Synthesis and biological activity of 2-hydroxy-N(5-methylene-4-oxo-2-aryl- thiazolidin-3-yl)-benzamide

Article abstract of DOI:10.1080/10426500903176521

2-Hydroxy benzoic acid hydrazide (1) undergoes facile condensation with aromatic aldehydes to afford the corresponding 2-hydroxy benzoic acid arylidene hydrazides (2a-h) in good yields. Cyclocondensation of compounds 2a-h with thioglycolic acid yields 2-hydroxy-N(4-oxo-2-aryl-thiazolidin-3-yl)-benzamides (3a-h). These 3a-h compounds are for the reacted with benzaldehyde in the presence of sodium ethanolate affords, giving 2-hydroxy-N(5-methylene-4-oxo-2- aryl-thiazolidin-3-yl)-benzamides (4a-h). The structures of these compounds were established on the basis of analytical and spectral data. All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903176521

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Synthesis and Biological Activity of 2-
Hydroxy-N(5-methylene-4-oxo-2-aryl-
thiazolidin-3-yl)-benzamide
Hasmukh S. Patel a & Sumeet J. Patel a
a Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar, India
Version of record first published: 02 Aug 2010.
To cite this article: Hasmukh S. Patel & Sumeet J. Patel (2010): Synthesis and Biological Activity of 2-
Hydroxy-N(5-methylene-4-oxo-2-aryl-thiazolidin-3-yl)-benzamide, Phosphorus, Sulfur, and Silicon and
the Related Elements, 185:8, 1632-1639
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Phosphorus, Sulfur, and Silicon, 185:1632–1639, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903176521
SYNTHESIS AND BIOLOGICAL ACTIVITY OF
2-HYDROXY-N(5-METHYLENE-4-OXO-2-ARYL-
THIAZOLIDIN-3-YL)-BENZAMIDE
Hasmukh S. Patel and Sumeet J. Patel
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, India
2-Hydroxy benzoic acid hydrazide (1) undergoes facile condensation with aromatic aldehy-
des to afford the corresponding 2-hydroxy benzoic acid arylidene hydrazides (2a–h) in good
yields. Cyclocondensation of compounds 2a–h with thioglycolic acid yields 2-hydroxy-N(4-
oxo-2-aryl-thiazolidin-3-yl)-benzamides (3a–h). These 3a–h compounds are for the reacted
with benzaldehyde in the presence of sodium ethanolate affords, giving 2-hydroxy-N(5-
methylene-4-oxo-2-aryl-thiazolidin-3-yl)-benzamides (4a–h). The structures of these com-
pounds were established on the basis of analytical and spectral data. All the newly synthesized
compounds were evaluated for their antibacterial and antifungal activities.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antibacterial activity; 2-hydroxy benzoic acid hydrazide; thiazolidin
INTRODUCTION
Hydrazides and their heterocyclized products display diverse biological activities in-
cluding antibacterial, antifungicidal, analgesic, and anti-inflammatory properties.1–15 These
heterocyclic systems find wide use in medicine, agriculture, and industry. One of the
hydrazides, 2-hydroxy benzoic acid hydrazide (i.e., salicylhydrazide) and its condensed
products play a vital role in medicinal chemistry.16–18 4-Thiazolidinones and their aryli-
dene compounds have good pharmacological properties.19–23 4-Thiazolidinones are also
known to exhibit antitubercular,24 antibacterial,25 antifungal,26 and anticonvulsant activities.
Hence, it was thought of interest to merge both of thiazolidinone’s and salicylhydrazide’s
moieties, which may enhance the drug activity of compounds to some extent, or they might
possess some of the above-mentioned biological activities. From this point of view, the
objective of the present work is to prepare new derivatives of salicylhydrazide containing
thiazolidinone moiety. This article comprises the synthesis of 2-hydroxy-N(5-methylene-
4-oxo-2-aryl-thiazolidin-3-yl)-benzamide. The synthetic approach is shown in Scheme 1.
Received 7 February 2009; accepted 10 July 2009.
The authors are thankful to Dr. J. S. Parmar, Head, Department of Chemistry, for providing laboratory
facilities.
Address correspondence to H. S. Patel, Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar– 388 120, India. E-mail: hsp13152@rediffmail.co.in
1632

