Efficient synthesis of 1,3,4-oxadiazoles promoted by NH4Cl

Article abstract of DOI:10.1016/j.tetlet.2014.10.028

An efficient and inexpensive approach to the synthesis of 2-substituted and 2,5-disubstituted 1,3,4-oxadiazoles from arylhydrazides and orthoesters is reported using catalytic NH₄Cl. The conditions are mild, and thus, compatible with a variety of functional groups. The optimized reaction is performed using 30 mol % of NH₄Cl in 100% EtOH and is generally complete within 1 h for non-aromatic orthoesters and 2-10 h for aromatic orthoesters. The reaction permits both electron-releasing and electron-withdrawing groups on the arylhydrazide substrate. Most products are formed in high yields and require only minimal purification. Compared with earlier reports, the current reactions proceed in shorter time and require less of the orthoester.

Full text of DOI:10.1016/j.tetlet.2014.10.028

Accepted Manuscript
Efficient synthesis of 1,3,4-oxadiazoles promoted by NH4Cl
Krishna Kumar Gnanasekaran, Baskar Nammalwar, Maeghan Murie, Richard
A. Bunce
PII:
S0040-4039(14)01711-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.028
TETL 45257
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 September 2014
2 October 2014
6 October 2014
Please cite this article as: Gnanasekaran, K.K., Nammalwar, B., Murie, M., Bunce, R.A., Efficient synthesis of 1,3,4-
oxadiazoles promoted by NH4Cl, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.028
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Efficient synthesis of 1,3,4-oxadiazoles
promoted by NH4Cl
∗
Krishna Kumar Gnanasekaran, Baskar Nammalwar, Maeghan Murie, and Richard A. Bunce
O
N
C
N
C
NH4Cl
R2
NHNH2
R2C(OEt)3
O
R1
R1
EtOH, reflux
9 a-d
10-17 (a-d)
1-8
30 examples
R1 = H, 4-CH3, 4-OCH3, 3-Br, 2-Cl, 4-Cl, 2-NO2, 4-NO2
R2 = H, CH3, CH3CH2, Ph

