Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety

Article abstract of DOI:10.1016/j.tetlet.2017.08.020

An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.

Full text of DOI:10.1016/j.tetlet.2017.08.020

Accepted Manuscript
Room-temperature synthesis of pharmaceutically important carboxylic acids
bearing the 1,2,4-oxadiazole moiety
Marina Tarasenko, Nikolay Duderin, Tatyana Sharonova, Sergey Baykov,
Anton Shetnev, Alexey V. Smirnov
PII:
S0040-4039(17)31009-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.020
TETL 49210
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 July 2017
2 August 2017
7 August 2017
Please cite this article as: Tarasenko, M., Duderin, N., Sharonova, T., Baykov, S., Shetnev, A., Smirnov, A.V.,
Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.020
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Graphical Abstract
Room-temperature synthesis of
pharmaceutically important carboxylic acids
bearing the 1,2,4-oxadiazole moiety
Leave this area blank for abstract info.
Marina Tarasenko, Nikolay Duderin, Tatyana Sharonova, Sergey Baykov, Anton Shetnev and Alexey V.
Smirnov

1
Tetrahedron Letters
journal homepage: www.els evier.com
Room-temperature synthesis of pharmaceutically important carboxylic acids bearing
the 1,2,4-oxadiazole moiety
Marina Tarasenkoa, Nikolay Duderinb, Tatyana Sharonovab, Sergey Baykovb,∗, Anton Shetnevс and
Alexey V. Smirnovb
aYaroslavl State Technical University, 88 Moscowsky Pr ,150023 Yaroslavl, Russian Federation
bPharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian
Federation
cOrganic Chemistry Department, Faculty of Science, RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles
via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium.
The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-
oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to
excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well
as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven
gram-scalability and the use of inexpensive starting materials, which from a process chemistry
point of view are essential for future industrial applications.
Available online
Keywords:
Heterocycles
Anhydride
Carboxylic acid
Superbase catalysis
Room temperature synthesis
2009 Elsevier Ltd. All rights reserved.
anti-inflammatory,3 lung and larynx carcinoma cell growth
inhibition,4 ανβ3 receptor antagonist,5 analgesic,6 niacin
receptor (GPR109A) agonist,7 dipeptidyl peptidase IV
Introduction
3-(Substituted-1,2,4-oxadiazol-5-yl)propanoic and butanoic
acids are valuable tools in drug discovery and in the parallel
synthesis of candidates for high throughput screening or “hit to
lead” optimization of bioactive compounds. The
pharmaceutical applications of small molecules based on these
motifs include nonpeptidic procollagen C-proteinase
inhibition,1 cannabinoid receptor 2 (CB2) agonist,2 nonsteroidal
inhibition,8 larvicide9 and antibiotic10 properties. Furthermore,
some acids are of interest as peptidomimetic building blocks11
or starting materials for the synthesis heterocyclic compounds,
as exemplified by benzimidazoles with antimicrobial
activities.12
Figure 1. Representative examples of bioactive alkyl carboxylic acid derivatives containing the 1,2,4-oxadiazole motif.
———
∗ Corresponding author. Tel.: +7 4852 305 661; fax: +7 4852 305 522; e-mail: sergei.v.baikov@yandex.ru

