1,
protectors.26) Some aryl pyrazoles were reported to have non- which was present in the compound 5, confirms the cycliza-
nucleoside HIV-1 reverse transcriptase inhibitory,27) COX-2 tion with the involvement of NH2 group. In addition, the ab-
inhibitory28) activator of the nitric oxide receptor and soluble sorption bands corresponding to CϭO and N–C–S of the thi-
guanylate cyclase activity.29)
azolidin-4-one ring were observed at about 1696 and
In view of these reports and in continuation of our ongoing 712 cmϪ1 respectively. Additional support, for the formation
research on the synthesis of new heterocyclic derivatives,30—36) of thiazolidin-4-one ring, was obtained from the H-NMR
1
it was thought of interest to accommodate pyrimidine, pyra- spectra; the CH2–CO protons of thiazolidin-4-one ring ap-
zole and thiazolidin-4-one moieties in a single molecular peared at 3.67—3.70 ppm, and the N–CH–S proton of thia-
frame work and to obtain new heterocyclic compounds with zolidin-4-one ring appeared at 5.86 ppm. In the 13C-NMR
potential biological activity. In the present study we report spectra, prominent signals corresponding to carbons of thia-
the synthesis and antimicrobial evaluation of some new 3-[4- zolidin-4-one, pyrimidine and pyrazole rings, for all the com-
(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)- pounds, were observed nearly at 39.1, 69.6 and 177.8 ppm, at
∗ To whom correspondence should be addressed. e-mail: chsrkuc@yahoo.co.in
© 2010 Pharmaceutical Society of Japan

December 2010
1623
Chart 1
Table 1. Physical Charecterization of Synthesized Compounds (2—6)
cillin (Table 2). For the determination of minimal inhibitory
concentration (MIC), bacteria were grown over night in Luria
Bertani (LB) broth at 37 °C harvested by centrifugation, and
then washed twice with sterile distilled water. Stock solutions
of the series of compounds were prepared in dimethyl sulfox-
ide (DMSO). Each stock solution was diluted with standard
method broth (Difco) to prepare serial two-fold dilutions in
the range of 50—0.8 mg/ml. Ten microliters of the broth con-
taining about 105 c.f.u./ml of test bacteria were added to each
well of 96-well microtiter plate. Culture plates were incu-
bated for 24 h at 37 °C and the growth was monitored visu-
ally and spectrometrically. The MIC, (mg/ml) values were
measured and compared with the standard drug penicillin
(Table 2).
Product
ArЈ
Mol. formula Yield (%) mp (°C)
2
3
4
5
—
—
—
—
C11H12N2
C12H12N2O
C20H17ClN2O
C21H18ClN5
C31H26ClN5OS
C30H23Cl2N5OS
C30H23ClN6O3S
C30H23ClN6O3S
C30H24ClN5O2S
C30H24ClN5O2S
C32H29ClN6OS
90
86
72
75
73
68
67
69
70
71
74
70
65
67
270—272
124—126
131—133
145—146
176—178
166—168
205—207
210—212
183—185
177—179
181—183
189—191
200—202
194—196
6a 4-(CH3)-C6H4-
6b 4-Cl-C6H4-
6c 4-(NO2)-C6H4-
6d 3-(NO2)-C6H4-
6e 4-(OH)-C6H4-
6f 2-(OH)-C6HH4-
6g 4-N(CH3)2-C6H4-
6h 4-(OH)-3-(OCH3)-C6H3- C31H26ClN5O3S
6i
6j 5-(1,3-Benzodioxole)
2-Furyl
C28H22ClN2O2S
C31H24ClN5O3S
Antibacterial screening data revealed that all the tested
compounds 6a—j are active and showed moderate to good
antibacterial activity towards all the tested strains. Com-
121.3, 158.5, 161.7 and 174.2 ppm and at 120.6, 140.4 and pounds containing 4-nitrophenyl (6c), 3-nitrophenyl (6d), 4-
141.0 ppm respectively, are proofs of further evidence of dimethylaminophenyl (6g) and 1,3-benzodioxole (6j) moi-
their structures. In summary, all the newly synthesized com- eties at 2-position of the thiazolidin-4-one ring exhibited po-
pounds showed satisfactory spectral data consistent with tent inhibitory activity towards all the tested microorganisms.
their structures. Elemental analyses are also consistent with Further, the compounds containing 4-methylphenyl (6a) and
structures proposed for compounds 6a—j.
