Entry into (E)-3-(1,2,4-oxadiazol-5-yl)acrylic acids via a one-pot ring-opening/ring-closing/retro-Diels-Alder reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2019.151543

A simple and convenient one-pot method is reported for the synthesis of (E)-3-(3-aryl(heteroaryl, alkyl)-1,2,4-oxadiazole-5-yl)acrylic acids utilizing readily accessible or commercially available substituted benzamidoximes and inexpensive exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride. The method is based on the reaction of amidoximes with the anhydride in a basic medium at RT followed by an acid-catalyzed retro-Diels-Alder reaction. The observed stereoselective heterocyclization/retro-Diels-Alder cascade process is suitable for the synthesis of a wide range of substituted (E)-1,2,4-oxadiazole-5-ylacrylic acids featuring electron donating and electron withdrawing groups on the aryl moiety, as well as heteroaryl or alkyl substituents at position 3 of the 1,2,4-oxadiazole ring (42–79%; 15 examples).

Full text of DOI:10.1016/j.tetlet.2019.151543

Journal Pre-proofs
Entry into (E)-3-(1,2,4-oxadiazol-5-yl)acrylic acids via a one-pot ring-opening/
ring-closing/retro-Diels-Alder reaction sequence
Sofia Presnukhina, Marina Tarasenko, Sergey Baykov, Sergey N. Smirnov,
Vadim P. Boyarskiy, Anton Shetnev, Mikhail K. Korsakov
PII:
S0040-4039(19)31342-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151543
TETL 151543
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 October 2019
14 December 2019
17 December 2019
Please cite this article as: Presnukhina, S., Tarasenko, M., Baykov, S., Smirnov, S.N., Boyarskiy, V.P., Shetnev, A.,
Korsakov, M.K., Entry into (E)-3-(1,2,4-oxadiazol-5-yl)acrylic acids via a one-pot ring-opening/ring-closing/
retro-Diels-Alder reaction sequence, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151543
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Entry into (E)-3-(1,2,4-oxadiazol-5-yl)acrylic acids via a one-pot ring-opening/ring-
closing/retro-Diels-Alder reaction sequence
Sofia Presnukhinaa, Marina Tarasenkoa, Sergey Baykovb*, Sergey N. Smirnovc, Vadim P.
Boyarskiyb, Anton Shetneva, and Mikhail K. Korsakova
aPharmaceutical Technology Transfer Centre, Ushinsky Yaroslavl State Pedagogical University,
108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
bInstitute of Chemistry, Saint Petersburg State University, 26 Universitetsky Pr, Peterhof, Saint
Petersburg 198504, Russian Federation
cMagnetic Resonance Research Centre, Saint Petersburg State University, 26 Universitetsky Pr,
Peterhof, Saint Petersburg 198504, Russian Federation
* Corresponding author.
E-mail: sergei.v.baikov@yandex.ru
Abstract
A simple and convenient one-pot method is reported for the synthesis of (E)-3-(3-
aryl(heteroaryl, alkyl)-1,2,4-oxadiazole-5-yl)acrylic acids utilizing readily accessible or
commercially available substituted benzamidoximes and inexpensive exo-3,6-epoxy-1,2,3,6-
tetrahydrophthalic anhydride. The method is based on the reaction of amidoximes with the
anhydride in a basic medium at RT followed by an acid-catalyzed retro-Diels-Alder reaction.
The observed stereoselective heterocyclization/retro-Diels-Alder cascade process is suitable for
the synthesis of a wide range of substituted (E)-1,2,4-oxadiazole-5-ylacrylic acids featuring

electron donating and electron withdrawing groups on the aryl moiety, as well as heteroaryl or
alkyl substituents at position 3 of the 1,2,4-oxadiazole ring (42–79%; 15 examples).
Keywords: Acrylic acids, heterocycles, retro-Diels-Alder reaction, dicarboxylic acid anhydrides
Introduction
Amides of (heteroaryl)-acrylic acids are a medicinally favorable motif, which is
incorporated in the structure of various marketed drugs (Fig. 1). For example, selinexor (the
hydrazide of (Z)-3-(1H-1,2,4-triazol-1-yl)acrylic acid) is a first-in-class selective inhibitor of
nuclear transport (SINE) and was recently approved for the treatment of multiple myeloma.1–4
Chidamide
–
N-(2-amino-5-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-
yl]amino]methyl]-benzamide – is a histone deacetylase inhibitor, which was applied for the
treatment of peripheral T-cell lymphoma (PTCL)5 and pancreatic cancer.6 Additionally, several
clinical or preclinical candidates based on heteroaryl acrylic acids, including the HCV
polymerase inhibitor deleobuvir7 and the anticancer agent KPT-9274 have been reported.8 (E)-N-
(4-(N-(3-Methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide
(also
known as necrosulfonamide) specifically blocks necrosis downstream of receptor-interacting
serine-threonine kinase 3 (RIP3) activation9 and can be used to treat sulfur mustard
intoxication.10 Moreover, there are a number of reported biologically active derivatives of
heterocyclic acrylic acids based on various heterocycles: pyridine (histone deacetylase
inhibitor),11 pyrazine (colorectal cancer),12 indole (tubulin polymerization inhibitor13 or cysteinyl
leukotriene receptor 1 antagonist14), thiazole (myeloid differentiation protein 2 inhibitor),15
imidazole (mGAT3 inhibitor),16 furan (orexin 1 receptor antagonists),17 and benzothiophene