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Efficient synthesis of 1,3,4-oxadiazoles promoted by NH4Cl
Krishna Kumar Gnanasekaran, Baskar Nammalwar, Maeghan Murie, and Richard A. Bunce∗*
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient and inexpensive approach to the synthesis of 2-substituted and 2,5-
disubstituted 1,3,4-oxadiazoles from arylhydrazides and orthoesters is reported using
catalytic NH4Cl. The conditions are mild, and thus, compatible with a variety of
functional groups. The optimized reaction is performed using 30 mol% of NH4Cl in
100% EtOH and is generally complete within 1 h for non-aromatic orthoesters and 2-
10 h for aromatic orthoesters. The reaction permits both electron-releasing and
electron-withdrawing groups on the arylhydrazide substrate. Most products are
formed in high yield and require only minimal purification. Compared with earlier
reports, the current reactions proceed in shorter time and require less of the orthoester.
Received in revised form
Accepted
Available online
Keywords:
1,3,4-Oxadiazole
Ammonium chloride
Heterocycle synthesis
Bioisostere
2009 Elsevier Ltd. All rights reserved.
The 1,3,4-oxadiazole scaffold has attracted considerable
attention in the field of medicinal chemistry.1 This interest stems
from their wide range of biological activities including
anticancer,2 antifungal,3,4 antibacterial,5 antimicrobial,6,7 anti-
inflammatory,8,9 anticonvulsant,10,11 analgesic,12 and as inhibitors
of HIV integrase13 and angiogenesis.14 Many commercial drugs,
such as the antihypertensives tiodiazosin15 and nesapidil,16 the
antibiotic furamizole,17 the HIV-integrase inhibitor raltegravir13
and the anticancer agent zibotentan,2 contain the oxadiazole
nucleus (Figure 1). In drug research, the oxadiazole moiety can
serve as a bioisostere for carboxylic acids, esters and amides.18-22
These rings are also important structural components of
agrochemicals such as herbicides,23 pesticides24 and plant growth
regulators.25-27 Beyond their medicinal and agricultural uses,
oxadiazoles find application in the field of organoelectronics due
to their electron transporting properties.28-31
In recent years, we have found that NH4Cl is a highly
efficient and mild catalyst for the synthesis of benzo-fused
heterocycles such as benzimidazoles, benzoxazoles and
benzothiazoles,33 and also for the preparation of α-aminonitriles
using a variant of the Strecker synthesis.34 To extend the scope
of this catalyst, optimization studies were performed for the
current reaction using benzhydrazide (1.0 eq) and triethyl
orthoformate (1.1 eq). The optimized transformation occurred
using 30 mol% of NH4Cl in refluxing ethanol, which afforded a
96% yield of the corresponding oxadiazole in less than 1 h.
Lower catalyst loadings gave slow and often incomplete reaction,
while more catalyst gave no additional rate enhancement. The
use of absolute EtOH proved essential to achieve maximum
conversion for these reactions. Attempts to use other solvents
(THF, dichloroethane, CH3OH, dioxane, CH3CN, benzene, 10:1
EtOH:H2O or 1:1 EtOH:H2O) either produced lower yields or
required longer reaction times (Figure 2). The current procedure
Due to the broad commercial potential of 1,3,4-oxadiazoles,
numerous methods for their synthesis have been developed over
the years. Most approaches are either multi-step or involve the
cyclization of hydrazides using harsh conditions such as
phosphorus oxychloride, thionyl chloride, sulfuric acid,
zirconium(IV) chloride, XtalFluor-E®, Burgess reagent, Deoxo-
Fluor®, acid chlorides, Nafion® NR50 or acetic acid, under reflux
or microwave heating.32 Due to the caustic nature of these
reagents, sensitive functional groups are often incompatible with
these earlier methods. To address this problem, we have
developed a mild protocol, which involves the formation of
1,3,4-oxadiazoles from arylhydrazides and orthoesters promoted
by catalytic NH4Cl.
represents
a considerable improvement over a previously
published uncatalyzed route that required 18 h and a five-fold
excess of the orthoester.35
The scope of this reaction was studied by refluxing a series
of arylhydrazides with various triethyl orthoesters in EtOH using
30 mol% of NH4Cl. Our results are summarized in Table I. The
mild reaction conditions offered a wide range of functional group
tolerance on the arylhydrazide including methyl, methoxy,
chloro, bromo and nitro. In most cases, the yields were high, and
the products were formed cleanly. Solid products were isolated
directly from the reaction mixture and did not require further
purification. Oils required purification by elution through a
———
∗ Corresponding author. Tel.: +1-405-744-5952 fax: +1-405-744-6007; e-mail: rab@okstate.edu