4-chlorophenyl (6b) moieties showed good activity towards
Biological Properties. Antibacterial Activity All the P. aeruginosa and C. violaceum. 6e containing 4-hydroxy-
newly synthesized compounds 6a—j were assayed for their phenyl moiety, also showed potent activity towards B. subtilis
antibacterial activity against Gram-positive bacteria viz. and B. sphaericus, and 6i containing 2-furyl moiety, showed
Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC good activity towards B. sphaericus, S. aureus and P. aerugi-
11), and Staphylococcus aureus (MTCC 96), and Gram-neg- nosa.
ative bacteria viz. Pseudomonas aeruginosa (MTCC 741),
Antifungal Activity Compounds 6a—j were also evalu-
Klobsinella aerogenes (MTCC 39), and Chromobacterium ated for their antifungal activity against Candida albicans
violaceum (MTCC 2625) by disc diffusion and broth dilution (ATCC 10231), Aspergillus fumigatus (HIC 6094), Tri-
methods.37) For the antibacterial assay, standard inoculums chophyton rubrum (IFO 9185) and Trichophyton mentagro-
(1—2ϫ107 colony forming unit (c.f.u.)/ml 0.5 Mc Farland phytes (IFO 40996) in DMSO by disc diffusion, broth dilu-
standards) were introduced on to the surface of sterile agar tion methods.37) For the antifungal assay, Sabourands agar
plates, and a sterile glass spreader was used for even distribu- media was prepared by dissolving peptone (1 g), D-glucose
tion of the inoculums. The discs measuring 6.26 mm in diam- (4 g) and agar (2 g) in distilled water (100 ml) and adjusting
eter were prepared from Whatman no. 1 filter paper and ster- the pH to 5.7. Normal saline was used to make a suspension
ilized by dry heat at 140 °C for 1 h. The sterile discs previ- of spore of fungal strain for lining. A loopful of particular
ously soaked in a known concentration of the test compounds fungal strain was transferred to 3 ml saline to get a suspen-
were placed in nutrient agar medium. The plates were in- sion of corresponding species. Twenty milliliters of agar
verted and incubated for 24 h at 37 °C. The inhibition zones media was poured into each petri-dish, excess of suspension
were measured and compared with the standard drug peni- was decanted and the plates were dried by placing in an incu-

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Vol. 58, No. 12
Table 2. Antibacterial Activity of Compounds (6a—j)
Minimal inhibitory concentration in mg/ml (zone of inhibition in mm)a)
Compound
B. subtilis
B. sphaericus
S. aureus
P. aeruginosa
K. aerogenes
C. violaceum
6a
6b
6c
6d
6e
6f
6g
6h
6i
26 (12)
30 (9)
14 (18)
13 (17)
18 (12)
25 (9)
15 (14)
27 (10)
30 (11)
13 (18)
1.56 (25)
25 (11)
27 (10)
18 (20)
19 (20)
20 (17)
30 (10)
18 (19)
26 (11)
21 (12)
15 (15)
3.12 (28)
26 (9)
30 (10)
17 (22)
18 (22)
30 (13)
28 (10)
17 (24)
28 (10)
20 (16)
16 (20)
1.56 (40)
20 (17)
20 (16)
18 (20)
19 (19)
26 (12)
28 (10)
20 (22)
30 (11)
21 (15)
20 (22)
6.25 (25)
30 (9)
26 (9)
20 (16)
19 (20)
25 (10)
30 (8)
20 (20)
28 (10)
28 (9)
20 (18)
6.25 (30)
20 (16)
20 (14)
17 (23)
18 (20)
25 (11)
28 (13)
18 (19)
27 (9)
26 (10)
16 (17)
12.5 (25)
6j
Penicillin
a) The values in parentheses indicate the zone of inhibition.
