Tetrahedron Letters 55 (2014) 6175–6179

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Tetrahedron Letters

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Organocatalysis in aqueous micellar medium: a new protocolfor the synthesis of [1,2,4]-triazolyl-thiazolidinones

http://dx.doi.org/10.1016/j.tetlet.2014.09.0300040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +91 9415218507.E-mail address: dr.jdsau@gmail.com (J. Singh).

Mandavi Singh, Mohammad Saquib, Shyam Babu Singh, Swastika Singh, Preyas Ankit, Shahin Fatma,Jagdamba Singh ⇑Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India

a r t i c l e i n f o

Article history:Received 10 June 2014Revised 6 September 2014Accepted 8 September 2014Available online 16 September 2014

Keywords:Triazole thiazolidinone hybridsEnvironmentally friendlyAqueous mediumAcetic acidCetyltrimethylammonium bromide

a b s t r a c t

A new environmentally friendly methodology for the efficient synthesis of biologically significant triazolethiazolidinone hybrids in aqueous medium, using acetic acid as an organocatalyst in the presence ofcetyltrimethylammonium bromide (CTAB) surfactant has been developed for the first time. The effectof several surfactants on the yield and completion time of the reaction was investigated and it was foundthat the use of CTAB at 60 �C gave the best results (79–96% in 20 min–35 min) for the synthesis of thetarget compounds.

� 2014 Elsevier Ltd. All rights reserved.

The remarkable ability of heterocyclic nuclei to serve both asbiomimetics and reactive pharmacophores has largely contributedto their use as scaffolds in the design of biologically active newcompounds.1 Thiazolidinone is one such heterocyclic moiety whichis finding increasing applications in the design of new bioactivecompounds,2 chiefly antimicrobial agents.3 1,2,4-Triazole isanother biologically important compound which is present as akey structural motif in diverse types of drug molecules andbioactive molecules.4

Hybrid molecules have recently come under focus due to theirpromising physical, chemical, and biological properties.5 Hybridmolecules are chemical units composed of two (or more) structuraldomains in which the characteristics of various constituents havebeen altered to give rise to altogether new properties.6

The concept of hybrid molecules or molecular hybridization isnow being increasingly used by pharmaceutical chemists in theirquest for potent new drugs as evidenced by the large number ofrecent literature reports on the synthesis of new bioactive hybridmolecules with the goal of creating new chemical entities moremedically effective than their precursors.6,7

Using the concept of molecular hybridization, 1,2,4-triazolesand thiazolidinones have been integrated unto one platform toobtain a new type of hybrid molecule, triazolyl-thiazolidinone,which is assumed to possess important medicinal properties. Their

importance is attested by the fact that a number of workers haveattempted their synthesis and the resulting hybrid-triazolylthiazolidinones have exhibited interesting biological properties,especially anti-bacterial, anti-tubercular, anti-fungal, insecticidaletc.8

In the last two decades there has been a growing emphasis onthe development of environmentally friendly green techniques inorganic syntheses so as to reduce harm to the environment withsingular emphasis on the use of water as a solvent and organocat-alysts for catalyzing the reaction.9 But the hydrophobicity of mostorganic substrates is a serious drawback for effecting theirreactions in an aqueous environment. In this scenario the use ofsurfactants provides an effective way to overcome this pitfall viathe formation of micelles or vesicular cavities enhancing thereactivity of water mediated reactions.10 In micellar catalysis, thesurfactant micelles act to concentrate all reacting molecules withinthe solution, both by solubilization due to hydrophobic effect andby counter ion binding due to electrostatic forces enhancing theefficiency as well as the rate of a chemical reaction.11

In the background of the above discussions we decided todevise a new, environmentally benign synthesis to access triazolylthiazolidinones 6a–g and 7a–g using water as solvent, acetic acidas an organocatalyst along with a surfactant, invoking the conceptof micellar catalysis to overcome the hydrophobic effect.

The synthetic strategy adopted to obtain the target compoundsis presented in Scheme 1. 1,2,4-Triazole 1 reacts with benzalde-hyde 2a–g in aqueous micellar medium to afford schiff bases

CTAB; CH3COOH; H2O

CTAB

CH3COOH

SH COOH

CHO

H2O

N

NH

NNH2

N

NH

N

N

CH

N

NH

N

NH

CH

S

OOH

N

NH

NN

S

O

Scheme 2. Diagramatic representation of progress of reaction.

Table 1Screening of surfactantsa

Entry Surfactant Temp. (�C) Time Yieldb (%)

1 SDS rt 4.5 h 492 CPC rt 4.0 h 223 MTPPB rt 4.0 h 204 CTAB rt 30 min 765 CTAB 60 20 min 916 CTAB 60 30 min 91

a Reaction conditions: benzaldehyde (1 mmol), [1,2,4]triazole (1 mmol), mercapto acetic acid/methyl mercapto acetic acid (1 mmol) and few drops of acetic acid, surfactant(10 mol %) in 5 ml water.

b Isolated yields.

N

N

NH

N CH

R2

R1

+

Water, Surfactants (10 mol%)

Temperature

1 2a-g

3a-g

4

6a-g 7a-g

5

R1 = H, OCH3, Cl, Br, NO2; R2=H, Cl, OCH3

SH COOHMe COOH

SH

N

N

NH

NH2

CHO

R2

R1

N

N

NH

NS

O

R1

R2

N

N

NH

NS

OCH3

R1

R2

Scheme 1. Diagramatic representation of formation of triazolyl-thiazolidinones.

