Solvent-free synthesis of 2-amino-5-aryloxymenthyl-1,3,4-thiadiazoles and their coumarin or benzofuran bis-heterocyclic derivatives

Article abstract of DOI:10.1080/104265090969577

2-amino-5-aryloxymethyl-1,3,4-thiadiazoles were synthesized rapidly by a microwave-accelerated solvent-free procedure in high yield via the condensation of thiosemicarbazide with aryloxyacetic acids using poly(ethylene glycol)-supported dichlorophosphate

Full text of DOI:10.1080/104265090969577

Phosphorus, Sulfur, and Silicon, 181:183–190, 2006
Copyright © Taylor & Francis LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090969577
Solvent-Free Synthesis of
2-Amino-5-Aryloxymenthyl-1,3,4-Thiadiazoles and Their
Coumarin or Benzofuran Bis-Heterocyclic Derivatives
Zheng Li
Jin-Lan Yu
Jing-Ya Yang
Wei Zhu
Yan-Long Zhao
Yu-Lin Xing
Xi-Cun Wang
Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu,
People’s Republic of China
2-amino-5-aryloxymethyl-1,3,4-thiadiazoles were synthesized rapidly by
microwave-accelerated solvent-free procedure in high yield via the condensation of
thiosemicarbazide with aryloxyacetic acids using poly(ethylene glycol)-supported
dichlorophosphate as a dehydration reagent. The solvent-free N-acylation of
2-amino-5-aryloxymethyl-1,3,4-thiadiazoles with coumarin-3-carboxylic acid chlo-
ride or benzofuran-2-carboxylic acid chloride efficiently afforded corresponding
bis-heterocyclic derivatives, 2-(coumarin-3-carboxamido)-5-aryloxymethyl-1,3,4-
thiadiazoles, and 2-(benzofuran-2-carboxamido)-5-aryloxymethyl-1,3,4-thiadia-
zoles. The strategy has advantages of no organic solvent pollution, an elevated
reaction rate, an improved yield, and a simple work-up procedure.
a
Keywords 1,3,4-Thiadiazoles; microwave irradiation; polymer-supported reagent; room
temperature grinding; solvent-free
INTRODUCTION
Heterocyclic compounds are important for their wide range of bi-
ological activities. Heterocycles containing 1,3,4-thiadiazole possess
Received January 6, 2005; in final form February 1, 2005.
The authors thank the Scientific and Technological Innovation Engineering of North-
west Normal University (NWNU-KJCXGC-02-08) for financial support of this work.
Address correspondence to Zheng Li, Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou,
Gansu, 730070 people’s Republic of China. E-mail: lizheng@nwnu.edu.cn
183

184
Z. Li et al.
antimicrobial, antidepressant, and antiinflammatory activities.1 Mean-
while, heterocycles bearing coumarin exhibit anti-HIV, antitu-
mor, antibacterial, anticoagulant, and vasorelaxant activities.2 In
addition, heterocycles including benzofuran also show insect an-
tifeedant, cannabimimetic, reductase inhibitory, and metallothioneino-
genic activities.3 Based on these facts, bis-heterocyclic compounds
involving both 1,3,4-thiadiazole and either coumarin or benzofuran
might be good candidates for biologically active compounds.
The development of a solvent-free organic synthesis is of current
interest because of the many advantages, such as reduced pollution,
low cost, simplicity in process and handling, and potential applications
in combinatorial chemistry and chemical industry.4
In continuation of our program to synthesize biologically active
compounds and develop a benign and rapid strategy for organic syn-
thesis under solvent-free conditions and the interest in green chem-
istry theme with a growing emphasis on pollution prevention, we
have explored an expeditious solvent-free route to prepare 2-amino-5-
aryloxymethyl-1,3,4-thiadiazoles and their bis-heterocyclic derivatives
involving coumarin or benzofuran under either microwave irradiation
or r.t.-grinding conditions.
RESULTS AND DISCUSSION
The mixture of thiosemicarbazide with an equivalent of aryloxy-
acetic acids and 2 equivalents of poly(ethylene glycol)(PEG)-supported
dichlorophosphate (PEG-O-P(O)Cl2) was irradiated in a microwave
oven to afford readily 2-amino-5-aryloxymethyl-1,3,4-thiadiazoles (1)
in a 72–89% yield (Scheme 1). Reactions could be monitored by TLC
and completed within 8–10 min at 490 W microwave power. This pro-
tocol using a recoverable polymer supported the dichlorophosphate as
a dehydration reagent and efficiently avoided the corrosion and en-
vironmental pollution caused by using traditional harsh reagents, e.g.,
concentrated sulfuric acid,5 phosphorus oxychloride,6 and concentrated
hydrochloric acid.7
The homogeneous mixture of compound 1 and an equivalent of
coumarin-3-carboxylic acid chloride was ground in a mortar with a pes-
tle for 15–18 min to efficiently afford 2-(coumarin-3-carboxamido)-5-
aryloxymethyl-1,3,4-thiadiazoles (2a–k) in a 76–90% yield (Scheme 1).
The progress of the reaction was readily monitored by TLC. The differ-
ent substituents on the thiadiazole ring appeared to have no significant
effect on the reaction rate and the yield of the products. The same reac-
tion also could be subjected to microwave irradiation for 5–8 min to give

