Copper-Catalyzed Amination of Vinyl Azides to α-Ketoamides

Abstract

An efficient approach for the amination of vinyl azides with N,N-dialkylacylamides has been developed. By using this protocol, structurally important α-ketoamides can be easily synthesized. The key to success is not only the introduction of a Cu(I)/oxygen catalytic system but also the utilization of t-BuOCl and benzoic acid as additives. The reaction is operationally simple, scalable, and displays broad scope and functional group tolerance. A possible mechanism involving copper-catalyzed oxidative generation of peroxide radicals is proposed.

Key words

amination - α-ketoamide - vinyl azide - copper-catalysis - N,N-dialkylacylamides

• References and Notes


For recent progress in the synthesis of vinyl azides, see:
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• 14 Synthesis of 4a; Typical Procedure: To a solution of α-azido styrene (1a; 72.5 mg, 0.5 mmol), tert-butyl hypochlorite (113.1 μL, 1.0 mmol), and benzoic acid (122.1 mg, 1.0 mmol) in N,N-diethylformamide (2b; 1 mL) at room temperature, CuI (28.6 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C and stirred for 5 h under an oxygen atmosphere, when TLC analysis confirmed that substrate 1a had been consumed. The resulting reaction mixture was cooled to room temperature and K₂CO₃ was added. The mixture was extracted with dichloromethane (3 × 15 mL), and the combined organic extracts were washed with brine (3 × 40 mL), dried over MgSO₄, filtered and concentrated. Purification of the crude product by flash column chromatography (silica gel; petroleum ether) afforded 4a (77% yield) as a yellow oil. N,N-Diethyl-2-oxo-2-phenylacetamide (4a): ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (d, J = 7.1 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 3.61–3.53 (m, 2 H), 3.29–3.20 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.16 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 191.5, 166.7, 134.5, 133.2, 129.6, 128.9, 42.0, 38.7, 14.0, 12.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₅NO₂: 206.1181; found: 206.1142.