Efficient synthesis of 1-(5′-acylamino-1′,3′,4′- thiadiazol-2′-yl)-4-acyl-thiosemicarbazides

Article abstract of DOI:10.1080/00397910600640164

Acyl chlorides reacted with ammonium thiocyanate and carbonic dihydrazide under phase-transfer catalysis to first afford 2,2′- bis(acylaminothiocarbonyl)-carbonic dihydrazides, which further cyclized in the presence of glacial acetic acid to efficiently give 1-(5′-acylamino- 1′,3′,4′-thiadiazol-2′-yl)-4-acyl-thiosemicarbazides in high yield. Copyright Taylor & Francis Group, LLC.

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Efficient Synthesis of
1‐(5′‐Acylamino‐1′,3′,4′‐thiadiazol‐2′‐yl)‐4‐acyl‐
Zheng Li a , Jing‐Ya Yang a & Xi‐Cun Wang a
a Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering , Northwest Normal University , Lanzhou, Gansu,
China
Published online: 22 Sep 2006.
To cite this article: Zheng Li , Jing‐Ya Yang & Xi‐Cun Wang (2006) Efficient Synthesis of
1‐(5′‐Acylamino‐1′,3′,4′‐thiadiazol‐2′‐yl)‐4‐acyl‐thiosemicarbazides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:16, 2355-2362, DOI:
10.1080/00397910600640164
To link to this article: http://dx.doi.org/10.1080/00397910600640164
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Synthetic Communicationsw, 36: 2355–2362, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600640164
Efficient Synthesis of 1-(50-Acylamino-
10,30,40-thiadiazol-20-yl)-4-acyl-
thiosemicarbazides
Zheng Li, Jing-Ya Yang, and Xi-Cun Wang
Gansu Key Laboratory of Polymer Materials, College of Chemistry
and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu, China
Abstract: Acyl chlorides reacted with ammonium thiocyanate and carbonic dihydra-
zide under phase-transfer catalysis to first afford 2,20-bis(acylaminothiocarbonyl)-
carbonic dihydrazides, which further cyclized in the presence of glacial acetic acid
to efficiently give 1-(50-acylamino-10,30,40-thiadiazol-20-yl)-4-acyl-thiosemicarbazides
in high yield.
Keywords: Carbonic dihydrazide, phase-transfer catalysis, 1,3,4-thiadiazole,
thiosemicarbazide
INTRODUCTION
Thiosemicarbazides have attracted much attention in recent years because of
their fungicidal,[1] bactericidal,[2] and antiamoebic[3] activities. In addition,
1,3,4-thiadiazole derivatives also have great biological importance because
of their antituberculosis,[4] anti-inflammatory,[5] antihypertensive,[6] and
anti-HIV-1[7] activities. These applications prompted us to develop a con-
venient synthetic method for a series of new compounds bearing both thio-
semicarbazide and 1,3,4-thiadiazole moieties, with the object of obtaining
new biologically active compounds.
Received in Japan October 7, 2005
Address correspondence to Zheng Li, Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, China. E-mail: lizheng@nwnu.ed.cn
2355

2356
Z. Li, J.-Y. Yang, and X.-C. Wang
Generally, substituted thiosemicarbazides are synthesized by reactions of
isothiocyanates with acid hydrazides under poly(ethylene glycol) (PEG) as
phase-transfer catalyst.[8] Meanwhile, 1,3,4-thiadiazoles are synthesized by
cyclization of various substituted thiosemicarbazides in the presence of
acetic acid.[9] Lau and co-workers also reported a solid-phase synthesis of
1,3,4-thiadiazoles.[10] However, to the best of our knowledge, there are no
any examples of reported synthetic routes for the compounds including both
thiosemicarbazide and thiadiazole moieties in one organic small molecule.
In continuation of our ongoing program to synthesize biologically active
compounds and develop efficient strategies for organic transformations, herein
we report a novel approach for preparation of thiadiazolyl-substituted
thiosemicarbazides.
RESULTS AND DISCUSSION
A variety of acyl chlorides (1a–k) were treated with ammonium thiocyanate
in the solution of methylene chloride at room temperature using PEG-400 as
phase-transfer catalyst to give corresponding acyl isothiocyanates (2a–k),
which did not need to be isolated and further reacted with 0.5 equiv of
carbonic dihydrazide in situ to afford 2,20-bis(acylaminothiocarbonyl)-
carbonic dihydrazides (3a–k) in 72–98% yield. It is noteworthy that PEG-
400 as a phase-transfer catalyst is indispensable for these reactions. It can
easily react with NH4SCN to form complex [PEG-400-NHþ4 ]SCN2, which
makes it possible for SCN2 to readily react with acyl chlorides and leads to
the formation of acyl isothiocyanates. However, if no PEG-400 is used,
there are no acyl isothiocyanates formed and therefore no target compounds
3a–k are produced at all. Compounds 3a–k were treated with glacial acetic
acid under reflux to successfully transform into 1-(50-acylamino-10,30,40-
thiadiazol-20-yl)-4-acyl-thiosemicarbazides (4a–k) via dehydration cycliza-
tion in 76–96% yield) (Scheme 1, Table 1).
Scheme 1.