Table 3. Antifungal Activity of Compounds (6a—j)
bator at 37 °C for 1 h. Using an agar punch wells were made
and each well was labeled. A control was also prepared in
triplicate and maintained at 37 °C for 3—4 d. The C. albicans
was grown for 48 h at 28 °C in YPD broth (1% yeast extract,
2% peptone and 2% dextrose), harvested by centrifugation
and then washed twice with sterile distilled water. A. fumiga-
tus, T. rubrum and T. mentagrophytes were plated in potato
dextrose agar (PDA) (Difco) and incubated at 28 °C for two
weeks. Spores were washed three times with sterile distilled
water and resuspended in distilled water to obtain an initial
inoculums size of 105 spores/ml. Each test compound was
dissolved in DMSO and diluted with potato dextrose broth
(Difco) to prepare serial two-fold dilutions in the range 100
to 0.8 mg/ml. Ten microliters of the broth containing about
Minimal inhibitory concentration in mg/ml
(zone of inhibition in mm)a)
Compound
C. albicans A. fumigatus T. rubrum T. mentagrophytes
6a
6b
6c
6d
6e
6f
6g
6h
6i
26 (10)
36 (11)
18 (17)
22 (12)
25 (10)
30 (10)
14 (23)
30 (12)
15 (21)
25 (15)
16 (22)
30 (9)
35 (12)
30 (8)
28 (16)
40 (10)
28 (9)
32 (13)
22 (16)
28 (9)
24 (16)
32 (11)
36 (10)
26 (10)
20 (18)
40 (14)
22 (19)
25 (17)
20 (22)
26 (8)
25 (8)
25 (15)
30 (12)
18 (21)
30 (14)
18 (23)
22 (16)
16 (20)
32 (10)
18 (22)
30 (10)
19 (20)
20 (16)
18 (20)
6j
103 (for yeast) and 104 (for filamentous fungi) cells/ml of test Fluconazole
fungi was added to each well of a 96-well microtiter plate.
a) The values in parentheses indicate the zone of inhibition.
Culture plates were incubated for about 48—72 h at 28 °C.
The inhibition zone and minimal inhibitory concentration
(MIC) were determined and compared with the standard
drug fluconazole (Table 3).
The antifungal screening data reveal that, most of the
newly synthesized compounds were active with moderate to
good antifungal activity. The compounds containing 4-di-
methylaminophenyl (6g) and 2-furyl (6i), moiety at 2-posi-
tion of the thiazolidin-4-one ring showed highest activity to-
wards all the tested strains. Further, the compound 6c con-
taining 4-nitrophenyl moiety showed good antifungal activity
towards C. albicans, A. fumigatus and T. rubrum. The com-
pound 6j containing 1,3-benzodioxole moiety also showed
potent activity towards A. fumigatus, T. rubrum and T. menta-
grophytes. The comparison of MIC values of the selected
compounds 6a—j and standard drug against different fungi
is presented in Fig. 1.
Fig. 1. Comparison of Antifungal Activity (MIC Values) of Selected
Compounds and Standard Drug
Amphotericin B (AB), C. albicans (CA), A. fumigatus (AF), T. rubrum (TR), T.
mentagrophytes (TM).
Conclusion
A series of linked heterocyclic compounds, 3-[4-(4-
chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(aryl/heteryl)-1,3-thiazolan-4-ones 6a—j has
been synthesized and assayed for their antimicrobial activity
against Gram-positive and Gram-negative bacteria, and
fungi. The compounds 6c, 6d, 6g, 6i and 6j exhibited potent
inhibitory activity towards all tested organisms.
