Oxidative cyclization of amidoximes and thiohydroximic acids: A facile and efficient strategy for accessing 3,5-disubstituted 1,2,4-oxadiazoles and 1,4,2-oxathiazoles

Article abstract of DOI:10.1016/j.tetlet.2017.04.045

A facile and practical protocol has been developed for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles and 1,4,2-oxathiazoles through oxidative cyclization of amidoximes and thiohydroximic acids, respectively at room temperature. Use of mild reaction

Full text of DOI:10.1016/j.tetlet.2017.04.045

Accepted Manuscript
Oxidative Cyclization of Amidoximes and Thiohydroximic Acids: A Facile and
Efficient Strategy for Accessing 3,5-Disubstituted 1,2,4-Oxadiazoles and 1,4,2-
Oxathiazoles
Jatin J. Lade, Bhausaheb N. Patil, Kamlesh S. Vadagaonkar, Atul C. Chaskar
PII:
S0040-4039(17)30484-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.045
TETL 48837
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 January 2017
12 April 2017
13 April 2017
Please cite this article as: Lade, J.J., Patil, B.N., Vadagaonkar, K.S., Chaskar, A.C., Oxidative Cyclization of
Amidoximes and Thiohydroximic Acids: A Facile and Efficient Strategy for Accessing 3,5-Disubstituted 1,2,4-
Oxadiazoles and 1,4,2-Oxathiazoles, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.045
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for Accessing 3,5-Disubstituted 1,2,4-Oxadiazoles and 1,4,2-Oxathiazoles
Jatin J. Lade,a† Bhausaheb N. Patil,a† Kamlesh S. Vadagaonkarb* and Atul C. Chaskarab*

Tetrahedron Letters
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Oxidative Cyclization of Amidoximes and Thiohydroximic Acids: A Facile and
Efficient Strategy for Accessing 3,5-Disubstituted 1,2,4-Oxadiazoles and 1,4,2-
Oxathiazoles
Jatin J. Lade,a† Bhausaheb N. Patil,a† Kamlesh S. Vadagaonkarb* and Atul C. Chaskarab*
aNational Centre for Nanosciences and Nanotechnology, University of Mumbai, Mumbai 400098, India
bDepartment of Dyestuff Technology, Institute of Chemical Technology, Mumbai 400019, India
Tel.: +91-7507375261; E-mail: achaskar25@gmail.com, vadgaonkarks@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and practical protocol has been developed for the synthesis of 3,5-disubstituted 1,2,4-
oxadiazoles and 1,4,2-oxathiazoles through oxidative cyclization of amidoximes and
thiohydroximic acids, respectively at room temperature. Use of mild reaction conditions,
inexpensive reagents, broad substrate scope and good to excellent yield of the products are the
salient features of this protocol.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Amidoximes
Thiohydroximic acids
Oxidative cyclization
Oxadiazole
Oxathiazole
Introduction
protocol involving O-acylation of amidoximes by using
carboxylic acids or their activated derivatives such as esters,
1,2,4-Oxadiazole is an important heterocyclic scaffold, as it is
prevalent in various bioactive molecules, pharmaceuticals and
functional materials.1-4 Particularly, 3,5-disubstituted 1,2,4-
oxadiazoles have been utilized as anti-asthmatics,5 anti-
inflammatory agents,6 anti-diabetics,7 anti-microbial agents8 and
anti-cancer agents.9
anhydrides and acid chlorides followed by intramolecular
cyclodehydration.16 Besides this, microwave assisted methods
and use of strong acids such as PTSA and ZnCl2 have also been
reported for the synthesis of these heterocycles.17 The other
common approach used for the synthesis of 1,2,4-oxadiazole
includes intermolecular cyclodehydration of amidoximes with