(antibiotic).18 In this context, the development of novel synthetic routes towards 3-heteroaryl
acrylic acids is an important task in modern organic chemistry.
Figure 1. Amides of (heteroaryl)-acrylic acids, which are marketed drugs.
Against this background, it seems unusual that only one synthesis of 1,2,4-oxadiazole
substituted acrylic acids has been reported,19 whereas the corresponding 1,3,4-isomeric
derivatives find many uses, including in crystal engineering,20 antibiotics,21 and fluorescent
materials.22 It should be noted that the population of reported 1,2,4-oxadiazoles is significantly
larger than for 1,3,4-oxadiazoles, and they are widely used in both medicinal chemistry23 and
material science.24,25 The practical absence of literature information on 1,2,4-oxadiazole-
substituted acrylic acids is presumably caused by the unsuitability of common methods of 1,2,4-
oxadiazole core assembly, which require harsh heating,26 for the preparation of compounds with
labile functionalities such as double C=C bonds.
Several years ago our group developed a novel procedure for 1,2,4-oxadiazole synthesis
from carboxylic compounds and amidoximes in NaOH/DMSO at ambient temperature.27–31 This
methodology was subsequently applied to the synthesis of various useful 1,2,4-oxadiazole
derivatives, namely carbonic anhydrase32,33 and monoamine oxidase inhibitors,34 as well as

anticancer agents.35 Moreover, a series of antibacterial 1,2,4-oxadiazoles containing a double
C=C bond attached to the 5-position of the heterocyclic ring was synthesized according to our
protocol.36
In our recent work,37 devoted to the coupling of maleic anhydride Diels-Alder adducts
with benzimidoximes we noted that the reaction of benzamidoxime with exo-3,6-epoxy-1,2,3,6-
tetrahydrophthalic anhydride in NaOH/DMSO resulted in the formation of (E)-3-(3-phenyl-
1,2,4-oxadiazol-5-yl)acrylic acid instead of the corresponding epoxycyclohexenyl product A
(Scheme 1). Evidently this was the result of a retro-Diels-Alder reaction (RDA) of the
intermediate bicyclic product. Examples of RDAs involving derivatives of exo-3,6-epoxy-
1,2,3,6-tetrahydrophthalic anhydride are known in the literature.38–40 This suggested the
possibility of developing a one-pot method for producing 3-(3-aryl-1,2,4-oxadiazol-5-yl)acrylic
acids from benzamidoximes and commercially available exo-3,6-epoxy-1,2,3,6-
tetrahydrophthalic anhydride. In this paper, we present the results of a full-scale study of this
synthetic possibility.
Scheme 1. Formation of (E)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)acrylic acid during the reaction of
benzamidoxime with exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride in NaOH/DMSO.
Results and Discussion

For the initial optimization studies, we selected commercially available 4-tolylamidoxime
1a. Initially, it was necessary to determine whether the RDA occurs simultaneously with the
formation of an intermediate, or if this is the result of acidification of the reaction mixture during
workup. We carried out the reaction of 1a with 2 (Scheme 2), the solvent was removed under
reduced pressure, and the residue was dissolved in D2O and analyzed by 1H NMR spectroscopy.
Analysis showed the absence of the corresponding acrylic acid salt in the mixture. This indicates
that the RDA occurs after the stage of obtaining the oxadiazole ring.
Scheme 2. Reaction of 4-tolylamidoxime 1a with anhydride 2.
Salt 3a(Na) is relatively stable, but when we tried to isolate the free acid 3a(H), it
decomposed. Since the resulting bicyclic compound 3a(H) is not stable enough, and the
conversion of the initial 4-tolylamidoxime was complete under the conditions used (according to
TLC) (Scheme 2), we then used a two-step protocol to optimize the RDA. Initially, the synthesis
of oxadiazole 3a(Na) was carried out, and then the conditions for the formation of substituted
acrylic acid were optimized.
It is known that RDA reactions can be accelerated by heating or acid catalysis.41,42 Both
approaches were tested for activation of the RDA reaction. Heating of the bicyclic acids in an
inert atmosphere at 100–144 °C without solvent, or in o-xylene, resulted in decomposition of the
reaction mixture, which is presumably due to partial oligomerization of the resulting 1,2,4-