6176 M. Singh et al. / Tetrahedron Letters 55 (2014) 6175–6179

3a–g which react in situ with mercapto acetic acid (4) or methylmercapto acetic acid (5) in the presence of a few drops of aceticacid to give the corresponding substituted thiazolidinones 6a–gand 7a–g. The reaction proceeds by attack of sulfur nucleophile,followed by intramolecular cyclization or elimination of water(Scheme 2).

In our initial investigation a variety of surfactants werescreened in order to identify the best surfactant for catalyzing thisreaction (Table 1). Consequently, different cationic surfactantssuch as cetyltrimethylammonium bromide (CTAB), cetylpyridin-ium chloride (CPC), and methyltriphenylphosphonium bromide(MTPPB) as well as an anionic surfactant, sodium dodecyl sulfate(SDS), were employed. It was observed that the cationic surfac-tants, CPC and MTPPB and the anionic surfactant, SDS gave thedesired product in low yields 22%, 20%, and 49%, respectively. Incontrast, the cationic surfactant, CTAB accelerated the model reac-tion to afford the desired product in excellent yield �76% in 30 minat rt and 91% in 20 min at 60 �C (Table 1, entries 4 and 5). These

results revealed that cationic surfactants performed better pre-sumably due to stronger binding of the CTAB to the substrate.

The structures of the synthesized compounds were confirmedby spectral data and elemental analysis and were in full agreementwith the proposed structure. The 1H NMR spectra of compound 6ashowed the presence of doublet signals at d 3.32, 3.40 ppm for thetwo protons of –S–CH2– and a singlet at d 5.99 ppm for –S–CH–N–which confirms the formation of the thiazolidinone ring.

Once the reaction conditions have been optimized for obtainingthe target triazolyl-thiazolidinone hybrids in good yield and shortreaction time, the developed synthetic protocol was used to accessa series of triazolyl-thiazolidinones, 6a–g, 7a–g, which wereobtained in excellent yields ranging from 79% to 96% (Table 2).

In summary, we have reported a new environmentally friendlymethodology for the synthesis of triazole thiazolidinone hybrids:substituted-2-phenyl-3-(1H-1,2,4-triazol-5-yl)thiazolidin-4-one(6a–g) and 5-methyl-substituted-2-phenyl-3-(1H-1,2,4-triazol-5-yl)thiazolidin-4-one (7a–g) in aqueous medium employing acetic

Table 2Synthesis of substituted 2-phenyl-3-(1H-1,2,4-triazol-5-yl)thiazolidin-4-one (6a–g) and 5-methyl-substituted 2-phenyl-3-(1H-1,2,4-triazol-5-yl)thiazolidin-4-one (7a–g)a

Entry Benzaldehyde Mercapto-acetic acid Triazolyl- thiazolidinones Time (min) Yieldb (%)

1

CHO HS COOH

N

N

NHN

S

O6a

20 91

2

CHO

OCH3

HS COOH

N

N

NHN

S

O

OC H3

6b

30 90

3

CHO

Cl

HS COOH

N

N

NHN

S

O

Cl

6c

20 92

4

CHO

Br

HS COOH

N

N

NHN

S

O

Br

6d

20 92

5

CHO

NO2

HS COOH

N

N

NHN

S

O

NO2

6e

+ 20 96

6

CHOCl

HS COOH

N

N

NHN

S

O

Cl

6f

20 94

7

CHO

OCH3

OCH3

HS COOH

N

N

NHN

S

O

OCH3

OCH3

6g

30 82

8

CHO

Me COOH

SH

N

N

NHN

S

OCH3

7a

30 86

9

CHO

OCH3

Me COOH

SH

35 85

(continued on next page)

M. Singh et al. / Tetrahedron Letters 55 (2014) 6175–6179 6177

Table 2 (continued)

Entry Benzaldehyde Mercapto-acetic acid Triazolyl- thiazolidinones Time (min) Yieldb (%)

N

N

NHN

S

O

OCH3

CH3

7b

10

CHO

Cl

Me COOH

SH

N

N

NHN

S

O

Cl

CH3

7c

25 88

11

CHO

Br

Me COOH

SH

N

N

NHN

S

O

Br

CH3

7d

25 90

12

CHO

NO2

Me COOH

SH

N

N

NHN

S

O

NO2

CH3

7e

25 92

13

CHOCl Me COOH

SH

N

N

NHN

S

O

Cl

CH3

7f

25 90

14

CHO

OCH3

OCH3 Me COOH

SH

N

N

NHN

S

O

OCH3

OCH3

CH3

7g

35 79

a Reaction conditions: aldehydes (1 mmol), [1,2,4]triazole (1 mmol), mercapto acetic acid/methyl mercapto acetic acid (1 mmol) and few drops of acetic acid, CTAB(10 mol %) in 5 ml water.

b Isolated yields.

6178 M. Singh et al. / Tetrahedron Letters 55 (2014) 6175–6179

acid as an organocatalyst, and using CTAB as a surfactant to sur-mount the problem of hydrophobicity of the intermediate. Thedesired hybrid triazolyl-thiazolidinones were formed in short reac-tion times and good to excellent yields.

Acknowledgments

The authors are thankful to SAIF, Punjab University, Chandigarh,India for providing spectral data. The authors are also thankful toUGC, New Delhi, India; DST, New Delhi, India and CSIR, New Delhi,India for financial support. Mohammad Saquib specifically thanksUGC, New Delhi for Dr. D.S. Kothari Postdoctoral Fellowship.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.030.

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