IBX/TEAB-mediated oxidative dimerization of thioamides: synthesis of 3,5-disubstituted 1,2,4-thiadiazoles

Article abstract of DOI:10.1016/j.tetlet.2009.07.155

Thioamides undergo oxidative dimerization on treatment with hypervalent iodine(V)-containing reagents, particularly o-iodoxybenzoic acid (IBX), in the presence of tetraethylammonium bromide (TEAB) to generate 3,5-disubstituted 1,2,4-thiadiazoles in excellent yield.

Full text of DOI:10.1016/j.tetlet.2009.07.155

Tetrahedron Letters 50 (2009) 5820–5822
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IBX/TEAB-mediated oxidative dimerization of thioamides: synthesis
of 3,5-disubstituted 1,2,4-thiadiazoles
*
Pravin C. Patil, Dinesh S. Bhalerao, Prasad S. Dangate, Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Thioamides undergo oxidative dimerization on treatment with hypervalent iodine(V)-containing
reagents, particularly o-iodoxybenzoic acid (IBX), in the presence of tetraethylammonium bromide
(TEAB) to generate 3,5-disubstituted 1,2,4-thiadiazoles in excellent yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 26 May 2009
Revised 28 July 2009
Accepted 31 July 2009
Available online 8 August 2009
Keywords:
Hypervalent iodine reagents
o-Iodoxybenzoic acid
TEAB
Thioamides
Thiadiazoles
1. Introduction
S
S
N
Ar
NH2
Thiadiazoles are important precursors for the synthesis of many
bioactive molecules belonging to various therapeutic categories,
such as anti-microbial agents,1 fungicides,2 herbicides,3 and anti-
biotics.4,5 The methods used for the preparation of 3,5-disubsti-
tuted 1,2,4-thiadiazoles may be divided into three categories,
which include intramolecular cyclization,6–8 intermolecular cycli-
zation,9,10 and oxidative dimerization.11–17 The latter has been car-
ried out by using different oxidizing agents, such as nitrous acid,11
polymer-supported diaryl selenoxide and telluroxide,12 organotel-
lurium,13 p-toluenesulfinic acid,14 phenyliodine (III) diacetate,15
t-butyl hypochlorite,16 and dimethylsulfoxide-electrophilic
reagents.17 Some of these methods suffer from drawbacks such
as the formation of nitriles and isothiocyanates as by-products.
In continuation of our ongoing studies18 exploring the use of
hypervalent iodine (V) in organic synthesis, we report herein
o-iodoxybenzoic acid (IBX) as an effective promoter of oxidative
dimerization of thiomides 1 to yield 3,5-disubstituted 1,2,4-thi-
adiazoles 2 as shown in Scheme 1.
Ar
Ar
N
1
2
Scheme 1. Oxidative dimerization of thioamides.
reaction was greatly accelerated and proceeded to completion
within just 5 min with an equimolar ratio of IBX and TEAB without
decreasing the yield. Various investigations toward optimization of
Table 1
Optimization of reagents and reaction conditionsa
S
N
S
Reagent
NH2
N
Solvent, rt
1a
2a
Entry
Reagent (mol equiv)
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
IBX (1.5)
MeCN
MeCN
MeCN
CH2Cl2
Toluene
MeCN
60
50
5
10
60
10
95
95
95
94
85
94
2. Result and discussion
IBX/TEAB (1.1/0.2)
IBX/TEAB (1.1/1.1)
IBX/TEAB (1.1/1.1)
IBX/TEAB (1.1/1.1)
DMPc/TEAB (1.1/1.1)
Treatment of phenylthioamide 1a with IBX in acetonitrile for
60 min generated 2a in 95% yield. When tetraethylammonium bro-
mide (TEAB) was used in combination with IBX, as expected, the
Bold entries indicates best reaction conditions.
a
Reactions were carried out on a 5-mmol scale at rt.
Yields obtained after column chromatography.
Dess–Martin periodinane.
b
c
* Corresponding author. Tel.: +91 22 24145616; fax: +91 22 24145614.