2
Tetrahedron
A condensation of amidoximes with dicarboxylic acid
Results and Discussion
anhydrides represents a general route to 1,2,4-oxadiazole-based
acids.13 Typically this reaction is carried out in “two-step, one-
pot” fashion via O-acylamidoxime intermediate generation and
subsequent thermal cyclodehydration to the corresponding 1,2,4-
oxadiazole. Unfortunately, the cyclodehydration process requires
high temperatures (~100-140 °C), which often results in poor
product yields and the formation of undesired by-products.13,14
For this reason, a number of reagents have been developed for
the room-temperature synthesis of 1,2,4-oxadiazoles: TBAF
(Gangloff in 2001),15a TBAH (Otaka in 2014),15b and
MOH/DMSO (our group, in 2016).15c These systems provided
good yields of the desired heterocycles at ambient temperature
with short reaction times. Nevertheless, examples of the room-
temperature synthesis of 1,2,4-oxadiazoles with the carboxyl
functionality have not been described at the present time.
Additionally, only O-acylamidoximes can be utilized as starting
materials for this approach. Thereby an extra stage for their
isolation and purification is necessary, which significantly
increases the work-up complexity of the procedure and reduces
the final yield of the 1,2,4-oxadiazoles. Thus, a mild and efficient
protocol for the synthesis of 1,2,4-oxadiazoles containing a
carboxyl functionality from readily available starting materials
such as amidoximes and dicarboxylic acid anhydrides is highly
desirable.
In the literature, only one unsuccessful example of the base-
catalyzed (TBAF in MeCN), room-temperature cyclodehydration
of O-acylamidoximes containing a carboxylic functionality has
been described.17 Initially, we investigated conversion of O-
acylamidoxime 3a, which was previously synthesized from
benzamidoxime 1a and succinic anhydride 2a,18 into 1,2,4-
oxadiazole 4a in the MOH/DMSO medium at ambient
temperature (Table 1). Alkali metal hydroxides in different
amounts were screened as the MOH-component, and NaOH (2.0
equiv.) was found to be the most effective.
Table 1. Cyclodehydration of O-acylamidoxime 3a.a
O
O
1) MOH, DMSO
r.t., 1 h
2) H+, H2O
O
O
N
N
N
O
OH
Ph
OH
Ph
NH2
4a
3a
Entry
MOH (equiv.)
KOH (1.1)
KOH (1.5)
KOH (2.0)
KOH (2.5)
KOH (3.0)
NaOH (2.0)
LiOH (2.0)
Yield 4a (%)
1
2
3
4
5
6
30
49
76
71
63
90
85
7
a
Reagents and conditions: О-acylamidoxime 3a (2 mmol), DMSO (2
mL).
Scheme 1. Direct reaction of amidoximes and dicarboxylic acid
anhydrides.
Having developed optimal conditions for the cyclodehydration
process, we transferred this to the reaction between
benzamidoxime 1a and succinic anhydride 2a. Initially, two
sequences of manipulations (A and B) were compared (Scheme
2). In the case of method A, anhydride 2a was treated with
amidoxime 1a in DMSO followed by the addition of NaOH (2
equiv.) after 4 hours. The alternative procedure B consisted of the
addition of anhydride 2a to a suspension of the amidoxime 1a
sodium salt, prepared previously by the treatment 1a with NaOH
(2 equiv.) in DMSO. The best result was obtained when the
reaction was carried out under the first sequence of manipulations
(A): 88% versus 68% yield of 4a (Scheme 2). Thus, all further
experiments were pursued according to method A.
Previously, we proposed a one-pot route to 1,2,4-oxadiazoles
based on the reaction between amidoximes and esters in a
NaOH/DMSO medium at ambient-temperature.16 This
achievement encouraged us to continue our research, and herein
we report a mild and gram-scalable procedure for the preparation
of 1,2,4-oxadiazoles from amidoximes and dicarboxylic acid
anhydrides.
Scheme 2. Reaction pathways for methods A and B. Reagents and conditions: amidoxime 1a (2.5 mmol), succinic anhydride 2a (2.5 mmol),
NaOH (5 mmol), DMSO (2 mL).
Next, we examined the effect of reaction time for both steps
(anhydride-amidoxime and cyclodehydration reactions) of this
one-pot process (Table 2). This showed that 2 h for the O-
acylation step and 1 h for the cyclodehydration step were the

