A mild, one-pot preparation of 1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2009.08.084

A mild and efficient one-pot protocol for the synthesis of 1,3,4-oxadiazoles from carboxylic acids and acylhydrazides was developed. Diacylhydrazide formation via HATU coupling followed by addition of Burgess reagent afforded the corresponding 1,3,4-oxadiazoles in 63-96% yields at room temperature. The reaction conditions are tolerant of a variety of functional groups, including esters, nitriles, alkynes, olefins, alkyl halides, phenols, carbamates and sulfonamides.

Full text of DOI:10.1016/j.tetlet.2009.08.084

Tetrahedron Letters 50 (2009) 6435–6439
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Tetrahedron Letters
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A mild, one-pot preparation of 1,3,4-oxadiazoles
*
Changkun Li, Hamilton D. Dickson
Department of Chemistry, HCV DPU, Infectious Diseases CEDD, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient one-pot protocol for the synthesis of 1,3,4-oxadiazoles from carboxylic acids and acy-
lhydrazides was developed. Diacylhydrazide formation via HATU coupling followed by addition of Bur-
gess reagent afforded the corresponding 1,3,4-oxadiazoles in 63–96% yields at room temperature. The
reaction conditions are tolerant of a variety of functional groups, including esters, nitriles, alkynes, ole-
fins, alkyl halides, phenols, carbamates and sulfonamides.
Received 15 June 2009
Revised 12 August 2009
Accepted 18 August 2009
Available online 29 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
desired oxadiazole in less than two hours in 80% yield. To the con-
trary, reaction with the more sterically encumbered 2,6-dimethyl-
1,3,4-Oxadiazoles are typically considered as bioisosteres for
carboxylic acids, esters and amides.1–3 Over the years, numerous
methods have been employed in the preparation of this class of
heterocycles.4–6 Brain and co-workers developed a procedure
wherein they first prepared and isolated diacylhydrazides. In a sec-
ond step, cyclodehydration with Burgess reagent by heating under
microwave irradiation gave the resulting 1,3,4-oxadiazole.4 Since
then, several new protocols utilizing microwave heating have been
reported in the preparation of 1,3,4-oxadiazoles.5 While micro-
wave irradiation is an excellent tool for reducing reaction time,
sensitive functionalities are often incompatible with elevated tem-
peratures. To address this limitation, we have developed a mild
and convenient one-pot protocol for the synthesis of 1,3,4-oxadiaz-
oles from carboxylic acids and hydrazides. Diacylhydrazide forma-
tion via HATU coupling was followed by addition of Burgess
reagent to the same reaction pot to induce cyclodehydration at
room temperature, typically within 1–3 hours.7
benzoic acid (entry 6) required heating at reflux for 2 days to form
the diacylhydrazide. Subsequent addition of Burgess reagent gen-
erated the desired product in 63% yield after stirring overnight at
room temperature. Alkyl substrates 7 and 8 demonstrated that
the scope of this reaction can be expanded beyond aryl substrates.
Our mild reaction conditions offer considerable functional
group tolerance (Table 2). The reaction worked well in the pres-
ence of a wide variety of functionalities, including nitriles, esters
and alkynes (entries 1, 2, and 3, respectively). We found that ole-
fins are also highly compatible (entry 4) and even substrates con-
taining alkyl halides (entry 5) resulted in excellent yields of
oxadiazole formation. Heteroaryl substrates (entries 6 and 7) also
produced oxadiazoles in excellent yields.
The limitations of our one-pot protocol greatly depended upon
the substrates’ compatibility with the Burgess reagent. During the
optimization of our reaction conditions, we discovered that, after
successful diacylhydrazide formation via HATU coupling, the first
equivalent of Burgess reagent was consumed without any evidence
of the diacylhydrazide undergoing cyclodehydration. We specu-
lated that this first equivalent is consumed by the 7-azabenzotria-
zole generated in the HATU coupling. Formation of the 1,3,4-
oxadiazole only occurred upon addition of another 1.5 equivalent
of Burgess reagent. Thus, a total of 2.5 equivalents of Burgess
reagent was required to drive the reactions to completion.
2. Results and discussion
Throughout our study, the hydrazide (phenyl hydrazide) was
kept constant while the carboxylic acids were varied (Scheme 1).
Our first goal was to evaluate how this transformation would re-
spond to electronic and steric alterations (Table 1). Both elec-
tron-donating (entry 2) and electron-withdrawing (entry 3)
substrates afforded high yields of the desired 1,3,4-oxadiazoles.
On the other hand, introduction of steric bulk required manipula-
tion of the standard reaction conditions; this was demonstrated
by the easy conversion of 2-methylbenzoic acid (entry 5) to the
In the course of our substrate exploration, this hypothesis was
further validated by the results obtained in experiments where
the carboxylic acid moiety contained heteroatoms acting as poten-
tial nucleophiles (Table 3). After successful diacylhydrazide forma-
tion of entry 1, addition of Burgess reagent lead to a variety of side
reactions (observed by LC–MS). One major side product observed
included a species with a mass consistent with the intermediate
shown in Figure 1. Entry 4 gave a similar result, while entry 5
* Corresponding author. Tel.: +1 919 483 3834; fax: +1 919 483 6053.
E-mail address: hamilton.d.dickson@gsk.com (H.D. Dickson).
afforded
a complex mixture of unidentifiable side products.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.084

