Synthesis of some biologically active pyrazole, thiazolidinone, and azetidinone derivatives

Article abstract of DOI:10.1023/B:COHC.0000027896.38910.d1

Pyrazole, thiazolidinone, and azetidinone derivatives were synthesized from chalcones of 4-hydroxycoumarin. The structures of all the synthesized compounds were confirmed on the basis of spectral and analytical data. The compounds were screened in vitro for their antibacterial activity against various bacterial strains.

Full text of DOI:10.1023/B:COHC.0000027896.38910.d1

Chemistry of Heterocyclic Compounds, Vol. 40, No. 2, 2004
SYNTHESIS OF SOME BIOLOGICALLY
ACTIVE PYRAZOLE, THIAZOLIDINONE,
AND AZETIDINONE DERIVATIVES
R. B. Pawar and V. V. Mulwad
Pyrazole, thiazolidinone, and azetidinone derivatives were synthesized from chalcones of
4-hydroxycoumarin. The structures of all the synthesized compounds were confirmed on the basis of
spectral and analytical data. The compounds were screened in vitro for their antibacterial activity
against various bacterial strains.
Keywords: azetidinones, biologically active pyrazoles, thiazolidinones.
1-Benzopyran-2-(2H)-ones are well known for their various biological activities [1, 2]. Pyrazoles and
several N-substituted pyrazoles are known to possess neuroleptic [3], analgesic and anti-inflammatory,
antipyretic [4], antiarrhythmic [5], sedative-hypnotic effect [6], and antimicrobial activity [7]. They are
inhibitors and deactivators of liver alcohol dehydrogenase [8], while 3,5-substituted pyrazoles are known for
hypoglycemic activity [4] in glucose primed and diabetic rats. 4-Thiazolidinones have been reported to
demonstrate a wide range of pharmacological activities such as hypnotic-sedative, analgesic activity,
anticonvulsant [9], antifungal [10], antibacterial [11], and antitubercular activity against M. tuberculosis H37Rv
[12]. β-Lactamase is generally considered to be responsible for microbial resistance against a broad spectrum of
β-lactam antibiotics [13].
In continuation of our work [14] we report here for the first time on the synthesis of some
dihydropyrazole, thiazolidinone, and azetidinone derivatives, and on estimation of their biological properties.
For this purpose chalcones of 4-hydroxy-1-benzopyran-2-(2H)-one and 3-(2H-4-hydroxy-2-oxobenzopyran-3-
yl)-ω-arylethenyl ketones 1a,b were treated with hydrazine hydrate in the presence of piperidine to yield
1
dihydropyrazole derivatives 2a,b. The H NMR spectrum of compound 2a showed the presence of a doublet at
δ 1.95 (J = 7 Hz) for two protons at C(4) and a triplet at δ 2.48 for one proton at C(5). It showed the presence of
a singlet at δ 3.68 for three protons of OCH3 along with signals at 7.18–8.41 for eight aromatic protons. It also
exhibited singlets at δ 8.74 and 10.04 for one proton each for the N–H and O–H groups, which were D2O
exchanged. Dihydropyrazoles 2a,b were treated with chloroacetyl chloride in the presence of triethylamine in
1
1,4-dioxane to give N-chloroacetyl derivatives 3a,b. The H NMR spectra of 3a,b did not show the signal at
δ 8.74 for N–H, but a singlet at δ 4.11 for two protons of CH2–CI was present along with other signals.
Chlorides 3a,b were treated with hydrazine hydrate in ethanol in the presence of piperidine to give
1
N-acetylhydrazines 4a,b. The H NMR spectra of 4a and 4b showed a signal at δ 4.46 for two protons of
CH2–NH and a broad signal at δ 4.30 for two protons of NH2 and δ 8.50 for one proton of NH, which are D2O
exchanged. Compounds 4a,b when treated with benzaldehyde gave the corresponding hydrazones 5a,b which
__________________________________________________________________________________________
Department of Chemistry, The Institute of Science, 15, Madam Cama Road, Mumbai 400 032, India;
e-mail: vinata_mulwad@indiatimes.com, roops_pawar@hotmail.com. Published in Khimiya Geterotsiklicheskikh
Soedinenii, No. 2, pp. 257-264, February, 2004. Original article submitted December 26, 2002.
