Facile room-temperature assembly of the 1,2,4-oxadiazole core from readily available amidoximes and carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2018.06.019

A one-pot ambient-temperature procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from amidoximes and carboxylic acids under superbase-promoted conditions is reported.

Full text of DOI:10.1016/j.tetlet.2018.06.019

Accepted Manuscript
Facile room-temperature assembly of the 1,2,4-oxadiazole core from readily
available amidoximes and carboxylic acids
Tatyana Sharonova, Vitalina Pankrat'eva, Polyna Savko, Sergey Baykov, Anton
Shetnev
PII:
S0040-4039(18)30761-5
https://doi.org/10.1016/j.tetlet.2018.06.019
TETL 50057
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 April 2018
4 June 2018
6 June 2018
Please cite this article as: Sharonova, T., Pankrat'eva, V., Savko, P., Baykov, S., Shetnev, A., Facile room-
temperature assembly of the 1,2,4-oxadiazole core from readily available amidoximes and carboxylic acids,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.019
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*Response to Reviewers
Answers for reviewers
Manuscript was corrected according to “TETL-D-18-00730 Marked Manuscript One.”
№
1
Reviewer comment
Reviewer #1:
Answer
Wide scope of structural variability on the
amidoximes side were observed in our
The work describes an evolution of a
synthetic procedure for the preparation of
oxadiazoles. the authors have already
published several works on the subject. In
particular this last work appears to be a
modification of a previous Tet. Lett 2017.
previous works. ( For example Baykov S,
Sharonova T, Shetnev A, Rozhkov S, Kalinin
S, Smirnov AV. Tetrahedron. 2017; 73: 945–
951; (b) Tarasenko M, Duderin N, Sharonova
T, Baykov S, Shetnev A, Smirnov AV.
Tetrahedron Lett. 2017; 58: 3672–3677.)
There is a lack of novelty and, although the In this article, we have focused more on a
work describes a large number of
variety of carboxylic acids.
examples, there is low structural variability
especially on the amidoximes side.
2
Reviewer #2:
The recommended reference (G.-B. Liang
and D. D. Feng, Tetrahedron Lett. 1996, vol.
37, 6627-6630) was added to manuscript
(Ref. 13e).
A key previous reference missed out is by
G.-B. Liang and D. D. Feng, Tetrahedron
Lett. 1996, vol. 37, 6627-6630. This
duplicates some of the advantages of the
current paper, using either EDC or CDI
and the non-toxic solvent diglyme. Once
this prior paper is considered, the
advantages of the current one seem less. In
many cases heating under neutral
conditions in diglyme would be preferable
to treatment with NaOH in DMSO. At the
very least the 1996 TL paper must be
mentioned.
3
Reviewer #2:
Manuscript was corrected according to
In addition to this there are problems in the “TETL-D-18-00730 Marked Manuscript
English that need extensive improvements. One” and with these comments
Most commonly, use of the article is poor
and there are some places where mistakes
make understanding difficult, such as:
Abstract - "...the safety solvent use
suggested approach is."
Page 1, column 1, 4th bottom line - "is

hurtfully limiting"
Page 2, column 1, 3rd bottom -
"Contrastly, previously reported by our
group reactivity levels of corresponding
esters varied"