E-mail address: kgap@rediffmail.com (K.G. Akamanchi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.155

P. C. Patil et al. / Tetrahedron Letters 50 (2009) 5820–5822
5821
the reaction conditions with respect to hypervalent iodine-con-
taining reagents, appropriate solvents, and the molar ratio (Table
1) were carried out. In the studies on solvents, acetonitrile was
found to be the best solvent.
As observed from Table 1, the reaction proceeded well in aceto-
nitrile and chlorinated solvents, such as CH2Cl2, and was slow and
incomplete in toluene; this could be attributed to the very low sol-
ubility of the reagent.
jected to the reaction under optimized conditions; the results are
summarized in Table 2.
As reported in Table 2, a variety of substrates—aromatic, hetero-
aromatic and benzylic thioamides—underwent oxidative dimeriza-
tion to form the corresponding 3,5-disubstituted 1,2,4-
thiadiazoles. All the reactions were clean, smooth, and achieved
completion within 5–15 min, providing high yield. A noteworthy
feature of the reaction was that the benzylic position and the pyr-
idine moiety remained unaffected (Table 2, entries 5, 6, and 8). In
conclusion, it has been established that hypervalent iodine (V)-
To establish the generality of the reaction, various types of thio-
amides have been prepared by established methods19 and sub-
Table 2
Oxidative dimerization of thioamides to 3,5-disubstituted 1,2,4-thiadiazolesa
Entry
Substrate (1)
Product (2)
Time (min)
Yieldb (%)
S
S
N
NH2
1
5
95
N
2a
1a
S
Cl
S
S
N
NH2
N
2
3
10
5
93
96
96
90
90
91
90
92
88
Cl
Cl
2b
1b
S
N
NH2
N
H3CO
H3C
OCH3
H3CO
2c
1c
S
S
N
NH2
4
5
N
N
CH3
H3C
2d
1d
NH2
S
N
5
10
10
15
15
10
15
S
N
1e
2e
Cl
Cl
NH2
S
N
N
6
S
Cl
1f
2f
S
S
N
NH2
7
N
O2N
NO2
O2N
2g
1g
S
S
N
NH2
S
8
N
N
N
N
2h
1h
S
N
NH2
9
N
Cl
Cl
Cl
O
2i
1i
S
N
NH2
O
N
10
O
S
1j
2j
a
Reactions were carried out on a 5-mmol scale in acetonitrile at room temperature with IBX (1.1 equiv) and TEAB (1.1 equiv).
Yields obtained after column chromatography.
b

5822
P. C. Patil et al. / Tetrahedron Letters 50 (2009) 5820–5822
containing reagent is suitable for the oxidative dimerization of
thioamides. A reagent system consisting of a combination of IBX/
TEAB has been developed for the clean, efficient, rapid, and chemo-
selective synthesis of 3, 5-disubstituted 1,2,4-thiadiazoles under
mild conditions.
4.6. 3,5-bis(4-chlorobenzyl)-1,2,4-thiadiazole (2f)
Solid, mp = 61–63 °C, [lit17 60–62 °C]. IR (KBr) mmax (cmÀ1):
3030, 1602, 1492. 1H NMR (60 MHz, CDCl3): d 7.75–7.48 (m, 8H),
4.26 (s, 2H), 4.17 (s, 2H) ppm.
4.7. 3,5-Bis(4-nitrophenyl)-1,2,4-thiadiazole (2g)
3. General experimental procedure for the synthesis of 3,5-
disubstituted 1,2,4-thiadiazoles
Solid, mp = 200–202 °C, [lit16 198–199 °C]. IR (KBr) max (cmÀ1):
m
1602, 1535, 1408, 1345, 1322, 850. 1H NMR (60 MHz, CDCl3): d
To a stirred suspension of IBX (1.54 g, 5.5 mmol) in MeCN
(20 mL) was added TEAB (1.16 g, 5.5 mmol). A yellow suspension
was observed to which substrate (5 mmol) was added in one por-
tion after 5 min at room temperature. Consumption of starting
material was observed by TLC. After completion of reaction, aceto-
nitrile was removed under reduced pressure and the resultant res-
idue was washed with ethyl acetate (25 mL) followed by 10%
sodium bisulfite solution (25 mL), saturated sodium carbonate
(25 mL), and brine (25 mL). The organic layer was dried over anhy-
drous sodium sulfate and concentrated under reduced pressure to
give crude product. Pure product was isolated after column chro-
matography (silica gel mesh size 60–120, eluent ethyl acetate/n-
hexane (5:95).
