Microwave assisted synthesis of some pyridine derivatives containing mercaptotriazole and thiazolidinone as a new class of antimicrobial agents

Article abstract of DOI:10.1080/10426500701557138

A fast and facile procedure for the synthesis of pyridomercaptotriazole 4a-e and pyridothiazolidinone 5a-e is being reported starting from dihydropyridine 1a-e. Subsequent oxidation with nitrating mixture (HNO3/H2SO4) produced the anticipated 2,6-dimethyl

Full text of DOI:10.1080/10426500701557138

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Microwave Assisted Synthesis
of Some Pyridine Derivatives
Containing Mercaptotriazole
and Thiazolidinone as a New
Class of Antimicrobial Agents
Sarika Mehta a , Neelam Swarnkar a , Ritu Vyas a ,
Jitendra Vardia a , Pinki B. Punjabi a & Suresh C.
Ameta a
a Microwave Chemistry Laboratory, Department of
Chemistry , University College of Science, M. L.
Sukhadia University , Udaipur, India
Published online: 20 Feb 2008.
To cite this article: Sarika Mehta , Neelam Swarnkar , Ritu Vyas , Jitendra Vardia ,
Pinki B. Punjabi & Suresh C. Ameta (2007) Microwave Assisted Synthesis of Some
Pyridine Derivatives Containing Mercaptotriazole and Thiazolidinone as a New Class
of Antimicrobial Agents, Phosphorus, Sulfur, and Silicon and the Related Elements,
183:1, 105-114, DOI: 10.1080/10426500701557138
To link to this article: http://dx.doi.org/10.1080/10426500701557138
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Phosphorus, Sulfur, and Silicon, 183:105–114, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701557138
Microwave Assisted Synthesis of Some Pyridine
Derivatives Containing Mercaptotriazole and
Thiazolidinone as a New Class of Antimicrobial Agents
Sarika Mehta, Neelam Swarnkar, Ritu Vyas,
Jitendra Vardia, Pinki B. Punjabi, and Suresh C. Ameta
Microwave Chemistry Laboratory, Department of Chemistry,
University College of Science, M. L. Sukhadia University, Udaipur, India
A fast and facile procedure for the synthesis of pyridomercaptotriazole 4a–e and
pyridothiazolidinone 5a–e is being reported starting from dihydropyridine 1a–
e. Subsequent oxidation with nitrating mixture (HNO /H SO ) produced the
3
2
4
anticipated 2,6-dimethylpyridine derivatives 2a–e, which were subsequently con-
densed with thiosemicarbazide in ethanol to produce the key intermediate 2,2ꢀ-[4-
(4-substituted phenyl)- 2,6-dimethylpyridine-3,5-diyl]dicarbonyldihydrazine car-
bothioamides 3a–e. In the final step pyridomercaptotriazole derivatives 4a–
e were synthesized by treating 3a–e in alkaline media. In parallel pyridoth-
iazolidinone derivatives 5a–e were obtained by the reaction of 3a–e with
ClCH COOH/CH COONa. All the reactions were carried out on microwave irra-
2
3
diation in good yield with short time. The structures of all the compounds have been
1
confirmed on the basis of their analytical, IR, H NMR, and Mass spectral data
(Tables I and II). The potent antimicrobial effects of the synthesized compounds
were also investigated.
Keywords Dihydropyridine; dihydrazinocarbothioamide; green chemical synthesis;
mercaptotriazole; microwave protocol; thiazolidinone
INTRODUCTION
In times where a premium is put on speed, diversity and efficiency
in the drug discovery process, MAOS1 (Microwave Assisted Organic
Received 5 May 2007; Accepted 5 June 2007.
The authors are thankful to Head, Department of Chemistry, M. L. Sukhadia Uni-
versity, Udaipur (Raj.) for providing laboratory facilities. The authors are also thankful
to the Director, RSIC, CDRI, Lucknow, for spectral and analytical studies. Additionally,
one of the authors (SM) is thankful to CSIR-New Delhi and one of the authors (RV) is
thankful to UGC-New Delhi for providing necessary financial assistance.
Address correspondence to Suresh C. Ameta, Microwave Chemistry Laboratory, De-
partment of Chemistry, University College of Science, M. L. Sukhadia University, Udaipur
313002, India. E-mail: ameta sc@yahoo.com
105