0009-3122/04/4002-0219©2004 Plenum Publishing Corporation
219

Scheme 1
1
O
8
5
5'
2'
R
O
9
O
R
O
O
6'
7
6
NH2NH2
4'
3'
2
4
3
10
1'
3
5
4
2N NH
OH
OH
1
2a,b
1a,b
Cl–CH2–CO–Cl
O
1
1
5'
2'
8
8
5
O
R
O
9
O
R
9
6'
7
6
7
6
4'
3'
2
2
4
4
NH2NH2
5
5
10
3
1'
3
3
10
4
3
4
5
N
N
OH
N
N 1
OH
NH2
2
1
2
CH2Cl
N
H
O
O
4a,b
3a,b
PhCHO
1
5'
8
9
O
O
R
6'
7
6
4'
3'
2
4
5'
5
3
3
6'
4'
3'
10
1'
4
2'
5
N
N
N
1
OH
1'
N
2
2'
H
O
5a,b
HS–CH2–COOH
1
5'
8
O
R
O
9
6'
7
4'
2
4
5
6
3'
10
3
1'
2'
4
3
5
6'
5'
3'
H
S
Cl–CH2COCl
N
N
1
OH
2
4'
N
N
1'
H
O
2'
6a,b
O
1
5'
2'
8
5
O
R
N
O
9
6'
7
4'
3'
2
4
5
6
10
3
1'
4
3
6'
5'
3'
H
N
N
OH
2
1
4'
N
H
1'
O
CI
2'
7a,b
O
H
2–7 a R = OMe, 2–7 b R = H
220

TABLE 1. Spectral Data of Compounds 2a,b-7a,b
Com-
pound
IR spectra, ν, cm-1, KBr
1H NMR spectra (δ, ppm), DMSO-d6 (J, Hz)
13C NMR spectra (δ, ppm), DMSO-d6
Mass spectra, m/z (%)
1
2
3
4
5
2a
2b
3a
3b
3426 (O–H and N–H),
2927 (C–H), 1724 (C=O),
1620 (C=N), 1544, 1440, 1373,
1257, 1027, 778
1.95 (2H, d, J = 7, 4-, 4-H2); 2.48 (1H, t, 5-H,
CH–NH), 3.68 (3H, s, OCH3); 7.18 (1H, d, J = 6,
8-H); 7.40 (2H, d, J = 8, 2'- and 6'-H); 7.59 (2H, d,
J = 8.5, 3'- and 5'-H); 7.80 (1H, d, J = 7.5, 5-H),
8.11 (1H, t, 6-H); 8.41 (1H, t, 7-H); 8.74 (1H, s, NH, (C-4')), 158.1 (C(3)), 162.0 (C(4)), 166.2 (C(2))
D2O exchanged); 10.04 (1H, s, OH, D2O exchanged)
41.3 (C(4)), 53.8 (OCH3), 56.1 (C(5), 100.2 (C(3)),
111.9 (C(10)), 116.4 (C(2')), 118.2 (C(8)), 119.9
(C(6')), 127.6 (C(5)), 128.6 (C(6)), 132.7 (C(7)),
136.0 (C(3')), 137.1 (C(1')), 151.2 (C(9)), 154.3
M+ 336 m/z 319, 305,
292, 280, 265, 254,
240, 223, 216, 200,
185, 176, 161, 152,
144, 135, 121, 105, 91,
77, 65,43, 42
3420 (O–H and N–H), 2928 (C–H), 1.90 (2H, d, J = 7, 4-, 4-H2); .42 (1H, t, 5-H);
1723 (C=O), 1614 (C=N), 1511, 7.05 (3H, m, 3'-, 4'- and 5'-H); 7.32 (2H, d, J = 8.5,
1459, 1380, 1250, 1177, 1031, 823 2'- and 6'-H); 7.50 (1H, d, J = 7, 8-H); 7.67 (1H, t,
6-H); 7.80 (1H, d, J = 7, 5-H); 8.60 (1H, s, NH,
42.0 (C(4)), 51.2 (C(5)), 103.9 (C(3)), 111.9 (C(10)), M+ 306, m/z 278, 270,
117.0 (C(2')), 118.2 (C(8)), 119.8 (C(6')), 120.9
(C(2')), 124.0 (C(6')), 127.4 (C(5)), 128.6 (C(6)),
132.5 (C(7)), 136.0 (C(3')), 137.0 (C(5')), 145.0
229, 221, 207, 201,
175, 161, 145,133,
121, 104, 90, 85, 77,
67, 57
D2O exchanged); 10.40 (1H, s, OH, D2O exchanged) (C(1')), 151.2 (C(9)), 158.0 (C(3)), 163.6 (C(4)),