aldehyde to form 4,5-dihydro-1,2,4-oxadiazoles, followed by
oxidative dehydrogenation.18 Another widely used method for the
synthesis of 1,2,4-oxadiazoles involves the 1,3-dipolar
cycloaddition of nitrile oxides to nitriles or azetine derivatives.19
N-acylamidines obtained by the condensation of amidines with
carboxylic acids were used as the intermediates which on tandem
reaction with hydroxylamine formed 1,2,4-oxadiazoles.20
Moreover, Vidavalur et al. reported Brønsted acid-catalyzed
synthesis of 1,2,4-oxadiazoles from 2,2,2-trichloroethyl imidates
by using polyethylene glycol (PEG) as a solvent,21 whereas Mirza
Figure 1. Examples of biologically active 1,2,4-oxadiazole scaffolds
Besides this, they have also been employed as ligands for the
transition metal complexes and as G-quadruplex ligands for
probing DNA superstructure in antitumor research.10,11 Moreover,
these five-membered heterocycles have also been applied as
stable ester or amide bioisosteres in peptide mimetics.12 On the
other hand, 1,4,2-oxathiazoles are the five-membered
heterocycles comprised of three different heteroatoms that are
barely reported in the literature.13 In addition, they are also
known to serve as useful isothiocyanate (ITC) precursors upon
their thermal decomposition.14 In view of these aforementioned
applications of 1,2,4-oxadiazoles, several methods have been
developed for their synthesis.
described
a one-pot synthesis of 1,2,4-oxadiazoles from
amidoximes and benzyl halides in the presence of a base.22
Recently, Jiang et al. disclosed the synthesis of 1,2,4-oxadiazoles
via copper-catalyzed cascade annulation of amidines with
methylarenes by using tert-butyl hydroperoxide (TBHP) as an
oxidant,23 while Hong and co-workers demonstrated copper-
catalyzed direct synthesis of 1,2,4-oxadiazoles from amides and
nitriles through oxidative N-O bond formation by employing O2
as the sole oxidant.24
The other scarcely used strategy for the synthesis of 1,2,4-
oxadiazoles involves oxidative cyclization of N-benzyl
amidoximes. In this context, Chiba et al.25 reported an oxidative
free radical transformation of N-benzyl amidoximes into 3,5-
disubstituted 1,2,4-oxadiazoles in the presence of K3PO4 at 60 oC
Conventional methods for the synthesis of 1,2,4-oxadiazoles
generally involve the use of amidoximes obtained by addition of
hydroxylamine to nitriles as starting materials or as
intermediates.15 1,2,4-oxadiazoles are prepared via a two-step
∗ Corresponding author. Tel.: +91-7507375261; e-mail: achaskar25@gmail.com, vadgaonkarks@gmail.com

2
whereas, Pierce et al. employed 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) as an oxidant for oxidative cyclization of
N-benzylamidoximes26 and thiohydroximic acids27 to form 1,2,4-
oxadiazoles and 1,4,2-oxathiazoles, respectively at high reaction
temperatures.
room temperature (Table 1, entry 4). The reaction with 1.0
equiv. N-chlorosuccinimide (NCS) as an oxidant was also carried
out to check the enhancement in the yield but it resulted in
moderate yield (65%) of the product 2a (Table 1, entry 5).
Table 1 Optimization of reaction conditionsa
However, these methods suffer from drawbacks such as use
of transition metal catalyst, harsh reaction conditions (microwave
conditions and higher reaction temperatures), longer reaction
times and low yield of the products. Therefore, development of a
facile and practical method for the synthesis of 1,2,4-oxadiazoles
and 1,4,2-oxathiazoles is highly desirable.