3
most suitable reaction times. Further increases in the reaction
non-equivalent acyl carbons, leading to two different 1,2,4-
time had no significant effect on the yield of 1,2,4-oxadiazole 4a.
Table 2. Cyclodehydration of O-acylamidoxime 3aa.
oxadiazoles. Although both compounds were formed, isomer 4u
was the major product (1H NMR analysis). This was isolated by
recrystallization from toluene in 62% yield, and its structure
determined by single-crystal X-ray analysis (Fig. 2).
The reaction of anhydrides 2e-k with amidoximes 1 followed
by 1,2,4-oxadiazole ring formation was hitherto unreported, and
1,2,4-oxadiazoles 4o-q, 4s, and 4u were not previously
synthesized via the anhydride route.19 Moreover, compound 4t
represents the novel backbone of carboxylic acids containing a
1,2,4-oxadiazole core.20
Entry
Reaction time (h)
Step 1 Step 2
Yield 4a (%)
1
2
3
5
6
1
2
3
2
2
1
61
88
88
76
88
1
1
0.5
2
Figure 2. Single-crystal X-ray structure of acid 4u (CCDC
1557057).
a Reagents and conditions: amidoxime 1a (2.5 mmol), succinic anhydride
2a (2.5 mmol), NaOH (5 mmol), DMSO (2 mL).
Finally, we decided to check the scalability of our method. To
this end, two selected 1,2,4-oxadiazoles 4a and 4r were
synthesized according to the general procedure on a 60 mmol
scale (Scheme 3). Both heterocycles were obtained in good
isolated yields (83% and 80%, respectively) and sufficient purity.
Another advantage of our approach in industrial applications is
the utilisation of a low-toxicity solvent (DMSO).21
The reaction scope and limitations were then examined using
different amidoximes as well as several anhydrides. Firstly,
aliphatic, aromatic (containing both electron donating and
withdrawing substituents), and heteroaromatic amidoximes 1b-k
were reacted with succinic anhydride 2a (Table 3, entries 1-10),
only indole-derivative 1f provided at unfavourable result (Table
3, entry 5). In the case of other amidoximes, 1,2,4-oxadiazole-5-
ylpropanoic acids were obtained in good yields. All substituents,
including primary sulfonamide (1h) and protected amino groups
(1i and 1j), were tolerated under these conditions. Moreover,
NaOH/DMSO was demonstrated as a convenient medium for the
synthesis of 1,2,4-oxadiazoles with an unprotected amino
functional group 4k (Table 3, entry 11). In comparison, the
synthesis of compound 4k in 1,4-dioxane at reflux for 6 h gave
the target acid 4k in only 11% yield after purification by column
chromatography (Table 3, entry 11).
Furthermore, the reactivity of cyclic anhydrides 2b-k was
explored (Table 3, entries 12-21). Most of the studied anhydrides
reacted with the amidoximes in moderate to excellent yields (>
50%). However, 1,8-naphthalic anhydride 2i demonstrated poor
reactivity, and the corresponding 1,2,4-oxadiazole derivative 4s
was only obtained in 43% yield (Table 3, entry 19).
Scheme 3. Gram-scale synthesis of 4a and 4r.
Satisfactory selectivity was observed for homophthalic
anhydride 2k (Table 3, entry 21), which can react via the two

4
Tetrahedron
Table 3. Investigation of the reaction scopea.
Entry
Amidoxime 1
Anhydride 2
1,2,4-oxadiazole 4
Yield (%)
81
1
1b
2a
4b
2
3
4
1c
1d
1e
2a
2a
2a
4c
4d
4e
71
94
89
-//-
-//-
-//-
5
6
1f
2a
2a
0
-//-
-//-
-
1g
4f
70
7
1h
2a
4g
61
-//-
8
9
1i
1j
2a
2a
4h
4i
80
74
-//-
-//-
10
11
1k
1l
2a
2a
4j
87
-//-
-//-
4k
77, (11b)
12
13
14
1a
1a
1a
2b
2c
2d
4l
78
86
81
4m
4n