Experimental
General Commercial grade reagents were used as supplied. Solvents
except analytical reagent grade were dried and purified according to the lit-
erature when necessary. Reaction progress and purity of the compounds
were checked by thin-layer chromatography (TLC) on pre-coated silica
gel F254 plates from Merck and compounds visualized either by exposure
to UV light. Silica gel chromatographic columns (70—230 mesh) were
used for separations. Melting points were determined on a Fisher–Johns ap-
paratus and are uncorrected. IR spectra were recorded as KBr disks on a

December 2010
1625
1
(300 MHz, DMSO-d6) d: 2.21 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.59 (s, 3H,
CH3), 3.67—3.70 (m, 2H, CH2–CO), 5.86 (s, 1H, N–CH–S), 7.15—7.30 (m,
12H, Ar-H), 7.49 (d, Jϭ8.1 Hz, 2H, Ar-H). 13C-NMR (75 MHz, DMSO-d6)
d: 11.9, 13.2, 22.0, 39.1, 69.6, 120.6, 121.3, 124.0, 124.9, 125.9, 127.0,
127.5, 128.1, 134.3, 134.9, 136.5, 137.4, 139.6, 140.0, 140.4, 141.0, 158.5,
161.7, 174.2, 177.8. MS m/z: 552 (Mϩ). Anal. Calcd for C31H26ClN5OS: C,
67.44; H, 4.75; N, 12.69. Found: C, 67.39; H, 4.78; N, 12.63.
2-(4-Chlorophenyl)-3-[4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-
4-pyrazolyl)-2-pyrimidinyl]-1,3-thiazolan-4-one (6b): Yield 68%, mp 166—
168 °C. IR (KBr) cmϪ1: 3032, 1698, 1603, 1597, 712, 687. 1H-NMR
(300 MHz, DMSO-d6) d: 2.42 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.67—3.70
(m, 2H, CH2-CO), 5.86 (s, 1H, N-CH-S), 7.15—7.30 (m, 12H, Ar-H), 7.48
(d, Jϭ8.1 Hz, 2H, Ar-H). 13C-NMR (75 MHz, DMSO-d6) d: 11.7, 13.1,
39.2, 69.5, 120.4, 121.5, 124.7, 125.6, 126.7, 127.3, 128.0, 128.9, 133.1,
134.3, 136.6, 137.7, 139.5, 140.0, 140.9, 141.2, 158.3, 161.3, 174.1, 177.0.
MS m/z: 572 (Mϩ). Anal. Calcd for C30H23Cl2N5OS: C, 62.94; H, 4.05; N,
12.23. Found: C, 62.90; H, 4.00; N, 12.16.
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(4-nitrophenyl)-1,3-thiazolan-4-one (6c): Yield 67%, mp
205—207 °C. IR (KBr) cmϪ1: 3035, 1699, 1603, 1596, 1520, 1370, 710,
686. 1H-NMR (300 MHz, DMSO-d6) d: 2.40 (s, 3H, CH3), 2.60 (s, 3H,
CH3), 3.67—3.70 (m, 2H, CH2–CO), 5.86 (s, 1H, N–CH–S), 7.15—7.30 (m,
8H, Ar-H), 7.40—7.45 (m, 4H, Ar-H), 7.71 (d, Jϭ8.6 Hz, 2H, Ar-H). 13C-
NMR (75 MHz, DMSO-d6) d: 11.7, 13.1, 39.1, 69.4, 120.2, 121.7, 123.9,
124.1, 124.9, 127.1, 127.9, 128.8, 136.4, 137.3, 139.1, 140.0, 140.7, 141.9,
142.1, 147.0, 157.5, 161.6, 174.1, 177.4. MS m/z: 584 (Mϩ). Anal. Calcd for
C30H23ClN6O3S: C, 61.80; H, 3.98; N, 14.41. Found: C, 61.74; H, 3.93; N,
14.36.