2-Amino-5-Aryloxymethyl-1, 3,4-Thiadiazoles
185
the products in a 87–93% yield with an exception of 2k, which needed
12 min to complete its reaction.
SCHEME 1
Similarly,
the
mixture
of
2-amino-5-aryloxymethyl-1,3,4-
thiadiazoles with an equivalent of benzofuran-2-carboxylic acid
chloride was ground in a mortar with a pestle for 12 min to afford
2-(benzofuran-2-carboxamido)-5-aryloxymethyl-1,3,4-thiadiazoles
(3a–f) in a 68–89% yield. The same reactions also could efficiently be
effected under microwave irradiation within 3 min with no significant
difference over various substituents in a very high yield (90–96%),
(Scheme 1). The related data are summarized in the Table I.
As a comparison, these reactions also were tested using the solu-
tion method. Therefore, the selected compounds 2a, 2g, and 2j were
attempted to be obtained by refluxing the corresponding reactants in
the solution of chloroform and DMSO in the presence of triethylamine
for 12 h. However, only moderate yields (58%, 49%, and 40%, respec-
tively) were obtained. The possible reason for lower yields is that the
large steric hindrance caused by two heterocyclic rings make the nucle-
ophilic substitutions more difficult in the solution condition than those
in the solvent-free condition.

186
Z. Li et al.
TABLE I The Solvent-Free Preparation of Bis-Heterocyclic
Compounds 2a–k and 3a–f
Microwave irradiation
Room-temperature grinding
Power
(W)
Time
(min)
Yield
(%)a
Time
(min)
Yield
(%)a
m.p.
(◦C)
Product
Ar
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
490
490
490
700
490
700
700
490
700
700
490
210
210
210
210
210
210
7
8
8
5
8
5
5
8
5
5
12
3
3
3
3
3
3
90
91
88
91
93
92
88
87
88
89
93
96
94
95
96
93
90
15
15
15
15
15
15
15
18
18
18
18
12
12
12
12
12
12
88
90
86
87
90
84
76
79
84
90
79
82
84
79
89
68
77
287–288
254–255
248–250
260–261
246–247
297–299
282–284
260–262
290–292
274–276
293–295
245–246
240–241
256–258
231–233
296–298
225–226
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
2,4-Cl2C6H3
3-O2NC6H4
4-O2NC6H4
1-Naphthyl
2-Naphthyl
C6H5
2-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-O2NC6H4
1-Naphthyl
2j
2k
3a
3b
3c
3d
3e
3f
aYields refer to the isolated products.
In conclusion, we have developed an efficient, expeditious, and
solvent-free method for the synthesis of 2-amino-5-aryloxymethyl-1,3,4-
thiadiazoles using a polymer-supported dehydration reagent and their
bis-heterocyclic compounds bearing coumarin or benzofuran via N-
acylation reactions, in which the steric hindered compounds readily can
be prepared within a shorter time in a much higher yield than in the
traditional solution method. Furthermore, the solvent-free strategy ex-
hibits advantages of no organic solvent pollution, an elevated reaction
rate, and a simple work-up procedure.
EXPERIMENTAL
IR were recorded using KBr pellets on an Alpha Centauri FTIR spec-
trophotometer and 1H NMR spectra on an Avanci-D2X-200 instrument
using (CD3)2SO as a solvent and Me4Si as an internal standard. Ele-
mental analyses were performed on a Vario E1 Elemental Analysis in-
strument. Mass spectra were recorded on a QP-1000A GC-MS using the
impact mode (70 eV). Melting points were observed in an electrother-
mal melting point apparatus and were uncorrected. Polymer-supported
dichlorophosphate was prepared according to a literature procedure.8