OH
O
N
N
N
oxidant, base,
solvent, time
N
H
1a
2a
In continuation with our interest in the development of mild,
operationally simple and environment-friendly protocols for the
synthesis of heterocyclic compounds,28 we envisaged to access
pharmaceutically important 1,2,4-oxadiazole and 1,4,2-
oxathiazole derivatives. In this context, herein we report the
synthesis of 1,2,4-oxadiazoles and 1,4,2-oxathiazoles by using
Time
(h)
1
Yield
Entry
Oxidant
Base
Solvent
(%)d
50
1
2
NBS
NBS
NBS
NBS
NCS
NBS
NBS
I2
K2CO3
NEt3
DCM
DCM
DCM
1
52
60
3
Pyridine
DBU
DBU
1
1
1
1
1
4
4
4
4
4
4
4
4
4
4
4
4
4
4
DCM
DCM
DMF
80
65
5
such
oxidizers
as
N-bromosuccinimide
(NBS)-1,8-
6
DBU
DBU
35
28
7
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-dioxane
CH3CN
DMF
diazabicyclo[5.4.0]-undec-7-ene (DBU) and I2-K2CO3 at room
temperature (Scheme 1). To the best of our knowledge, this is the
first report for oxidative cyclization of N-benzyl amidoximes and
thiohydroximic acids at room temperature.
8
Na2CO3
K2CO3
Cs2CO3
DBU
33
72
9
I2
10
11
12
13
14
15
16b
17c
18
19
20
I2
58
53
I2
I2
Pyrrolidine
Piperidine
Pyridine
NEt3
42
47
35
20
I2
I2
I2
-
I2
K2CO3
-
-
-
I2
K2CO3
K2CO3
K2CO3
Trace
Trace
Trace
I2
I2
aReaction conditions: 1a (1.0 mmol), oxidant (1.0 mmol), base (1.0 mmol)
b
and solvent (5 mL) for 1-4 h at room temperature. Reaction in the absence of
an oxidant. cReaction in the absence of a base. dIsolated yields.
The reaction was also conducted in different solvents such as
DMF and CH3CN which afforded the product 2a in low yields
(Table 1, entries 6 and 7). Similarly, we also employed I2 as an
oxidant for this oxidative cyclization. Use of 1.0 equiv. of I2 as an
oxidant and 1.0 equiv. of Na2CO3 as a base in toluene at room
temperature after 4 h furnished product 2a in low yield (26%)
(Table 1, entry 8), while the reaction by using K2CO3 (1.0 equiv.)
as a base led to 72% yield of the product (Table1, entry 9). The
reaction carried out by using Cs2CO3 and DBU as the bases
offered product 2a in 58% and 53% yield, respectively (Table 1,
entries 10 and 11) whereas use of pyrrolidine, piperidine,
pyridine and NEt3 as the bases for this reaction offered product
2a in low yields (20-47%) (Table 1, entries 12-15).The reaction
in the absence of an oxidant failed to give product (Table 1, entry
16), thereby indicating significant role played by oxidant in this
reaction. The reaction could not occur in the absence of a base
too (Table 1, entry 17), thereby clearly highlighting the key role
played by base in this reaction. Further, various solvents such as
1,4-dioxane, CH3CN and DMF were tested to check if any of
these could improve the yield of the product. The reactions in
1,4-dioxane, acetonitrile and DMF afforded product 2a only in
trace amounts (Table 1, entries 18-20). Similar results were
obtained when oxidative cyclization of thiohydroximic acids to
3,5-diphenyl 1,4,2-oxathiazole was carried out under the same
reaction conditions.
Scheme 1 Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles and
1,4,2-oxathiazoles
Results and Discussion
N-Benzyl amidoximes15 1a-1j and thiohydroximic acids27 3a-
3j were prepared by using previously reported method in the
literature staring from readily available aldehydes. An oxidative
cyclization of N-benzyl-N'-hydroxybenzimidamide was used as a
model for optimizing reaction conditions. The reaction carried
out by using 1.0 equiv. N-bromosuccinimide (NBS) as an oxidant
and 1.0 equiv. of K2CO3 as a base in DCM as a solvent at room
temperature for 1 h afforded 3,5-diphenyl 1,2,4-oxadiazole (2a)
in 50% yield (Table 1, entry 1). We next screened different bases
to study their effect on the oxidative cyclization with an intention
to increase the yield of the product. The reaction with 1.0 equiv.
