Solvent-free synthesis of 2-furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles under microwave irradiation

Article abstract of DOI:10.1081/SCC-120022179

A practical solvent-free method for the preparation of 2-furyl-5-aryl-oxyacetylamido-1,3,4-thiadiazoles under microwave irradiation is described.

Full text of DOI:10.1081/SCC-120022179

This article was downloaded by: [University of Haifa Library]
On: 03 September 2013, At: 00:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Solvent-Free Synthesis of 2-Furyl-5-
aryloxyacetylamido-1,3,4-thiadiazoles Under
Microwave Irradiation
a
a
a
a
a
Xicun Wang , Zheng Li , Zhengjun Quan , Xinsheng Lu & Ruhu Gou
a
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou,
Gansu, P.R. China
Published online: 19 Aug 2006.
To cite this article: Xicun Wang , Zheng Li , Zhengjun Quan , Xinsheng Lu & Ruhu Gou (2003) Solvent-Free Synthesis of 2-
Furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles Under Microwave Irradiation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:16, 2891-2897, DOI: 10.1081/SCC-120022179
To link to this article: http://dx.doi.org/10.1081/SCC-120022179
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 16, pp. 2891–2897, 2003
Solvent-Free Synthesis of
-Furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles
Under Microwave Irradiation
2
Xicun Wang, Zheng Li,* Zhengjun Quan, Xinsheng Lu,
and Ruhu Gou
College of Chemistry and Chemical Engineering,
Northwest Normal University,
Lanzhou, Gansu, P.R. China
ABSTRACT
A practical solvent-free method for the preparation of 2-furyl-5-aryl-
oxyacetylamido-1,3,4-thiadiazoles under microwave irradiation is
described.
Key Words: Solvent-free; 1,3,4-Thiadiazole; Microwave irradia-
tion.
*
Correspondence: Zheng Li, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, P.R. China; E-mail:
lizheng@nwnu.edu.cn.
2
891
DOI: 10.1081/SCC-120022179
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
892
Wang et al.
Substituted 1,3,4-thiadiazoles have attracted much attention due to
[2]
[
their diverse biological activities, such as antimicrobial, antibacterial,
1]
[
3]
[4]
anesthetic, anticonvulsant, cardiotonic, antihypertensive, anti-
[5]
[6]
[7]
[8]
inflammatory and antiulcer activities. Meanwhile, aryloxyacetic acid
[
derivatives have also been used as herbicides, diuretics,
growthregulators.
derivatives also possess local anesthesia,
cannabimimetic,
histaminic and anti-allergic, reductase inhibitory,
metallothioneinogenic activities.
9]
[10]
and plant-
In addition, benzofuran or aryl substituted furan
[11]
[
12]
[13]
analgesic,
anti-arrhythmic and hypotensive,
insect antifee-
[16]
[14]
[15]
dant,
anti-
[19]
estrogenic,
[
17]
[18]
[20]
Based on the above facts, the species bearing all of 1,3,4-thiadiazole,
aryloxyacetyl and furyl moieties in one molecular are possibly poten-
tial candidates of biologically active compounds. Consequently, there
is a need to explore an expeditious, environmentally benign synthetic
protocol to get a library of this kind of compounds.
The development of solvent-free organic synthesis is of current
interest because of the many advantages, such as reduced pollution,
low cost, simplicity in process and handling, potential applications in
[
21]
combinatorial chemistry and chemical industry.
Microwave energy has now developed into a useful technique for a
variety of application in organic synthesis, especially for the solventless
[22]
reactions since the solvent-free MW-assisted reactions can provide an
opportunity to work with open vessels thus avoiding the risk of high-
pressure development and increasing the potential of such reaction to
upscale.
In continuation of ongoing program to synthesize biologically active
compounds and develop benign and rapid strategy for organic trans-
formation under solventless conditions using microwave irradiation
and the interest in green chemistry theme with growing emphasis on
pollution prevention, we have explored an expeditious solvent-free
route to prepare 2-furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles under
microwave irradiation.
The required 2-amino-5-furyl-1,3,4-thiadiazoles (1a–b) are prepared
by the reaction of benzo-2-furancarboxylic acid or 5-(2-chlorophenyl)-
2-furancarboxylic acid with thiosemicarbazide in the presence of the same
equivalent of phosphorus oxychloride under microwave irradiation. In
contrast, the conventional heating method have to use much more
excess of phosphorus oxychloride both as dehydrant and solvent, and
the mixture have to reflux for many hours before the product is afforded
[23]
in good yield.
Aryloxyacetic acid is ground withequivalent of potassium cabonate in
a motar until the acid disappeared and potassium aryloxyacetate formed

