An efficient one pot synthesis of 1,3,4-oxadiazoles

Article abstract of DOI:10.1081/SCC-100103993

Various 1,3,4-oxadiazoles have been synthesized in excellent yields by BF₃·Et₂O promoted cyclodehydration of 1,2-diacyl and diaroyl hydrazines prepared in situ from corresponding acid chlorides and hydrazine.

Full text of DOI:10.1081/SCC-100103993

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AN EFFICIENT ONE POT
SYNTHESIS OF 1,3,4-
OXADIAZOLES
a
b
Vishnu K. Tandon & Rakeshwar B. Chhor
a
Department of Chemistry, Lucknow University,
Lucknow, 226 007, India
b
Central Drug Research Institute, Lucknow, 226
001, India
Published online: 09 Nov 2006.
To cite this article: Vishnu K. Tandon & Rakeshwar B. Chhor (2001) AN EFFICIENT
ONE POT SYNTHESIS OF 1,3,4-OXADIAZOLES, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:11, 1727-1732, DOI: 10.1081/SCC-100103993
To link to this article: http://dx.doi.org/10.1081/SCC-100103993
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SYNTHETIC COMMUNICATIONS, 31(11), 1727–1732 (2001)
AN EFFICIENT ONE POT SYNTHESIS OF
1
,3,4-OXADIAZOLES
1
,
2
Vishnu K. Tandon * and Rakeshwar B. Chhor
1
Department of Chemistry, Lucknow University,
Lucknow-226 007, India
Central Drug Research Institute, Lucknow-226 001, India
2
ABSTRACT
Various 1,3,4-oxadiazoles have been synthesized in excellent
yields by BF ꢀEt O promoted cyclodehydration of 1,2-diacyl
3
2
and diaroyl hydrazines prepared in situ from corresponding
acid chlorides and hydrazine.
1,3,4-oxadiazoles have attracted significant interest in medicinal chem-
istry as ester bioesters in a number of biological targets including benzodia-
1
2
3
zepine receptor agonists, 5-HT receptor agonists, muscarinic agonists, 5-
4
HT antagonists, Human NK antagonists, antirhinoviral compounds and
5
6
1
7
antiinflammatory agents. This has ledto uncover a variety of cyclo de hy-
drating agents including solid phase methodology for the synthesis of 1,3,4-
–11
8
oxadiazoles in recent years.
In the course of our studies towards synthesis of 1,3,4-oxadiazoles in
solution phase, we foundBF 3ꢀEt O, a reagent of choice for cyclode-
2
hydration of 1,2-diacyl and 1,2-diaroyl hydrazines. The previous routes to
*
Corresponding author. Fax: þ91-0522-326665; E-mail: tandon_vk@yahoo.com
727
1
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1
728
TANDON AND CHHOR
1
cyclodehydration in solution phase involving SOCl , PPA, H SO and
2
13
14
2
2
4
1
5
POCl3 have certain disadvantages e.g.; (1) the reagents are harsh and may
be sensitive to functionalities requiredin the oxa di azole synthesis (2) the
reaction conditions for the synthesis of oxadiazoles involve longer duration
of time (3) the yields of oxadiazoles are low or moderate. We now describe
a simple, efficient andconvenient synthesis of 1,3,4-oxa ida zoles using
BF ꢀEt O as a cyclodehydrating agent as shown in Scheme-1.
3
2
Scheme 1.
Table 1.
ꢁ
Substrate (1)
(R)
Time
(h)
Yield M.P. ( C)
(%)
Entry
1
Product (2)
Phenyl
2.5
2,5-diphenyl-
,3,4-oxadiazole(2a)
98
137–139
1
6
1
(Lit.
38–140)
1
Oil
2
3
4
Methyl
1.5
1.5
2.5
1.5
2,5-dimethyl-
,3,4-oxadiazole(2b)
2,5-diethyl-
,3,4-oxadiazole(2c)
2,5-di(3-chlorophenyl)-
,3,4-oxadiazole(2d)
2,5-di(4-aminophenyl)-
,3,4-oxadiazole(2e)
97
91
91
90
1
Ethyl
Oil
1
3-Chlorophenyl
4-Aminophenyl
154–156
1
5
.
253–255
1
6b
(Lit.
50–254)
1
2
6
7
8
9
1
2-Hydroxyphenyl
2-Fluorophenyl
Cyclohexyl
2.5
1.5
1.5
2.5
1.5
2,5-di(2-hydroxyphenyl)-
,3,4-oxadiazole(2f)
2,5-(2-fluorophenyl)-
,3,4-oxadiazole(2g)
2,5-dicyclohexyl-
,3,4-oxadiazole(2h)
2,5-di(3-nitrophenyl)-
,3,4-oxadiazole(2i)
2,5-dibenzamidomethyl-
,3,4-oxadiazole(2j)
98
93
93
94
96
213–214
180–185
Oil
1
1
1
3-Nitrophenyl
Hippuryl
105–108
198–200
1
0
1