7.68–7.61 (m, 4H), 7.88 (d, 2H), 8.19 (d, 2H) ppm.
4.8. 3,5-Bis(3-pyridinyl)-1,2,4-thiadiazole (2h)
Solid, mp = 133–135 °C, [lit16 136–137 °C]. IR (KBr) max (cmÀ1):
m
1588, 1482, 1405, 1345, 1300, 1035, 723. 1H NMR (60 MHz, CDCl3):
d 9.60–9.56 (m, 1H), 9.30–9.25 (m, 1H), 8.81–8.76 (m, 2H), 8.74–
8.33 (m, 2H), 7.53–7.45 (m, 2H) ppm.
4.9. 3,5-Bis(4-chlorophenyl)-1,2,4-thiadiazole (2i)
Solid, mp = 161–162 °C, [lit17 161.5–162 °C]. IR (KBr) mmax
(cmÀ1): 3035, 1595, 1492. 1H NMR (60 MHz, CDCl3): d 8.26–7.99
(m, 4H), 7.72–7.42 (m, 4H) ppm.
4. Spectral data for 3,5-disubstituted-1,2,4-thiadiazoles
4.1. 3,5-Diphenyl-1,2,4-thiadiazole (2a)
Acknowledgments
One of the authors (P.C.P.) wishes to thank the World Bank for
its financial support under the Technical Education Quality-
Improvement Program (TEQIP). In addition, the authors thank M/
s Omkar Chemicals, Thane, Maharashtra, India, for their generous
gift of IBX.
Solid, mp = 90–92 °C, [lit17 91–91.5 °C]. IR (KBr) mmax (cmÀ1):
3050, 1590, 1472. 1H NMR (60 MHz, CDCl3): d 8.37–8.28 (m, 2H),
7.92–8.03 (m, 2H), 7.41–7.79 (m, 6H) ppm. 13C NMR (60 MHz,
CDCl3): d 188.07, 173.72, 140.86, 132.78, 131.88, 130.59, 130.31,
129.21, 128.64, 128.28, 127.80, 127.4 ppm.
References and notes
4.2. 3,5-Bis(2-chlorophenyl)-1,2,4-thiadiazole (2b)
1. Craig, E. M.; George, A. B. U.S. Patent 4,209,522, 1980.
2. Lamrencce, E. K. U.S. Patent 4,263,312, 1981.
3. Walter, A. G. U.S. Patent 4,207,089, 1980.
Solid, mp = 92–95 °C, [lit20 93–96 °C]. IR (KBr) mmax (cmÀ1):
3055, 1570, 1478. 1H NMR (60 MHz, CDCl3): d 8.71–8.57 (m, 1H),
8.07–7.98 (m, 1H), 7.54–7.31 (m, 6H) ppm. 13C NMR (60 MHz,
CDCl3): d 183.05, 173.98, 133.90, 133.50, 132.50, 132.18, 132.00,
130.91, 130.82, 130.63, 130.44, 129.7, 127.51, 126.7 ppm.
4. Teraji, T.; Sakane, K.; Goto, J. E.P. Patent 13762, 1980.
5. Teraji, T.; Sakane, K.; Goto, J. E.P. patent 27599, 1981.
6. Kurzer, F.; Taylor, S. A. J. Chem. Soc. 1958, 379–386.
7. Joshua, C. P.; Verma, V. K. J. Indian Chem. Soc. 1961, 38, 988–994.
8. Kihara, Y.; Kabasima, S.; Uno, K.; Okawara, T.; Yamasaki, T.; Furukawa, M.
Synthesis 1990, 1020–1023.