2-HYDROXY-N(5-METHYLENE-4-OXO-2-ARYL-THIAZOLIDIN-3-YL)-BENZAMIDE 1633
CONHNH2
OH
[1]
[1] RCHO
[2] EtOH
H
CONHN
C
R
OH
[2a-h]
[1] SHCH2COOH
[2] Anh. ZnCl
2 / DMF
H
CONHN
C
S
R
C
OH
O
[3a-h]
[1]
C2H5ONa
[2]
benzaldehyde
H
CONHN
C
S
R
C
OH
O
CH
[4a-h]
Where, R = (a) C6H5
(e) 4-CH3-C6H4
(b) 4-OCH3-C6H4
(c) 4-OH-C6H4
(d) 2-OH-C6H4
(f) 3,4-CH2O2-C6H4
(g) 4-OH-3-OCH3-C6H3
(h) 3,4-C2H5-C6H4
Scheme 1

1634
H. S. PATEL AND S. J. PATEL
RESULTS AND DISCUSSION
It was observed that 2-hydroxy benzoic acid hydrazide (1), upon condensation with
aromatic aldehydes, yields 2-hydroxy benzoic acid arylidene hydrazides (2a–h). The struc-
tures of 2a–h were confirmed by elemental analysis and IR spectra, which showed an
absorption band at 1620–1640 (C N), 3030–3080 cm−1 (C H, of Ar.), 3450–3550 cm−1
1
( OH), 2815–2850 cm−1 ( OCH3), 2950, 1370 cm−1 ( CH3). H NMR: 6.95–7.91
(9H, m) (Ar H), 11.200–11.209 (1H, s) ( OH), 11.800–11.809 (1H, s) ( CONH),
8.43–8.80 (1H, s) ( N CH), 2e; 2.41 (3H, s) ( CH3), 2b, 2g; 3.90 (3H, s) ( OCH3),
2h; 4.09 (4H, q) (CH2), 1.33 (6H, t) (CH3), 2f; 6.09 (2H, s) ( OCH2O cyclic). 13C
NMR:117.9–118.1, 118.2–118.4, 121.8–122.0, 128.9–129.1, 129.2–129.4, 129.5–130.0,
131.2–131.5, 133.6–133.8, 133.9–134.3, 159.6–160.0 (Ar–10C), 163.5–163.8 ( CONH),
146.9–150.4 ( CH); 2b, 2g: 55.5–56.7 ( OCH3); 2e: 22.5 (CH3); 2f: 103.5 (OCH2O
cyclic); 2h: 65.3 (OCH2), 15.0 (CH3). The C, H, N analysis data of all compounds are
presented in Table I.
The structures assigned to 2-hydroxy-N(4-oxo-2-aryl-thiazolidin-3-yl)-benzamides
(3a–h) were supported by the elemental analysis and IR spectra showing an absorption
bands at 1690 cm−1 (C O of thiazolidinone ring), 718 cm−1 (C S C of thiazolidinone
ring), 3075–3095 cm−1 (CH2 of thiazolidinone ring), 3030–3080 cm−1 (C H, of Ar.),
3450–3550 cm−1 ( OH), 1660–1670 cm−1 ( CONH) for 3a compound.
1H NMR: 3.85–3.95 (2H, s) ( CH2 of the ring), 5.950–5.959 (1H, s) ( CH),
6.90–7.95 (9H, m) (Ar-H), 8.20–8.22 (1H, s) ( CONH), 11.200–11.209 (1H, s) ( OH),
3e; 2.43 (3H, s) ( CH3), 3b, 3g; 3.91 (3H, s) ( OCH3), 3h; 4.07 (4H q) (CH2), 1.33
(6H, t) (CH3), 3f; 6.09 (2H, s) ( OCH2O cyclic). 13C NMR: 115.9–116.2, 121.3–121.5,
126.9–127.3, 127.4–127.6, 128.3–128.5, 128.6–128.8, 128.9–129.2 139.2–139.4,
156.9–157.5, 168.9–169.3 (Ar-10C), 38.9–39.5 ( CH2 of the ring), 67.8–68.3 ( CH),
164.8–165.9 ( CONH), 168.9–169.9 ( CO of the ring); 3b, 3g: 56.0–56.4 ( OCH3);
3e: 22.9 (CH3); 3f: 102.2 (OCH2O cyclic); 3h: 65.8 (OCH2), 15.5 (CH3). The C, H, N, S
analysis data of all compounds are presented in Table II.
The IR spectra of 4a–h closely resemble those of the corresponding 3a–h, with
the only discernable difference observed that the new band at 1625cm−1 ( C CH-Ar) is
observed (but not strong) in all the spectra of 4a–h, which might be responsible.
1H NMR: 7.762 (1H, s) ( CH), 6.90–7.98 (9H, m) (Ar-H), 8.20–8.28 (1H, s)
( CONH), 5.350–5.359 (1H, s) ( OH), 4e; 2.41 (3H, s) ( CH3), 4b, 4g; 3.92 (3H,
s) ( OCH3), 4h; 4.04, (4H, q) ( CH2), 1.33 (6H, t) ( CH3), 4f; 6.09 (2H, s) ( OCH2O
cyclic). 13C NMR: 117.9–118.2, 118.5–119.9, 121.6–121.9, 125.9–126.3, 127.3–127.6,
128.7–128.8, 128.9–129.1, 133.8–134.0, 141.9–142.3, 159.5–160.8 (Ar-10C), 143.4–143.7
( C of the ring), 73.1–73.4 ( CH of the ring), 114.9–115.3 ( CH2), 166.5–166.7
( CO), 166.8–166.9 ( CONH); 4b, 4g: 55.956.7 ( OCH3); 4e: 21.8 (CH3); 4f: 102.8
(OCH2O); 4h: 66.1 (OCH2), 14.9 (CH3). The C, H, N, S analysis data of all compounds
are presented in Table III.
The examination of elemental analytical data reveals that the elemental contents are
consistence with the predicted structure shown in Scheme 1. The IR data also direct for
assignment of the predicted structure. The final structures of all compounds are confirmed
by LC-MS. LC-MS data for all compounds are presented in Tables I–III.