2-Amino-5-Aryloxymethyl-1, 3,4-Thiadiazoles
187
Coumarin-3-carboxylic acid chloride and benzofuran-2-carboxylic acid
chloride were prepared by the reactions of the corresponding acids with
thionyl chloride.
General Procedure for the Preparation of 2-amino-5-
aryloxymethyl-1,3,4-thiadiazoles
Thiosemicarbazide (1 mmol), aryloxyacetic acids (1 mmol) and PEG-
supported dichlorophosphate (2 mmol) was mixed in a mortar using a
pestle until a fine and homogeneous mixture was obtained. Then the
mixture was placed in a microwave oven and irradiated for 8–10 min
at 490 W power by means of 1 min of irradiation and then at a 30 s
interval in order to keep the temperature at ca. 120◦C. The completion
of the reactions was monitored by TLC using ethyl acetate, acetone,
and petroleum ether (3:2:4) as eluent. Then distilled water was added
to the resulting mixture, and the precipitate was collected by filtration
and recrystallized from DMF-EtOH to afford the products. The physical
and spectral data of representative compounds 1a and 1e are shown
below:
2-amino-5-phenoxymethyl-1,3,4-thiadiazole (1a): Yield: 84%; m.p.:
1
201–202◦C; H NMR: (DMSO-d6, 200 MHz): δ 6.28 (2H, s, NH2, ex-
changeable with D2O), 6.84–7.28 (5H, m, Ar-H), 5.27 (2H, s, OCH2);
IR (KBr, ν, cm−1): 3264, 3097 (N H), 1637 (C N), 1509, 1362, 1246,
1040 (1,3,4-thiadiazole nucleus). MS: m/z, 207 (M+). Anal. calcd. for
C9H9N3OS: C, 52.16; H, 4.38; N, 20.27. Found: C, 52.04; H, 4.44; N,
20.19.
2-amino-5-(4-methoxylphenoxymethyl)-1,3,4-thiadiazole (1e): Yield:
1
74%; m.p.: 210–212◦C; H NMR: (DMSO-d6, 200 MHz): δ 6.29 (2H, s,
NH2, exchangeable with D2O), 6.90–7.24 (4H, m, Ar-H), 5.28 (2H, s,
OCH2), 3.82 (3H, s, OCH3); IR (KBr, ν, cm−1 ): 3265, 3094 (N H), 1639
(C N), 1507, 1363, 1246, 1036 (1,3,4-thiadiazole nucleus). MS: m/z, 237
(M+). Anal. calcd. for C10H11N3O2S: C, 50.62; H, 4.67; N, 17.71. Found:
C, 50.57; H, 4.74; N, 17.85.
General Procedure for the Preparation of Compounds 2a–k
and 3a–f
The mixture of 2-amino-5-aryloxymethyl-1,3,4-thiadiazole (0.5 mmol)
and coumarin-3-carboxylic acid chloride or benzofuran-2-carboxylic
acid chloride (0.5 mmol) was ground in a mortar with a pestle until
the mixture was homogeneous. Then the resulting mixture was either
irradiated in a microwave oven at an appropriate power for a certain
time or was ground for a certain time at r.t. The progress of the re-
actions was monitored by TLC using acetone/ethyl acetate/petroleum