5
Entry
15
Amidoxime 1
Anhydride 2
1,2,4-oxadiazole 4
Yield (%)
95
1a
2e
4o
16
17
18
1a
1m
1a
2f
2g
2h
4p
4q
4r
52
78
91
19
1n
2i
4s
43
20
21
1o
1n
2j
4t
85
62
2k
4u
a Reagents and conditions: amidoxime 1 (2.5 mmol), anhydride 2 (2.5 mmol), NaOH (5.0 mmol), DMSO (2-3 mL).
b Reaction was carried out in 1,4-dioxane at 100 °C for 6 h.
Conclusion
In conclusion, an effective, convenient and scalable one-pot
References and notes
1. Fish, P.; Allan, G.; Bailey, S.; Blagg, J.; Butt, R.; Collis, M.;
Greiling, D.; James, K.; Kendall, J.; McElroy, A.; McCleverty, D.;
Reed, C.; Webster, R.; Whitlock, G. J. Med. Chem. 2007, 50,
3442-3456.
2. (a) Lueg, C.; Galla, F.; Frehland, B.; Schepmann, D.; Daniliuc, C.;
Deuther-Conrad, W.; Brust, P.; Wünsch, B. Arch. Pharm. Chem.
Life Sci. 2013, 347, 21-31; (b) Lueg, C.; Schepmann, D.; Günther,
R.; Brust, P.; Wünsch, B. Bioorg. Med. Chem. 2013, 21, 7481-
7498.
protocol for the synthesis of 1,2,4-oxadizoles bearing carboxyl
group from dicarboxylic acid anhydrides and amidoximes has
been developed. The present method could be applied to various
five-, six-, and seven-membered anhydrides, as well as aliphatic,
aromatic and heteroaromatic amidoximes. We hope that the
simple work-up procedure, mild condition (particularly, the
ambient temperature), inexpensive and readily available starting
materials, and a low-toxicity solvent, will make this method a
useful tool in medicinal and process chemistry.
3. Hershberger, P.; Peddibhotla, S.; Sessions, E.; Divlianska, D.;
Correa, R.; Pinkerton, A.; Reed, J.; Roth, G. Beilstein J. Org.
Chem. 2013, 9, 900-907.
4. Janaına V. dos Anjos, J.; Neves Filho, R.; Silene do Nascimento,
́
S.; Srivastava, R.; de Melo, S.; Sinou, D. Eur. J. Med. Chem.
2009, 44, 3571-3576.
Acknowledgments
5. Boys, M.; Schretzman, L.; Chandrakumar, N.; Tollefson, M.;
Mohler, S.; Downs, V.; Penning, T.; Russell, M.; Wendt, J.; Chen,
B.; Stenmark, H.; Wu, H.; Spangler, D.; Clare, M.; Desai, B.;
Khanna, I.; Nguyen, M.; Duffin, T.; Engleman, V.; Finn, M.;
Freeman, S.; Hanneke, M.; Keene, J.; Klover, J.; Nickols, G.;
Nickols, M.; Steininger, C.; Westlin, M.; Westlin, W.; Yu, Y.;
Wang, Y.; Dalton, C.; Norring, S. Bioorg. Med. Chem. Lett. 2006,
16, 839-844.
This paper was financially supported by the Ministry of
Education and Science of the Russian Federation as part of the
program to improve the competitiveness of the People's
Friendship University (RUDN University) among the world's
leading research and education centers in 2016-2020 (Agreement
number 02.a03.21.0008). The authors also express their gratitude
to Dr. Alexander Sapegin (St. Petersburg State University) for his
strong support of this research.
6. (a) Srivastava, R.; da Conceicao Pereira, M.; Hallwass, F.;
Santana, S. J. Mol. Struct. 2002, 604, 177-187; (b) Farooqui, M.;
Bora, R.; Patil, C. Eur. J. Med. Chem. 2009, 44, 794-799.
Supplementary data
7.
(a) Shen, H.; Ding, F.; Raghavan, S.; Deng, Q.; Luell, S.; Forrest,
M.; Carballo-Jane, E.; Wilsie, L.; Krsmanovic, M.; Taggart, A.;
Wu, K.; Wu, T.; Cheng, K.; Ren, N.; Cai, T.; Chen, Q.; Wang, J.;
Wolff, M.; Tong, X.; Holt, T.; Waters, M.; Hammond, M.; Tata,
J.; Colletti, S. J. Med. Chem. 2010, 53, 2666-2670; (b) Schmidt,
D.; Smenton, A.; Raghavan, S.; Shen, H.; Ding, F.; Carballo-Jane,
E.; Luell, S.; Ciecko, T.; Holt, T.; Wolff, M.; Taggart, A.; Wilsie,
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/