1635

1636

1637

1638
H. S. PATEL AND S. J. PATEL
EXPERIMENTAL
Melting points were determined in open capillary tubes and were uncorrected. The
1
IR spectra were recorded in KBr pellets on a Nicolet 400D spectrometer, and H NMR
and 13C NMR spectra were recorded in DMSO with TMS as internal standard on a Bruker
spectrometer at 400 MHz and 100 MHz, respectively. LC-MS of selected samples were
taken on an LC-MSD-Trap-SL 01046.
Preparation of 2-Hydroxy Benzoic Acid Arylidene Hydrazide (2a–h)
An equimolecular mixture of 2-hydroxy benzoic acid hydrazide (1), (0.01 mol) and
the aromatic aldehydes (a–h) in ethanol (15 mL) was refluxed on a water bath for 1–2 h.
The solid separated was collected by filtration, dried, and recrystallized from ethanol. The
yields, melting points, and other characterization data of these compounds are given in
Table I.
Preparation of 2-Hydroxy-N-(4-oxo-2-aryl-thiazolidin-3-yl)-benzamide
(3a–h)
A mixture of 2-hydroxy benzoic acid arylidene hydrazide (2a–h) (0.01 mol) in THF
(30 mL) and mercaptoacetic acid (thioglycolic acid) (0.01 mol) with a pinch of anhydrous
ZnCl2 was refluxed for 12 h. The solvent was then removed to get a residue, which was
dissolved in benzene and passed through a column of silica gel using a benzene/chloroform
(8:2; v/v) mixture as eluent. The eluent was concentrated, and the product was crystallized
from alcohol to give 4-thiazolidinones (3a–h), which were obtained in 50–65% yield. The
yields, melting points, and other characterization data of these compounds are given in
Table II.
Preparation of 2-Hydroxy-N(5-methylene-4-oxo-2-aryl-
thiazolidin-3-yl)-benzamide (4a–h)
An equimolar solution of N-(3-chloro-2-oxo-4-aryl-azetidin-1-yl)-2-hydroxy-
benzamide) (3a–h) and benzaldehyde in dioxane (50 mL) in the presence of C2H5ONa
was refluxed for about 3 h. The solvent was removed in vacuo. The resulting product was
recrystallized from methanol to yield compound 4a–h. The yields, melting points, and
other characterization data of these compounds are given in Table III.
BIOLOGICAL SCREENING
Antibacterial Activities
The antibacterial activities of all the compounds were studied against Gram-positive
bacteria (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (E.coli
and Klebsiella promioe) at a concentration of 50 µg/mL by agar cup plate method. For
results, see the Supplemental Materials, Tables S1–S4, available online.

2-HYDROXY-N(5-METHYLENE-4-OXO-2-ARYL-THIAZOLIDIN-3-YL)-BENZAMIDE 1639
Antifungal Activities
The fungicidal activity of all the compounds was studied at 1000 ppm concentration
in vitro. Plant pathogenic organisms used were Nigrospora Sp, Aspergillus niger, Botry-
depladia thiobromine, Rhizopus nigricum, and Fusarium oxyporium. For results, see the
Supplemental Materials, Tables S1–S4, available online.
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