6436
C. Li, H. D. Dickson / Tetrahedron Letters 50 (2009) 6435–6439
O
O
1. HATU, DIEA
O
R
H2N
+
N
OH
R
H
2. Burgess Reagent
THF
N
N
r.t., 1-3 hours
Scheme 1.
Table 1
Electronic and steric effects
Entry
Acid
Product
Yieldsa,b,c (%)
O
O
1
88
OH
N N
O
O
O
2
3
4
5
6
7
88
OH
N N
O
O
O2N
O
OH
96
N N
O2N
O
O
O
O
O
O
86
OH
OH
N N
O
80
N N
63d,e
O
OH
N N
OH
O
94
O
N N
O
O
8
89
OH
N N
a
Yields refer to pure (by 1H NMR and LC–MS) product after column chromatography.
All reactions were performed using 1.0 equiv phenyl hydrazide, 1.0 equiv carboxylic acid, 1.0 equiv HATU, 2.0 equiv Hunig’s base, and 2.5 equiv Burgess reagent in
b
reaction concentration of 0.11 M THF, unless otherwise noted.
c
All reactions were complete in less than 3 h unless otherwise noted.
Required reflux heating for two days to afford diacylhydrazide, and overnight stirring at room temperature to form oxadiazole.
Required 6.0 equiv Burgess reagent for cyclodehydration to go to completion.
d
e

C. Li, H. D. Dickson / Tetrahedron Letters 50 (2009) 6435–6439
6437
Table 2
Functional group compatibility
Entry
Carboxylic acid
Product
Yielda,b,c (%)
O
NC
O
1
96
86
95
88
95
96
95
OH
N N
NC
O
O
O
O
2
3
4
5
6
OH
O
O
N N
H
O
O
OH
N N
O
O
N N
OH
Cl
O
O
OH
OH
Cl
N N
O
N
O
N
Cl
N N
Cl
Br
O
S
S
Br
7
O
N N
OH
a
Yields refer to pure (by 1H NMR and LC–MS) product after column chromatography.
All reactions were performed using 1.0 equiv phenyl hydrazide, 1.0 equiv carboxylic acid, 1.0 equiv HATU, 2.0 equiv Hunig’s base, and 2.5 equiv Burgess reagent and
b
reaction concentration of 0.11 M THF, unless otherwise noted.
c
All reactions were complete in less than 3 h unless otherwise noted.
Table 3
Functional group compatibility
Entry
Carboxylic acid
Product
Yielda,b,c (%)
H2N
O
H2N
1
0
OH
O
O
N N
O
S
Cl
O
Cl
OH
N
2
69
O
S
O
O
N
H
N
N
(continued on next page)