Synthesis of Thiosemicarbazides
Table 1. Efficient synthesis of 3a–k and 4a–k
2357
Compound
R
Mp (8C)
Yield (%)a
3a
3b
3c
3d
3e
3f
C6H5
198–200
190–192
174–176
182–184
175–177
227–229
162–164
199–201
164–166
189–191
97
96
98
82
86
97
97
96
72
89
4-CH3OC6H4
2-CH3C6H4
3-CH3C6H4
2-ClC6H4
4-ClC6H4
3g
3h
3i
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
C6H5CH2
3j
3k
159–161
96
4a
4b
4c
4d
4e
4f
C6H5
232–234
214–216
216–218
223–225
193–195
242–244
224–226
256–258
259–261
132–134
92
88
82
90
76
86
78
84
87
89
4-CH3OC6H4
2-CH3C6H4
3-CH3C6H4
2-ClC6H4
4-ClC6H4
4g
4h
4i
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
C6H5CH2
4j
4k
190–192
96
aYields refer to the isolated products.
In conclusion, we have developed an efficient methodology for thiadiazo-
lyl-substituted thiosemicarbazides using PEG-400 as phase-transfer catalyst
and dehydration cyclization. It has advantages of mild conditions, high
yields, and simple manipulation.
EXPERIMENTAL
IR spectra were recorded using KBr pellets on a Digilab FTS 3000 FTIR
1
spectrophotometer and H NMR spectra on a Mercury Plus-400 instrument
using (CD3)2SO as solvent and Me4Si as internal standard. Elemental
analyses were performed on a Vario E1 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 electrothermal melting-
point apparatus and are uncorrected. Carbonic dihydrazide was prepared
by reaction of dimethyl carbonate with 2 equiv of hydrazine hydrate under
reflux.

2358
Z. Li, J.-Y. Yang, and X.-C. Wang
General Procedure for the Preparation of Compounds 3a–k
Ammonium thiocyanate (6 mmol) and PEG-400 (0.1 mmol) were added to a
solution of an acyl chloride (4.2 mmol) in 15 mL of methylene chloride.
The mixture was stirred for 2 h at room temperature. Then carbonic
dihydrazide (2mmol) was added, and the reaction mixture was stirred for
another 4 h at room temperature. The resulting suspension was filtered, and
the solid was washed with water (2 ꢀ 10 mL), and recrystallized from
DMF–EtOH–H2O (6 : 3 : 1) to give products 3a–k. The analytic data for
compounds 3a–k are given next.
Data
3a: White crystal. 1H NMR (DMSO-d6): d 12.57 (bs, 2H, NH), 11.78 (s, 2H,
NH), 9.75 (bs, 2H, NH), 7.52–7.98 (m, 10H, Ar–H). IR (KBr, n, cm21): 3302,
3213 (N–H), 1674 (C55O), 1204 (C55S). MS: m/z, 416 (Mþ). Anal. calcd. for
C17H16N6O3S2: C, 49.03; H, 3.87; N, 20.18. Found: C, 48.92; H, 3.92; N,
20.22.
3b: Yellow crystal. 1H NMR (DMSO-d6): d 12.59 (bs, 2H, NH), 11.79 (s, 2H,
NH), 9.77 (bs, 2H, NH), 7.03–7.87 (m, 8H, Ar–H), 3.75 (s, 6H, CH3). IR
(KBr, n, cm21): 3340, 3236 (N–H), 1672 (C55O), 1176 (C55S). MS: m/z,
476 (Mþ). Anal. calcd. for C19H20N6O5S2: C, 47.89; H, 4.23; N, 17.64.
Found: C, 47.96; H, 4.15; N, 17.53.
3c: Yellow crystal. 1H NMR (DMSO-d6): d 12.56 (bs, 2H, NH), 11.77 (s, 2H,
NH), 9.74 (bs, 2H, NH), 7.32–7.86 (m, 8H, Ar–H), 2.35 (s, 6H, CH3). IR
(KBr, n, cm21): 3372, 3228 (N–H), 1680 (C55O), 1176 (C55S). MS: m/z,
444 (Mþ). Anal. calcd. for C19H20N6O3S2: C, 51.34; H, 4.53; N, 18.91.
Found: C, 51.46; H, 4.61; N, 18.95.
3d: Yellow crystal. 1H NMR (DMSO-d6): d 12.55 (bs, 2H, NH), 11.76 (s, 2H,
NH), 9.74 (bs, 2H, NH), 7.35–7.79 (m, 8H, Ar–H), 2.34 (s, 6H, CH3). IR
(KBr, n, cm21): 3228 (N–H), 1686, 1674 (C55O), 1188 (C55S). MS: m/z,
444 (Mþ). Anal. calcd. for C19H20N6O3S2: C, 51.34; H, 4.53; N, 18.91.
Found: C, 51.27; H, 4.44; N, 18.84.
3e: Yellow crystal. 1H NMR (DMSO-d6): d 12.60 (bs, 2H, NH), 11.80 (s, 2H,
NH), 9.79 (bs, 2H, NH), 7.36–7.92 (m, 8H, Ar–H). IR (KBr, n, cm21): 3256
(N–H), 1670 (C55O), 1184 (C55S). MS: m/z, 484 (Mþ). Anal. calcd. for
C17H14Cl2N6O3S2: C, 42.07; H, 2.91; N, 17.31. Found: C, 42.14; H, 2.97;
N, 17.24.
3f: Yellow crystal. 1H NMR (DMSO-d6): d 12.60 (bs, 2H, NH), 11.81 (s, 2H,
NH), 9.79 (bs, 2H, NH), 7.49–7.92 (m, 8H, Ar–H). IR (KBr, n, cm21): 3180