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(3-nitrophenyl)-1,3-thiazolan-4-one (6d): Yield 69%, mp
210—212 °C. IR (KBr) cmϪ1: 3062, 2980, 1689, 1600, 1595, 1517, 1365,
714, 685. 1H-NMR (300 MHz, DMSO-d6) d: 2.41 (s, 3H, CH3), 2.60 (s, 3H,
CH3), 3.67—3.70 (m, 2H, CH2–CO), 5.94 (s, 1H, N–CH–S), 7.15—7.30 (m,
8H, Ar-H), 7.40—7.45 (m, 4H, Ar-H), 7.80—7.95 (m, 2H, Ar-H). 13C-NMR
(75 MHz, DMSO-d6) d: 11.8, 13.1, 39.1, 70.1, 118.8, 119.6, 120.3, 122.4,
123.9, 124.9, 127.1, 128.5, 129.1, 131.3, 136.2, 137.1, 138.0, 139.7, 140.3,
140.5, 141.2, 147.1, 158.7, 161.3, 173.2, 176.8. MS m/z: 584 (Mϩ). Anal.
Calcd for C30H23ClN6O3S: C, 61.80; H, 3.98; N, 14.41. Found: C, 61.74; H,
3.92; N, 14.34.
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(4-hydroxyphenyl)-1,3-thiazolan-4-one (6e): Yield 70%, mp
183—185 °C. IR (KBr) cmϪ1: 3400—3320, 3047, 2922, 1695, 1603, 1595,
715, 689. 1H-NMR (300 MHz, DMSO-d6) d: 2.40 (s, 3H, CH3), 2.60 (s, 3H,
CH3), 3.68—3.70 (m, 2H, CH2–CO), 5.27 (s, 1H, OH), 5.85 (s, 1H,
N–CH–S), 6.92 (d, Jϭ8.6 Hz, 2H, Ar-H), 7.15—7.30 (m, 10H, Ar-H), 7.48
(d, Jϭ8.2 Hz, 2H, Ar-H). 13C-NMR (75 MHz, DMSO-d6) d: 12.0, 13.7,
40.2, 69.5, 115.0, 121.6, 122.3, 123.9, 125.0, 126.1, 127.5, 128.1, 129.7,
136.5, 138.4, 139.2, 140.5, 140.2, 142.1, 156.3, 158.4, 161.3, 174.1, 177.2.
MS m/z: 554 (Mϩ). Anal. Calcd for C30H24ClN5O2S: C, 65.03; H, 4.37; N,
12.64. Found: C, 65.00; H, 4.31; N, 14.66.
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(2-hydroxyphenyl)-1,3-thiazolan-4-one (6f): Yield 71%, mp
177—179 °C. IR (KBr) cmϪ1: 3400—3300, 3027, 2922, 1696, 1600, 1592,
717, 685. 1H-NMR (300 MHz, DMSO-d6) d: 2.44 (s, 3H, CH3), 2.59 (s, 3H,
CH3), 3.66—3.70 (m, 2H, CH2–CO), 5.87 (s, 1H, OH), 5.96 (s, 1H,
N–CH–S), 6.85—6.90 (m, 2H, Ar-H), 7.15—7.30 (m, 10H, Ar-H), 7.48 (d,
Jϭ8.1 Hz, 2H, Ar-H). 13C-NMR (75 MHz, DMSO-d6) d: 11.2, 13.6, 39.4,
62.1, 115.2, 119.2, 120.9, 121.6, 122.3, 124.3, 125.7, 126.0, 126.7, 127.2,
128.3, 136.4, 137.4, 139.6, 140.4, 140.8, 141.0, 152.6, 158.0, 161.2, 174.1,
177.4. MS m/z: 554 (Mϩ). Anal. Calcd for C30H24ClN5O2S: C, 65.03; H,
4.37; N, 12.64. Found: C, 64.98; H, 4.32; N, 14.60.