166.8 (C(2))
3300 (OH), 2959 (CH), 1707
(C=O), 1621 (C=N), 1510, 1447,
1253, 1099, 1027, 806
2.01 (2H, d, J = 6, 4-, 4-H2); 2.50(1H, t, H(5)),
3.56 (3H, s, OCH3); 4.11 (2H, s, Cl–CH2–C=O);
6.49 (2H, d, J = 6, 2'- and 6'-H); 6.73 (1H, t, 6-H),
6.91(1H, t, 7-H); 7.13(1H, d, J = 7, 8-H);
7.16 (2H, d, J = 6, 3'- and 5'-H); 7.39 (1H, d,
J = 6, 5-H); 10.92 (1H, s, OH, D2O exchanged)
43.0 (C(4)), 54.2 (OCH3), 57.7 (C(5)), 61.0
(CI–CH2–C=O), 100.5 (C(3)), 111.0 (C(10)), 116.5
(C(2')), 118.2 (C(8)), 119.9 (C(6')), 127.6 (C(5)),
128.6 (C(6)), 132.7 (C(7)), 136.0 (C(3')), 137.1
(C(1')), 151.2 (C(9)), 154.3 (C(4')), 158.1 (C(3),
162.0 (C(4)), 166.2 (C(2)), 169.1 (N–C=O)
M+ 412, M+2 414, m/z
384, 353, 335, 323,
305, 290, 268, 251,
237, 223, 204, 175,
161, 144, 121, 107
3432 (OH), 3017 (CH), 1721
(>C=O), 1623 (C=N), 1553, 1442, 4.15 (2H, s, CH2–C=O); 6.60 (2H, t, 6- and 7-H);
1249, 1136, 1111, 996, 833
2.20 (2H, d, J = 6.5, 4-, 4-H2); 2.75 (1H, t, 5-H);
41.2 (C(4)), 56.0 (C(5)), 61.0 (CI–CH2–C=O), 99.5
(C(3)), 111.9 (C(10)), 117.2 (C(2')), 118.2 (C(8)),
119.8 (C(6')), 120.9 (C(3')) and C(5')), 127.5 (C(5)),
128.6 (C(6)), 132.6 (C(7)), 136.0 (C(4')), 137.1
(C(1')), 151.2 (C(9)), 158.0 (C(3)), 161.8 (C(4)),
163.5 (C(2)), 166.9 (N–C=O)
M+ 382, M+2 384, m/z
354, 339, 315, 305,
276, 270, 247, 227,
221, 207, 199, 175,
161, 145, 133, 121,
105, 90, 85, 77, 67, 56
6.75 (1H, d, J = 7, H-8); 6.85 (1H, d, J = 7.5, 5-H);
7.15 (2H, d, J = 7, 2'- and 6'-H); 7.35 (3H, m,
3'-, 4'-H and 5'-H); 10.40 (1H, s,
OH, D2O exchanged)

TABLE 1 (continued)
1
2
3
4
5
4a
3433 (OH, NH and NH2),
2955(CH), 1727 (C=O), 1617,
1541, 1444, 1378, 1259, 1159,
1115, 992, 778
2.34 (2H, d, J = 6, 4,- 4-H2); 2.77 (1H, t, 5-H);
3.48 (3H, s, OCH3); 4.30 (2H, b, NH2);
4.46 (2H, s, CH2–C=O); 7.06 (2H, d, J = 8.5,
2'- and 6'-H); 7.10 (1H, t, 6-H); 7.27 (1H, t, 7-H);
7.90 (2H, d, J = 7.5, 3- and 5'-H); 7.82 (1H, d, J = 7, C(5')), 140.5 (C(1')), 150.0 (C(9)), 154.0 (C(4'),
8-H); 8.00 (1H, d, J = 7.5, 5-H); 8.50 (1H, s, NH, C–OCH3), 159.4 (C(3)), 163.4 (C(4)), 164.6 (C(2)),
D2O exchanged); 10.42 (1H, s, OH, D2O exchanged) 170.0 (N–C=O)
43.2 (C(4)), 54.7 (OCH3), 56.9 (C(5)),
M+ 408, m/z 380, 354,
331, 305, 287, 270,
247, 241, 227, 221,
175, 161, 133, 121,
104, 90, 84, 77, 67, 56