Tetrahedron Letters
journal homepage: www.elsevier.com
Facile room-temperature assembly of the 1,2,4-oxadiazole core from readily available
amidoximes and carboxylic acids
a
a
a
b
a,
Tatyana Sharonova, Vitalina Pankrat’eva, Polyna Savko, Sergey Baykov, and Anton Shetnev
a
Pharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian
Federation
b
Institute of Chemistry, Saint Petersburg State University, Universitetsky pr. 26, Saint Petersburg, 198504, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot ambient-temperature procedure for the synthesis of 3,5-disubstituted-1,2,4-
oxadiazoles from amidoximes and carboxylic acids under superbase-promoted conditions is
reported.
2
018 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Heterocycles
Amidoximes
Carboxylic acids
Superbase promoted
Room temperature synthesis
1
9
problem, some basic catalysts were proposed. The latter
allow the cyclodehydration of O-acylamidoxime 3 to be
performed at ambient temperature, nevertheless this
intermediate requires a separate step and isolation. In our
Introduction
1
,2,4-Oxadiazoles constitute an important class of
heterocyclic compounds, which continues to attract the
growing attention of medicinal chemists due to a broad
2
0
1
previous work we reported the MOH/DMSO system to be
more effective than other known catalysts in terms of yield,
cost, and reaction time. Furthermore, it was successfully
applied to the synthesis of different 1,2,4-oxadiazoles,
including a series of selective and potent carbonic anhydrase
isoform II (CAII) inhibitors. Simultaneously, our efforts were
focused on the development of one-pot protocols and
expanding reagent diversity. Herein, we report a one-pot
room temperature protocol for CDI-promoted amidoxime
carboxylic acid coupling as a powerful tool for the synthesis of
2
spectrum of exhibited bioactivity, such as antimicrobial,
3
4
5
6
antiviral,
antidiabetic,
anticancer,
antifungal,
anti-inflammatory,
neuroprotective,
21
7
8
9
antitubercular,
and
1
0
antiglaucoma properties. Moreover, the 1,2,4-oxadiazole
motif has an acceptable ADME profile, giving rise to its use in
the “hit-to-lead” optimization of drug candidates.
representative example of the above mentioned optimization
tactic is the bioisosteric replacement of amide and ester
functional groups.
1
0
1
1
A
2
2
1
2
1
,2,4-oxadiazoles.
From a drug discovery point of view, the most attractive
procedure to assemble the 3,5-disubstituted 1,2,4-oxadiazole
ring is the reaction of amidoximes with carboxylic acids
Results and Discussion
1
3
(
1
Scheme 1). In comparison to other known approaches, i.e.
Initially, we evaluated several activating agents commonly
applied in the pharmaceutical industry for amide synthesis: N-
1
4
,3-dipolar cycloaddition of nitriles to nitrile oxides,
15
oxidative coupling reactions, oxidation of N-substituted
amidoximes, and the rearrangement of other heterocycles,
this method has a number of advantages. In particular, easy
handling and commercially/synthetically available starting
materials are complemented by the possibility of process
(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
1
6
17
(EDC), 1,1’-carbonyldiimidazole (CDI), isobutyl
23
chloroformate (IBCF), and ethyl chloroformate (ECF), using
the coupling between benzoic acid 1a and 4-tolylamidoxime 2a
in DMSO as a model reaction. NaOH was chosen for catalysis
of the cyclodehydration step since it provided the best yield in
1
8
1
3a,d,f
“
parallelization.”
for the conversion of O-acylamidoxime intermediate 3 into the
,2,4-oxadiazole is limiting for the reaction scope, resulting in
decreased yields and product purity. In order to solve this
However, the prolonged heating required
22
our previous studies. In the case of IBCF and ECF, additional
1
base was required for the acylation step due to the release of
HCl. As shown in Table 1 CDI (Entry 2) is the most suitable
—
——

Corresponding author. Tel.: +7-485-232-9863; fax: +7-485- 230-5459; e-mail: a.shetnev@yspu.org

