N-Methylpyridinium tosylate catalyzed green and efficient synthesis of some novel 2,4-disubstituted thiazoles and 4-thiazolidinones

Article abstract of DOI:10.1016/j.cclet.2012.10.002

A convenient solvent less cyclocondensation from thiosemicarbazone of benzofuranone and chloroacetic acid using an ionic liquid, N-methylpyridinium tosylate for obtaining novel 4-thiazolidinones in excellent yields is reported. Also, the green expedient synthesis of new 2,4-disubstituted thiazoles under grinding condition from phenacyl bromides and thiosemicarbazide derivatives in quantitative yields is reported.

Full text of DOI:10.1016/j.cclet.2012.10.002

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1221–1224
www.elsevier.com/locate/cclet
N-Methylpyridinium tosylate catalyzed green and efficient synthesis
of some novel 2,4-disubstituted thiazoles and 4-thiazolidinones
*
Deepika Gautam, Poonam Gautam, R.P. Chaudhary
Department of Chemistry, Sant Longowal Institute of Engineering & Technology, Longowal, Sangrur, Punjab 148106, India
Received 29 June 2012
Available online 24 October 2012
Abstract
A convenient solvent less cyclocondensation from thiosemicarbazone of benzofuranone and chloroacetic acid using an ionic
liquid, N-methylpyridinium tosylate for obtaining novel 4-thiazolidinones in excellent yields is reported. Also, the green expedient
synthesis of new 2,4-disubstituted thiazoles under grinding condition from phenacyl bromides and thiosemicarbazide derivatives in
quantitative yields is reported.
# 2012 R.P. Chaudhary. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 4-Thiazolidinones; Thiazoles; Grinding; Ionic liquid; Cyclocondensation; Thiosemicarbazones
Thiazoles and 4-thiazolidinones are the heterocyclic compounds with multiple applications and, they have been
known from long ago to be biologically active [1,2]. They show, for example, very intensive antitumor activity especially
the phenyl substituted benzothiazoles [3], while 4-thiazolidinones and their derivatives exert antimicrobial activity [4].
These heterocycles have been reported to show a broad spectrum of biological activities [5,6] and a wide range of
pharmacological activities such as analgesic [7], anticonvulsant [8] and antitumor [9] activities. Various approaches for
the synthesis of 4-thiazolidinones are available in the literature [10,11]. Nevertheless a common synthetic strategy to
construct imino thiazolidinones is the cyclization of thiosemicarbazide derivatives with a-halo esters or acids in presence
of inorganic base (i.e. NaOAc) in polar solvents using either a conventional or microwave irradiation methods [12,13].
However, most of the reported procedures suffer from drawbacks of long reaction times, use of hazardous solvents and
moderateyields. InthepresentpaperwehavesuccessfullyattemptedtheuseofN-methylpyridiniumtosylatefirsttime for
synthesis of some new 2,4-disubstituted thiazoles and 4-thiazolidinones from cyclocondensation reaction of phenacyl
bromides and chloroacetic acid respectively with thiosemicarbazone of benzofuranone. To the best of our knowledge this
type of system is not reported in the literature by any other solvent free method or microwave method.
1. Result and discussion
Benzofuranone 1 was prepared from furan and succinic anhydride following the reported [14] procedure.
Benzofuranone was condensed with thiosemicarbazide by literature [15] procedure in presence of conc. HCl to give 2,
* Corresponding author.
E-mail address: rpchaudhary65@gmail.com (R.P. Chaudhary).
1001-8417/$ – see front matter # 2012 R.P. Chaudhary. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.10.002

