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

doi:10.1016/j.tetlet.2019.151543

Tetrahedron Letters

Volume 61, Issue 9, 27 February 2020, 151543

https://doi.org/10.1016/j.tetlet.2019.151543 Get rights and content

Highlights

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1,2,4-Oxadiazole-5-ylacrylic acids have been synthesized at the first time.
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Desired products obtained by the one-pot reaction sequence.
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The key step is retro-Diels-Alder elimination.
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The developed method provides only trans-isomers.

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).

Graphical abstract

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], [2], [3], [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 deleobuvir [7] 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) activation [9] 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 inhibitor [13] or cysteinyl leukotriene receptor 1 antagonist [14]), 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.

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 chemistry [23] 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 double bond 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], [28], [29], [30], [31]. This methodology was subsequently applied to the synthesis of various useful 1,2,4-oxadiazole derivatives, namely carbonic anhydrase [32], [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 double bond 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], [39], [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.

Section snippets

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

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

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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).

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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

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

Declaration of Competing Interest

Acknowledgments

Clin. Lymphoma Myeloma Leuk.

Biochem. Biophys. Res. Commun.

Cell

Chem. Biol. Interact.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

J. Mol. Struct.

Adv. Heterocycl. Chem.

Comprehensive Heterocyclic Chemistry III Elsevier

TetrahedronLett.

Tetrahedron

Tetrahedron Lett.

Tetrahedron Lett.

Bioorg. Chem.

Eur. J. Med. Chem.

Eur. J. Org. Chem.

Dye Pigment.

TetrahedronLett.

J. Mol. Struct.

J. Clin. Oncol.