Electrochemically initiated oxidative cyclization: A versatile route for the synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles

Article abstract of DOI:10.1007/s00706-011-0711-3

A rapid, improved, and environmentally benign synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles by one-pot electrocyclization of acylthiosemicarbazones is reported. Controlled potential electrolysis was performed at room temperature in acetonitrile as

Full text of DOI:10.1007/s00706-011-0711-3

Monatsh Chem (2012) 143:1427–1430
DOI 10.1007/s00706-011-0711-3
ORIGINAL PAPER
Electrochemically initiated oxidative cyclization: a versatile route
for the synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles
•
Sushma Singh Laxmi Kant Sharma
•
•
Apoorv Saraswat R. K. P. Singh
Received: 2 June 2011 / Accepted: 22 December 2011 / Published online: 24 January 2012
Ó Springer-Verlag 2012
Abstract A rapid, improved, and environmentally benign
synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles by
one-pot electrocyclization of acylthiosemicarbazones is
reported. Controlled potential electrolysis was performed at
room temperature in acetonitrile as non-aqueous solvent
and LiClO4 as supporting electrolyte. The reaction prod-
ucts were characterized by spectroscopic methods and a
mechanism was deduced from voltammetric data. Better
yields at room temperature, shortest reaction time, and easy
work-up are attractive features of this green procedure.
[12], antiparasitic [13], antiviral [14], antihypoglycemic
[15], hypotensive [16], 5-HT-receptor antagonist [17], and
muscarinic receptor agonist [18]. Some material applications
of 1,3,4-oxadiazole derivatives are in photosensitizers [19],
liquid crystals [20], and organic light-emitting diodes
(OLEDs) [21].
Development of eco-friendly synthetic methods in
chemical research has great importance [8, 22–28] because
conventional organic synthesis involves multistep proce-
dures with complex isolation, and expensive and toxic
solvents and reagents. With increasing public concern over
environmental degradation, use of electrochemical tech-
nology can be a valuable alternative to conventional
reagents for fine chemical synthesis [29–31]. Because of
electron transfer between an electrode and substrate mole-
cules, formation of highly reactive intermediates is
achieved under mild conditions, avoiding acids and bases as
reducing or oxidizing agents and related waste by-products.
It seems that electrochemical procedures will emerge as a
new tool in which the special advantages of electrochem-
istry, for example energy specificity, chemical selectivity,
and specific activation of small molecules can be applied
without toxic reagents and solvents.
Keywords Controlled potential electrolysis Á
Cyclic voltammetry Á Electrochemical synthesis Á
Electron transfer Á Oxadiazoles
Introduction
1,3,4-Oxadiazoles are a class of heterocycles which have
attracted significant interest in medicinal chemistry. These
compounds have a wide range of pharmaceutical and
biological activity including anti-inflammatory [1], antimi-
crobial [2], antimalarial [3], antifungal [4], muscle relaxant
[5], anticancer [6], analgesic [7], anti-HIV [8], antitubercular
[9], anticonvulsant [10], antiproliferative [11], insecticidal
Results and discussion
1,3,4-Oxadiazoles are an important class of heterocyclic
compounds with a wide range of pharmaceutical and bio-
logical activity. Their synthesis and transformation have
been of interest for a long time, as documented by a
steadily increasing number of publications and patents
[32]. However, despite their common use, various reported
methods for preparation of 1,3,4-oxadiazoles [9] suffer
from harsh conditions or stoichiometric formation of
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0711-3) contains supplementary
material, which is available to authorized users.
S. Singh Á L. K. Sharma Á A. Saraswat Á R. K. P. Singh (&)
Electrochemical Laboratory of Green Synthesis,
Department of Chemistry, University of Allahabad,
Allahabad 211002, U.P., India
e-mail: rkp.singh@rediffmail.com
123

