A convenient and mild method for 1,2,4-oxadiazole preparation: Cyclodehydration of O-acylamidoximes in the superbase system MOH/DMSO

Article abstract of DOI:10.1016/j.tetlet.2016.05.071

Herein, we reported a general, convenient, and efficient synthesis of 3,5-disubstituted-1,2,4-oxadiazoles via cyclodehydration of O-acylamidoximes in the superbase system MOH/DMSO (M = Li, Na, K). Excellent isolated yields (up to 98%) were attained within

Full text of DOI:10.1016/j.tetlet.2016.05.071

Accepted Manuscript
A convenient and mild method for 1,2,4-oxadiazole preparation: cyclodehydra-
tion of O-acylamidoximes in the superbase system MOH/DMSO
Sergey Baykov, Tatyana Sharonova, Angelina Osipyan, Sergey Rozhkov,
Anton Shetnev, Alexey Smirnov
PII:
S0040-4039(16)30604-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.071
TETL 47690
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
12 April 2016
12 May 2016
18 May 2016
Please cite this article as: Baykov, S., Sharonova, T., Osipyan, A., Rozhkov, S., Shetnev, A., Smirnov, A., A
convenient and mild method for 1,2,4-oxadiazole preparation: cyclodehydration of O-acylamidoximes in the
superbase system MOH/DMSO, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.071
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Graphical Abstract
A convenient and mild method for 1,2,4-oxadiazole preparation: cyclodehydration of O-acylamidoximes
in the superbase system MOH/DMSO

1
Tetrahedron Letters
A convenient and mild method for 1,2,4-oxadiazole preparation:
cyclodehydration of O-acylamidoximes in the superbase system MOH/DMSO
Sergey Baykova, Tatyana Sharonovaa, Angelina Osipyana, Sergey Rozhkovb, Anton Shetnev a,  and Alexey
Smirnova
a The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation.
b Yaroslavl State Technical University Yaroslavl, 88 Moscowsky Pr., Yaroslavl , 150023, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein,we reported a general, convenient and efficient synthesis of 3,5-disubstituted-1,2,4-
oxadiazoles via cyclodehydration of O-acylamidoximes in the superbase system MOH/DMSO
(M = Li, Na, K). Excellent isolated yields (up to 98%) were attained within short reaction times
(10-20 minutes). In addition, mild reaction conditions and a simple work-up procedure allow the
synthesis of a wide range of heat-labile 1,2,4-oxadiazole-containing substances.
Available online
Keywords:
1,2,4-Oxadiazoles,
Cyclodehydration
Superbase system
O-acylamidoximes
DMSO
2015 Elsevier Ltd. All rights reserved.
1,2,4-Oxadiazoles are one of the most popular objects in
effect is explained by the basic catalytic action of the
fluoride anion (pKa = 15 in DMSO). In subsequent years
TBAF was used in the laboratory synthesis of various 3,5-
disubstituted-1,2,4-oxadiazoles.12 However, the corrosive
effects of fluoride anion makes this method unsuitable for
industrial application.5 Therefore, in recent years several
alternative basic reagents have been suggested. Lukin and
co-workers reported the synthesis of 1,2,4-oxadiazoles in the
presence of DBU (pKa = 12 in DMSO14) where heterocycle
formation was occurred at 60 °C within 1 h.13 Furthermore,
tetrabutylammonium hydroxide (TBAH, pKa = 32 in
DMSO) as proposed by Otaka was more effective.5
Reactions were complete within 10 minutes at room
temperature with reported product yields in excess of 90%.
The capacity of these reagents to catalyze
cyclodehydration is determined by their basicity. It is known
that in DMSO the strength of many bases are significantly
higher than in other solvents.14 Additionally, the formation of
the 1,2,4-oxadiazole ring from O-acylamidoximes in DMSO
at room temperature was previously reported.15 The reaction
proceeded in the absence of additional base, however
complete conversion required 10 days. We have suggested
that the addition of a base can significantly reduce the
reaction time without increasing of the temperature.
Primarily potassium hydroxide was proposed a base, since
the superbase system KOH/DMSO is widely used in organic
chemistry, including in the synthesis of heterocyclic
compounds.16 Furthermore, we have examined the
medical chemistry and material science.1 For example,
translarna (ataluren or PTC124) is a drug for the treatment of
cystic fibrosis and Duchenne disease, caused by nonsense
mutation, which has successfully passed three phases of
clinical trials.2 Also, 1,2,4-oxadiazoles possessing
antimicrobial, antibacterial, antitumor, antiinflammatory and
antiviral properties are described.3 1,2,4-Oxadiazoles are also
actively used in the development of new materials with
useful properties: solar cells, fluorogenic chemosensory
polymers, liquid crystals, organic light emitting diodes
(OLEDs) and high energy materials (HEDM).4 Considering
the many applications of 3,5-disubstituted-1,2,4-oxadiazoles,
our goal was to provide a more efficient and convenient
method by which they could be prepared.
The cyclodehydration of O-acylamidoximes is the most
important method for 1,2,4-oxadiazole ring construction.5
The reaction has been known for over a hundred years6 and
has been extensively studied.7 Traditionally, it is carried out
with prolonged heating at high temperature.8 In some cases
such harsh conditions are the reason for the low yield of the
desired products or their total absence. Consequently,
approaches have been proposed for improvement of the
cyclodehydration: the use of a microwave irradiation9 or
ultrasound.10 Gangloff and co-workers showed that in the
presence of tetrabutylammonium fluoride (TBAF) O-
acylamidoximes closed to give 1,2,4-oxadiazoles even at
room temperature and with a short reaction times.11 This
———
 Corresponding author. Tel.:+7-4852-305-661; fax: +7-4852-305-522; e-mail: a.shetnev@yspu.org