58.9 (NH–CH2–C=O), 104.1 (C(3)), 111.5 (C(10)),
118.0 (C(8)), 120.7 (C(6')), 120.8 (C(2')), 123.9
(C(5)), 124.3 (C(6)), 132.2 (C(7)), 137.6 (C(3') and
4b
5a
3420 (OH, NH and NH2), 2928
(CH), 1725 (>C=O), 1613, 1511,
1459, 1250, 1177, 1031, 823
2.10 (2H, d, J = 6, 4-, 4-H2); 2.42 (1H, t, 5-H, CH–NH);
4.20 (2H, b, NH2); 4.45 (2H, s, CH2–C=O);
7.04 (2H, d, J = 8.5, 6- and 7-H); 7.25 (1H, d, 8-H);
7.49 (3H, m, 3'-H, 4'- and 5'-H); 7.75 (1H, d,
J = 7, 5-H); 8.00 (2H, d, 2'- and 6'-H); 8.80 (1H, s,
NH, D2O exchanged); 10.43 (1H, s, OH, D2O
exchanged)
42.0 (C(4)), 56.8 (C(5)), 60.0 (CI–CH2–C=O), 98.8
(C(3)), 112.0 (C(10)), 117.3 (C(2')), 118.3 (C(8)),
119.9 (C(6')), 121.0 (C(3') and C(5')), 127.5 (C(5)),
128.6 (C(6)), 132.6 (C(7)), 135.9 (C(4')), 137.0
(C(1')), 151.3 (C(9)), 158.0 (C(3)), 161.9 (C(4)),
163.6 (C(2)), 167.0 (N–C=O)
3479 (OH and NH), 2877 (CH),
1719 (>C=O), 1623, 1556, 1453,
1313, 1213, 999, 784
2.09 (2H, d, J = 8, 4-, 4-H2); 2.75 (1H, t, 5-H); 3.48
42.5 (C(4)), 52.9 (OCH3), 53.9 (C(5)),
(3H, s, OCH3); 4.33 (2H, s, CH2–C=O); 6.55 (1H, s, 55.4 (NH–CH2–C=O), 98.1 (C(3)), 111.5 (C(10)),
N=CH–Ph); 7.02 (2H, d, J = 7.5, 2''- and 6''-H); 7.07 112.2 (C(3'') and C(5'')), 117.3 (C(4'')), 118.0 (C(8)),
(3H, m, 3''-, 4''- and 5''-H); 7.19 (2H, d, J = 9, 2'- and 120.7 (N=CH–Ph), 120.8 (C(2'), C(6'), C(2'') and
6'-H); 7.34 (2H, t, 6- and 7-H); 7.45 (1H, d, J = 7.5,
8-H); 7.57 (1H, d, J = 7, 5-H); 7.69 (2H, d, J = 8,
3'- and 5'-H); 8.27 (1H, s, NH, D2O exchanged),
10.30 (1H, s, OH, D2O exchanged)
2.05 (2H, d, J = 8, 4-, 4-H2); 2.49 (1H, t, 5-H); 4.38
(2H, s, CH2–C=O); 6.60 (1H, s, N=CH–Ph); 7.35
(2H, t, 6- and 7-H); 7.57 (3H, m, 3''-, 4''- and 5''-H);
C(6'')), 123.9 (C(5)), 124.3 (C(6)), 132.2 (C(7)),
137.6 (C(3') and C(5')), 140.5 (C(1')), 152.0.0 (C(9)),
154.2 (C(4')), 159.4 (C(3)), 160.0 (C(4)), 165.0
(C(2)), 172.0 (N–C=O)
41.3 (C(4)), 53.8 (OCH3), 56.1 (C(5)), 59.9
(NH–CH2–C=O), 100.2 (C(3)), 111.9 (C(10)), 116.4 280, 251, 238, 228,
(C(2') and C(6')), 118.2 (C(8)), 119.9 (C(2'') and 204, 190, 175, 145,
5b
3440 (OH and NH), 3081 (CH),
1711 (>C=O), 1613, 1546, 1438,
1380, 1207, 1135, 1021, 824
M+ 466, m/z 434, 300,
7.73 (2H, d, J = 8.5, 2''- and 6''-H); 8.00 (3H, m, 3'-, C(6'')), 121.0 (N=CH–Ph), 127.6 (C(5)), 128.6 (C(6)), 135, 121, 105, 91, 77,