Synthesis of Thiosemicarbazides
2359
(N–H), 1692, 1678 (C55O), 1190 (C55S). MS: m/z, 484 (Mþ). Anal. calcd.
for C17H14Cl2N6O3S2: C, 42.07; H, 2.91; N, 17.31. Found: C, 42.00; H,
2.83; N, 17.37.
3g: Yellow crystal. 1H NMR (DMSO-d6): d 12.62 (bs, 2H, NH), 11.83 (s, 2H,
NH), 9.80 (bs, 2H, NH), 7.77–8.37 (m, 8H, Ar–H). IR (KBr, n, cm21): 3384,
3240 (N–H), 1692 (C55O), 1186 (C55S). MS: m/z, 506 (Mþ). Anal. calcd. for
C17H14N8O7S2: C, 40.32; H, 2.79; N, 22.12. Found: C, 40.24; H, 2.88; N, 22.19.
3h: Brown crystal. 1H NMR (DMSO-d6): d12.61 (bs, 2H, NH), 11.81 (s, 2H, NH),
9.79 (bs, 2H, NH), 7.70–8.88 (m, 8H, Ar–H). IR (KBr, n, cm21): 3328, 3280,
3240 (N–H), 1680 (C55O), 1182 (C55S). MS: m/z, 506 (Mþ). Anal. calcd. for
C17H14N8O7S2: C, 40.32; H, 2.79; N, 22.12. Found: C, 40.41; H, 2.72; N, 22.21.
3i: Yellow crystal. 1H NMR (DMSO-d6): d 12.63 (bs, 2H, NH), 11.83 (s, 2H,
NH), 9.81 (bs, 2H, NH), 8.21–8.37 (m, 8H, Ar–H). IR (KBr, n, cm21): 3244
(N–H), 1684 (C55O), 1178 (C55S). MS: m/z, 506 (Mþ). Anal. calcd. for
C17H14N8O7S2: C, 40.32; H, 2.79; N, 22.12. Found: C, 40.37; H, 2.85; N, 22.05.
3j: Yellow crystal. 1H NMR (DMSO-d6): d 12.58 (bs, 2H, NH), 11.79 (s, 2H,
NH), 9.77 (bs, 2H, NH), 7.10–7.16 (m, 10H, Ar–H), 3.46 (s, 4H, CH2). IR
(KBr, n, cm21): 3252, 3232, 3212 (N-H), 1708, 1696 (C55O), 1176 (C55S).
MS: m/z, 444 (Mþ). Anal. calcd. for C19H20N6O3S2: C, 51.34; H, 4.53; N,
18.91. Found: C, 51.26; H, 4.46; N, 18.99.
3k: Brown crystal. 1H NMR (DMSO-d6): d 12.60 (bs, 2H, NH), 11.79 (s, 2H,
NH), 9.78 (bs, 2H, NH), 7.12–7.79 (m, 14H, Na–H), 3.89 (s, 4H, CH2). IR
(KBr, n, cm21): 3364, 3184 (N–H), 1694 (C55O), 1190 (C55S). MS: m/z,
544 (Mþ). Anal. calcd. for C27H24N6O3S2: C, 59.54; H, 4.44; N, 15.43.
Found: C, 59.62; H, 4.50; N, 15.35.
General Procedure for the Preparation of Compounds 4a–k
Compounds 3a–k (0.5 mmol) were dissolved in 10 mL of glacial acetic acid
and refluxed for 8 h. The reaction was monitored by TLC. The excess of
glacial acetic acid was removed under reduced pressure, and the residue
was poured into 50 g of ice water. Then the resulting solid was collected
by filtration, washed with water (3 ꢀ 10 mL), and recrystallized from
DMF–EtOH–H2O (6 : 3 : 1) to afford products 4a–k. The analytic data for
compounds 4a–k are given next.
Data
1
4a: White crystal. H NMR (DMSO-d6): d 13.92 (s, 1H, NH), 13.76 (s, 1H,
NH), 12.41 (s, 1H, NH), 12.31 (s, 1H, NH), 7.53–8.05 (m, 10H, Ar–H). IR