106
S. Mehta et al.
Synthesis) strategies offer significant advantages over conventional
synthesis. Considering these benefits, the present article reports a con-
venient green chemical synthesis2,3 methods of mercaptotriazole,4 and
thiazolidinone5derivatives by means of a four-pot reaction route us-
ing dihydropyridine as starting material. The formation of heterocyclic
rings by cyclocondensation reaction6–9 is typically a process well suited
for microwave technology. The starting nuclei dihydropyridine was syn-
thesized according to reported method using microwave protocol.10 In
spite of literature reported on the chemistry of dihydropyridine and
pyridine11 nucleus, no attention has been paid to the chemistry of
pyridine nucleus containing thiosemicarbazide12,13 groups, although
it should be an excellent material for synthesis of targeted moieties
of the present study. This work assumes importance in view of the
fact that pyridine derivatives display a number of important biolog-
ical activities such as antimicrobial,14 anticonvulsant, antiparkinso-
nian, and analgesic15 and hence possess great chemotherapeutic poten-
tial. Moreover synthesis of mercaptotriazole has attracted widespread
attention due to their diverse applications as anti-inflammatory,16
antimycotic,17 and antinociceptive18 activity. Along with this a vast
amount of published material is available describing a wide range of
biological activity19–21of thiazolidinone derivatives. Thus with an ef-
fort to capitalize the pharmacological potential of the above nucleus
and to improve the efficiency, output and quality of the process, the
present work reports on the formation of targeted moieties by the an-
nulations and fictionalization of pyridine derivatives under microwave
irradiation.
RESULTS AND DISCUSSION
The first step of this multistep sequence involves an important mi-
crowave mediated MCR (Multicomponent Reaction), which is the
Hantzsch synthesis of dihydropyridine by the condensation of methy-
lacetoacetate, ammonia, and various aromatic aldehydes. The main
building blocks 2, 6-dimethylpyridine derivatives 2a–e were obtained
by the oxidation of 1a–e with nitrating mixture (HNO3/H2SO4).
The next microwave-driven conversion of ester derivatives 2a–e into
thiosemicarbazide derivatives 3a–e were completed under mildly ba-
sic condition using pyridine as catalyst and provided the desired
product in overall yield and purity. The structures of compounds
3a–e were established by analytical and spectral data. The IR spec-
trum of 3a showed the presence of N H str. at 3338 cm−1 and C S