188
Z. Li et al.
ether (1:1:2) as an eluent. The resulting solid was crystallized from
AcOH or AcOH-DMF to afford the products. The analytic data for com-
pounds 2a–k and 3a–f are as follows:
2a: White crystal. 1H NMR (DMSO-d6): δ 12.35 (1H, s, NH), 8.97 (1H,
s, CH), 6.90–7.94 (9H, m, Ar-H), 5.50 (2H, s, CH2). IR (KBr,ν, cm−1):
3189 (N H), 1713 (C O), 1666 (C O). MS: m/z, 379 (M+). Anal. calcd.
for C19H13N3O4S: C, 60.15; H, 3.45; N, 11.08. Found: C, 60.21; H, 3.38;
N, 11.01.
2b: White crystal. 1H NMR (DMSO-d6): δ 12.36 (1H, s, NH), 9.00 (1H,
s, CH), 6.93–8.02 (8H, m, Ar-H), 5.52 (2H, s, CH2), 2.24 (3H, s, CH3).
IR (KBr, ν, cm−1): 3206 (N H), 1718 (C O), 1669 (C O). MS: m/z, 393
(M+). Anal. calcd. for C20H15N3O4S: C, 61.06; H, 3.84; N, 10.68. Found:
C, 61.18; H, 3.90; N, 10.72.
2c: White crystal. 1H NMR (DMSO-d6): δ 12.39 (1H, s, NH), 9.01 (1H,
s, CH), 6.94–7.98 (8H, m, Ar-H), 5.51 (2H, s, CH2), 2.22 (3H, s, CH3).
IR (KBr, ν, cm−1): 3205 (N H), 1715 (C O), 1666 (C O). MS: m/z, 393
(M+). Anal. calcd. for C20H15N3O4S: C, 61.06; H, 3.84; N, 10.68. Found:
C, 60.98; H, 3.88; N, 10.70.
2d: White crystal. 1H NMR (DMSO-d6): δ 12.38 (1H, s, NH), 9.00 (1H,
s, CH), 6.95–8.00 (8H, m, Ar-H), 5.50 (2H, s, CH2), 2.23 (3H, s, CH3).
IR (KBr, ν, cm−1): 3204 (N H), 1716 (C O), 1667 (C O). MS: m/z, 393
(M+). Anal. calcd. for C20H15N3O4S: C, 61.06; H, 3.84; N, 10.68. Found:
C, 61.11; H, 3.78; N, 10.57.
2e: Yellow crystal. 1H NMR (DMSO-d6): δ12.40 (1H, s, NH), 9.01 (1H,
s, CH), 6.97–8.02 (8H, m, Ar-H), 5.53 (2H, s, CH2), 3.52 (3H, s, CH3).
IR (KBr, ν, cm−1): 3199 (N H), 1724 (C O), 1670 (C O). MS: m/z, 409
(M+). Anal. calcd. for C20H15N3O5S: C, 58.67; H, 3.69; N, 10.26. Found:
C, 58.74; H, 3.60; N, 10.19.
2f: Yellow crystal. 1H NMR (DMSO-d6): δ 12.41 (1H, s, NH), 9.02 (1H,
s, CH), 6.94–8.03 (8H, m, Ar-H), 5.54 (2H, s, CH2). IR (KBr, ν, cm−1):
3202 (N H), 1726 (C O), 1679 (C O). MS: m/z, 413 (M+). Anal. calcd.
for C19H12ClN3O4S: C, 55.14; H, 2.92; N, 10.15. Found: C, 55.07; H, 3.00;
N, 10.10.
1
2g: Yellow crystal. H NMR (DMSO-d6): δ 12.43 (1H, s, NH), 9.04
(1H, s, CH), 6.94–8.07 (7H, m, Ar-H), 5.54 (2H, s, CH2). IR (KBr, ν,
cm−1): 3212 (N H), 1729 (C O), 1689 (C O). MS: m/z, 447 (M+). Anal.
calcd. for C19H11Cl2N3O4S: C, 50.91; H, 2.47; N, 9.37. Found: C, 50.84;
H, 2.53; N, 9.44.
2h: White crystal. 1H NMR (DMSO-d6): δ 12.42 (1H, s, NH), 9.04 (1H,
s, CH), 7.01–8.09 (8H, m, Ar-H), 5.53 (2H, s, CH2). IR (KBr, ν, cm−1):
3207 (N H), 1724 (C O), 1667 (C O). MS: m/z, 424 (M+). Anal. calcd.
for C19H12N4O6S: C, 53.77; H, 2.85; N, 13.20. Found: C, 53.86; H, 2.78;
N, 13.14.