4'- and 5'-H); 8.25 (3H, d, J = 8.5, 2'-, 6'- and 8-H);
8.55 (1H, d, J = 7, 5-H); 9.04 (1H, s, NH, D2O
exchanged); 10.41 (1H, s, OH, D2O exchanged)
132.7 (C(7)), 136.0 (C(3'), C(4') and C(5')), 137.1
(C(3''), C(4'') and C(5'')), 140.2 (C(1') and C(1'')),
151.2.0 (C(9)), 158.1 (C(3)), 162.0 (C(4)), 166.2
(C(2)), 169.1 (N–C=O)
43

TABLE 1 (continued)
1
2
3
4
5
6a
3464 (OH and NH), 2897 (CH),
1710 (>C=O), 1607, 1511, 1442,
1251, 1176, 1031, 829
2.31 (2H, d, J = 7, 4-, 4-H2); 2.76 (1H, t, 5-H); 3.48
(3H, s, OCH3); 3.73 (2H, s, S–CH2–C=O); 4.53 (2H, (C(5)), 59.0 (S–CH2–C=O), 62.5 (NH–CH2–C=O),
s, N–CH2–C=O); 4.90 (1H, s, N–CH–S); 6.82 (2H, d, 102.8 (C(3)), 111.5 (C(10)), 112.2 (C(2'), C(6'),
J = 7.5, 2'- and 6'-H); 6.87 (2H, d, J = 7.5, 2''- and
6''-H); 7.00 (2H, d, J = 7, 3'- and 5'-H); 7.17 (1H, t,
6-H); 7.44 (3H, t, 3''-, 4''- and H-5''); 7.58 (1H, d,
J = 7, 8-H); 7.76 (1H, t, 7-H); 8.06 (1H, d, J = 8,
5-H); 8.67 (1H, s, NH, D2O exchanged); 10.52 (1H,
s, OH, D2O exchanged)
41.6 (N–CH–S), 45.1 (C(4)), 53.5 (OCH3), 55.4
M+ 570, m/z 550, 493,
450, 392, 361, 284,
252, 232, 204, 190,
175, 144, 134, 115,
105, 91, 77
C(2''') and C(6''')), 117.3 (C(3'''), C(4''') and C(5''')),
118.0 (C(8)), 123.9 (C(5)), 124.3 (C(6)), 132.2
(C(7)), 137.7 (C(3') and C(5')), 140.5 (C(1') and
C(1''')), 150.2 (C(9)), 152.2 (C(4'), C–OCH3), 158.0
(C(3)), 162.4 (C(4)), 163.0 (C(2)), 166.0 (S–C=O),
172.0 (N–C=O)
6b
7a
3431 (OH and NH), 2928 (CH),
1727 (C=O), 1607, 1542, 1445,
380, 1260, 1159, 1023, 779
1.99 (d, 2H, J = 7, 4-, 4-H2); 2.53 (1H, t, 5-H); 3.80
(2H, s, S–CH2–C=O); 4.42 (2H, s, N–CH2–C=O);
4.80 (1H, s, N–CH–S); 7.42 (3H, m, 3'-, 4'- and
5'-H); 7.72 (2H, d, J = 7.5, 2'- and 6'-H); 8.00 (2H,
41.9 (N–CH–S), 45.5 (C(4)), 53.3 (C(5)),
56.8 (S–CH2–C=O), 61.0 (NH–CH2–C=O), 99.0
(C(3)), 111.9 (C(10)), 117.2 (C(2') and C(6')), 118.2
(C(8)), 119.8 (C(2''') and C(6''')), 127.5 (C(5)), 128.6
m, 6- and 7-H); 8.20 (1H, d, J = 7, 8-H); 8.40 (3H, m, (C(6)), 132.6 (C(7)), 136.0 (C(3'), C(4') and C(5')),
3''-, 4''- and 5''-H); 8.60 (2H, d, 2''- and 6''-H); 8.80
(1H, d, J = 7.5, 5-H); 9.61 (1H, s, NH, D2O
exchanged); 10.85 (1H, s, OH, D2O exchanged)
137.1 (C(3'''), C(4''') and C(5''')), 142.2 (C(1') and
C(1''')), 151.3 (C(9)), 158.0 (C(3)), 161.9 (C(4)),
163.6 (C(2)), 166.7 (S–C=O), 170.0 (N–C=O)