6
Tetrahedron
L.; Krsmanovic, M.; Ren, N.; Blom, D.; Cheng, K.; McCann, P.;
diluted with cold water (30 mL) followed by the addition of
hydrochloric acid to pH ~ 1. The resulting precipitate was filtered
off, washed with cold water (25 mL) and dried in air at 50 °C.
Method B. To a solution of amidoxime 1 (2.5 mmol) in DMSO (2-
3 mL) was rapidly added powdered NaOH (5 mmol). The reaction
mixture was stirred at room temperature for 20 min, then to the
mixture was added cyclic anhydride 2 (2.5 mmol). The reaction
mixture was stirred at room temperature for 3 h. The reaction
mixture was diluted with of cold water (30 mL) followed by the
addition of hydrochloric acid to pH ~ 1. The resulting precipitate
was filtered off, washed with cold water (25 mL) and dried in air
at 50 °C.
Note 1: In the case of compounds 4d and 4k acetic acid was used
instead hydrochloric acid and the pH was ~ 5.
Note 2: The gram-scale synthesis of acids 4a and 4r was carried
out according to method A: using amidoxime 1a (8.17 g, 60
mmol), anhydride 2 (60 mmol), NaOH (120 mmol) and DMSO
(45 mL).
Waters, M.; Tata, J.; Colletti, S. Bioorg. Med. Chem. Lett. 2010,
20, 3426-3430.
8. Xu, J.; Wei, L.; Mathvink, R.; Edmondson, S.; Eiermann, G.; He,
H.; Leone, J.; Leiting, B.; Lyons, K.; Marsilio, F.; Patel, R.; Patel,
S.; Petrov, A.; Scapin, G.; Wu, J.; Thornberry, N.; Weber, A.
Bioorg. Med. Chem. Lett. 2006, 16, 5373-5377.
9. Oliveira, V.; Pimenteira, C.; da Silva-Alves, D.; Leal, L.; Neves-
Filho, R.; Navarro, D.; Santos, G.; Dutra, K.; dos Anjos, J.;
Soares, T. Bioorg. Med. Chem. 2013, 21, 6996-7003.
10. Tale, R. H.; Rodge, A. R.; Keche, A. P.; Hatnapure, G. D.; Padole,
P. R.; Gaikwad, G. S.; Turkar, S. S. J. Chem. Pharm. Res. 2011, 3,
496-505.
11. Jakopin, Ž.; Roškar, R.; Dolenc, M. Tetrahedron Lett. 2007, 48,
1465-1468.
12. Jadhav, G.; Shaikh, M.; Kale, R.; Ghawalkar, A.; Gill, C. J.
Heterocycl. Chem. 2009, 46, 980-987.
13. Katritzky, A.; Ramsden, C.; Scriven, E.; Taylor, R.; Padwa, A.;
Stevens, C.; Jones, G.; Joule, J.; Zhdankin, V.; Black, D.; Aitken,
R.; Turnbull, K.; Jones, R.; Cossy, J.; Jones, K.; Newkome, G.
Comprehensive Heterocyclic Chemistry III; Elsevier: Amsterdam,
2008.
14. (a) Godovikova, T.; Vorontsova, S.; Konyushkin, L.; Firgang, S.;
Rakitin, O. Russ. Chem. Bull. 2008, 57, 2440-2442; (b) Grant, D.;
Dahl, R.; Cosford, N. J. Org. Chem. 2008, 73, 7219-7223; (c)
Neves, R.; Srivastava, R. Molecules 2006, 11, 318-324.
15. (a) Gangloff, A.; Litvak, J.; Shelton, E.; Sperandio, D.; Wang, V.;
Rice, K. Tetrahedron Lett. 2001, 42, 1441-1443; (b) Otaka, H.;
Ikeda, J.; Tanaka, D.; Tobe, M. Tetrahedron Lett. 2014, 55, 979-
981; (c) Baykov, S.; Sharonova, T.; Osipyan, A.; Rozhkov, S.;
Shetnev, A.; Smirnov, A. Tetrahedron Lett. 2016, 57, 2898-2900.
16. Baykov, S.; Sharonova, T.; Shetnev, A.; Rozhkov, S.; Kalinin, S.;
Smirnov, A. Tetrahedron 2017, 73, 945-951.
17. Nishiwaki, N.; Ariga, M.; Tamura, M.; Ise, Y.; Okajima, Y.
Synthesis 2006, 20, 3453-3461.
18. Preparation of (E)-4-(((amino(phenyl)methylene)amino)oxy)-
4-oxobutanoic acid 3a. To a solution of amidoxime 1a (7.48 g, 55
mmol) in acetone (50 mL) succinic anhydride 2a (5.50 g, 55