1222
D. Gautam et al. / Chinese Chemical Letters 23 (2012) 1221–1224
Ar
H3C
S
N
H
O
O
N
O
N
S
N
H
N
H
N
5
4
5 a) Ar = p-Cl-C6H4
b) Ar = p-O2N-C6H4
ArCOCH2Br
CH3-CH(Br)COOH
S
O
O
N
O
O
N-NHCSNH2
O
N
H
N
ClCH2COOH
NH2NHCSNH2
2
1
3
Scheme 1. Synthesis of 4-thiazolidinones and thiazoles with tetrahydrobenzofuran moiety.
characterized by IR and NMR spectral data. In the IR the appearance of peaks at 1628 and 1234 cmÀ1 corresponds
to C N and C S groups. The appearance of two triplets at d 2.50 and d 2.77 and one multiplet at d 2.12 are
attributed to benzofuran ring. Two doublets at d 6.60 and d 7.31 are assigned to furan ring. Compound 2 on
refluxing with chloroacetic acid or 2-bromopropionic acid in presence of sodium acetate yields compounds 3 and
4 respectively (Scheme 1). These compounds are also synthesized under solvent free conditions, i.e. by heating
chloroacetic acid or 2-bromopropionic acid with compound 2 at 90–100 8C for 2–3 hrs in presence of N-
methylpyridinium tosylate. Conventional methods require long refluxing time of 7–8 h and the yield of the
product isolated is moderate, i.e. between 50 and 60%. However, in case of solvent free synthesis the reaction
completes in 2–3 h and the products are obtained in excellent yields 80–85%. Compounds 3 and 4 were
characterized by the IR, NMR and mass spectral data. The appearance of a peak at 1713 cmÀ1 in IR spectrum of 3
1
is attributed to the C O group. In the H NMR spectrum appearance of a singlet at d 3.78 is due to the SCH2 of
the thiazolidinone ring. 13C NMR shows C O peak at d 173.01. The appearance of a peak at m/z 250 (M+H+)
(100%) in the mass spectrum confirms the proposed structure for compound 3. Compound 4 was obtained as light
yellow crystals. In the IR spectrum of compound 4 the peak at 1697 cmÀ1 is due to C O group of thiazolidinone
ring. The appearance of a doublet at d 1.65 and a quartet at d 4.06 in the 1H NMR corresponds to H and CH3 group
of the thiazolidinone ring. 13C NMR shows C O peak at d 176.17. The structure is further confirmed by
appearance of a peak at m/z 264 (M+H+) (100%) in mass spectrum of compound 4.
Thiazoles 5a and 5b were prepared from 2 under grinding conditions in presence of N-methylpyridinium tosylate as
well as by conventional refluxing in ethanol. The appearance of singlet at d 6.71 and d 7.06 in 1H NMR spectrum of 5a
and 5b respectively are characteristic of thiazole ring. The elemental analysis data of all the compounds is in good
agreement of calculated values. In case of 3, 4, 5a, 5b, the conventional procedure needs a much longer reaction time
and yields are also not very good. Solvent free method, i.e. heating reactants with ionic liquid in case of 3 and 4 and
grinding the reactants in case of 5a and 5b gives better yields and the reaction completes faster. The ionic liquid was
recovered at the end of reaction and it was found suitable for two more uses without any loss in activity. The
comparison of yields and reaction conditions is reported in Table 1.
Table 1
Synthesis of 2,4-disubstituted thiazoles and 4-thiazolidinones by conventional and solvent free conditions.
Compound
Reaction time
Yield (%)
Conventional method
Solvent free method
Conventional method
Solvent free method
3
7 h
8 h
2.5 h
3.0 h
56%
52%
62%
65%
84%
82%
82%
85%
4
5a
5b
30 min
30 min
10 min
12 min