1428
S. Singh et al.
Scheme 1
Scheme 2
byproducts. Approaches are based on bromine oxidation of
semicarbazide derivatives and on cyclodesulfurization of
acylthiosemicarbazide derivatives in solution using I2/
NaOH or 1,3-dicyclohexylcarbodiimide (DCC) [33–36],
mercury(II) acetate or yellow mercury(II) oxide [37, 38],
and highly reactive alkylating agents, for example methyl
iodide [39] and ethyl bromoacetate [9]. Evans [40] syn-
thesized oxadiazole derivatives by parallel synthesis in an
efficient one-pot preparation using resin-bound reagents.
All these methods are usually carried performed in differ-
ent synthetic steps and require high temperature, and
extraction and purification of the products from the mixture
requires great precautions.
Experimental
Cyclic voltammetric experiments were performed using an
Alsch Instruments model 600A electrochemical analyzer.
IR spectra (KBr) were recorded on a Shimadzu 8201 PC IR
spectrophotometer. H and 13C NMR spectra were recor-
1
ded on a Bruker DRX 400 spectrometer (400 MHz) in
CDCl3 using TMS as an internal standard. Chemical shifts
(d) are quoted in ppm. Mass spectra were acquired on a
Jeol SX-1020/PA-6000 (EI) spectrometer. Melting points
were determined by the open tube capillary method.
A1
0.04
The objective of our research program is to find a new
general route for eco-friendly efficient synthesis [41–46] of
important organic compounds without the use of toxic
reagents. We propose electrooxidative cyclization of acyl-
thiosemicarbazones 3 in the presence of acetonitrile as
solvent and LiClO4 as background electrolyte. The reaction
involves two discrete synthetic steps; in the first step,
reaction of acylhydrazide 1 with an isothiocyanate 2 pro-
vides the acylthiosemicarbazone 3. In the second step,
electrooxidative cyclization of acylthiosemicarbazone 3
gives oxadiazoles 4 (Scheme 1).
0.03
0.02
0.01
0
-0.01
-0.02
-0.03
C1
0.0
0.50
1.0
1.50
Potential/V vs. Ag/AgCl
In the proposed mechanism (Scheme 2) the acylthiose-
micarbazone undergoes one-electron oxidation followed by
dehydrosulfidation, i.e., evolution of H2S (confirmed by
use of lead tetraacetate paper) and results in the formation
of products in 70–95% yield.
Fig. 1 Cyclic voltammogram of 3a in 0.1 M LiClO4 at a platinum
electrode (area 1 9 1 cm2) at a scan rate of 100 mV s-1, counter
electrode: platinum mesh, reference electrode: Ag/AgCl, T = 25
1
°C. The corresponding CV contains one anodic peak at 1.24 V. This
peak corresponds to oxidation of acylthiosemicarbazone
123