NBS and 1.0 equiv. NEt3 gave 52% yield of the product 2a in 1 h
(Table 1, entry 2), while a higher yield (60%) was obtained by
using 1.0 equiv. of pyridine as a base (Table 1, entry 3). To our
delight, the use of 1.0 equiv. of NBS as an oxidant and 1.0 equiv.
of DBU as a base was found to be the best reaction condition for
this conversion resulting in 80% yield of the product in 1 h at
The scope and limitations of this oxidative cyclization was
investigated by conducting the reaction of different N-benzyl
amidoximes (1) under these optimized conditions (Table 2). The
yields of products obtained by using NBS-DBU and I2-K2CO3
were found to be comparable. The protocol is robust and can
tolerate a variety of substituents. Amidoximes bearing halogen

3
substituents (-F, -Cl and -Br) at the ortho and para position of
phenyl ring afforded products 2b-2e in 65-79% yields. Oxidative
cyclization of amidoximes bearing electron donating substituents
such as -CH3, -OMe and -OPh at the ortho and para position of
phenyl ring occurred smoothly to offer products 2f-2h in
moderate yields (58-65%). Amidoximes bearing electron
withdrawing substituents such as -NO2 and -CN easily underwent
oxidative cyclization to give product 2i and 2j in good to
excellent yields (73-84%). Higher yields could be attributed to
more stable imine double bond. We also carried out oxidative
cyclization of amidoximes with substituents such as 4-OMe and
4-F on aromatic ring of the benzylic portion, which afforded
product 2k and 2l in moderate yields (50-65%).
aReaction conditions: Thiohydroximic acid 3 (1.0 mmol), oxidant (1.0 mmol),
b
base (1.0 mmol) and solvent (5 mL) at room temperature. Isolated yields by
using NBS-DBU. cIsolated yields by using I2-K2CO3.
The yields of products obtained by using both oxidants were
found to be similar. Oxidative cyclization of thiohydroximic acid
with no substituent on the phenyl ring formed product 3,5-
diphenyl 1,4,2-oxathiazole 4a in 75-79% yields. Thiohydroximic
acids bearing halogen substituents (-F, -Cl and -Br) at the ortho
and para position of phenyl ring resulted in formation of
products 4b-4e in 64-79% yields. Oxidative cyclization of
thiohydroximic acids bearing electron donating substituents such
as -CH3, -OMe and -OPh at the ortho and para position of phenyl
ring proceeded smoothly to afford products 4f-4h in yields
ranging from 55-66%. Thiohydroximic acids bearing electron
withdrawing substituents such as -NO2 and -CN at the para
position of the phenyl ring furnished product 4i and 4j in good to
excellent yields (73-83%). Higher yields could be attributed to
more stable imine double bond. We also performed oxidative
cyclization of thiohydroximic acid with 4-Cl substituent on
aromatic ring of the benzylic portion, which afforded product 4k
in good yields (62-68%).
Table 2 Substrate scope study for oxidative cyclization of N-
benzyl amidoximesa
The possible mechanistic pathways for the formation of 3,5-
diphenyl 1,4,2-oxadiazole in the presence of NBS-DBU and I2-
K2CO3 are depicted in Figure 2 and 3, respectively. The reaction
presumably occurs through N-halogenation of amidoxime (1a) to
form halogenated derivative which in the presence of a base
undergoes dehydrohalogenation to form intermediate A.
Intermediate A via cyclization-aromatization sequence offers 3,5-
diphenyl 1,2,4-oxadiazole (2a).
aReaction conditions: N-benzyl amidoxime 1 (1.0 mmol), oxidant (1.0 mmol),
b
base (1.0 mmol) and solvent (5 mL) at room temperature. Isolated yields by
using NBS-DBU. cIsolated yields by using I2-K2CO3.
Encouraged with these results, we turned our attention to
oxidative cyclization of thiohydroximic acids under similar
reaction conditions. We found that the above mentioned protocol
can be successfully applied for oxidative cyclization of various
thiohydroximic acids. Concomitant results were obtained in
comparison with amidoximes.