2
hydroxides of other alkali metals (LiOH, NaOH), a series of
carbonates and bicarbonates (Na2CO3, K2CO3, Cs2CO3,
NaHCO3, KHCO3), and also several organic bases (TEA,
AcONa).
The cyclization of O-benzoylbenzamidoxime 1a to 3,5-
diphenyl-1,2,4-oxadiazol 2a was used as a model reaction to
study the effect of varrious bases (Table 1). The synthesis
was carried out for 10 minutes at room temperature. Addition
of powdered potassium hydroxide (1 equivalent) to a
solution of compound 1a in DMSO led to precipitation of the
product 2a after 1.5 minutes. Similar results were obtained
with NaOH and LiOH (entries 2 and 3). Cs2CO3 and K2CO3
gave lower yields of 2a (entries 5 and 6). Using other bases
(entries 7-10) gave a trace amounts of the desired product 2a.
Thus, alkali metal hydroxides are the most suitable reagents
for cyclodehydration under mild conditions. Moreover,
hydrolysis of 1a to the corresponding benzamidoxime was
not observed when alkali metal hydroxides in DMSO were
employed. In contrast, Itaka noted the hydrolysis of 1a when
a 25% aqueous NaOH solution in THF was used.5
Table 1. Influence of bases on cyclodehydratation of O-
benzoylbenzamidoxime 1a to 3,5-diphenyl-1,2,4-oxadiazole
2a
Entry
1
2
Base
KOH
LiOH
Yield, %
98
98
We also studied the reaction with the catalytic amount of
base (0.1 equivalent, entry 11). In this case, complete
conversion of compound 1a into 1,2,4-oxadiazol 2a has
required 15 minutes.
The cyclization of O-benzoylbenzamidoxime with alkali
work well both in an open flask with aged DMSO without
protection from CO2 and under a blanket of inert gas with an
initially anhydrous solvent.
3
4
5
6
7
8
9
10
11
NaOH
Na2CO3
K2CO3
Cs2CO3
NaHCO3
KHCO3
TEA
98
trace
71
86
trace
trace
trace
trace
96a
AcONa
KOH
а 0.1 eq. KOH, reaction time 15 min
Scheme 1. Cyclization of various O-acylamidoximes 1b-w into 3,5-disubstituted-1,2,4-oxadiazoles 2b-w.