2
Tetrahedron
CH3
O
N
NH2
N
CH3
CH3
O
O
N
N
Table 1. Synthesis of 2- and 2,5-disubstituted 1,3,4-oxazoles
O
N
O
NH2
N
N
N
N
N
N
O2N
O
N
N
N
O
O
SCH3
O
HO
O
CH3
O
NH4Cl
R2
NHNH2
R2C(OEt)3
O
R1
R1
Tiodiazosin (1)
Nesapidil (2)
Furamizole (3)
EtOH
reflux
CH3
O
N
CH3
9 (a-d)
a (R2 = H)
b (R2 = CH3)
10-17 (a-d)
(refer to table)
1-8
1 (R1 = H)
2 (R1 = 4-CH3)
3 (R1 = 4-OCH3)
4 (R1 = 3-Br)
O
N
N
CH3
N
OH
H
N
F
HN
N
N
N
H
O
O S O
N
CH3
O
O
O
N
c (R2 = CH2CH3)
d (R2 = Ph)
Raltegravir (4)
Zibotentan (5)
Figure 1. Drugs containing an oxadiazole ring
5 (R1 = 2-Cl)
6 (R1 = 4-Cl)
7 (R1 = 2-NO2)
8 (R1 = 4-NO2)
Entry
R1
R2
Time
Yield (%)
H
H
H
H
CH3
30 min
45 min
45 min
95b
93b
98a
10a
10b
CH3CH2
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
14a
14d
15a
15b
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
H
Ph
H
2.5 h
30 min
45 min
45 min
2.5 h
30 min
45 min
45 min
2 h
96a
88b
53b
95b
96a
98a
90b
93b
97a
82b
89b
86b
80b
28b
97a
90b
75b
95a
70b
22b
25b
38b
55b
74b
81b
69b
92b
4-CH3
4-CH3
4-CH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
H
CH3
CH3CH2
Ph
H
Figure 2. Effect of solvent with time in the reaction
CH3
CH3CH2
Ph
short column of silica gel. The reaction was successful with both
electron-releasing and electron-withdrawing substituents on the
arylhydrazide reactant. The yield of oxadiazole was only
decreased when an electron-withdrawing group was positioned
ortho to the hydrazide carbonyl. This presumably results from an
electronic effect, which should exert a greater impact on the
carbonyl reactivity from this position. Most notably, the
presence of an electron-withdrawing chloro or nitro at the ortho
position of the arylhydrazide resulted in lower yields, especially
with non-aromatic orthoesters.
H
30 min
45 min
45 min
3 h
CH3
CH3
CH3CH2
Ph
CH3CH2
Ph
2-Cl
H
30 min
3 h
2-Cl
Ph
4-Cl
H
30 min
45 min
45 min
3 h
4-Cl
CH3
CH3CH2
Ph
4-Cl
Several observations were made regarding the series of
orthoesters used in these reactions. With respect to reaction
times, orthoformate, orthoacetate and orthopropionate were
completely consumed in less than 1 h, while orthobenzoate
4-Cl
2-NO2
2-NO2
2-NO2
2-NO2
4-NO2
4-NO2
4-NO2
4-NO2
H
1 h
CH3
CH3CH2
Ph
1 h
1 h
required extended reaction times of 2-10 h.
However,
10 h
orthobenzoate seemed to give the most consistent yields, while
the smaller orthoesters afforded more variable results.
H
1 h
CH3
CH3CH2
Ph
1 h
A proposed mechanism for oxadiazole formation is given in
Scheme 1. Initial protonation and loss of EtOH from 9a would
1 h
6 h
OEt
EtO
+
NH4
aProduct was isolated by filtration. bProduct was isolated by
column chromatography
EtO
H
H
EtO
–EtOH
OEt
9a
18
..
HN NH
..
HN NH
+
EtO
EtO
H
N
give the ether-stabilized carbocation 18. Attack on this species
by hydrazide 1 to give 19 would be followed by protonation and
loss of a second molecule of EtOH to give 20. Ring closure to
generate 21 and elimination of EtOH would then afford
oxadiazole 10a.
NH4
..
NH2
Ph
OEt
OEt
H
H
Ph
Ph
H
–EtOH
O
O
O
OEt
1
19
20
18
+
N
NH
N
N
NH4
OEt
H
Ph
Ph
O
O
–EtOH
H
In summary, we have developed an efficient and
inexpensive approach to the synthesis of 2-substituted and 2,5-
disubstituted 1,3,4-oxadiazoles using NH4Cl as catalyst. The
conditions are mild, and thus, compatible with a variety of
functional groups. The optimized reaction is performed using 30
21
10a
Scheme 1. Proposed mechanism for formation of oxadiazole 10a
from 1 and 9a.

3
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for orthobenzoate. In most cases, the yields are high, and the
isolated products require only minimal purification. The reaction
is successful with electron-releasing and electron-withdrawing
groups on the arylhydrazide substrate and proceeds smoothly for
both non-aromatic and aromatic orthoesters. Compared with
earlier reports, the current reactions proceed in shorter time and
require considerably less orthoester.
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M.M. wishes to thank Oklahoma State University for a
Niblack Scholarship to support her undergraduate research.
Funding for the 400 MHz NMR spectrometer of the state-wide
shared NMR facility was provided by the Oklahoma State
Regents for Higher Education, the Keck Foundation and Conoco,
Inc. Finally, the authors wish to express their appreciation to the
OSU College of Arts and Sciences for funds to upgrade our
departmental FT-IR instruments.
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