Synthesis of α-Keto Amides by a Pyrrolidine/TEMPO-Mediated Oxidation of α-Keto Amines

Abstract

A mild procedure has been developed for the synthesis of α-keto amides by α-oxidation of the corresponding α-keto amines ­mediated by pyrrolidine and TEMPO. The method can also be applied to the synthesis of α-keto thioamides and α-keto amidines.

Key words

oxidation - catalysis - amides - ketones - amines - thioamides

• References and Notes

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• 17 N-(4-Methoxyphenyl)-N-methyl-2-oxo-2-phenylacetamide (2k); Typical Procedure Pyrrolidine (123 μL, 1.5 mmol) was added to a solution of amino ketone 1k (76.5 mg, 0.3 mmol) and TEMPO (4.7 mg, 0.03 mmol) in MeCN (1 mL) under O₂ (balloon pressure). The mixture was then stirred at r.t. for 20 h (TLC monitoring) then was concentrated. The residue was purified by column chromatography [silica gel, heptane–EtOAc (5:1)] to give a slightly yellow oil; yield: 63.4 mg (79%); ¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.77 (m, 2 H), 7.58–7.49 (m, 1 H), 7.45–7.35 (m, 2 H), 7.08–7.00 (m, 2 H), 6.74–6.63 (m, 2 H), 3.68 (s, 3 H), 3.42 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 191.1, 167.1, 158.9, 134.1, 133.5, 133.4, 129.2, 128.6, 128.3, 114.5, 55.2, 36.3; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆NO₃: 270.1130; found: 270.1128.
• 18 (3E)-N-Methyl-2-oxo-N,4-diphenylbut-3-enamide (2j) Slightly yellow oil; yield: 34.6 mg (43%); ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (d, J = 16.3 Hz, 1 H), 7.56–7.49 (m, 2 H), 7.47–7.37 (m, 3 H), 7.36–7.26 (m, 3 H), 7.23–7.16 (m, 2 H), 6.77 (d, J = 16.3 Hz, 1 H), 3.45 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 190.1, 167.0, 147.5, 141.7, 134.0, 131.3, 129.6, 129.0, 128.7, 128.1, 126.5, 123.4, 36.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NO₂: 266.1181; found: 266.1179.