oxadiazoleacrylic acid. Therefore we focused on acid catalysis; the data obtained are presented in
Table 1.
Table 1. Reaction condition screening for the synthesis of (E)-3-(3-(4-tolyl)-1,2,4-oxadiazol-5-
yl)acrylic 4a acid via a retro-Diels-Alder reaction.
Entry
Reaction conditions
(acid, solvent, T, time)
Isolated yield 4a
(%)
1
2
10 equiv. AcOH, RT, 0.5 h
10 equiv. AcOH, 70 °C, 1 h
23
23
31
45
3
6 equiv. H2SO4, RT, 3 h
6 equiv. H2SO4/1,4-dioxane, RT, 3 h
4
6 equiv. H2SO4/1,4-dioxane, RT, 1.5 h
10 equiv. H2SO4/1,4-dioxane, RT, 1.5 h
10 equiv. H2SO4/CHCl3, RT, 1.5 h
10 equiv. H2SO4/AcOH, RT, 1.5 h
10 equiv. H2SO4/AcOH, 70 °C, 1 h
10 equiv. H2SO4/AcOH, 100 °C, 1 h
10 equiv. TFA, 100 °C, 1 h
5
47
47
6
47
52
7
8
60
9
resin
53
10
11
12
6 equiv. TFA, RT, 2 h
60

6 equiv. TFA, RT, 1 h; then 70 °C, 2 h
6 equiv. TFA, RT, 1 h; then 70 °C, 1 h
6 equiv. TFA, RT, 1 h; then 100 °C, 1 h
75
79
56
13
14
15
The reaction in acetic acid at RT or at 70 °C afforded poor yields of the desired product
(23% in both cases) (Table 1, entries 1 and 2). The acidity of the reaction medium was increased
by using stronger acids – concentrated H2SO4 and mixtures of H2SO4 with various organic
solvents: 1,4-dioxane, AcOH, CHCl3. However, the RDA reaction of bicyclic acid 3a(H) gave
moderate yields of the target compound (<60%) (Entries 3–10). It was shown that prolonged
heating, especially at temperatures above 70 °C in the presence of acids, negatively affects the
yield of the target product. More acceptable results were achieved using trifluoroacetic acid
(Table 1, entries 11–15). The best yield of acrylic acid 4a was obtained with mild heating and a
short reaction time (0.5–2 hours) (Table 1, entries 13 and 14).
With the optimised reaction conditions in hand, we investigated the scope of the one-pot
1,2,4-oxadiazole-5-ylacrylic acid synthesis using a range of substituted amidoximes. The
reaction did not appear to be sensitive to substituent effects on the amidoxime moiety (Scheme
3).

Scheme 3. (E)-3-(3-Aryl(heteroaryl, alkyl)-1,2,4-oxadiazol-5-yl)acrylic acids synthesized in this
work.
It should be noted that in all the cases we observed stereoselective formation of the trans-
1
isomer of acids 4 exclusively (based on H NMR data). In our opinion, the reason for the
stereoselectivity lies in the diastereoselectivity of trans-isomer formation for bicyclic
intermediates 3(Na), similar to the examples described in our previous work.37 The RDA
reaction, like any concerted process, proceeds stereospecifically, which in our case leads to the
production of trans isomers of the acrylic acid products. The structure of (E)-3-(3-(4-

methoxyphenyl)-1,2,4-oxadiazol-5-yl)acrylic acid was additionally proved by X-ray analysis of
compound 4d as shown in Figure 2.
Figure 2. General view of compound 4d (CCDC 1957930) showing 50% probability
displacement ellipsoids.
3. Conclusion
We have developed a new simple, stereoselective, and convenient one-pot method for the
synthesis of (E)-3-(3-aryl(heteroaryl, alkyl)-1,2,4-oxadiazole-5-yl)acrylic acids from readily
available exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride 2 and substituted benzamidoximes.
The method is based on the reaction of amidoximes with 2 in a basic medium at RT followed by
an acid-catalyzed retro-Diels-Alder reaction. This method can significantly expand the range of
attractive building blocks for organic synthesis.
Acknowledgments
This work was supported by the Russian Foundation for Basic Research (grant 19-33-60064).
Physicochemical studies were performed at the Magnetic Resonance Research Centre, Centre for
X-ray Diffraction Studies, Chemical Analysis and Materials Research Centre (all belong to Saint
Petersburg State University).
Appendix A. Supplementary data

Supplementary data related to this article can be found at http: //
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 1,2,4-Oxadiazole-5-ylacrylic acids have been synthesized at the first time.
 Desired products obtained by the one-pot reaction sequence.
 The key step is retro-Diels-Alder elimination.
 The developed method provides only trans-isomers.

Graphical Abstract
Leave this area blank for abstract info.
Entry into (E)-3-(1,2,4-oxadiazol-5-yl)acrylic
acids via ring-opening/ring-closing/retro-
Diels-Alder one-pot reaction sequence
Sofia Presnukhinaa, Marina Tarasenkoa, Sergey Baykovb*, Sergey N. Smirnovc, Vadim P.
Boyarskiyb, Anton Shetneva, and Mikhail K. Korsakova