D. Gautam et al. / Chinese Chemical Letters 23 (2012) 1221–1224
1223
2. Experimental
All the chemicals used were obtained from Sigma and used without further purification. Melting points were
determined in open capillaries and are uncorrected. Elemental analysis was done on a Carlo-Erba 1108 elemental
analyzer. Mass spectra were recorded on a TOF MS ES+ 2.44e4 instrument. 1H NMR and 13C NMR were recorded in
CDCl3 on a BRUKER AVANCE II 400 NMR spectrometer using tetramethylsilane (TMS) as an internal standard. The
chemical shifts are reported in ppm. IR spectra were recorded on ABB FTIR spectrometer and the results are reported
in cmÀ1. Thin layer chromatography (TLC) was performed on silica gel G coated plates and using iodine vapour as
visualizing agent.
2-(6,7-Dihydrobenzofuran-4(5H)-ylidene)hydrazinecarbothioamide (2): White solid; yield: 90%; mp: 158 8C;
Anal. Calcd. for C9H11N3SO: C 51.67; H 5.26; N 20.09; S 15.31 (%); Found: C 51.54; H 5.20; N 19.96; S 15.24 (%); IR
(cmÀ1): 3402, 3202, 3114 (NH), 1628 (C N), 1589 (C C), 1234 (C S); 1H NMR (400 MHz, CDCl3): d 2.06–2.12 (m,
2H, CH2), 2.50–2.53 (t, 2H, J = 5.8 Hz, CH2), 2.77–2.80 (t, 2H, J = 6.2 Hz, CH2), 6.35 (br, 1H, NH), 6.60 (s, 1H, CH
furan ring), 7.31 (s, 1H, CH furan ring), 8.76 (br, 1H, NH2).
N-Methylpyridinium tosylate mediated general procedure for synthesis of (3 and 4): An equimolar mixture of 2
(0.12 mmol) and chloroacetic acid or 2-bromopropionic acid (0.12 mmol) in premolten ionic liquid 2.0 g was stirred at
90–100 8C for 2–3 h. The reaction was monitored by TLC, poured in to ice cold water, filtered the solid obtained, dried
and recrystallized from ethanol.
Conventional procedure for synthesis of (3 and 4): A mixture of 2 (0.1 mmol), chloroacetic acid or 2-
bromopropionic acid (0.1 mmol), anhydrous sodium acetate (0.2 mmol), in absolute ethanol (5.0 mL) was heated
under reflux for 7–8 h. The reaction mixture was cooled to room temperature and then poured into ice cold water. The
solid thus separated was filtered, washed with water and recrystallized from ethanol.
(Z)-2-((E)-(6,7-Dihydrobenzofuran-4(5H)-ylidene)hydrazono)thiazolidin-4-one (3): Shining white solid; yield:
84%; mp: 168–170 8C; Anal. Calcd. for C11H11N3SO2: C 53.01; H 4.41; N 16.86; S 12.85 (%); found: C 53.12; H 4.36;
N 16.78; S 12.76 (%); IR (cmÀ1): 3117 (NH), 1713 (N–C O), 1620 (C N); 1H NMR (400 MHz, CDCl3): d 1.96–2.03
(m, 2H, CH2), 2.73–2.80 (m, 4H, 2CH2), 3.78 (s, 2H, SCH2), 6.730–6.735 (d, 1H, J = 1.96 Hz, CH furan ring), 7.30–
7.31 (d, 1H, J = 2.04 Hz, CH furan ring); 13C NMR (100 MHz, CDCl3): d 173.01 (C O), 159.68 (C N), 159.62
(C N), 142.09, 141.11, 118.23, 106.56 (C6H6), 33.00 (SCH2), 25.65 (CH2), 23.18 (CH2), 22.34 (CH2); MS m/z 250
(M+H)+ (100%).
(Z)-2-((E)-(6,7-Dihydrobenzofuran-4(5H)-ylidene)hydrazono)-5-methylthiazolidin-4-one (4): Light yellow solid;
yield: 82%; mp: 130 8C; Anal. Calcd. for C12H13N3SO2: C 54.75; H 4.94; N 15.96; S 12.16 (%); found: C 54.68; H
1
4.90; N 15.86; S 12.10 (%); IR (cmÀ1): 3155 (NH), 1697 (N–C O), 1620 (C N); H NMR (400 MHz, CDCl3): d
1.65–1.67 (d, 3H, J = 7.28 Hz, CH3), 1.95–2.03 (m, 2H, CH2), 2.74–2.82 (m, 4H, 2CH2), 4.01–4.06 (q, 1H, SCH),
6.721–6.726 (d, 1H, J = 2.00 Hz, CH furan ring), 7.301–7.306 (d, 1H, J = 2.00 Hz, CH furan ring); 13C NMR
(100 MHz, CDCl3): d 176.17 (C O), 159.68 (C N), 159.60 (C N), 142.09, 118.23, 106.54 (C6H6), 42.42 (SCH),
25.68 (CH3), 23.19 (CH2), 22.34 (CH2), 19.22 (CH2); MS m/z 264 (M+H)+ (100%).
General procedure for synthesis of 5a and 5b under grinding conditions: To an equimolar mixture of 2 (0.12 mmol)
and p-substituted phenacyl bromide (0.12 mmol), ionic liquid (2.0 g) is added and the reaction mixture was grinded in
pestle mortar in a solvent free environment for 10–15 min at ambient temperature. The progress of the reaction was
monitored by TLC. After completion of reaction, the product was extracted using ethyl acetate. The solvent was
removed under reduced pressure to obtain the crude solid. The crude product was recrystallized from ethanol.
Conventional procedure for synthesis of (5a and 5b): An equimolar mixture of 2 (0.12 mmol) and p-substituted
phenacyl bromide (0.12 mmol) in absolute ethanol (5.0 mL) was heated under reflux for 30 min. Cooled and the solid
thus separated was filtered and washed with ethanol. The crude solid was recrystallized from ethanol.
(E)-4-(4-Chlorophenyl)-2-(2-(6,7-dihydrobenzofuran-4(5H)-ylidene)hydrazinyl)thiazole (5a): Orange solid; yield:
82%; mp: 198–200 8C; Anal. Calcd. for C17H14N3OSCl: C 59.47; H 4.08; N 12.24; S 9.32 (%); found: C 59.42; H 4.04; N
12.20; S 9.28 (%); IR (cmÀ1): 3070 (NH), 1612 (C N), 1489 (C C), 741 (C–Cl); 1H NMR (400 MHz, CDCl3): d 2.08–
2.11 (m, 2H, CH2) 2.76–2.82 (m, 4H, 2CH2), 6.65–6.66 (d, 1H, J = 1.96 Hz, CH furan ring), 6.71 (s, 1H, thiazole ring,
CH) 7.20–7.22 (d, 1H, J = 7.96 Hz, C6H5), 7.32–7.33 (d, 1H, J = 2.00 Hz, CH furan ring), 7.41–7.42 (d, 1H,
J = 1.88 Hz, C6H5), 7.65–7.66 (d, 1H, J = 2.56 Hz, C6H5), 7.80–7.82(d, 1H, J = 6.52 Hz, C6H5), 13.07 (br, 1H, NH).
(E)-2-(2-(6,7-Dihydrobenzofuran-4(5H)-ylidene)hydrazinyl)-4-(4-nitrophenyl)thiazole (5b): Brown solid; yield:
85%; mp: 210–211 8C; Anal. Calcd. for C17H14N4O3S: C 57.62; H 3.95; N 15.81; S 9.03 (%); found: C 57.60; H 3.90;