ONE POT SYNTHESIS OF 1,3,4-OXADIAZOLES
1729
Figure 1.
A typical reaction procedure in a single pot involves the addition
ꢁ
of a solution of hydrazine hydrate to acid chloride (2 eq.) at 0 C in d ry
dioxane and stirring for 30 min at r.t to furnish corresponding diacyl or
diaroyl hydrazine, BF ꢀEt O in dry dioxane was added to the 1,2-diacyl
3
2
or 1,2-diaroyl hydrazine without isolating the product and the reaction
mixture refluxed for 1–2 h. The yields of 1,3,4-oxadiazoles are excellent
and independent upon various substituents present in the precursor
(
Table-1).
We foundBF ꢀEt O equally effective and efficient cyclodehydrating
3
2
agent for the synthesis of non-symmetrical 1,3,4-oxadiazole in very good
yieldfrom non-symmetrical hy dr azine (Experimental Section 21).
The plausible mechanism of cyclodehydration of 1,2-diacyl or 1,2-di-
aroyl hydrazine 3 is outlined in Figure-1 which most likely proceeds by
concertedprocess.
In summary, the present communication describes a simple and
efficient one pot synthesis of 1,3,4-oxadiazoles in excellent yields using
BF ꢀEt O as cyclodehydrating agent.
3
2
Our methodof synthesis of 1,3,4-oxa di azoles has following specific
advantages over previous known methods of synthesis: (i) the precursors
diacyl or diaroyl hydrazines need not be isolated before cyclodehydration
(
(
ii) the cyclodehydration can be accomplished in situ in one pot
iii) BF ꢀEt O is efficient andless expensive comparedto solidphase
3
2
support employed for cyclodehydration procedure. BF ꢀEt O is tolerant to
3
2
a number of substitutedaromatics, unsubstitutedaliphatics andnon-
symmetrical substrates.
EXPERIMENTAL
M.p’s are uncorrected. I.R. spectra were recorded on a Perkin-Elmer
1
model 137 spectrometer. H NMR (200 MHz) spectra were recorded on a