Microwave Synthesis of Some Pyridine Derivatives
107
1
str. at 1228 cm−1 and its H NMR spectrum displayed a singlet for
four protons around δ 6.70 due to two equivalent NH2 group. 3a
also gave one singlet centered at δ 9.83 due to –NH proton adja-
cent to C O group and one singlet centered at δ 9.60 due to NH
proton adjacent to C S group. Subsequent intramolecular cyclization
reaction in the presence of alkaline media (1N NaOH solution) af-
forded 5, 5’-[4-(4-substituted phenyl)-2, 6-dimethylpyridine-3, 5-diyl]-
bis-(4H)-1, 2, 4-triazole-3-thiol 4a–e. Among these derivatives 4a pos-
sessed the strong –SH band around 2530 cm−1 in IR spectra and
NH band at 3430 cm−1. The 1H NMR spectra of 4a gave a sin-
glet at δ 11.48 for two protons of two equivalents –SH group and
one singlet at δ 12.60 for two protons of two equivalents –NH group
of mercaptotriazole moieties. Another pathway of this step involves
cyclocondensation of 3a–e with ClCH2COOH/CH3COONa produced
the anticipated thiazolidinone derivatives 4-(4-substituted phenyl)-
2, 6-dimethyl pyridine Nꢀ3, Nꢀ5-bis-(4-oxo-1, 3-thiazolidin-2ylidene)-
pyridine-3, 5-dicarbohydrazide 5a–e. The IR spectra of 5a gave two
sharp peaks at 1705 and 1680 cm−1 corresponding to C O str. present
in thiazolidinone ring and adjacent to pyridine ring respectively, it also
gave a strong –NH band at 3426 cm−1. A characteristic C-S-C band of
1
thiazolidinone ring appeared at 699 cm−1. The H NMR spectra of 5a
displayed a singlet around δ 4.20 for four protons of two equivalents
CH2 groups of two thiazolidinone moieties. Finally, conclusive evi-
dence has been gathered from the Mass spectra of all final compounds.
The reaction depicted in Scheme 1 is one of the growing numbers of
examples where not only one, but all steps in the sequence have been
performed by microwave dielectric heating.
EXPERIMENTAL
All the melting points were determined in open capillaries. TLC on
silica gel-G-plates was used to access the reaction and purity of the
synthesized compounds using ethyl acetate: n-hexane (7:3) as irrigant.
IR spectra (KBr Pallets) were recorded on Perkin-Elmer 1800 (FTIR)
Spectrometer. 1H NMR spectra (DMSO-d6) were taken in a Bruker DRX
spectrometer (300 MHz FT NMR) using TMS as internal standard and
chemical shift are expressed in δ ppm and Mass spectra were taken on
Jeol sx-102/PA-6000 (EI) spectrometer. Elemental analyses were per-
formed by Perkin Elmer series C, H, N, and S analyzer-2400. Reactions
were carried out in a domestic microwave oven (Kenstar, OM-26 EGO).

108
S. Mehta et al.
SCHEME 1
Synthesis of Dimethyl-4-(4-substituted phenyl)-2, 6-dimethyl
1, 4-dihydropyridine-3,5-dicarboxylate (1a–e)
These compounds were prepared according to a reported Hantzsch syn-
thesis method.10
Synthesis of Dimethyl-4-(4-substituted phenyl)-2,
6-dimethylpyridine-3, 5-dicarboxylates (2a–e)
Compounds 1a–e (10 mmol) (1a = 3.19 g, 10 mmol) were dissolved in
ice-cold water and nitrating mixture (HNO3/H2SO4 in 3:1 ratio) was
added to it. Then reaction mixture was irradiated under microwave till
yellow color solution is obtained. After cooling the reaction mixture, it

Microwave Synthesis of Some Pyridine Derivatives
109
was poured in ice-cold water and neutralized by ammonia solution. The
solid thus obtained was recrystallized from ethanol to give 2a–e.
Synthesis of 2, 2’-[4-(4-Substituted phenyl)-2,
6-dimethylpyridine-3,5-di-yl]-dicarbonyl dihydrazine
carbothioamides (3a–e)
A mixture of 2a–e (10 mmol) (2a = 3.17 g, 10 mmol) and thiosemicar-
bazide (1.82 g, 20 mmol) in ethanol was heated under microwave for
8.0–10.0 min. using pyridine in catalytic amount and then allowed to
cool in ice-bath overnight. The resulting solid was filtered and recrys-
tallized from ethanol to give 3a–e.
Synthesis of 5, 5ꢀ-[4-(4-Substituted phenyl)-2,
6-dimethylpyridine-3, 5-diyl]-bis-(4H)-1, 2, 4-triazole-3-thiol
(4a–e)
A reaction mixture of 3a–e (10 mmol) (3a = 4.35 g, 10 mmol) and NaOH
(1N, 25 mL) was refluxed for 1.50–3.30 min under microwave. The re-
action mixture was cooled, diluted with water, and filtered. The filtrate
on acidification with glacial acetic acid gave the crude product, which
was filtered, washed with water, and recrystallized from ethanol to give
4a–e.
Synthesis of 4-(4-Substituted phenyl)-2, 6-dimethylpyridine
Nꢀ3, Nꢀ5-bis-(4-oxo-1, 3-thiazolidin-2ylidene)-pyridine-3,
5-dicarbohydrazide (5a–e)
To a suspension of compounds 3a–e (10 mmol) (3a = 4.35 g, 10 mmol),
in absolute alcohol, chloroacetic acid (1.88 g, 20 mmol) and anhydrous
sodium acetate (3.28 g, 40 mmol) was added. The solution was heated
under microwave irradiation for 6.00–8.30 min. Resulting solution was
cooled and left for overnight. Solid thus obtained, was filtered, washed
with water, and recrystallized from ethanol.
ANTIMICROBIAL ACTIVITY
Preliminary antimicrobial susceptibility tests for all the synthesized
pyridomercaptotriazole 4a–e and pyridothiazolidinone 5a–e were per-
formed by using cup and well method22 at a concentration of 500 ppm
against some selected pathogenic strains—Pseudomonas aerugi-
nosa, Proteus mirabilis, Klebsiella pneumoniae, and Bacillus subtilis