3
Wilschanski, M.; Elborn J. S.; Melotti, P.; Bronsveld, I.;
Fajac, I.; Malfroot, A.; Rosenbluth, D. B.; Walker, P. A.;
McColley, S. A.; Knoop, C.; Quattrucci, S.; Rietschel, E.;
Zeitlin, P. L.; Barth, J.; Elfring, G. L.; Welch, E. M.;
Branstrom, A.; Spiegel, R. J.; Peltz, S. W.; Ajayi, T.; Rowe,
S. M. Lancet Respir. Med. 2014, 1.
Leveling the harmful effects of carbon dioxide is
achieved by using the equimolar ratio of alkali and O-
acylamidoxime.
Furthermore, we examined the KOH/DMSO system for
the
synthesis
of
3,5-disubstituted-1,2,4-oxadiazoles
containing different functional groups (Scheme 1).
3.
(a) Patwardhan, N. N.; Morris, E. A.; Kharel, Y.; Raje, M.
R.; Gao, M.; Tomsig, J. L.; Lynch, K. R.; Santos, W. L. J.
Med. Chem. 2015, 58, 1879. (b) Bolli, M. H.; Abele, S,
Birker, M.; Bravo, R.; Bur, D.; de Kanter, R.; Kohl, C.;
Grimont, J.; Hess, P.; Lescop, C.; Mathys, B.; Muller, C.;
Nayler, O.; Rey, M.; Scherz, M.; Schmidt, G.; Seifert, J.;
Steiner, B.; Velker, J.; Weller, T. J. Med. Chem. 2014, 57,
110. (c) Spimk, E.; Ding D.; Spimk, E.; Ding D.; Peng, Z.;
Boudreau M. A.; Leemans, E.; Lastochkin, E.; Song, W.;
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G. G.; Danilova, A. S.; Baikov S. V.; Kofanov E. R. Russ. J.
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Most of the substituents considered were stable to the
super basic medium and the corresponding 3,5-disubstituted-
1,2,4-oxadiazoles were prepared in good yield. Nevertheless,
in some cases side reactions were observed. For example,
compound 1h was successfully cyclized, although the nitrile
was also partially hydrolyzed to form amide 2x when the
reaction was allowed to proceed for 2 hours. However, due
to significant differences in the relative rates of the
cyclodehydration and the nitrile hydrolysis reactions, we
were able to prepare nitrile 2h in 89% yield by halting the
reaction after 10 min. The 1,2,4-oxadiazole amide 2x also
could be obtained as a single product simply by increasing
the reaction time to 20 hours (Scheme 2).
4.
5.
Scheme 2. Cyclization of O-acylamidoxime 1h into 1,2,4-
oxadiazole 2x.
6.
7.
In general, no significant effect of electron withdrawing
and electron donating groups on the reaction on rate was
detected. Also, the position of the group in the aromatic ring
showed no effect, even thought it was earlier reported that
the presence of a substituent in the ortho- position
significantly reduces the reactivity of O-acylamidoximes.5
8.
9.
In conclusion, we have described an efficient and
convenient method for 1,2,4-oxadiazole ring construction by
the cyclodehydratation of O-acylamidoximes in the
superbase system MOH/DMSO (M = Na, K, Li). This
method uses the use of widely available and inexpensive
reagents (DMSO, hydroxides of alkali metals) and provides
good yields of the desired compounds. The reaction scope
includes a wide range of aliphatic, aromatic, and heterocyclic
substituents with both electron donating and electron
withdrawing groups.
(a) Burns, A. R.; Kerr, J. H.; Kerr, W. J.; Passmore, J.;
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Acknowledgments
The authors would like to thank all reviewers who have
contributed to the manuscript. The authors gratefully
acknowledge financial support of this research from the
Russian Scientific Fund (Project Grant 16-13-10243).
13. Lukin, K.; Kishore, V. J Het. Chem. 2014, 51, 256.
14. (a) Bordwell, F. B. Acc. Chem. Res. 1988, 21, 456. (b)
Kolthoff, I. M.; Chantooni, M. K., Jr.; Bhowmik, S. J. Am.
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References and notes
1.
(a) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337 .
(b) Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.;
Plowright, A. T. J. Med. Chem. 2012, 55, 1817.
2.
(a) Peltz, S. W.; Morsy, M.; Welch, E. M.; Jacobson, A.
Annu. Rev. Med. 2013, 64, 407. (b) Kerem, E.; Konstan, M.
W.; de Boeck, K.; Accurso, F. J.; Sermet-Gaudelus, I.;

