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 by-products. 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.

Key words

domino reactions - amino alcohols - epoxides - hetero­cycles - fused-ring systems

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• 21 Synthesis of (Z)-2-(4′-Chlorobenzylidene)-2H-imidazo-[1,2-a]pyridin-3-one; Typical Procedure (Table 2): To a mixture of 2-aminopyridine (47 mg, 0.5 mmol) and ethyl 3-(4′-chlorophenyl)oxirane-2-carboxylate (113 mg, 0.5 mmol) in a round-bottom flask, was added PPA (1.5 g), and the mixture was magnetically stirred at 110 °C under open air. Upon completion of the reaction as indicated by TLC (1–1.5 h), the resultant mixture was poured into crushed ice (2 g) and neutralized with 5% aq NaOH. The mixture was extracted with CH₂Cl₂ (2 × 25 mL) and the organic layer was washed with brine (5 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. Column chromatographic purification of the crude mass on silica gel (EtOAc–hexane, 1:6) gave (Z)-2-(4-chlorobenzylidene)-2H-imidazo[1,2-a]pyridin-3-one (3a; 106 mg, 83%) as a red solid. Mp 182–184 °C; R_f = 0.33 (EtOAc–hexane, 10%). Compounds 3a–o were prepared by following a similar procedure. Data for 3a: See Figure 2 for numbering. ¹H NMR (400 MHz, CDCl₃): δ = 8.16 (d, J = 8.3 Hz, 2 H, H_j), 7.62 (d, J = 6.8 Hz, 1 H, H_a), 7.40 (d, J = 8.3 Hz, 2 H, H_k), 7.23 (s, 1 H, H_h), 7.17 (dd, J = 6.6, 9.2 Hz, 1 H, H_c), 6.93 (d, J = 9.4 Hz, 1 H, H_d), 6.25 (dd, J = 6.6, 6.6 Hz, 1 H, H_b); ¹³C NMR (100 MHz, CDCl₃): δ = 167.4 (C_g), 156.7 (C_e), 138.6 (C_f), 137.9 (C_c), 136.4 (C_i), 133.7 (C_j), 133.2 (C_l), 129.1 (C_k), 127.2 (C_a), 126.0 (C_d), 119.3 (C_b), 109.3 (C_h); IR (neat): 2879, 1707, 1650, 1601 cm^–1; HRMS (ESI): m/z [M(³⁵Cl) + H]⁺ calcd. for C₁₄H₉ClN₂O: 257.0481; found: 257.0477.