α,β-Epoxy Esters in Multiple C–O/C–N Bond-Breaking/Formation with 2-Aminopyridines; Synthesis of Biologically Relevant (Z)-2-Methylene­imidazo[1,2-a]pyridin-3-ones

Abstract

A new reaction of aryl 2,3-epoxy esters with 2-aminopyridines has been developed that involves multiple C-O/C-N bond-breaking/formation reactions in one chemical step. Compared with known reactions of α,β-epoxy esters, which take place through oxiranyl C-O or C-C bond cleavage, the present reaction exploits the tendency of the oxirane ring to act as a bi-electrophile. Thus, the reaction follows a unique cascade pathway of epoxide C-O bond cleavage, formation of an α-enamine ester, and intramolecular transamidation with chemo-, regio-and diastereoselectivity. The reaction allows access to biologically relevant (Z)-2-methyleneimidazo[1,2-a]pyridin-3-ones. Water and ethanol are the only byproducts. The reaction is flexible, and aryl 2,3-epoxy esters as well as 2-aminopyridines possessing either electron-donating or -withdrawing functionalities, can be used. In contrast to various Brønsted and Lewis acid catalysts, polyphosphoric acid plays a multifunctional role in this intermolecular cascade reaction.Oxiranes are important building blocks in organic synthesis because of their easy accessibility, their propensity for opening of the strained ring, and because of their use in the preparation of versatile organic motifs. Most ringopening reactions of oxiranes involve C-O bond cleavage, although C-C bond cleavage is also known. The cascade reaction 1 involving epoxide C-O bond cleavage in the synthesis of polycyclic natural products is well known. 2 In the context of exploring the use of the oxirane class of compounds for various reactions, the 2,3-epoxy esters/ketones have attracted significant attention because of their use as multifunctional substrates 3 and because of their ease of preparation. 4 A remarkable example is the reaction of glycidic ester with 2-aminothiophenol, which provides 1,4-benzothiazepinone, a synthetic precursor of calcium channel blocker drug diltiazem. 5 Aryl oxiranylcarboxylates/ketones undergo interesting C-C bond heterolysis of the oxirane ring, generating carbonyl ylides 6 that undergo dipolar cycloaddition with various π-systems. For example, the [3+2] cycloaddition of aryl oxiranyl-dicarboxylate/diketone/cyanoketone with indole, 7 alkyne, 8 or [60]fullerene 9 furnishes furo[3,4-b]indole, 2,5-dihydrofuran, or C60-fused tetrahydrofuran, respectively. Other significant applications of 2,3-epoxy esters/ketones include [3+2] heterocyclization for the construction of quaternary imidazole skeletons, 10 palladium(0)-catalyzed transformation into β-diketone, 11 and SmI 2 -mediated deoxygenation to produce the α,β-unsaturated ester. 12 Herein, we report a new reaction of aryl α,β-epoxy esters with 2-aminopyridines that exploits the tendency of the oxirane ring to act as a bi-electrophile. The reaction involves a cascade pathway of epoxide C-O bond cleavage, formation of α-enamine ester, and intramolecular transamidation with chemo-, regio-and diastereoselectivity. The approach allows access to biologically relevant (Z)-2-methyleneimidazo[1,2-a]pyridin-3-one. (Z)-2-Methyleneimidazo[1,2-a]pyridin-3-...

Scaffold-Hopping Strategies in Aurone Optimization: A Comprehensive Review of Synthetic Procedures and Biological Activities of Nitrogen and Sulfur Analogues

“…From a mechanistic point of view, this method exploits the tendency of the oxirane ring to act as a bielectrophile. In detail, the mechanism consists of a unique process: cleavage of the epoxydic C–O bond, the formation of an α-enamine ester via a PPA-mediated aziridine intermediate, and intramolecular transamidation with only water and ethanol as byproducts [ 51 , 52 ].…”

Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents

“…Recently, we have developed a new cascade reaction of 2-aminopyridine with 2,3-epoxyesters to produce 2-arylideneimidazo­[1,2- a ]­pyridinones . The reaction involves a set of sequential transformations: epoxide ring opening, aziridination, nucleophilic opening of aziridine, elimination to form enamine, and intramolecular transamidation.…”

“…However, the IC 50 for control compounds C1 and C2 in MDA-MB-231 and MDA-MB-468 were found to be much higher, 840–600 nM (Table S2). To further confirm the cytotoxicity a long-term cell survival assay (clonogenic assay) was performed . For compounds 3a – d , 3i , 3k , 3n , 3o , and 3r the LC 50 values (50% cell death in culture) in HEK 293T cells were found to be 55, 60, 60, 75, 40, 20, 40, 40, and 50 nM, respectively, and in VERO cells 1000, 1500, 1500, 1500, 1500, 1500, 1500, 1500, and 1500 nM, respectively (Table S1b).…”