2-Amino-5-Aryloxymethyl-1, 3,4-Thiadiazoles
189
2i Yellow crystal. 1H NMR (DMSO-d6): δ 12.41 (1H, s, NH), 9.03 (1H,
s, CH), 7.03–8.12 (8H, m, Ar-H), 5.54 (2H, s, CH2). IR (KBr, ν, cm−1):
3210 (N H), 1730 (C O), 1669 (C O). MS: m/z, 424 (M+). Anal. calcd.
for C19H12N4O6S: C, 53.77; H, 2.85; N, 13.20. Found: C, 53.70; H, 2.91;
N, 13.13.
2j: White crystal. 1H NMR (DMSO-d6): δ 12.38 (1H, s, NH), 9.00 (1H,
s, CH), 6.93–7.99 (11H, m, Ar-H), 5.51 (2H, s, CH2). IR (KBr, ν, cm−1):
3206 (N H), 1720 (C O), 1668 (C O). MS: m/z, 429 (M+). Anal. calcd.
for C23H15N3O4S: C, 64.33; H, 3.52; N, 9.78. Found: C, 64.25; H, 3.48;
N, 9.86.
1
2k: Yellow crystal. H NMR (DMSO-d6): δ 12.40 (1H, s, NH), 8.98
(1H, s, CH), 6.97–8.01 (11H, m, Ar-H), 5.52 (2H, s, CH2). IR (KBr, ν,
cm−1): 3205 (N H), 1723 (C O), 1676 (C O). MS: m/z, 393 (M+). Anal.
calcd. for C23H15N3O4S: C, 64.33; H, 3.52; N, 9.78. Found: C, 64.40; H,
3.49; N, 9.71.
1
3a: White crystal. H NMR (DMSO-d6): δ 13.44 (1H, s, NH), 6.96–
8.10 (10H, m, Ar-H and Fu-H), 5.53 (2H, s, CH2). IR (KBr, ν, cm−1): 3218
(N H), 1676 (C O). MS: m/z, 351 (M+). Anal. calcd. for C18H13N3O3S:
C, 61.53; H, 3.73; N, 11.96. Found: C, 61.46; H, 3.80; N, 12.00.
1
3b: White crystal. H NMR (DMSO-d6): δ 13.43 (1H, s, NH), 7.04–
8.21 (9H, m, Ar-H and Fu-H), 5.52 (2H, s, CH2), 2.30 (3H, s, CH3). IR
(KBr, ν, cm−1): 3212 (N H), 1675 (C O). MS: m/z, 365 (M+). Anal. calcd.
for C19H15N3O3S: C, 62.45; H, 4.14; N, 11.50. Found: C, 62.33; H, 4.10;
N, 11.58.
3c: White crystal. 1H NMR (DMSO-d6): δ 13.45 (1H, s, NH), 7.03–8.19
(9H, m, Ar-H and Fu-H), 5.53 (2H, s, CH2), 2.28 (3H, s, CH3). IR (KBr,
ν, cm−1): 3213 (N H), 1674 (C O). MS: m/z, 365 (M+). Anal. calcd. for
C19H15N3O3S: C, 62.45; H, 4.14; N, 11.50. Found: C, 62.51; H, 4.08; N,
11.44.
1
3d: White crystal. H NMR (DMSO-d6): δ 13.48 (1H, s, NH), 7.02–
8.14 (9H, m, Ar-H and Fu−H), 5.54 (2H, s, CH2), 3.51 (3H, s, CH3).
IR (KBr, ν, cm−1): 3108 (N H), 1677 (C O). MS: m/z, 381 (M+). Anal.
calcd. for C19H15N3O4S: C, 59.83; H, 3.96; N, 11.02. Found: C, 59.76; H,
4.01; N, 11.12.
1
3e: White crystal. H NMR (DMSO-d6): δ 13.50 (1H, s, NH), 7.21–
8.29 (9H, m, Ar-H and Fu-H), 5.55 (2H, s, CH2). IR (KBr, ν, cm−1): 3105
(N H), 1674 (C O). MS: m/z, 396 (M+). Anal. calcd. for C18H12N4O5S:
C, 54.54; H, 3.05; N, 14.13. Found: C, 54.62; H, 3.11; N, 14.04.
1
3f:White crystal. H NMR (DMSO-d6): δ 13.45 (1H, s, NH), 7.01–
8.14 (12H, m, Ar-H and Fu-H), 5.53 (2H, s, CH2). IR (KBr, ν,
cm−1): 3213 (N H), 1688 (C O). MS: m/z, 401 (M+). Anal. calcd. for
C22H15N3O3S: C, 65.82; H, 3.77; N, 10.47. Found: C, 65.75; H, 3.82;
N, 10.54.

