Synthesis of 2-(N-formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles with potential bioactivity in PEG-400

Article abstract of DOI:10.1016/j.cclet.2009.11.045

An environmental benign procedure for synthesis of 2-(N-formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles has been developed by reaction of 2-amino-5-aryl/aryloxymethyl-1,3,4-thiadiazoles with formic acid in PEG-400. The key advantages of this protocol are

Full text of DOI:10.1016/j.cclet.2009.11.045

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 301–304
www.elsevier.com/locate/cclet
Synthesis of 2-(N-formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles
with potential bioactivity in PEG-400
*
Xi Cun Wang , Xiao Mei Ding, Sheng Qing Wang, Xue Fei Chen,
Zheng Jun Quan
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China. Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
Received 14 July 2009
Abstract
An environmental benign procedure for synthesis of 2-(N-formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles has been developed
by reaction of 2-amino-5-aryl/aryloxymethyl-1,3,4-thiadiazoles with formic acid in PEG-400. The key advantages of this protocol
are the shorter reaction time, higher yields, lower cost, simple workup, and environment-friendly compared to conventional organic
solvent reaction. The present method does not involve any hazardous organic solvent or catalyst.
# 2009 Xi Cun Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2-(N-Formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles; 2-Amino-5-aryl/aryloxymethyl-1,3,4-thiadiazoles; PEG-400; Synthesis
The 1,3,4-thiadiazole derivatives have attracted continuing interest over the years because of their varied biological
activities, such as antituberculosis, anticancer, antibacterial, antifungal and anticonvulsant activities [1–7]. 2-Amino-
1,3,4-thiadiazoles of 1,3,4-thiadiazole derivatives provided a useful method for the synthesis of 1,3,4-thiadiazoles, it
has been used for synthesis of various compounds possessing biological activities as intermediates [8–11]. On the
other hand, formamides are valuable intermediates in the construction of various pharmaceutically important
compounds and useful reagents in Vilsmeier formylation reactions. Besides, formamides can catalyze several organic
transformations as Lewis bases. The formyl group is also an important protecting group of amines in peptide synthesis
[12–17]. Based on the principle of superposition, a higher biological activity compound may be obtained by
connecting 1,3,4-thiadiazole and formamides groups in one molecule. Here, we report an environmental benign
synthesis of such compounds.
Developing green chemical reactions is one of the most important purposes of modern organic synthesis.
Polyethylene glycol (PEG) and its monomethyl ethers have emerged as alternative green reaction media with unique
properties such as thermal stability, commercial availability, non-volatility, immiscibility with a number of organic
solvents, and recyclability [18]. On the other hand, PEGs are inexpensive, completely non-halogenated, and low toxic.
Recently, PEGs have received considerable attention in synthetic organic chemistry as green organic solvent [19–23].
In the present conversion, it has efficiently been utilized for the preparation of various N-formyl compounds [12].
* Corresponding author.
E-mail address: wangxicun@nwnu.edu.cn (X.C. Wang).
1001-8417/$ – see front matter # 2009 Xi Cun Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.11.045

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X.C. Wang et al. / Chinese Chemical Letters 21 (2010) 301–304
As part of our ongoing interest in the 2-amino-5-aryl/aryloxymethyl-1,3,4-thiadiazoles for synthesis of various
compounds as intermediates [20,24] and taking all the above-mentioned evidence into account, a series of novel 2-(N-
formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles were designed and synthesized.
1. Result and discussion
As described in Scheme 1, the starting material 2-amino-5-aryl/aryloxymethyl-1,3,4-thiadiazoles 2a–n were
synthesized as the previous work [25]. When 2-amino-5-aryl/aryloxymethyl-1,3,4-thiadiazoles and HCOOH are
stirred at room temperature or heated without any solvent, the product was not found and all starting materials were
recovered. Then we tested the model reaction 3a (A mixture of 2-amino-5-phenoxymethyl-1,3,4-thiadia-zoles and
HCOOH was heated in PEG-400) and found that the reaction proceeded under polyethylene glycol (PEG) and gave
1
high yield, so we haven’t further studied for other solvent. The compound 3a was confirmed by IR, H NMR, 13C
NMR. The IR spectrum of 3a displayed bands at 3163 cmÀ1 and 1693 cmÀ1 due to –NH– and –C O stretching
1
frequencies, respectively. The H NMR spectrum of 3a exhibited one singlet at d 5.46 which accounts for two
methylene protons on the –OCH2–protons. A singlet at d 8.74 accounts for the –CHO proton and a singlet about d
12.78 is due to the –NH–proton. The 13C NMR displayed peaks at d 64.6 (CH2), 114.8 (2C), 122.1, 129.8 (2C), 157.4,
158.5, 161.9 (C O).
In following study of model reaction 3a, we examined the reaction in different conditions to find out the effect of
temperature and time on the reaction. It was found that low yield was obtained at lower temperature, even if the
reaction time was prolonged (entry 1). Higher yield was obtained under higher temperature and longer time (entry 7).
But when the reaction solution was heated at 130 8C, such high temperature did not further improve yield. From
Table 1 it can be seen that if this reaction was performed at 110 8C for 2 h, the desired product 3a was produced in the
highest yield (Table 1 entry 5, 11).
With the optimized condition in hand, a series of 2-(N-formyl)-5-aryl/aryloxymethyl-1,3,4-thiadiazoles were
synthesized in PEG-400 with high yields without additional solvent or catalyst (Table 2) [26]. Both electron-donating
and electron-withdrawing groups are tolerated in the reaction, and we found that the N-formylation of 5-aryl/
Scheme 1.
Table 1
Synthesis of 3a at different temperature and time.
Entry
Solvent
Temperature (8C)
Time (h)
Yielda (%)
1
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
25
2
10
55
73
84
94
94
94
61
73
86
93
2
80
2
3
90
2
4
100
110
120
130
110
110
110
110
2
5
2
6
2
7
2
8
0.5
1
9
10
11
1.5
2.5
a
Isolated yield.