1224
D. Gautam et al. / Chinese Chemical Letters 23 (2012) 1221–1224
1
N 15.78; S 9.01 (%) IR (cmÀ1): 3340 (NH), 1651 (C N), 1504 (C C), 1558, 1355 (NO2), 1512 (C C). H NMR
(400 MHz, CDCl3): d 2.09–2.12 (m, 2H, CH2) 2.56–2.59 (t, 2H, J = 6.56 Hz, CH2), 2.77–2.80 (t, 2H, J = 6.24 Hz,
CH2), 6.70–6.71 (d, 1H, J = 1.84 Hz, CH furan ring), 7.06 (s, 1H, CH thiazole ring) 7.323–7.327 (d, 1H, J = 1.88 Hz,
CH furan ring), 7.92–7.95 (d, 2H, J = 8.92 Hz, C6H5), 8.26–8.28 (d, 2H, J = 8.92 Hz, C6H5).
Acknowledgments
The facilities provided by authorities of Sant Longowal Institute of Engineering and Technology, Longowal are
gratefully acknowledged.
References
[1] K. Tsuji, H. Ishikawa, Bioorg. Med. Chem. Lett. 4 (1994) 1601.
[2] W.L. Dong, J.Y. Xu, X.H. Liu, et al. Chem. J. Chinese U. 29 (2008) 1359.
[3] A. Furlan, F. Colombo, A. Kover, et al. Eur. J. Med. Chem. 47 (2012) 239.
[4] S.G. Patil, R.R. Bagul, M.S. Swami, et al. Chin. Chem. Lett. 22 (2011) 883.
[5] K. Liu, W. Rao, H. Parikh, et al. Eur. J. Med. Chem. 47 (2012) 125.
[6] D. Havrylyuk, L. Mosula, B. Zimenkovsky, et al. Eur. J. Med. Chem. 45 (2010) 5012.
[7] R.P. Tenorio, C.S. Carvalho, C.S. Pessanha, et al. Bioorg. Med. Chem. Lett. 15 (2005) 2575.
[8] K. Omar, A. Geronikaki, P. Zoumpoulakis, et al. Bioorg. Med. Chem. 18 (2010) 426.
[9] Y.X. Li, X. Zhai, W.K. Liao, et al. Chin. Chem. Lett. 23 (2012) 415.
[10] (a) P.M. Shah, M.P. Patel, Indian J. Chem. 50B (2011) 310;
(b) D.V. Jawale, U.R. Pratap, D.L. Lingampalle, et al. Chin. J. Chem. 29 (2011) 942.
[11] T. Srivastava, W. Haq, S.B. Katti, Tetrahedron 58 (2002) 7619.
[12] D.P. Gouvea, V.D.O. Bareno, J. Bosenbecker, et al. Ultrason. Sonochem. 19 (2012) 1127.
[13] X. Li, Z. Qin, T. Yang, et al. Bioorg. Med. Chem. Lett. 22 (2012) 2712.
[14] P.K. Sen, U.K. Saha, T. Das, Indian J. Chem. 38B (1999) 648.
[15] P. Venkateswarlu, N.R. Vasireddy, Indian J. Chem. 44B (2005) 783.