mmol) was added. The reaction mixture was stirred at room
temperature for 2 h. Upon reaction completion, acetone was
evaporated under reduced pressure and water (50 mL) was added
to the residue. The resulting precipitate was filtered off, washed
with cold water (25 mL) and dried in air (room temperature).
White powder, 11.82 g (91%) yield, mp 133-134 °C. 1H NMR
(400 MHz, DMSO-d6): δ 2.54-2.58 (m, 2H), 2.64-2.77 (m, 2H),
6.78 (br. s, 2H), 7.39-7.58 (m, 3H), 7.68-7.77 (m, 2H), 12.28 (br.
s, 1H). 13С NMR (100 MHz, DMSO-d6): δ 28.4, 29.3, 127.2,
128.8, 130.9, 132.1, 157.1, 170.8, 174.1. HRMS (ESI) calcd for
C11H13N2O4 [M+H]+ 237.0870, found 237.0879.
19. (a) Graham, K.; Klar, U.; Briem, H.; Hitchcock, M.; Bareaker, L.;
Eis, K.; Schulze, V.; Siemeister, G.; Bone, W.; Schroder, J.;
Holton, S.; Lienau, P.; Temple, R.; Sonnenschein, H.; Balint, J.;
Graubaum, H. 3-Amino-1,5,6,7-tetrahydro-4h-indol-4-ones. U.S.
Patent 1,010,391, April 13, 2017; (b) Marui, S. Benzoxazepine
compound. E.P. Patent 1,650,201, April 26, 2006; (c) Leclerc, J.
P.; Falgueyret, J. P.; Girardin, M.; Guay, J.; Guiral, S.; Huang, Z.;
Sing, C. L.; Oballa, R.; Ramtohul, Y. K.; Skorey, K.; Tawa, P.;
Wang, H.; Zhang, L. Bioorg. Med. Chem. Lett. 2011, 2, 6505–
6509; (d) Harris, P. A.; Berger, S. B.; Jeong, J. U.; Nagilla, R.;
Bandyopadhyay, D.; Campobasso, N.; Capriotti, C. A.; Cox, J. A.;
Dare, L.; Dong, X.; Eidam, P. M.; Finger, J. N.; Homan, S. J.;
Kang, J.; Kasparcova, V.; King, B. W.; Lehr, R.; Lan, Y.; Leister,
L. K.; Lich, J. D.; MacDonald, T. T.; Miller, N. A.; Ouellette, M.
T.; Pao, C. S.; Rahman, A.; Reilly, M. A.; Rendina, A. R.; Rivera,
E. J.; Schaeer, M. C.; Sehon, C. A.; Singhaus, R. R.; Sun, H. H.;
Swift, B. A.; Totoritis, R. D.; Vossenkamper, A.; Ward, P.;
Wisnoski, D. D.; Zhang, D.; Marquis, R. W.; Gough, P. J.; Bertin,
J. J. Med. Chem. 2017, 60, 1247-1261.
20. SciFinder® search performed of July 18, 2017.
21. Jacob, S.; Rosenbaum, E. Headache: The Journal of Head and
Face Pain 1966, 6, 127-136.
22. Starting amidoximes 1a-o were prepared by heating commercially
available nitriles (1 equiv.) with hydroxylamine hydrochloride
(1.5 equiv.) and NaHCO3 (1.5 equiv.) in EtOH (50 mL) at reflux
for 6 h. This procedure was described in Srivastava, R.; Pereira,
M.; Faustino, W.; Coutinho, K.; dos Anjos, J.; de Melo, S.
Monatsh Chem. 2009, 140, 1319-1324.
23. General procedure for the synthesis of 1,2,4-oxadiazoles 4a-u
from amidoximes 1 and cyclic anhydrides 2 in DMSO.
Method A. To a solution of amidoxime 1 (2.5 mmol) in DMSO (2-
3 mL) cyclic anhydride 2 (2.5 mmol) was added. The reaction
mixture was stirred at room temperature for 2 h. Next, powdered
NaOH (5 mmol) was rapidly added and the reaction mixture was
stirred at room temperature for 1 h. The reaction mixture was then

Highlights for
Room-temperature synthesis of pharmaceutically important carboxylic acids
bearing the 1,2,4-oxadiazole moiety
•
An efficient protocol for the 1,2,4-oxadiazoles preparation were developed.
Amidoximes and dicarboxylic acid anhydrides were used as starting materials.
The reaction carries out at room temperature due to the strong base effect.
The method can be scaled.
•
•
•