Iodine(III)-Promoted Synthesis of Oxazoles through Oxidative Cyclization of N-Styrylbenzamides

Abstract

The hypervalent iodine reagent PhI(OTf)₂, generated in situ, has been successfully utilized in an intramolecular oxidative cyclization of N-styrylbenzamides. In remarkably short reaction times, the desired 2,5-disubstituted oxazoles were isolated in high yields in this metal-free oxidative C–O bond-forming reaction.

Key words

hypervalent iodine - umpolung - oxazoles - cyclization - heterocycles

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• 16 Synthesis of Oxazoles 4a–m; General Procedure: The appropriate N-styrylbenzamide (3a–m; 0.015 mmol, 1.0 equiv) was suspended in a 1:1 mixture of anhydrous CH₂Cl₂ and Et₂O (3 mL) and cooled to –78 °C. PIFA (1.2 equiv) and TMSOTf (2.2 equiv) were added and the reaction mixture was stirred at 0 °C until full conversion of the starting material was observed by TLC monitoring. The reaction mixture was diluted with CH₂Cl₂ (3 mL), washed with NaHCO₃ (1 M, 3 mL) and the aqueous phase was extracted with CH₂Cl₂ (3 × 3 mL). The combined organic layers were dried over Na₂SO₄ and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (cyclohexane–EtOAc). Compound 4l: Mp 130–132 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (s, 2 H), 7.95 (s, 1 H), 7.78–7.75 (m, 2 H), 7.52–7.47 (m, 3 H), 7.43–7.38 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.4, 152.9, 132.7 (q, J = 34.0 Hz), 129.5, 129.4, 129.3, 127.4, 126.3, 124.7, 124.1, 123.6-123.4 (m), 123.1 (q, J = 271 Hz). MS (FAB): m/z = 358.1 [M+H]⁺. IR: 1736, 1380, 1277, 1130, 943, 901, 843, 767, 730, 681 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₉F₆NO: 358.06611; found: 358.06579.