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
-Furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles
2893
Scheme 1.
according to TLC analysis. Then equivalent of phenylsulfonyl
chloride is added and the mixture is ground again until a viscous
paste is observed and a mixed anhydride formed. After that, 2-amino-5-
furyl-1,3,4-thiadiazole is added, and the mixture is irradiated in a
microwave oven until all paste solidified. The completion of the
reaction is monitored by TLC using ethyl acetate and petroleum oil
(
3:2) as eluent. The product, 2-furyl-5-aryloxyacetylamido-1,3,4-
thiadiazoles (2a–t), those are of acceptable purity for most purpose,
are given in excellent yield only by washing the resulting solid using
distilled water. If greater purity is required, the product can be recrys-
tallized from acetic acid and water (Sch. 1). In order to compare the
difference between microwave and traditional method, the same
reactions for compound 2a–t are designed to proceed in the solution
of acetonitrile and reflux for four hours, but no any products are
isolated.
The characterization of compounds 2a–t is based on their IR (KBr),
H NMR, and elemental analyses. The IR spectra exhibit a characteristic
1
ꢀ
1
strong absorption at 1699–1723 cm for carbonyl. The H NMR spectral
1
data of 2a–t in d -dimethylsulfoxide show peaks at 13.07–13.26 (NH) and
6
4.86 4.93 ppm (CH ). All data of elemental analysis are good agreement
2
with the structure proposed. The yield and melting point of 2a–t are
summarized in the Table 1.
In conclusion, we have found an efficient protocol for the
preparation of title compounds by solvent-free MW-assisted reaction.
This strategy can also be readily suitable for the preparation of the
libraries of various substituted 1,3,4-thiadiazoles.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
894
Wang et al.
Table 1. Solvent-free preparation of 2-furyl-5-aryloxyacetylamido-1,3,4-
thiadiazoles under MWI.
ꢁ
a
Yield (%)
Product
Substrate
Ar
M.p. ( C)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
C H
6
216–217
246–247
258–259
260–261
269–270
239–240
272–273
315–316
266–267
251–252
201–202
234–235
200–201
260–261
190–191
216–217
277–278
269–270
213–214
260–261
88
85
90
86
91
88
90
87
89
88
86
87
85
91
84
91
88
85
88
92
5
2-CH
3-CH
3
C
C
6
H
H
4
3
6
4
4-CH C H
3
6
4
4-CH
2-ClC
3
OC
6
H
4
6
H
4
g
h
i
4-ClC H
6
4
2,4-Cl C H
3
2
6
2-Naphthyl
j
4-O
C H
2
NC
6
H
4
k
l
6
5
4-CH
2-ClC
3
OC
6
H
4
m
n
o
p
q
r
6
H
4
4-ClC H
6
4
2 6 3
2,4-Cl C H
2-Naphthyl
4-O NC H
2
2
2
6
6
6
4
4
4
3-O
2-O
NC
NC
H
H
s
t
1-Naphthyl
a
Yields refer to the isolated products.
EXPERIMENTAL
Infrared spectra were recorded using KBr pellets on an Alpha
1
Centauri FTIR spectrophotometer and H NMR spectra on a FT-80A
instrument using (CD ) SO as solvent and Me Si as internal standard.
3
2
4
Elemental analyses were performed on a Vario El Elemental Analysis
instrument. Mass spectra were recorded on a QP-1000A GC-MS using