9. Howe, R. K.; Franz, J. E. J. Org. Chem. 1974, 39, 962–964.
10. Rothgery, E.; Schroeder, H. J. A. U.S. Patent 4,143,044, 1979.
11. Cronyn, M. W.; Nakagawa, T. W. J. Am. Chem. Soc. 1952, 74, 3693.
12. Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Bull. Chem. Soc. Jpn. 1986, 59, 879–884.
13. Matsuki, T.; Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Bull. Chem. Soc. Jpn. 1988, 61,
2117–2121.
14. Shutalev, A. D.; Kishko, E. A.; Alekseeva, S. G. Chem. Hetrocycl. Compd. 1997, 33,
352–354.
15. (a) Yan, M.; Chen, Z.; Zheng, Q. J .Chem. Research (S) 2003, 618–619; (b) Cheng,
D.-P.; Chen, Z.-C. Synth. Commun. 2002, 32, 2155–2159.
16. El-Wassimy, M. T. M.; Jørgensen, K. A.; Lawesson, S. O. Tetrahedron 1983, 39,
1729–1734.
4.3. 3,5-Bis(4-methoxylphenyl)-1,2,4-thiadiazole (2c)
Solid, mp = 139–140 °C, [lit17 139–139.5 °C]. IR (KBr) mmax
(cmÀ1): 3035, 1602, 1489. 1H NMR (60 MHz, CDCl3): d 8.30–7. 93
(m, 4H), 7.18–7.06 (m, 4H), 3.85 (s, 6H) ppm. 13C NMR (60 MHz,
CDCl3): d 187.39, 173.34, 162.46, 161.25, 135.66, 133.99, 131.12,
129.88, 129.15, 127.79, 125.99, 123.64, 114.53, 113.96 ppm.
4.4. 3,5-Bis(4-methylphenyl)-1,2,4-thiadiazole (2d)
17. Takikawa, Y.; Shimada, K.; Sato, K.; Sato, S.; Takizawa, S. Bull. Chem. Soc. Jpn.
1985, 58, 995–999.
18. (a) Bellale, E. V.; Bhalerao, B. S.; Akamanchi, K. G. J. Org. Chem. 2008, 73, 7324–
7327; (b) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J.
Org. Chem. 2007, 73, 662–665; (c) Arote, N. D.; Bhalerao, D. S.; Akamanchi, K. G.
Tetrahedron Lett. 2007, 48, 3651–3653; (d) Chaudhari, K. H.; Mahajan, U. S.;
Bhalerao, D. S.; Akamanchi, K. G. Synlett 2007, 18, 2815–2818; (e) Bhalerao, D.
S.; Mahajan, U. S.; Akamanchi, K. G. Synth. Commun. 2008, 38, 2814–2819.
19. (a) Manaka, A.; Sato, M. Synth. Commun. 2005, 35, 761–764; (b) Kaboudin, B.;
Elhamifar, D. Synthesis 2006, 224–226; (c) Lin, P. Y.; Ku, W. S.; Shiao, M. J.
Synthesis 1992, 1219–1220.
Solid, mp = 130–131 °C, [lit17 130.5–131 °C]. IR (KBr) mmax
(cmÀ1): 3042, 1599, 1485. 1H NMR (60 MHz, CDCl3): d 8.24–7.96
(m, 4H), 7.56–7.30 (m, 4H), 2.40 (s, 6H) ppm.
4.5. 3,5-Dibenzyl-1,2,4-thiadiazole (2e)
Oil, (lit17 = oil). IR (neat)
m
max (cmÀ1): 3029, 1598, 1488. 1H NMR
20. Komatsu, M.; Shibata, J.; Ohshiro, Y.; Agava, T. Bull. Chem. Soc. Jpn. 1983, 56,
180–183.
(60 MHz, CDCl3): d 7.35 (s, 10H), 4.32 (s, 2H), 4.27 (s, 2H) ppm.