3464 (OH and NH), 2897 (CH),
1710 (>C=O), 1607, 1511, 1442,
1251, 1176, 1031, 829
2.20 (2H, d, J = 7, 4-, 4-H2); 2.63 (1H, t, 5-H); 3.38
(1H, d, J = 6, CI–CH–C=O); 3.55 (3H, s, OCH3);
4.46 (2H, s, N–CH2–C=O); 4.47 (1H, d, J = 6,
N–CH–Ar); 6.68 (1H, d, J = 7.5, 8-H); 6.95 (2H, d,
J = 7.5, 2''-H, 6''-H); 7.10 (2H, m, 6- and 7-H); 7.27
31.6 (N–CH–Ph), 40.5 (CI–CH–C=O), 45.1 (C(4)),
53.5 (OCH3), 55.4 (C(5)), 59.0 (S–CH2–C=O), 62.5
(NH–CH2–C=O), 102.8 (C(3)), 111.5 (C(10)), 112.2 392, 361, 300, 284,
(C(2'), C(6'), C(2''') and C(6''')), 117.3 (C(3'''), C(4''') 251, 232, 204, 190,
and C(5''')), 118.0 (C(8)), 123.9 (C(5)), 124.3 (C(6)), 175, 145, 134, 115,
M+ 572 M+2 574 m/z
550, 495, 464, 434,
(3H, t, 3''-, 4''- and 5''-H); 7.49 (2H, d, J = 7.5, 2'- and 132.2 (C(7)), 137.7 (C(3') and C(5')), 140.5 (C(1') and 105, 91, 77, 43
6'-H); 7.85 (1H, d, J = 7, 5-H); 7.91 (2H, d,
J = 7, 3'- and 5'-H); 8.67 (1H, s, NH, D2O
exchanged); 10.52 (1H, s, OH, D2O exchanged)
C(1''')), 150.2 (C(9)), 152.2 (C(4')), 158.0 (C(3)),
162.4 (C(4)), 163.0 (C(2)), 166.0 (S–C=O), 172.0
(N–C=O)
7b
3433 (OH and NH), 2927 (CH),
1726 (>C=O), 1606, 1541, 1445,
1375, 1261, 1115, 1025, 779
1.80 (2H, d, J = 7, 4-, 4-H2); 2.60 (1H, t, 5-H);
3.40 (1H, d, J = 6, CI–CH–C=O); 4.20 (2H, s,
N–CH2–C=O); 4.49 (1H, d, J = 6, N–CH–Ph); 7.05
29.9 (N–CH–Ph), 39.1 (CI–CH–C=O), 45.0 (C(4)),
53.0 (C(5)), 62.3 (NH–CH2–C=O), 102.5 (C(3)),
113.4 (C(10)), 114.2 (C(2'), C(6'), C(2''') and C(6''')),
(2H, t, 6-H and 7-H); 7.22 (3H, m, 3'-, 4'- and 5'-H); 119.2 (C(8)), 119.3 (C(3''), C(4'') and C(5'')), 122.8
7.38 (1H, d, J = 8, 8-H); 7.50 (1H, d, J = 7.5, 5-H);
7.67 (3H, m, 3''-, 4''- and 5''-H); 7.80 (4H, m, 2'-H,
(C(3'), C(4') and C(5')), 125.0 (C(5)), 125.4 (C(6)),
133.0 (C(7)), 140.1 (C(1''')), 142.2 (C(1')), 151.1
6'-, 2''- and 6''-H); 8.50 (1H, s, NH, D2O exchanged); (C(9)), 162.6 (C(3)), 164.0 (C(4)), 167.3 (C(2)),
10.51 (1H, s, OH, D2O exchanged)
172.2 (N–C=O)

did not show signals at δ 4.46 for NH2 but showed the presence of a signal at δ 6.55 for one proton of
N=CH–Ph. Hydrazones 5a,b on further treatment with either mercaptoacetic acid or chloroacetyl chloride gave
1
thiazolidinones 6a,b or azetidinones 7a,b respectively. The H NMR spectra of 6a,b showed the presence of