Electrochemically initiated oxidative cyclization
1429
Table 1 Current–potential data, yields, and melting points of 5-substituted 2-amino-1,3,4-oxadiazoles 4a–4k from electroorganic synthesis
Product
R1
R2
Time/h
Applied
potential/V
Current/A
Yield/%
M.p. (Lit. m.p.)/°C
4a
4b
4c
4d
4e
4f
4-C5H4N
C6H5
3
3
3
4
4
3
3
3
4
3
3
1.24
1.33
1.52
1.40
1.42
1.44
1.46
1.28
1.30
1.33
1.42
0.04
0.07
0.04
0.06
0.05
0.04
0.06
0.07
0.09
0.08
0.05
90
92
90
95
88
85
70
72
87
85
75
267 (266–268 [47])
276 (276–278 [47])
279 (278–280 [47])
237 (236–238 [47])
281 (280–282 [47])
238 (238–240 [47])
139 (139–141 [48])
140 (140–141 [48])
134 (134–135 [48])
142 (141–142 [48])
202 (203 [49])
4-C5H4N
o-CH3C6H4
p-CH3C6H4
o-OCH3C6H4
p-OCH3C6H4
p-Cl-C6H4
CH3
4-C5H4N
4-C5H4N
4-C5H4N
4-C5H4N
4g
4h
4i
b-C10H7-O-CH2
b-C10H7-O-CH2
b-C10H7-O-CH2
b-C10H7-O-CH2
b-C10H7-O-CH2
C2H5
CH2-CH=CH2
C6H5
4j
4k
m-Cl-C6H4
References
All chemicals used were AnalaR grade purchased from
Merck and Loba Chem, and were used without purification.
Water used in the reaction was double-distilled. The
acylthiosemicarbazones 3 were prepared by acylation of
commercially available hydrazides 1 with the appropriate
isothiocyanates 2 by a known method [28] (Fig. 1).
1. Omar FA, Mahfonz NM, Rahman MA (1996) Eur J Med Chem
31:819
2. Bhat KS, Karthikeyan MS, Holla BS (2004) Indian J Chem
43B:1765
3. Mogilaiah K, Babu HR, Rao RB (2000) Indian J Heterocycl
Chem 10:109
4. Laddi UV, Desai SR, Bennur RS, Bennur SC (2002) Indian J
Heterocycl Chem 11:319
5. Palaska E, Sohin G, Kclicen P, Darlu NT, Altinok G (2002)
Farmaco 57:101
Electroorganic synthesis of 5-substituted 2-amino-
1,3,4-oxadiazoles 4a–4k — controlled potential
electrolysis (CPE)
6. Zou XJ, Lai LH, Jin GY, Zhang ZX (2002) J Agric Food Chem
50:3757
Acylthiosemicarbazone 3 (8.0 mmol) and lithium perchlo-
rate (4.0 mmol) were dissolved in 100 cm3 acetonitrile.
Preparative-scale controlled potential electrolysis was per-
formed at room temperature in a 250 cm3 three-electrode
cell with platinum plate (flattened sheet of dimensions
1.0 cm 9 1.0 cm) as working and counter electrodes and
saturated calomel electrode (SCE) as reference electrode. A
magnetic stirrer was used to ensure complete mixing of the
reaction mixture during electrolysis. All electrolysis reac-
tions were carried out at the corresponding oxidation
potential of the substrate (1.24 V for 3a) and were complete
in 3–4 h. The progress of the reactions was monitored by
TLC. The current–potential data were recorded by use of a
potentiostat at intervals of 15 min and are listed in Table 1.
After electrolysis the solvent was evaporated under reduced
pressure and the product was purified by column chroma-
tography over silica gel. All products were analyzed by
spectral techniques.
7. Clapp LB, Katritzky AR, Rees CW (1984) Comprehensive Het-
erocyclic Chemistry. Pergamom Press, Oxford
8. Anastas PT (1999) Critical Rev Anal Chem 29:167
9. Kucukguzel SG, Omic EE, Roilas S, Sahin F, Ozbek A (2006)
Eur J Med Chem 37:197
10. Khan MSY, Khan RM (2001) Susma Draber. Indian J Heterocycl
Chem 11:119
11. Jin L, Chen J, Song B, Chen Z, Yang S, Li Q, Hu D, Xu R (2006)
Bioorg Med Chem Lett 16:5036
12. Zheng X, Li Z, Wang Y, Chen W, Huang Q, Liu C, Song G
(2003) J Fluorine Chem 123:163
13. Omar MT (1997) Arch Pharm Res 20:662
14. Karthikeyan MS, Prasad DJ, Mahalinga M, Holla BS, Kumari NS
(2008) Eur J Med Chem 43:25
15. Goankar SL, Rai KML, Prabhuswamy B (2006) Eur J Med Chem
41:8416
16. Deshmukh AA, Sattur PB, Sheth UK (1976) Indian J Exp Biol
4:166
17. Swain CJ, Baker R, Kneen C, Moseley J, Saunders J, Seward EM,
Stevenson G, Beer M, Stanton J, Watling K (1991) J Med Chem
34:140
18. Orlek BS, Blaney FE, Brown F, Clark MSG, Hadley MS, Hatcher
J, Riley GJ, Rosenberg HE, Wadsworth HJ, Wyman P (1991) J
Med Chem 34:2726
19. Schinzel E, Martini T, Spatzeier W, Probst H (1983) Bis(ox-
adiazolyl)naphthalene Fluorescent Whiteners. Ger Offen DE
3126464 A1; Chem Abst 98:199850
20. Chudgar NK, Shah SN, Vora RA (1989) Mol Cryst Liq Cryst
172:51
Acknowledgments The authors are grateful to the Head, Depart-
ment of Chemistry, University of Allahabad, for providing the
necessary facilities, the Sophisticated Analytical Instrument Facility
(SAIF), a division of CDRI (Central Drug Research Institute), Luc-
know, for spectra, and the University Grants Commission (UGC),
New Delhi, India, for providing financial assistance.
123