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-[4-(dimethylamino)phenyl]-1,3-thiazolan-4-one (6g): Yield
74%, mp 181—183 °C. IR (KBr) cmϪ1: 3042, 2965, 1698, 1599, 1592, 716,
686. 1H-NMR (300 MHz, DMSO-d6) d: 2.42 (s, 3H, CH3), 2.61 (s, 3H,
CH3), 2.91 (s, 6H, 2ϫN–CH3), 3.67—3.70 (m, 2H, CH2–CO), 5.82 (s, 1H,
N–CH–S), 6.80 (d, Jϭ8.5 Hz, 2H, Ar-H), 7.15—7.30 (m, 10H, Ar-H), 7.49
(d, Jϭ8.1 Hz, 2H, Ar-H). 13C-NMR (75 MHz, DMSO-d6) d: 12.2, 13.5,
39.1, 43.6, 69.5, 111.4, 120.6, 121.3, 123.9, 125.9, 127.1, 127.5, 128.1,
130.7, 134.5, 137.1, 139.6, 140.0, 140.9, 141.9, 142.3, 158.7, 162.7, 174.6,
176.6. MS m/z: 582 (Mϩ). Anal. Calcd for C32H29ClN6OS: C, 66.14; H,
5.03; N, 14.46. Found: C, 66.10; H, 4.98; N, 14.40.
Perkin–Elmer Fourier transform-infrared (FT-IR) spectrometer. The H- and
13C-NMR spectra were recorded on a Varian Gemini spectrometer (300 MHz
for H and 75 MHz for 13C). Chemical shifts are reported as d ppm against
1
tetramethyl silane (TMS) as an internal standard and coupling constants (J)
are reported in Hz units. Mass spectra were recorded on a VG micro mass
7070H spectrometer. Elemental analyses (C, H, N) determined by a
Perkin–Elmer 240 CHN elemental analyzer, are within Ϯ0.4% of theoreti-
cal.
Typical Procedure. 3,5-Dimethyl-1-phenyl-1H-pyrazole (2) A mix-
ture of acetyl acetone 1 (0.02 mol), and phenyl hydrazine hydrochloride
(0.02 mol) in ethanol (20 ml) was heated under reflux for 3 h on a water bath.
After completion of the reaction ethanol was evaporated, the residue was
dissolved in water, neutralized with sodium bicarbonate and extracted with
ether. The solvent was evaporated under reduced pressure to get the com-
pound 2 as yellow-brown liquid. Yield 90%, bp 270—272 °C. IR (KBr)
cmϪ1: 3010, 2962, 1516, 1510. H-NMR (300 MHz, CDCl3) d: 2.22 (s, 3H,
CH3), 2.36 (s, 3H, CH3), 6.21 (s, 1H, Ar-H), 7.10—7.20 (m, 5H, Ar-H). MS
m/z: 172 (Mϩ). Anal. Calcd for C11H12N2: C, 76.71; H, 7.02; N, 16.27.
Found: C, 76.77; H, 6.95; N, 16.16.
1
Typical Procedure. 3,5-Dimethyl-1-phenyl-1H-4-pyrazolecarbalde-
hyde (3) To a cold solution of N,N-dimethylformamide (0.02 mol), freshly
distilled phosphorous oxychloride (0.01 mol) was added with stirring over a
period of 30 min. When formylation solution was obtained, a solution of
compound 2 (0.01 mol) in N,N-dimethylformamide (5 ml) was added drop
wise while maintaining the temperature 0—5 °C. The resulting mixture was
heated under reflux for 1 h, cooled and poured with continuous stirring onto
crushed ice and the formed yellow precipitate was filtered, crystallized from
aqueous ethanol to get the pure compound 3 as yellow solid. Yield 86%, mp
124—126 °C. IR (KBr) cmϪ1: 3012, 2961, 2854, 1700, 1516, 1505. 1H-
NMR (300 MHz, CDCl3) d: 2.64 (s, 3H, CH3), 2.71 (s, 3H, CH3), 7.15—
7.25 (m, 5H, Ar-H), 9.98 (s, 1H, CHO). MS m/z: 200 (Mϩ). Anal. Calcd for
C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.94; H, 6.00; N, 14.02.