Table 3 Substrate scope study for oxidative cyclization of
thiohydroximic acidsa
Figure 2 Proposed reaction mechanism for 3,5-diphenyl 1,2,4-oxadiazole in
the presence of NBS-DBU.
Figure 3 Proposed reaction mechanism for 3,5-diphenyl 1,2,4-oxadiazole in
the presence of I2-K2CO3
The possible mechanistic pathways for the formation of 3,5-
diphenyl 1,4,2-oxathiazole in the presence of NBS-DBU and I2-
K2CO3 are depicted in Figure 4 and 5, respectively. The reaction
presumably occurs through halogenation of thiohydroximic acid

4
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(3a) to form halogenated derivative which in the presence of a
base undergoes dehydrohalogenation to form intermediate B.
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2677–2682.
Intermediate
oxathiazole (4a).
B
on cyclization offers 3,5-diphenyl 1,4,2-
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O
OH
OH
OH
S
Br
N
N
N
N
H
Base (B)
S
O
S
Br
B
3a
O
N
H
O
O
S
N
N
O
S
4a
5. Palmer, J. T.; Rydzewski, R. M.; Mendonca, R. V.; Sperandio, D.;
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Figure 4 Proposed reaction mechanism for 3,5-diphenyl 1,4,2-oxathiazole in
the presence of NBS-DBU.
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S
OH
OH
S
N
N
N
H
Base (B)
I
I
S
I
-
I
3a
B
I
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In Conclusion, we have developed a mild, efficient and
operationally simple method for the synthesis of 3,5-disubstituted
1,2,4-oxadiazoles and 1,4,2-oxathiazoles via oxidative
cyclization of N-benzyl amidoximes and thiohydroximic acids,
respectively at room temperature. We strongly believe that this
protocol will be widely adopted and serve as practical and
economical approach for straightforward synthesis of
functionally diverse 1,2,4-oxadiazoles and 1,4,2-oxathiazoles
having broad substrate scope and forming important motifs to
drugs, natural products, pharmaceutical and agrochemical
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J.J.L. and B.N.P. thank UGC-New Delhi for providing
fellowships. K.S.V. and A.C.C. thanks DST-SERB (sanction no.
SB/FT/CS-147/2013) for financial support. Authors gratefully
acknowledge V.N.K., K.M.S. and ORL, Department of
Chemistry, University of Mumbai for their generous help and
support.
Author Contributions
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†These authors contributed equally to this work.
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29. General experimental procedure for the synthesis of 3,5-
disubstituted-1,2,4-oxadiazole and
3, 5-disubstituted-1,4,2-
oxathiazole: To the solution of N-benzyl amidoxime 1/
thiohydroximic acid 3 (1.0 mmol) in an appropriate solvent (5
mL) were added oxidant (1.0 mmol) and base (1.0 mmol) at room
temperature. The resulting mixture was then stirred at room
temperature for an appropriate time. After completion of reaction
(monitored by TLC), 10 mL of saturated Na2S2O3 solution and
DCM (10 mL) were added to the reaction mixture. The organic
layer after separation was washed with water (10 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue thus obtained was purified by column chromatography on
60:120 mesh silica gel by using n-hexane:ethyl acetate (95:5) as
the eluent to obtain the pure 3,5-disubstituted-1,2,4-oxadiazole
(2)/ 3,5-disubstituted-1,4,2-oxathiazole (4).
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Supplementary Material
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Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
23. Guo, W.; Huang, K.; Ji, F.; Wu, W.; Jiang, H. Chem. Commun.
2015, 51, 8857–8860.
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Highlights of the work
• Room temperature protocol to access 1,2,4-
oxadiazoles and 1,4,2-oxathiazoles
• A metal-free protocol
• Use of inexpensive oxidants such as N-
bromosuccinimide and iodine
• Operational Simplicity
• Good to excellent yields of the products