2360
Z. Li, J.-Y. Yang, and X.-C. Wang
(KBr, n, cm21): 3306, 3252, 3116 (N–H), 1645 (C55O), 1581, 1505, 1475,
1301, 1265, 1223 (C55N–N55C), 1188 (C55S). MS: m/z, 398 (Mþ). Anal.
calcd. for C17H14N6O2S2: C, 51.24; H, 3.54; N, 21.09. Found: C, 51.30; H,
3.50; N, 21.12.
1
4b: White crystal. H NMR (DMSO-d6): d 13.93 (s, 1H, NH), 13.77 (s, 1H,
NH), 12.41 (s, 1H, NH), 12.31 (s, 1H, NH), 7.03–7.91 (m, 8H, Ar–H),
3.73 (s, 6H, CH3). IR (KBr, n, cm21): 3338, 3216 (N–H), 1664 (C55O),
1582, 1506, 1478, 1304, 1268, 1228 (C55N–N55C), 1178 (C55S). MS:
m/z, 458 (Mþ). Anal. calcd. for C19H18N6O4S2: C, 49.77; H, 3.96; N,
18.33. Found: C, 49.69; H, 4.10; N, 18.39.
1
4c: Yellowish crystal. H NMR (DMSO-d6): d 13.91 (s, 1H, NH), 13.75
(s, 1H, NH), 12.40 (s, 1H, NH), 12.30 (s, 1H, NH), 7.31–7.89 (m, 8H, Ar–
H), 2.35 (s, 6H, CH3). IR (KBr, n, cm21): 3362, 3248 (N–H), 1670
(C55O), 1588, 1516, 1474, 1310, 1268, 1218 (C55N–N55C), 1176 (C55S).
MS: m/z, 426 (Mþ). Anal. calcd. for C19H18N6O2S2: C, 53.50; H, 4.25; N,
19.70. Found: C, 53.56; H, 4.27; N, 19.62.
1
4d: White crystal. H NMR (DMSO-d6): d 13.90 (s, 1H, NH), 13.75 (s, 1H,
NH), 12.39 (s, 1H, NH), 12.30 (s, 1H, NH), 7.34–7.78 (m, 8H, Ar–H),
2.34 (s, 6H, CH3). IR (KBr, n, cm21): 3362, 3226 (N–H), 1676 (C55O),
1578, 1512, 1484, 1308, 1266, 1220 (C55N–N55C), 1188 (C55S). MS:
m/z, 426 (Mþ). Anal. calcd. for C19H18N6O2S2: C, 53.50; H, 4.25; N,
19.70. Found: C, 53.44; H, 4.28; N, 19.78.
4e: Yellow crystal. 1H NMR (DMSO-d6): d 13.95 (s, 1H, NH), 13.78 (s, 1H,
NH), 12.43 (s, 1H, NH), 12.34 (s, 1H, NH), 7.33–7.90 (m, 8H, Ar–H). IR
(KBr, n, cm21): 3326, 3246 (N–H), 1662 (C55O), 1594, 1516, 1488, 1316,
1262, 1230 (C55N–N55C), 1182 (C55S). MS: m/z, 466 (Mþ). Anal. calcd.
for C17H12Cl2N6O2S2: C, 43.69; H, 2.59; N, 17.98. Found: C, 43.66; H,
2.54; N, 18.04.
4f: Yellowish crystal. 1H NMR (DMSO-d6): d 13.95 (s, 1H, NH), 13.79 (s, 1H,
NH), 12.43 (s, 1H, NH), 12.33 (s, 1H, NH), 7.46–7.90 (m, 8H, Ar–H). IR
(KBr, n, cm21): 3314, 3240 (N–H), 1670 (C55O), 1596, 1512, 1484, 1308,
1268, 1226 (C55N–N55C), 1192 (C55S). MS: m/z, 466 (Mþ). Anal. calcd.
for C17H12Cl2N6O2S2: C, 43.69; H, 2.59; N, 17.98. Found: C, 43.62; H,
2.56; N, 18.01.
4g: Yellow crystal. 1H NMR (DMSO-d6): d 14.17 (s, 1H, NH), 13.88 (s, 1H,
NH), 12.68 (s, 1H, NH), 12.44 (s, 1H, NH), 7.78–8.38 (m, 8H, Ar–H). IR
(KBr, n, cm21): 3234, 3168 (N–H), 1684 (C55O), 1598, 1520, 1495, 1332,
1262, 1230 (C55N–N55C), 1180 (C55S). MS: m/z, 488 (Mþ). Anal. calcd.

