Electrophile-Promoted Cyclization of Propargylic Amides

Abstract

Electrophilic cyclization of N-(3-arylprop-2-ynyl)amides to functionalized 4H-1,3-oxazines is described. It was found that the presence of an electron-rich aryl group next to the triple bond is crucial for a smooth and highly regioselective 6-endo-dig ring closure process.

Key words

propargylic amides - electrophile - cyclization - ­oxazines - oxazolines

• References and Notes

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• 11 General Procedures for the Synthesis of 6-Aryl-5-iodo-2-phenyl-4H-1,3-oxazines 2: To the solution of the corresponding N-[(3-substituted)prop-2-ynyl]benzamide 1 (1 mmol) in CH₂Cl₂ (5 mL) N-iodosuccinimide (0.23 g, 1 mmol; method A) or phenyl hypochloroselenoite (95.96 mg, 0.5 mmol) together with potassium tert-butanoate (0.5 mmol; method B), or 1-methoxyisochromane (90.2 mg, 0.55 mmol) followed by trimethylsilyl triflate (0.09 mL, 0.5 mmol; method C) were added. The mixture was stirred at r.t. When reaction was complete (TLC), the solution was quenched with aq sodium thiosulfate. The organic layer was separated, washed with aq sodium thiosulfate (2 × 20 mL), and H₂O (2 × 20 mL), and dried over anhyd Na₂SO₄. After filtration and evaporation of the solvent under reduced pressure, the residue was purified by flash column chromatography eluting with hexane–EtOAc mixtures. 5-Iodo-6-(4-methoxyphenyl)-2-phenyl-4H-1,3-oxazine (2aa): white solid; mp 119–120 °C; yield: 72%. ¹H NMR (400 MHz, CDCl₃): δ = 3.86 (s, 3 H, OMe), 4.56 (s, 2 H, CH₂), 6.96 (d, ³ J = 8.8 Hz, 2 H, ArH), 7.40 (t, ³ J = 7.6 Hz, 2 H, ArH), 7.48 (tt, ³ J = 7.6 Hz, ⁴ J = 2.4 Hz, 1 H, ArH), 7.63 (d, ³ J = 8.8 Hz, 2 H, ArH), 7.95–7.97 (m, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 55.2 (CH₂), 55.4 (OMe), 69.8 (CI), 113.6 (ArC), 126.6 (ArC), 127.4 (ArC), 128.4 (ArC), 130.5 (ArC), 131.1 (ArC), 131.7 (ArC), 147.7 (Csp ²), 153.7 (Csp ²), 160.6 (ArC). HRMS (ESI): m/z [M + H⁺] calcd for C₁₇H₁₅INO₂: 392.0142; found: 392.0148. Compounds 1–11 were also fully characterized by IR, ¹H NMR, ¹³C NMR spectroscopic and microanalytical data.