110

111

112

Microwave Synthesis of Some Pyridine Derivatives
113
TABLE III Antimicrobial Activity of some Synthesized Compounds—
Zone of Inhibition (mm) (Activity Index)*
Antibacterial Activity
(500 ppm)
Antifungal Activity
(500 ppm)
P.
P.
K.
B.
A.
C.
Compd.
aeruginosa
mirabilis
pneumoniae
subtilis
fumigatus
albicans
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
C1
C2
9 (0.56)
14 (0.87)
10 (0.62)
13 (0.81)
12 (0.75)
11 (0.68)
10 (0.62)
12 (0.75)
10 (0.62)
6 (0.37)
16
20 (0.86)
21 (0.91)
20 (0.86)
17 (0.74)
15 (0.65)
18 (0.78)
20 (0.86)
16 (0.69)
13 (0.56)
12 (0.52)
23
—
8 (0.66)
—
—
—
—
7 (0.63)
—
—
—
—
—
—
—
23 (1.15)
21 (1.05)
18 (0.90)
17 (0.85)
17 (0.85)
19 (0.95)
21 (1.05)
16 (0.80)
14 (0.70)
15 (0.75)
—
12 (0.85)
10 (0.71)
9 (0.64)
8 (0.57)
5 (0.35)
13 (0.92)
11 (0.78)
10 (0.71)
11 (0.78)
8 (0.57)
—
—
10 (0.83)
7 (0.58)
—
—
12
—
—
11
—
—
—
20
14
∗Activity index = Inhibition area of the sample/inhibition area of the standard; C1
Ciprofloxacin; C2 = Amphotericin B. Diameter of disc in 5 mm.
=
were used for bacterial activity and Aspergillus fumigatus and Candida
albicans for antifungal activity. Commercial antibacterial Ciprofloxacin
and antifungal Amphotericin B were also screened under similar con-
ditions for comparison. The results have been tabulated in the form of
inhibition zones and an activity index in Table III.
The results reveal that all the synthesized compounds have shown
moderate to good activity against P. mirabilis and P. aeruginosa while
compounds showed nil activity against K. pneumoniae, B. subtilis. In
case of antifungal activity compounds 4a, 4b, and 5b showed a better
activity than standard and compounds 4c, 5a, and 5c exhibited com-
parable activity to standard drug and remaining compounds exhibited
moderate activity as compare to the standard. Although all the com-
pounds show less to moderate activity against bacteria, they possess
very strong activity against fungi, which reveals that pyridomercap-
totriazole and pyridothiazolidinone derivatives are better antifungal
agents as compared to antibacterial.
CONCLUSION
We have developed a fast and convenient microwave assisted procedure
for the rapid generation of 4a–e and 5a–e by key intermediate 3a–e.
All the reactions were completed within 4–10 minutes of microwave

114
S. Mehta et al.
irradiation and give the desired products in high yields and excellent
purities. Further structural identification was achieved by elemental
and spectral data. Further, it is observed that some of the screened
compounds were highly active against the test microorganism.
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