An expeditious and convenient one pot synthesis of 2,5-disubstituted-1,3,4-oxadiazoles

Article abstract of DOI:10.1081/SCC-120021845

A convenient, one pot procedure is reported for the synthesis of a variety of 2,5-disubstituted-1,3,4-oxadiazoles by condensing monoarylhydrazides with acid chlorides in HMPA solvent under the microwave heating. The yields are good to excellent, the process is rapid and does not need any added acid catalyst or dehydrating reagent.

Full text of DOI:10.1081/SCC-120021845

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An Expeditious and Convenient One Pot Synthesis of
2,5-Disubstituted-1,3,4-oxadiazoles
Sabir H. Mashraqui a , Shailesh G. Ghadigaonkar a & Rajesh S. Kenny a
a Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai, India
Version of record first published: 20 Aug 2006.
To cite this article: Sabir H. Mashraqui , Shailesh G. Ghadigaonkar & Rajesh S. Kenny (2003): An Expeditious and Convenient
One Pot Synthesis of 2,5-Disubstituted-1,3,4-oxadiazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:14, 2541-2545
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 14, pp. 2541–2545, 2003
An Expeditious and Convenient One Pot
Synthesis of 2,5-Disubstituted-1,3,4-oxadiazoles
*
Sabir H. Mashraqui, Shailesh G. Ghadigaonkar,
and Rajesh S. Kenny
Department of Chemistry, University of Mumbai,
Vidyanagari, Santacruz (E), Mumbai, India
ABSTRACT
A convenient, one pot procedure is reported for the synthesis of a
variety of 2,5-disubstituted-1,3,4-oxadiazoles by condensing mono-
arylhydrazides with acid chlorides in HMPA solvent under the
microwave heating. The yields are good to excellent, the process is
rapid and does not need any added acid catalyst or dehydrating
reagent.
2,5-Disubstituted-1,3,4-oxadiazoles find applications in the areas of
pesticides and pharmaceutical preparations, stabilizers in photography,
*Correspondence: Sabir H. Mashraqui, Department of Chemistry, University
of Mumbai, Vidyangari, Santacruz (E), Mumbai 400098, India; E-mail:
sh_mashraqui@yahoo.com.
2541
DOI: 10.1081/SCC-120021845
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2542
Mashraqui, Ghadigaonkar, and Kenny
liquid solution scintillators and thermostable polymers.[1,2] A general
methodology for preparing 2,5-disubstituted-1,3,4-oxadiazoles involves
first the synthesis of dihydrazide, followed by cyclization with acids or
dehydrating agents. Both two steps procedures[3–9] and one pot ver-
sions[10–17] have been described in the literature. However, many of
these methods require rather aggressive conditions i.e., strong acids and
prolonged heating at elevated temperatures.
In a project concerning nonlinear optic materials, we needed a milder
and rapid method to provide ready access to a variety of donor–acceptor
oxadiazoles. Our efforts have resulted in a new one-pot procedure for the
synthesis of 2,5-disubstituted-1,3,4-oxadiazoles as per the generalized
Eq. (1). The method consists of reacting appropriate monoarylhydrazide
(1–4)[18a–c] with a slight excess of a given acid chloride (5–12) in HMPA
solvent (caution! carcinogen due care need be exercised) without the need
for any acidic or dehydrating reagent. The reaction is left at roomtem-
perature for about 1h to allow the initial exothermic reaction to subside
and then without isolating the intermediate dihydrazide, it is subjected to
irradiation in a domestic microwave oven to effect the cyclization. As
indicated by TLC analysis, a maximum of 40 s of heating suffices to
produce nearly complete conversion. However, in the absence of micro-
wave heating, poor conversions (ca. 40% or less) to oxadiazoles
were realized when the reactions were heated at 130–150ꢀC in an oil
bath for upto 2 h. Other solvents such as dry DMF, dioxane or NMP
resulted in poor yields either under the microwave irradiation or
conventional heating. Our results of the present procedure are collected
in the Table 1.
O
C
R1
O
R2
O
C
1) HMPA, 1h, R. T
2) MW, 40 Sec
)
(
1
+
NHNH2
Cl
R2
R1
N
N
1; R1= Ph-
5; R2= Ph-
13-25 (see Table)
2; R2= 4-NO2-Ph- 6; R2= 2-furyl-
3; R1= 4-CH3OPh- 7; R2= -CH2-Ph-
4; R1= 4-pyridyl-
8; R2= -CH3
9; R2= -CH (CH3)2
10; R2= 4-O2NPh-
11; R2= 2-thienyl-
12; R2= 4-CH3OPh-
Scheme 1.