Synthesis of Thiosemicarbazides
2361
for C17H12N8O6S2: C, 41.80; H, 2.48; N, 22.94. Found: C, 41.84; H, 2.53; N,
22.88.
4h: Yellow crystal. 1H NMR (DMSO-d6): d 14.16 (s, 1H, NH), 13.89 (s, 1H,
NH), 12.67 (s, 1H, NH), 12.43 (s, 1H, NH), 7.79–8.84 (m, 8H, Ar–H). IR
(KBr, n, cm21): 3322, 3232, 3180 (N–H), 1666 (C55O), 1580, 1529, 1493,
1348, 1313, 1233 (C55N–N55C), 1160 (C55S). MS: m/z, 488 (Mþ). Anal.
calcd. for C17H12N8O6S2: C, 41.80; H, 2.48; N, 22.94. Found: C, 40.87; H,
2.52; N, 22.86.
1
4i: Yellow crystal. H NMR (DMSO-d6): d 14.18 (s, 1H, NH), 13.91 (s, 1H,
NH), 12.68 (s, 1H, NH), 12.45 (s, 1H, NH), 8.22–8.38 (m, 8H, Ar–H). IR
(KBr, n, cm21): 3326, 3246 (N–H), 1674 (C55O), 1588, 1526, 1502, 1352,
1258, 1224 (C55N–N55C), 1166 (C55S). MS: m/z, 488 (Mþ). Anal. calcd.
for C17H12N8O6S2: C, 41.80; H, 2.48; N, 22.94. Found: C, 41.83; H, 2.45;
N, 22.89.
1
4j: Brown crystal. H NMR (DMSO-d6): d 13.93 (s, 1H, NH), 13.77 (s, 1H,
NH), 12.43 (s, 1H, NH), 12.32 (s, 1H, NH), 7.08–7.16 (m, 10H, Ar–H),
3.45 (s, 4H, CH2). IR (KBr, n, cm21): 3362, 3226, 3214 (N–H), 1670
(C55O), 1584, 1506, 1472, 1308, 1262, 1208 (C55N–N55C), 1162 (C55S).
MS: m/z, 426 (Mþ). Anal. calcd. for C19H18N6O2S2: C, 53.50; H, 4.25; N,
19.70. Found: C, 53.43; H, 4.26; N, 19.68.
4k: Off-white crystal. 1H NMR (DMSO-d6): d 13.95 (s, 1H, NH), 13.78 (s, 1H,
NH), 12.43 (s, 1H, NH), 12.34 (s, 1H, NH), 7.20–7.70 (m, 14H, Ar–H), 3.56
(s, 4H, CH2). IR (KBr, n, cm21): 3304, 3184 (N–H), 1666 (C55O), 1588,
1510, 1482, 1300, 1264, 1200 (C55N–N55C), 1168 (C55S). MS: m/z, 526
(Mþ). Anal. calcd. for C27H22N6O2S2: C, 61.58; H, 4.21; N, 15.96. Found:
C, 61.64; H, 4.23; N, 15.88.
ACKNOWLEDGMENT
The authors thank the Chunhui Project of Ministry of Education of China
(Z2004-1-62034) for the financial support of this work.
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