2
Tetrahedron
coupling agent for this reaction, while EDC demonstrated the
worst result, which could be explained by the interaction of the
in the one-pot protocol providing 1,2,4-oxadiazole 4a in
excellent (95%) yield.
2
4
carbodiimide with DMSO. Subsequent optimization of the
reagents ratio and reaction time (Table 1, entries 8-11) resulted
Scheme 1. The evolution of 1,2,4-oxadiazole synthesis from carboxylic acids and amidoximes.
a
Table 1. Reaction conditions optimization.
methyl 4-methoxybenzoate into 1,2,4-oxadiazole required 16 h,
while methyl 4-(trifluoromethyl)benzoate and methyl 4-
methylbenzoate completely react after 4 h.
a
Table 2. Investigation of the reaction scope.
Entry
Coupling agent (equiv.)
EDC (1.0)
CDI (1.0)
Base (equiv.)
Yield 4a (%)
1
2
3
4
5
6
7
8
9
-
0
-
65
23
56
22
41
76
89
87
ECF (1.0)
TEA (1.0)
IBCF (1.0)
ECF (1.0)
TEA (1.0)
1
2
Entry
1
1
a
R
2
R
Yield(%)
Py (1.0)
4
b
b
8
5
IBCF (1.0)
ECF (1.5)
Py (1.0)
TEA (1.5)
4c
2
3
a
a
c
9
1
CDI (1.5)
-
-
-
-
CDI (1.2)
4d
d
7
8
b
1
0
CDI (1.2)
95
c
1
1
CDI (1.2)
95
4
80
e
4
a
e
a
Reagents and conditions: benzoic acid 1a (1.1 mmol), p-tolylamidoxime 2a
1.0 mmol), NaOH (1.2 mmol), DMSO (1 mL).
Cyclodehydration step 2 h.
Cyclodehydration step 3 h.
(
b
c
4f
84
5
6
b
c
f
f
Since the amidoxime scope was exhaustively investigated in
4g
79
2
0-22
our previous work,
in the present study we predominantly
varied the carboxylic acids in combination with representative
amidoximes (Table 2, entries 1-4). Carboxylic acids were divided
into 4 groups: 1) aromatic acids bearing strong electron-donating
or electron-withdrawing moieties (Table 2, entries 5 and 6); 2)
acids with different functionalities (Table 2, entries 7-10); 3)
heterocyclic acids (Table 2, entries 11-19); and 4) substituted
acetic acids (Table 2, entries 20-26).
4
8
h
7
7
d
f
4i
8
8
9
e
f
a
f
2
4
7
j
4
The first group of acids (1b and 1c) demonstrated comparable
reactivity regardless of the substituent electronic effect. In
contrast, the reactivity levels of the esters previously reported by
2
2a
our group varied significantly. In particular, full conversion of

Table 2 (continued)
acidic CH group. Similar difficulties were observed in the
2
1
2
Yield,
%)
present study for 2-arylacetic acids 1o-q (Table 2, entries 20-22).
However, the reaction did proceed where the aromatic ring was
separated from the methylene group by a heteroatom: O (1r), N
(1s, 1t), S (1u) (Table 2, entries 23-26).
Entry
1
R
2
g
R
(
4
k
1
0
g
8
2
Conclusion
4
l
1
1
1
2
h
i
f
f
7
8
A novel one-pot ambient-temperature protocol was developed
for the synthesis of disubstituted 1,2,4-oxadiazoles from readily
available starting materials. For many reasons i.e. simple work-
up and excellent functional group compatibility, this
methodology appears to be more practical than those reported
earlier, and represent an improvement in comparison to our
previous studies in this field.
4
m
8
6
4
n
1
1
3
4
j
a
f
8
8
4
o
k
7
6
Acknowledgment
4
7
p
3
1
5
l
f
Sergey Baykov thanks Saint Petersburg State University for
financial support (grant No 12.37.214.2016). The authors also
gratefully acknowledge Research Centre for Magnetic Resonance
and Center for Chemical Analysis and Materials Research of
Saint Petersburg State University for NMR and HR-Mass spectra
synthesized compounds.
4
5
q
6
1
1
1
7
8
9
m
n
f
f
4
9
r
0
Supplementary data
4
8
s
4
h
c
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/
b
2
2
0
1
o
f
f
0
0
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a
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25
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5. General procedure for the synthesis of 1,2,4-oxadiazoles 4a-w.
To a solution of carboxylic acid 1 (1.1 mmol) in dry DMSO (0.5-1
mL) CDI (195 mg, 1.2 mmol) was added. The reaction mixture
was stirred at room temperature for 30 min, then amidoxime 2 (1.0
mmol) was added. The reaction mixture was stirred at room
temperature for another 18 h, then to the reaction mixture
powdered NaOH (1.2 mmol) was added rapidly. The reaction
mixture was stirred at room temperature for 2 h. Then the reaction
mixture was diluted with cold water (30 mL). The resulting
precipitate was filtered off, washed with cooled water (25 mL) and
dried in air at 50 °C.






Described method provide a simple access to 1,2,4-oxadiazole diversity.
Two key reaction steps are carried out one-pot in DMSO medium.
Readily available starting materials.
Excellent functional group compatibility.
Simple work up procedure.

1
Graphical Abstract
Facile room-temperature assembly of 1,2,4-
oxadiazole core from easily available
amidoximes and carboxylic acids
Leave this area blank for abstract info.
a
a
a
b
a
Tatyana Sharonova, Vitalina Pankrat’eva, Polyna Savko, Sergey Baykov, and Anton Shetnev