the impact mode (70 eV). Melting points were observed in an open
[
24]
capillary tube and uncorrected. Aryloxyacetic acids,
carboxylic acid
benzo-2-furan-
[26]
and 5-(2-chlorophenyl)-2-furancarboxylic acid
[25]
were prepared according to literature procedures. Phenylsulfonyl chloride
and phosphorus oxychloride were commercially available and used
as received.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
-Furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles
2895
Preparation of 2-Amino-5-(benzo-2-furyl)-
,3,4-thiadiazole (1a)
1
The mixture of 0.81 g (5.0 mmol) of benzo-2-furancarboxylic
acid, 0.50 g (5.5 mmol) of thiosemicarbazide and 0.2 mL of POCl was
3
irradiated in a microwave oven (490 W) for 6 min. The completion of the
reaction was monitored by TLC. The resulting mixture was poured into
ice water (30 mL) and centralized withaqueous solution of NaOH (3 M)
until the PH ¼ 9–10. Then the suspension was filtered and the solid was
recrystallized from DMF–C H OH to give product 1a. Yield: 95%. m.p.:
2
5
ꢁ
78–279 C. H NMR (80 MHz, DMSO-d ): ꢀ 6.31 (2H, s, NH ,
6 2
1
2
exchangeable with D O), 7.0–8.0 (5H, m, Ar-H&Fu-H). IR (KBr, ꢁ,
2
ꢀ
1
ꢀ1
cm ): 3415, 3281 (N-H), 1631 (C¼N), 1504, 1347, 1250, 1066 cm
(
1,3,4-thiadiazole nucleus). Anal. calcd. for C H N OS: C, 55.29; H,
10 7 3
3
.25; N, 19.34. Found: C, 55.12; H, 3.16; N, 19.23.
0 00 0
2
-Amino-5-(5 -(2 -chlorophenyl)-2 -furyl)-1,3,4-thiadiazole (1b) was
prepared according to the similar procedure using 5-(2-chlorophenyl)-2-
furancarboxylic acid instead of benzo-2-furancarboxylic acid. Yield:
ꢁ
2%. m.p.: 203–204 C. H NMR (80 MHz, DMSO-d ): ꢀ 6.36 (2H, s,
6
1
9
NH , exchangeable with D O), 7.1–8.1 (6H, m, Ar-H&Fu-H). IR
2
2
ꢀ1
ꢀ1
(
(
KBr, ꢁ, cm ): 3420 (N-H), 1628 (C¼N), 1510, 1350, 1246, 1057 cm
1,3,4-thiadiazole nucleus). Anal. calcd. for C H ClN OS: C, 51.90; H,
3
1
2
8
32.90; N, 15.13. Found: C, 52.01; H, 2.96; N, 15.21.
General Procedure for Preparation of 2a–t
The mixture of aryloxyacetic acid (1.0 mmol) and anhydrous K CO3
2
(
(
1.0 mmol) was ground in a motar for 2 min, then phenylsulfonyl chloride
1.0 mmol) was added, and the mixture was further ground for 5 min until
a paste was obtained. After 2-amino-5-furyl-1,3,4-thiadiazole (1.0 mmol)
was added, the resulting mixture was irradiated in a microwave oven
(
350 W) for 3 min until the solidification of the paste was observed. The
completion of reaction was monitored by TLC using ethyl acetate and
petroleum oil (3:2) as eluent. Then the resulting solid was washed with
distilled water (10 mL) and compound 2 was afforded as a solid. The
analytic sample was obtained by recrystallizing from AcOH-H O (4:1).
2
1
The data for representative compound are given below: 2e: H NMR
(
H), 4.86 (2H, s, CH ), 3.82 (3H, s, CH ). IR (KBr, ꢁ, cm ): 3287 (N-H),
80 MHz, DMSO-d ): ꢀ 13.13 (1H, s, NH), 7.0–8.2 (10H, m, Ar-H&Fu-
6
ꢀ
1
2
3
þ
1
702 (C¼O), 1499, 1350, 1247, 1071 (N¼C-S-C¼N). MS: m/z, 381 (M ).