1
730
TANDON AND CHHOR
Perkin-Elmer model R-32 spectrometer in CDCl using TMS as internal
3
stan da rdandMass spectra on a Joel-JMS-D-300 spectrometer. Spectral
facilities andelemental micro-analysis were carriedout by R.S.I.C. of
Central Drug Research Institute, Lucknow. Analysis of C, H, N was found
within difference of ꢂ0.4%.
General Procedure for Synthesis of 1,3,4-oxadiazoles: To a stirredsol-
ution of acid chloride or aroyl chloride (0.01 mole) in dry dioxane (50 ml)
ꢁ
was added hydrazine hydrate (0.005 mole) at 0 C andstirredfurther for
3
added dropwise to the above stirred reaction mixture in 15 min and reaction
0 min at room temp. BF ꢀEt O (0.025 mole) in dry dioxame (5 ml) was
3
2
ꢁ
mixture further refluxedfor 1 to 2 h at 130 C. The resulting solution was
ꢁ
concentratedin vacuo, saturatedNH Cl solution added at 0 C till the pH
4
becomes 6, ectractedwith EtOAc, dr iedover Na SO andconcentratedin
2
4
vacuo to give the crude product, which was further purified by column
chromatography [SiO -(MeOH-CHCl , 1:4)] to give 1,3,4-oxadiazoles
2
3
(
91–98%).
2
1
6a
ꢃ1
,
,5-Diphenyl-1,3,4-oxadiazole (2a) : ꢀmax 968, 1024, 1548, 1639 cm
þ
dH 7.26–8.19 (m, 10H, Ar-H), M , 222 (m/z), 165.
ꢃ1
2
,5-Dimethyl-1,3,4-oxadiazole (2b): ꢀ
1024, 1460, 1602 cm , dH
max
þ
1
.18 (s, 6H, 2 Â CH ), M , 98 (m/z).
3
ꢃ1
þ
2
,5-Dimethyl-1,3,4-oxadiazole (2c): ꢀ
929, 1022, 1531, 1678 cm
,
max
dH 0.98 (t, J ¼ 4 Hz, 6H, 2 Â CH ), 2.2 (q, J ¼ 4Hz, 4H, 2 Â CH ), M ,
3
2
1
26 (m/z).
2
ꢃ1
,5-Di(3-chlorophenyl)-1,3,4-oxadiazole(2d):ꢀmax1074,1569,1695cm
,
þ
dH 7.30–7.60 (m, 6H, Ar-H), 7.89–7.92 (m, 2H, Ar-H), M , 293 (m/zþ2),
2
91 (m/z), 289 (m/z-2).
2
1
6b
,5-Di-(4-aminophenyl)-1,3,4-oxadiazole (2e) : ꢀmax 1033, 1406,
ꢃ1
1
645 cm , dH 6.61–6.66 (m, 4H, m to ArNH ), 7.85–7.87 (m, 4H, 0 to
2
þ
ArNH ), 7.16 (s, 4H, 2 Â NH ), M , 252 (m/z).
2
2
2
,5-Di-(2-hydroxyphenyl)-1,3,4-oxadiazole (2f): ꢀmax 1033, 1556,
ꢃ1
3
(
093 cm , dH 6.97 (d, J ¼ 8 Hz, 2H, ArH), 7.44–7.51 (m, 4H, ArH), 7.94
þ
d, J ¼ 8H, 2H, ArH), 10.91 (s, 1H, OH), M , 254 (m/z).
2
,5-Di-(4-fluorophenyl)-1,3,4-oxadiazole (2g): ꢀ
929, 1014, 1550,
þ
max
ꢃ1
1
602 cm , dH 6.99–7.15 (m, 4H, ArH), 7.96–8.16 (m, 4H, ArH), M ,
2
58 (m/z).
2
ꢃ1
,5-Dicyclohexyl-1,3,4-oxadiazole (2h): ꢀ
956, 1033, 1550, 1670 cm
,
max
þ
dH 1.17–2.38 (m, 22H, cyclohexyl), M , 234 (m/z).
2
,5-Di(3-nitrophenyl)-1,3,4-oxadiazole (2i): ꢀ
914, 1082, 1352, 1583,
max
ꢃ1
þ
1
618 cm , dH 7.58-8.61 (m, 8H, ArH), M , 312 (m/z).
,5-Dibenzamidomethyl-1,3,4-oxadiazole (2j): ꢀmax 929, 1055, 1593,
2
1
2
631, 1737; dH 2.50 (s, 4H, 2CH ), 8.24–8.89 (m, 10H, ArH), 9.28 (s, 2H,
NH), M , 336 (m/z).
2
þ

ONE POT SYNTHESIS OF 1,3,4-OXADIAZOLES
1731
2
-(4-Nitrophenyl)-5-(4-methylphenyl)-1,3,4-oxadiazole (21): 4-methyl
benzoylhydrazine (1.5 g, 0.01 mole) was added to a stirred solution
of 4-nitrobenzoyl chloride (1.85 g, 0.01 mole) in dry dioxane (50 ml).
The reaction mixture was stirredat room temp. for 30 min. BF 3 ꢀ Et O
2
(3.16 ml, 0.025 mole) in dry dioxane (5 ml) was added dropwise to the stirred
reaction mixture in 15 min andreaction mixture further refluxedfor 2 h at
ꢁ
1
(
(
30 C. The reaction was workedup as illustratedin general procedure; 2.3 g
ꢁ
ꢃ1
83%), m.p. 122–23 C; ꢀ
m, 8H, ArH), 2.19 (s, 3H, CH ), M , 281 (m/z).
965, 1085, 1352, 1530, 1618 cm , dH 7.0–8.12
max
þ
3
ACKNOWLEDGMENT
R.B. thanks C.D.R.I., Lucknow, for the awardof a fellowship.
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ꢁ
ꢁ
6. (a) m.p. 138–140 C, (b) m.p. 250–254 C Aldrich Catalog Hand Book of
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