6438
C. Li, H. D. Dickson / Tetrahedron Letters 50 (2009) 6435–6439
Table 3 (continued)
Entry
Carboxylic acid
Product
Yielda,b,c (%)
O
O
S
H2N
OH
3
4
71
O
O
H2N
S
N
N
O
O
O
N
O
HN
N
0
0
OH
O
N
N
N
H
N
N
O
OH
5
6
N
H
N
H
N
N
O
H
O
69
77
N
Boc
HO
Boc
HO
OH
N
H
N N
O
7
OH
O
N N
a
Yields refer to pure (by 1H NMR and LC–MS) product after column chromatography.
All reactions were performed using 1.0 equiv phenyl hydrazide, 1.0 equiv carboxylic acid, 1.0 equiv HATU, 2.0 equiv Hunig’s base, and 2.5 equiv Burgess reagent and
b
reaction concentration of 0.11 M THF, unless otherwise noted.
c
All reactions were complete in less than 3 h unless otherwise noted.
O
O
S
O
.
N+
O
O
O
O
N
O
N
N
O
N
N
O
O
H
H
H
H
.
S
NH2
N
N
O
H
H
presumed intermediate observed in LCMS
Figure 1. Side reaction of aniline functionality with Burgess reagent.
Interestingly, incorporation of electron-withdrawing substituents
(entries 2 and 3) attenuated the nucleophilicity of the nitrogen,
such that less of the undesired side reactions were observed. Con-
sequently, entries 2 and 3 gave respectable yields of the desired
1,3,4-oxadiazole products (69% and 71% yields, respectively). For
reaction times. The mild reaction conditions are tolerant of various
functional groups, including esters, alkynes, nitriles, alkyl halides,
olefins, phenols, carbamates and sulfonamides.
References and notes
the same reason, useful chemical synthon Boc-D-alanine (entry 6)
1. (a) Oriek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.; Hadley, M. S.; Hatcher, J.;
Riley, G. J.; Rosenberg, H. E.; Wadsworth, H. J.; Wyman, P. J. Med. Chem. 1991, 34,
2726–2735; (b) Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J. Med.
Chem. 1991, 34, 2060–2067; (c) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.;
Chambers, M. S. J. Med. Chem. 1996, 39, 2907–2914.
gave good yields of the desired 1,3,5-oxadiazole. Finally, phenolic
substrates (entry 7) did not have the same problem as aniline
counterpart (entry 1) and gave oxadiazole in good yield.
2. Husain, A.; Alam, M. M.; Zaman, M. S.; Ahuja, P. Ind. J. Heterocycl. Chem. 2008, 17,
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3. Conclusions
In conclusion, we have developed a mild and efficient one-pot
protocol for the synthesis of 1,3,4-oxadiazoles from carboxylic
acids and acyl hydrazides at room temperature. Oxadiazole forma-
tion proceeds equally well for electron-withdrawing as well as
electron-donating substrates, while steric hindrance prolonged

C. Li, H. D. Dickson / Tetrahedron Letters 50 (2009) 6435–6439
6439
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7. Typical experimental procedure: (Table 2, entry 4) 2-(3-buten-1-yl)-5-phenyl-
1,3,4-oxadiazole: solution of benzohydrazide (150 mg, 1.102 mmol),4-
A
pentenoic acid (110 mg, 1.102 mmol), HATU (419 mg, 1.102 mmol), and
Hunig’s base (0.385 mL, 2.203 mmol) in tetrahydrofuran (10 mL) was stirred
at room temperature for 45 min. Next, Burgess reagent (656 mg, 2.75 mmol)
was added and the reaction mixture was stirred for 1 h at room temperature.
The reaction mixture was adsorbed onto silica gel and the crude material was
purified via silica gel chromatography (5–40% ethyl acetate/hexanes as eluent)
to give 2-(3-buten-1-yl)-5-phenyl-1,3,4-oxadiazole (194 mg, 88% yield) 1H NMR
(400 MHz, DMSO-d6) d ppm 7.96 (dd, J = 7.78, 1.74 Hz, 2 H), 7.54–7.62 (m, 3H),
5.88 (m, 1H), 5.10 (dd, J = 17.03, 1.65 Hz, 1H), 5.01 (dd, J = 10.26, 1.47 Hz, 1H),
3.03 (t, J = 7.42 Hz, 2H), 2.51–2.55 (m, 2H). LC–MS (ES+) m/z, 200.63 [M+H].
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Bahramnejad, M. Synth. Commun. 2007, 37, 1201–1209; (g) Rajapakse, H. A.;
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