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2,5-Disubstituted-1,3,4-oxadiazoles
2543
Table 1. 2,5-Disubstituted-1,3,4-oxadiazole (13–25)a prepared as per the Eq. (1).
Product no.
R1
R2
Yield (%)b,c M.p. (ꢀC) Lit. m.p. (ꢀC)
13
14
15
16
17
18
19
20
21
22
23
24
25
Ph
Ph
Ph
2-furyl
95
77
85
45
90
60
80
88
74
80
62
95
75
134–136
101–103
138–140
165–167
105–107
134–137
225–227
216–218
226–228
145–147
216–218
143–145
182–183
136–317[16]
103[16]
4-O2NPh CH2Ph
4-O2NPh CH3
4-O2NPh Ph
140–141[16]
165–167[19]
107–109[16]
134–135[21]
227–228[20]
216–217[22]
227–228[23]
145–147[16]
218[22]
4-O2NPh 2-propyl
4-O2NPh 2-furyl
4-O2NPh 2-thienyl
4-MeOPh 4-O2NPh
4-MeOPh Ph
4-MeOPh 2-thienyl
4-pyridyl Ph
4-pyridyl 4-MeOPh
145[16]
183[24]
aAll reactions were uniformly conducted using 10 mmol of hydrazide with acid
chloride (11–12 mmol) in 10 mL HMPA.
bYield refer to t.l.c homogenous products and are unoptimized.
cElemental analysis and 1H NMR data are consistent with the product structures.
It may be noted that a variety of 2,5-diaryl (alkyl) oxadiazoles includ-
ing donor–acceptor oxadiazoles (products 15–21 and 24–25) are readily
accessible in high yields within a short time. The work-up of the reaction
simply consists of diluting the reaction with cold water, followed by
filtration of precipitated solid and crystallization to afford pure 2,5-dis-
ubstituted oxadiazoles. It appears that hydrochloric acid generated in the
initial reaction between monoacylhydrazine and acid chloride catalyzes
the subsequent cyclodehydration of diacyl hydrazide during the course of
microwave heating. This is borne out from the observation that when
pyridine is added in above reactions to neutralize the acid, oxadiazoles
are formed in poor yields; the major products being identified as the
uncyclized diacylhydrazines.
It is noteworthy that unlike the reported methods for oxadiazole
synthesis, the present method using a combination of HMPA solvent
and the microwave irradiation obviates the need for the addition of a
strong acid or any cyclodehydrating agent. In conclusion, we have
developed a very efficient and a convenient procedure for a high yield
synthesis of a variety of 2,5-disubstituted-1,3,4-oxadiazoles.

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2544
Mashraqui, Ghadigaonkar, and Kenny
A TYPICAL PROCEDURE IS AS FOLLOWS
To a solution of isonicotinoyl hydrazide 4 (1.37 g, 5 mmol) in HMPA
(10 mL; caution! carcinogen, use with utmost care) was added benzoyl
chloride 5 (1.27 mL, 11 mmol) in one lot and the resulting exothermic
reaction was left at roomtemperature for 1 h. The reaction was then
irradiated in a domestic microwave oven (Samsung model C-945 G,
power output 900 W) for 40 s during which period the reaction boils
briefly. The microwave oven was switched off and the reaction allowed
to cool to room temperature. The reaction mixture was then poured over
crushed ice and the precipitated solid filtered, washed with cold water
and air-dried. Crystallization fromethanol gave colorless crystals of
oxadiazole 24, m.p. 143–45ꢀC (lit.[16] m.p. 145ꢀC) in 95% yield.
ACKNOWLEDGMENT
Thanks are due to the C.S.I.R. New Delhi, India for financial
support and to Dr. S. Kumar for technical assistance.
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Received in the Netherlands October 16, 2002

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