signals at δ 3.73 for two protons of S–CH2 and at δ 4.90 for S–CH–N, which confirm the formation of the
1
thiazolidinone ring. Also the H NMR spectra of 7a,b showed the presence of doublets at δ 3.38 (J = 6 Hz) for
one proton of CI–CH and δ 4.47 (J = 6 Hz) for one proton of N–CH–Ph along with other signals, which confirm
the formation of the azetidinone ring. The structures of all the above-synthesized compounds are confirmed on
the basis of spectral (Table 1) and analytical data (Table 2). All compounds were screened in vitro for their
antibacterial activity against a variety of bacterial strains (Table 3).
Antimicrobial activity. The minimum inhibition concentration (MIC) was determined using the Tube
Dilution method according to the standard procedure [15]. All the compounds were screened in vitro for their
antimicrobial activity against a variety of bacterial strains such as Staphylococcus aureus, Salmonella paratyphi,
and Escherichia coli (Table 3). The standard drugs used for comparison were ciprofloxacin (MIC 5 µg/ml),
cloxacillin (MIC 10 µg/ml), and gentamycin (MIC 5 µg/ml).
The antimicrobial data of the above compounds reveal that compounds having the methoxy group
have increased antibacterial activity while azetidinones are found to be more biologically active than
thiazolidinones.
TABLE 2. Physical and Analytical Data of Compounds 2a,b-7a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
mp, °C
C
H
N
2a
C19H16N2O4
C18H14N2O3
C21H17N2O5Cl
C20H15N2O4Cl
C21H20N4O5
C20H18N4O4
C28H24N4O5
C27H22N4O4
C30H26N4O6S
C29H24N4O5S
C30H25N4O6Cl
C29H23N4O5Cl
68.10
67.85
70.15
70.58
60.87
61.16
63.10
62.82
61.95
61.76
63.85
63.49
67.87
67.74
69.86
69.52
63.40
63.15
64.67
64.44
63.05
62.93
64.35
64.20
8.43
8.33
4.69
4.69
4.33
4.12
4.05
3.92
5.05
4.90
4.70
4.76
4.55
4.83
4.50
4.72
4.65
4.56
4.23
4.44
4.49
4.37
4.15
4.24
4.76
4.55
9.15
9.45
6.85
6.79
7.15
7.32
13.85
13.72
14.90
14.81
11.36
11.29
11.86
12.01
9.70
9.82
10.25
10.37
9.53
9.79
10.21
10.33
190
168
238
225
256
265
213
226
245
>300
>300
287
75
70
72
68
76
80
79
77
67
70
65
63
2b
3a*
3b*2
4a
4b
5a
5b
6a*3
6b*4
7a*5
7b*6
_______
* Found, %: Cl 9.03. Calculated, %: Cl 9.16.
*3 Found, %: S 5.43. Calculated, %: S 5.61.
*4 Found, %: S 5.98. Calculated, %: S 4.81.
*5 Found, %: Cl 6.13. Calculated, %: Cl 6.11.
*6 Found, %: Cl 6.30. Calculated, %: Cl 6.45.