4
16. Trofimov, B. A.; Schmidt, E. Yu. Russ. Chem. Rev. 2014, 83,
600.
7.52 (m, 3Н), 7.56 (t, J = 7.8 Hz, 2H), 7.67 (t, J = 7.5 Hz,
1H), 7.78 (d, J = 7.3 Hz, 2H), 8.20 (d, J = 7.5 Гц, 2H). 13С
NMR (DMSO-d6, 100 MHz): δ 127.0, 128.4, 128.6, 128.7,
129.6, 130.6, 131.9, 133.1, 157.1, 163.7. MS (ESI+): m/z 241
[M+H]+.
General procedure for the synthesis of 3,5-diphenyl-1,2,4-
oxadiazoles 2a-w. To a solution of O-acylamidoxime 1 (2
mmol) in DMSO (2-3 mL) was added KOH (2 mmol). The
reaction mixture was stirred at room temperature for 10-20
min (TLC or precipitation of the product). The reaction
mixture was diluted with 30 ml of cold water. The resulting
precipitate was filtered off, washed with water (30 mL) and
dried in air at 50°C.
Spectral Data of 2a White powder, 96 % yield, mp 107-109
°C. 1H NMR (DMSO-d6, 400 MHz): δ 7.59-7.64 (m, 3H),
7.68 (m, 2Н), 7.75 (m, 1Н), 8.11 (m, 2Н), 8.20 (m, 2Н). 13С
NMR (DMSO-d6, 100 MHz): δ 123.5, 126.3, 127.2, 128.0,
129.3, 129.6, 131.7, 133.4, 168.4, 175.5. MS (ESI+): m/z
223 [M+H]+. Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54;
N, 12.60. Found: C, 75.43; H, 4.54; N, 12.54.
General procedures for the synthesis of O-
acylamidoximes 1a-w a) To a mixture of the carboxylic acid
(5 mmol) in acetone (20 mL) was added EDC (5.5 mmol).
The reaction mixture was stirred at room temperature for 30
min, then the amidoxime (5 mmol) was added. The resulting
mixture was stirred at room temperature for 12 h. Acetone
was evaporated at reduced pressure and to the residue was
added water (100 mL). The resulting precipitate was filtered
off, washed with water (50 ml) and dried and dried in air at
RT.
b) To a cooled to 0 °C mixture of amidoxime (5 mmol) and
TEA (5.5 mmol) in acetone (20 mL) was added acyl chloride
(5.5 mmol). Reaction mixture was stirred at room
temperature for 12 h. Acetone was evaporated at reduced
pressure and to the residue was added water (100 mL). The
resulting precipitate was filtered off, washed with water (50
ml) and dried in air at RT.
Spectral Data of 1a White powder, 91 % yield, mp 124-125
°C. 1H NMR (DMSO-d6, 400 MHz): δ 6.99 (br. s, 2H), 7.47-
Supplementary Material
Supplementary data associated with this article can be found, in
the online version.