1430
S. Singh et al.
21. Zhan S, Ying XG, Xia L, Tao Y (2006) J Microelectronics 37:714
22. Anastas PT, Warner JC (1998) Green Chemistry: Theory and
Practice. Oxford University Press, Oxford
23. Collins TJ (1997) Green Chemistry. In: Encyclopedia of Chem-
istry, vol 2. Macmillan, New York
24. Tundo P, Selva M, Marques CA (1996) Green Chemistry. In:
Anastas PT, Williamson TC.(eds) Designing Chemistry for the
Environment. ACS Symposium Series, vol 626, p 81
25. Wilkinson SL (1997) Chem Eng News 75:35
26. Anastas PT, Farris CT (1994) Benign by design: Alternative
Synthetic design for Pollution Prevention. ACS Symposium
Series, vol 557
27. Tundo P, Anastus PT (2000) Green Chemistry: Challenging
Perspectives. Oxford University Press, Oxford
28. Colanceska-Ragenovic K, Dimova V, Kakurinov V, Gabor DM
(2003) J Heterocycl Chem 40:905
29. Mann CK, Barnes KK (1970) Electrochemical Reactions in non-
aqueuos Systems. Marcel Dekker, New York
30. Fry AJ (1989) Synthetic Organic Electrochemistry, 2nd edn.
Wiley, New York
35. Liu FM, Wang BL, Zhang ZF (2001) Youji Huaxue 21:1126
36. Aboulwafa OM, Omar OMME (1992) Sulfur Lett 14:181
37. Zou X, Zhan Z, Jin G (2002) J Chem Res (228)
38. Faidallah HM, Sharshira EM, Basaif SA, A-Ba-Oum AE (2002)
Phosphorus. Sulfur Silicon Relat Elem 177:67
39. Fulop F, Semega E, Dombi G, Bernath G (1990) J Heterocycl
Chem 27:951
40. Cappo FT, Evans KA, Graybill TL, Burton G (2004) Tetrahedron
Lett 45:3257
41. Sharma LK, Kumar S, Singh RKP (2007) Bull Electrochem
23:453
42. Sharma LK, Kumar S, Yadav P, Singh RKP (2008) Indian J
Chem 47B:2277
43. Kumar S, Sharma LK, Singh RKP (2009) J Indian Chem Soc
86:1129
44. Sharma LK, Singh S, Kumar S, Singh RKP (2010) Russian J
Electrochem 46:37
45. Sharma LK, Kumar S, Singh RKP, Siddiqui IR (2010) J Indian
Chem Soc 87:1117
46. Sharma LK, Singh S, Singh RKP (2011) Indian J Chem 50B:110
47. Yar MS, Akhter MW (2009) Acta Pol Pharm 66:393
48. Palaska E, Sahin G, Kelicen P, Durlu NT, Altinok G (2002) Il
Farmaco 57:101
31. Shono T (1991) Electroorganic Synthesis. Academic Press Ltd,
London
32. Lee CH, Cho HI, Lee KJ (2001) Bull Korean Chem Soc 22:1153
33. Gani RS, Pujar RS, Gadaginamath GS (2002) Indian J Heterocycl
Chem 12:25
49. Yar MS, Siddiqui AA, Ali MA (2007) J Chin Chem Soc 54:5
34. Golovlyova SM, Moskvichey YA, Alov EM, Kobylinskey DB,
Ermolaeva VV (2001) Chem Heterocycl Comp 37:1102
123