224

TABLE 3. Antibacterial Activity of 2a,b-7a,b
Activity, µg/ml
Activity, µg/ml
Compound
Compound
S. aureus
50
S. typhi
50
E. coli
100
150
50
S. aureus
25
S. typhi
50
E. coli
50
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
100
50
100
100
100
50
50
100
25
100
100
100
50
50
50
100
100
50
100
25
50
50
25
100
50
50
25
50
EXPERIMENTAL
Melting points were taken in open capillaries and are uncorrected. IR spectra (νmax, cm-1) were recorded
13
on Perkin–Elmer FTIR, and NMR (1H and C) were recorded on Bruker AMX (500 MHz) and AC (200 MHz)
using TMS as standard. Mass spectra were recorded on Shimadzu GC-MS.
5-Aryl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole
(2a,b).
Chalcones
of
4-hydroxybenzopyran-2-one 1a,b (0.01 mol) and hydrazine hydrate (0.01 mol, 0.5 ml) in the presence of
piperidine (1.0 ml) in alcohol were refluxed for 7-8 h. The reaction was monitored on TLC. On the completion
of the reaction the reaction mixture was poured onto crushed ice and neutralized with dilute HCI to give a solid
product, which was then crystallized from alcohol to afford 2a,b in 70-75% yield.
5-Aryl-1-chloroacetyl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole
(3a,b).
5-p-Methoxyphenyl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazoles 2a,b (0.01 mol) were taken
in hot benzene, and chloroacetyl chloride (0.015 mol, 1.68 ml) was added dropwise. The reaction mixture was
stirred at room temperature for 8 h and was then cooled to give a pale yellow solid. This solid was recrystallized
from methanol to give 3a,b in 65-72% yield.
5-Aryl-1-hydrazinoacetyl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydropyrazole (4a,b). A
mixture of compound 3a,b (0.01 mol) and hydrazine hydrate (0.01 mol, 1.40 ml) in alcohol was refluxed for
7-8 h. The reaction mixture was then poured onto crushed ice to give a solid product, which was then
recrystallized from alcohol to give hydrazines 4a,b in 75-80% yield.
5-Aryl-1-[(benzylidenehydrazino)acetyl]-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-4,5-dihydro-
pyrazole (5a,b). An equimolar mixture of hydrazines 4a,b (0.01 mol) and benzaldehyde (0.01 mol, 1.06 ml) in
ethanol (30 ml) containing acetic acid (0.5 ml) was refluxed for 6 h. The excess solvent was distilled off and the
residue was poured onto crushed ice to give a solid. The separated solid was filtered off and recrystallized from
methanol to give hydrazones 5a,b in 77-79% yield.
5-Aryl-3-[2H-4-hydroxy-2-oxobenzopyran-3-yl]-1-[(2-phenyl-4-oxothiazolidin-3-ylamino)-acetyl]-
4,5-dihydropyrazole (6a,b). A mixture of hydrazones 5a,b (0.01 mol) and thioglycolic acid (0.02 mol, 1.84 ml)
in DMF was refluxed for 12 h. The reaction mixture was cooled and poured into ice-cold sodium bicarbonate
solution to remove traces of acid, if any. Finally the solid obtained was filtered off, dried, and recrystallized from
alcohol to give 6a,b in 65-70% yield.
5-Aryl-N-[(3-chloro-2-oxo-4-phenylazetidin-1-ylamino)acetyl]-3-[2H-4-hydroxy-2-oxo-benzopyran-
3-yl]-4,5-dihydropyrazoles (7a,b). To the hydrazones 5a,b (0.01 mol) in 1,4 dioxane (40 ml) was added
chloroacetyl chloride (0.01 mol, 1.12 ml) and triethylamine (0.01 mol, 1 ml) while stirring at 0-5°C. The reaction
mixture was stirred at this temperature for 1 h and then refluxed for 7 h. The excess solvent was removed and the
residue was poured onto crushed ice to afford a solid product. The solid was filtered off, washed, and
recrystallized from methanol to give 7a,b in 77-82% yield.
225

The authors are thankful to Mumbai University for financial assistance. The authors are grateful to
National Facility for High Field NMR, TIFR Mumbai. The authors are also grateful to the Padmaja Occupational
Hygiene & Diagnostic Centre, Navi Mumbai, and Prof. Vaidya, Head of the Microbiology Dept., Institute of
Science, Mumbai for biological testing. The authors are also thankful to Mr. S. V. Chiplunkar, UDCT, Mumbai
for elemental analysis.
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226