Typical Procedure. (E)-1-(4-Chlorophenyl)-3-(3,5-dimethyl-1-phenyl-
1H-4-pyrazolyl)-2-propen-1-one (4)
A
solution of compound
3
(0.01 mol) and 4-chloroacetophenone (0.01 mol) in ethanol (20 ml) was
treated with 60% aq. KOH solution (20 ml) at 5—10 °C. The reaction mix-
ture was stirred at room temperature for 6 h. It was then diluted with water
(20 ml) and extracted with diethyl ether (3ϫ20 ml). The aqueous solution
was acidified with dilute HCl. The solid obtained was filtered washed thor-
oughly with water and dried. The crude product was purified by crystalliza-
tion from benzene : methanol (3 : 2) to get the pure compound 4 as yellow
solid. Yield 72%, mp 131—133 °C. IR (KBr) cmϪ1: 3015, 2965, 1690, 1571,
1482, 1224, 685. 1H-NMR (300 MHz, CDCl3) d: 2.31 (s, 3H, CH3), 2.40 (s,
3H, CH3), 7.08 (d, Jϭ16.2 Hz, 1H, a-H), 7.15—7.35 (m, 7H, Ar-H), 7.69 (d,
Jϭ16.2 Hz, 1H, b-H), 7.80 (d, Jϭ7.1 Hz, 2H, Ar-H). MS m/z: 336 (Mϩ).
Anal. Calcd for C20H17ClN2O: C, 71.32; H, 5.09; N, 8.32. Found: C, 71.27;
H, 5.03; N, 8.30.
Typical Procedure. 4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-
4-pyrazolyl)-2-pyrimidinamine (5) To
a mixture of compound 4
(0.01 mol) and guanidine hydrochloride (0.02 mol) in ethanol (20 ml), aq.
NaOH (0.02 mol, 5 ml) was added and refluxed for 6 h (TLC,
EtOAc : petrolium–ether, 2 : 1), then poured the mixture in 10% cold HCl so-
lution (30 ml). The solid product obtained was filtered, washed with water
until free from acid and recrystallized from ethanol to get the pure com-
pounds 5 as yellow solid. Yield 75%, mp 145—146 °C. IR (KBr) cmϪ1
:
1
3390—3250, 3015, 1614, 1510, 1465, 685. H-NMR (300 MHz, DMSO-d6)
d: 2.43 (s, 3H, CH3), 2.68 (s, 3H, CH3), 5.17 (bs, 2H, NH2), 6.92 (s, 1H, Ar-
H), 7.10—7.25 (m, 7H, Ar-H), 7.75 (d, Jϭ8.1 Hz, 2H, Ar-H). MS m/z: 377
(Mϩϩ1). Anal. Calcd for C21H18ClN5: C, 67.11; H, 4.83; N, 18.63. Found:
C, 67.07; H, 4.89; N, 18.65.
Typical Procedure. 3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-
1H-4-pyrazolyl)-2-pyrimidinyl]-2-(aryl/heteryl)-1,3-thiazolan-4-one
(6a—j) To a stirred mixture of compound 5 (0.01 mol), aryl/heteroaryl
aldehyde (0.01 mol) and thioglycolic acid (0.02 mol) in dry toluene (15 ml),
ZnCl2 (0.01 mol) was added and refluxed for 5 h at 110 °C. After cooling, the
filtrate was concentrated to dryness under reduced pressure and the residue
was taken-up in ethyl acetate. The ethyl acetate layer was washed with brine,
5% sodium bicarbonate solution and finally with brine. The organic layer
was dried over Na2SO4 and evaporated to dryness at reduced pressure; the
crude product thus obtained was purified by column chromatography on sil-
ica gel with hexane-ethyl acetate as eluent to get the pure compounds.