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
896
Wang et al.
Anal. calcd. for C H N O S: C, 59.83; H, 3.96; N, 11.02. Found: C,
1
9
15
3
4
1
9.98; H, 4.03; N, 11.12. 2p: H NMR (80 MHz, DMSO-d ): ꢀ 13.13 (1H,
5
s, NH), 6.9–8.2 (13H, m, Ar-H&Fu-H), 4.87 (2H, s, CH ). IR (KBr, ꢁ,
6
2
ꢀ
1
cm ): 3166 (N-H), 1701 (C¼O), 1498, 1360, 1246, 1079 (N¼C-S-C¼N).
þ
MS: m/z, 461 (M ). Anal. calcd. for C H N O SCl: C, 62.40; H, 3.49;
3
2
4
16
3
N, 9.10. Found: C, 62.61; H, 3.56; N, 9.21.
ACKNOWLEDGMENT
The authors thank the Scientific and Technological Innovation
Engineering of Northwest Normal University (NWNU-KJCXGC-02-
0
8), Natural Science Foundation of Gansu Province (ZS021-A25-006-
Z), Environmental Protection Foundation of Gansu Province
GH2002-16) and YouthFoundation of Nort hw est Normal University
for the financial support of this work.
(
REFERENCES
. Mamolo, M.; Vio, L.; Banfi, E. Farmaco 1996, 51, 71.
. Kidwai, M.; Misra, P.; Kumar, R.; Saxena, R.K.; Gupta, R.;
Bradoo, S. Monatsh. Chem. 1998, 129, 961.
1
2
3
4
5
. Mazzone, G.; Pignatello, R.; Mazzone, S.; Panico, A.; Pennisi, G.
Farmaco 1993, 48, 1207.
. Chufan, E.E.; Pedregosa, J.C.; Badini, O.N.; Bruno-Blanch, L.
Farmaco 1999, 54, 838.
. Nomoto, Y.; Takai, H; Hirata, T.; Teranishi, M.; Ohno, T.; Kubo,
K. Chem. Pharm. Bull. 1991, 39, 86.
6
7
. Vio, L.; Mamolo, M.G.; Laneve, A. Farmaco 1989, 44, 165.
. Amir, M.; Oberoi, A.; Alam, S. Indian J. Chem. Sect. B 1999,
38, 237.
8. Nishino, C.; Sato, F.; Uetake, T.; Fukunish, H.; Kojima, N.
US5912258 1999; Chem. Abstr. 131, 31943.
9. Shi, Y.N.; Lu, Y.C.; Fang, J.X.; Hua, Y.L. Chem. J. Chin. Univ.
(Chinese) 1995, 16, 1710; Chem. Abstr. 124, 316654.
0. Kitagawa, M.; Yamamoto, K.; Katakura, S.; Kanno, H.; Yamada,
K. Chem. Pharm. Bull. 1991, 39, 2681.
1
1
1
1. Jain, P.K.; Srirastara, S.K. J. Indian Chem. Soc. 1992, 69, 402.
2. Mukhanova, T.I.; Granik, V.G.; Denisov, A.V.; Trubitsina, T.K.;
Shvarts, G.Ya.; Mashkovskii, M.D. Pharm. Chem. J. (Engl.
Transl.) 1994, 28 (12), 893–897.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2
-Furyl-5-aryloxyacetylamido-1,3,4-thiadiazoles
2897
1
1
1
1
1
1
1
2
3. Burch, H.A.; Write, R.E.; Wright, G.C.; Goldenberg, M.M.
J. Pharm. Sci. 1980, 69, 107.
4. Morimoto, M.; Urakawa, M.; Fujitaka, T.; Komai, K. Biosci.
Biotechnol. Biochem. 1999, 63 (5), 840.
5. Mechoulam, R.; Breuer, A.; Jaerbe, T.U.C.; Hiltunen, A.J.; Glaser,
R. J. Med. Chem. 1990, 33 (3), 1037.
6. Ragab, F.A.; Tawfeek, H. Eur. J. Med. Chem. Chim. Ther. 1987,
22, 265.
7. Takeuchi, N.; Kasama, T.; Ikeda, R.; Shimizu, K.; Hatakeyama, K.
Chem. Pharm. Bull. 1984, 32 (6), 2249.
8. Ishibashi, K.; Nakajima, K.; Sugioka, Y.; Sugiyama, M.; Hamada,
T. Bioorg. Med. Chem. Lett. 1998, 8 (6), 561.
9. Diwani, H.I.E.; Abu-Bakr, S.M.; Hishmat, O.H.; Arbid, M.S.
Indian J. Chem. Sect. B 1993, 32 (4), 494.
0. Rott, G.M.; Shevchenko, L.I.; Smoryzanova, O.A.; Savina, E.P.;
Deeva, V.S.; Skvortsov, V.G.; Trofimov, F.A. Pharm. Chem. J.
(
Engl. Transl.) 1998, 32 (2), 652.
2
1. (a) Metzger, J.O. Angew. Chem., Int. Ed. 1998, 37, 2975; (b)
Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025; (c) Loupy, A.;
Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe, D.
Synthesis 1998,1213; (d) Varma, R.S. Green Chem. 1999, 1, 43; (e)
Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.L.; Petit, A.
Tetrahedron 1999, 55, 10851.
22. (a) Varma, R.S.; Kumar, D. Synth. Commun. 1999, 29 (8), 1333; (b)
Olsson, R.; Hansen, H.C.; Andersson, C.-M. Tetrahedron Lett.
2000, 41 (41), 7947; (c) Loupy, A.; Petit, A.; Hamelin, J.; Texier-
Boullet, F.; Jacquault, P.; Mathe, D. Synthesis 1998, (9), 1213.
3. Wasfy, A.A. F.; Nassar, S.A.; Eissa, A. M. F. Indian J. Chem.
Sect. B 1996, 35 (11), 1218.
2
2
4. Li, Y.J.; Dai, Y.J.; Chen, J.C. Chem. J. Chin. Univ. (Chinese) 1988,
9
, 584; Chem. Abstr. 110: 74986h.
2
2
5. Farrar, M.W.; Levinl, R.J. Am. Chem. Soc. 1950, 72, 4433.
6. Krutosikova, A.; Kovac, J.; Sykova, V. Collection Czecholov.
Chem. Commun. 1974, 39, 1892.
Received in Japan December 9, 2002

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.