190
Z. Li et al.
REFERENCES
[1] (a) M. Mamolo, L. Vio, and E. Banfi, Farmaco, 51, 71 (1996); (b) F. Clerici, D. Pocar, M.
Guido, A. Loche, and V. Perlini, J. Med. Chem., 44, 931 (2001); (c) L. Labanauskas, V.
Kalcas, E. Udrenaite, P. Gaidelis, A. Brukstus, and V. Dauksas, Pharmazie, 56, 617
(2001).
[2] (a) Y. Shikishima, Y. Takaishi, G. Honda, M. Ito, Y. Takeda, O. K. Kodzhimatov, O.
Ashurmetov, and K. H. Lee, Chem. Pharm. Bull., 49, 877 (2001); (b) S. Shah, D. Desai,
and R. H. Mehta, J. Indian Chem. Soc., 76, 507 (1999); (c) A. H. Abdel-Rahman, A. M.
Khalil, and M. M. Girges, Boll. Chim. Farm., 137, 387 (1998); (d) M. Campos-Toimil,
F. Orallo, L. Santana, and E. Uriarte, Bioorg. Med. Chem. Lett., 12, 783 (2002).
[3] (a) M. Morimoto, M. Urakawa, T. Fujitaka, and K. Komai, Biosci. Biotechnol.
Biochem., 63, 840 (1999); (b) K. Ishibashi, K. Nakajima, Y. Sugioka, M. Sugiyama, and
T. Hamada, Bioorg. Med. Chem. Lett., 8, 561 (1998); (c) G. M. Rott, L. I. Shevchenko,
O. A. Smoryzanova, E. P. Savina, V. S. Deeva, V. G. Skvortsov and F. A. Trofimov,
Pharm. Chem. J. (Engl. Transl.), 32, 652 (1998).
[4] K. Tanaka and F. Toda, Chem. Rev., 100, 1025 (2000).
[5] E. E. Oruc, S. Rollas, F. Kandemirli, N. Shvets, and A. S. Dimoglo, J. Med. Chem., 47,
6760 (2004).
[6] A. A. F. Wasfy, S. A. Nassar, and A. M. F. Eissa, Indian J. Chem. Sect., B, 35, 1218
(1996).
[7] Z. G. Le, J. H. Ding, and S. J. Yang, Huaxue Shijie (Chinese), 43, 366 (2002).
[8] Z. Li, J. L. Yu, R. B. Ding, Z. Y. Wang, and X. C. Wang, Synth. Commun., 34, 2981
(2004).