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(4-methylphenyl)-1,3-thiazolan-4-one (6a): Yield 73%, mp
3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(4-hydroxy-3-methoxyphenyl)-1,3-thiazolan-4-one (6h):
176—178 °C. IR (KBr) cmϪ1: 3037, 1696, 1604, 1595, 712, 690. H-NMR
1

1626
Vol. 58, No. 12
Yield 70%, mp 189—191 °C. IR (KBr) cmϪ1: 3350—3300, 2967, 1697,
1598, 1590, 1067, 716, 686. 1H-NMR (300 MHz, DMSO-d6) d: 2.40 (s, 3H,
CH3), 2.62 (s, 3H, CH3), 3.67—3.70 (m, 2H, CH2–CO), 3.80 (s, 3H, OCH3),
5.10 (s, 1H, OH), 5.83 (s, 1H, N–CH–S), 6.81 (s, 1H, ArH), 7.15—7.30 (m,
10H, Ar-H), 7.48 (d, Jϭ8.1 Hz, 2H, Ar-H). 13C-NMR (75 MHz, DMSO-d6)
d: 11.6, 13.5, 39.4, 54.8, 70.0, 109.8, 116.6, 118.8, 120.1, 121.5, 124.4,
125.4, 127.1, 128.7, 132.3, 136.6, 137.4, 139.6, 140.5, 141.9, 142.3, 146.4,
148.6, 158.1, 161.8, 174.2, 177.1. MS m/z: 584 (Mϩ). Anal. Calcd for
C31H26ClN5O3S: C, 63.75; H, 4.49; N, 11.99. Found: C, 63.70; H, 4.44; N,
11.92.
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3-[4-(4-Chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-
pyrimidinyl]-2-(2-furyl)-1,3-thiazolan-4-one (6i): Yield 65%, mp 200—
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(1999).
1
202 °C. IR (KBr) cmϪ1: 3039, 1694, 1600, 1594, 1592, 1030, 715, 682. H-
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NMR (300 MHz, DMSO-d6) d: 2.42 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.67—
3.70 (m, 2H, CH2–CO), 5.98 (s, 1H, N–CH–S), 6.30—6.40 (m, 2H, Ar-H),
7.15—7.30 (m, 8H, Ar-H), 7.45—7.50 (m, 3H, Ar-H). 13C-NMR (75 MHz,
DMSO-d6) d: 11.9, 13.2, 39.3, 63.2, 101.8, 109.2, 120.6, 121.2, 124.4,
125.6, 127.5, 128.1, 136.5, 137.7, 139.6, 140.4, 141.3, 144.4, 158.5, 160.8,
161.7, 173.2, 176.1. MS m/z: 528 (Mϩ). Anal. Calcd for C28H22ClN5O2S: C,
63.69; H, 4.20; N, 13.26. Found: C, 63.63; H, 4.24; N, 13.21.
2-(1,3-Benzodioxol-5-yl)-3-[4-(4-chlorophenyl)-6-(3,5-dimethyl-1-
phenyl-1H-4-pyrazolyl)-2-pyrimidinyl]-1,3-thiazolan-4-one (6j): Yield 67%,
mp 194—196 °C. IR (KBr) cmϪ1: 3042, 1695, 1603, 1592, 1120, 717, 682.
1H-NMR (300 MHz, DMSO-d6) d: 2.42 (s, 3H, CH3), 2.61 (s, 3H, CH3),
3.67—3.70 (m, 2H, CH2–CO), 5.65—5.70 (m, 2H, O–CH2–O), 5.85 (s, 1H,
N–CH–S), 7.15—7.30 (m, 9H, Ar-H), 6.83 (s, 1H, Ar-H), 7.45—7.50 (m,
3H, Ar-H). 13C-NMR (75 MHz, DMSO-d6) d: 12.1, 13.2, 39.1, 70.1, 99.7,
105.8, 109.9, 119.1, 121.6, 122.3, 124.9, 125.9, 127.5, 128.8, 132.4, 136.5,
137.4, 139.6, 141.4, 142.0, 145.6, 147.3, 158.5, 161.7, 173.2, 176.8. MS
m/z: 582 (Mϩ). Anal. Calcd for C31H24ClN5O3S: C, 63.97; H, 4.16; N, 12.03.
Found: C, 63.92; H, 4.10; N, 12.00.
Acknowledgements The authors are grateful to the Director, Indian In-
stitute of Chemical Technology, Hyderabad, India, for providing NMR and
Mass spectral data. Financial assistance from the UGC SAP (Phase-I)-DRS
Programme, New Delhi, India, is greatly acknowledged.
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