X.C. Wang et al. / Chinese Chemical Letters 21 (2010) 301–304
303
Table 2
Synthesis of 2a–o refluxed in PEG-400.
Entry
Product
R
Product
Mp (8C)
Yielda (%)
1
3a
3b
3c
3d
3e
3f
C6H5OCH2
C10H9N3O2S
C10H8ClN3O2S
C11H11N3O2S
C10H9N3O2S
C10H8ClN3O2S
C11H11N3O3S
C11H11N3O3S
C11H11N3O2S
C10H8N4O3S
C10H8N4O4S
C9H7N3OS
136–138
250–252
209–211
247–249
218–220
171–173
183–185
190–192
219–221
225–227
201–203
248–250
179–181
213–215
96
92
94
94
91
96
95
94
87
89
94
92
94
85
2
2-ClC6H4OCH2
2-CH3C6H4OCH2
4-CH3OC6H4
3
4
5
4-ClC6H4OCH2
4-CH3OC6H4OCH2
2-CH3OC6H4OCH2
3-CH3C6H4OCH2
2-NO2C6H4OCH2
4-NO2C6H4OCH2
C6H5
6
7
3g
3h
3i
8
9
10
11
12
13
14
3j
3k
3l
2-CH3OC6H4
C9H6ClN3OS
C10H9N3OS
3m
3n
3-CH3C6H4
3-NO2C6H4
C9H6N4O3S
a
Isolated yield.
aryloxymethyl-1,3,4-thiadiazoles having electron-donating groups such as methyl and methoxy in the aromatic ring
occured in higher yields than having electron-withdrawing groups such as chloro and nitro groups. In particularly, for
compounds with nitro, the yields were a little lower because of the stronger ability of electron-withdrawing (Table 2,
entries 9, 10, 14).
In summary, we have developed a convenient method for preparation of 2-(N-formyl)-5-aryl/aryloxy-methyl-1,3,4-
thiadiazoles. The advantages of this methodology lie in higher yields, operational simplicity, lower cost, and less
pollution to environment. Moreover, this procedure will provide a good to excellent method for synthesis of 1,3,4-
thiadiazoles derivatives.
Acknowledgments
We are thankful for the financial support from the Natural Science Foundation of Gansu Province (No. 3ZS061-
A25-019), the Scientific Research fund of Gansu Provincial Education Department(No. 0601-25).
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mixture of thiadiazoles (1 mmol) and HCOOH (3 mmol), then the mixture was heated at 110 8C for 2 h and the progress of the reaction was
monitored by TLC. After completion, the mixture was diluted with water (10 mL) and filtered. The residue was subjected to column
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NMR, MS, Anal.) data. 3a Mp: 136–138 8C. IR (KBr) n: 3163, 1693, 1247 cmÀ1 1H NMR (400 MHz, CDCl3): d 12.78 (s, 1H, NH), 8.74(s, 1H,
.
CHO), 7.35–7.02 (m, 5H, ArH), 5.45 (s, 2H, OCH2). 13C NMR (100 MHz, CDCl3): d 64.6, 114.8, 122.1, 129.8, 157.4, 158.5, 161.9. MS: m/z
236 (M+). Anal. calcd. for C10H9N3O2S: C, 51.05; H, 3.86; N, 17.86. Found: C, 51.97; H, 3.79; N, 17.92. 3g Mp: 183–185 8C. IR (KBr) n: 3164,
1696, 1259 cmÀ1. 1H NMR (400 MHz, DMSO-d6): d 12.75 (s, 1H, NH), 8.54(s, 1H, CHO), 7.10–6.86 (m, 4H, ArH), 5.45 (s, 2H, OCH2), 3.77
(s, 3H, OCH3). 13C NMR (100 MHz, DMSO-d6): d 55.7, 65.0, 112.7, 115.0, 120.8, 122.6, 146.8, 149.5, 157.9, 160.1, 161.2. MS: m/z 266 (M+)
Anal. calcd. for C11H11N3O3S: C, 49.80; H, 4.18; N, 15.84. Found: C, 49.72; H, 4.25; N, 15.90. 3h Mp: 190–192 8C. IR (KBr) n: 3165, 1689,
1261 cmÀ1. 1H NMR (400 MHz, DMSO-d6): d 12.77 (s, 1H, NH), 8.54(s,1H, COH), 7.22–6.81 (m, 4H, ArH), 5.48 (s, 2H, OCH2), 2.28 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): d 21.2, 63.9, 111.9, 115.7, 122.5, 129.5, 139.4, 157.4, 157.8, 160.1, 161.3. MS: m/z 249 (M+) Anal.
calcd. for C11H11N3O2S: C, 51.00; H, 4.45; N, 16.86. Found: C, 51.08; H, 4.37; N, 12.80.