Copper and N-Heterocyclic Carbene-Catalyzed Oxidative Amidation of Aldehydes with Amines

Abstract

A one-pot two-step oxidative process has been developed for the tert-butyl hydroperoxide mediated transformation of aldehydes and amines into amides catalyzed by copper(I) iodide and an N-heterocyclic carbene. The process is additive-free and does not require the amine to be transformed into its hydrochloride salts. The method is simple and practicable, has a broad substrate scope, and uses economical, feasible, and abundant reagents.

Keywords

N-heterocyclic carbenes - copper catalysis - organocatalysis - aldehydes - amines - amides

Publication History

Received: 03 November 2020

Accepted after revision: 28 December 2020

Accepted Manuscript online:
28 December 2020

Article published online:
15 February 2021

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• 27 Amides 3a–y; General Procedure An oven-dried Schlenk tube was charged with a solution of NHC precursor 1a (10 mol%) and CuI (10 mol%) in CH₃CN (3 mL) under N₂. NaH (10 mol%) was added, and the resulting mixture was stirred vigorously for about 20–30 min and then the appropriate aldehyde (2.5mmol) and amine (2.5mmol) were added to the flask together with TBHP (3 equiv). The mixture was refluxed for 6 h in an oil bath then cooled to r.t., filtered through a Celite pad, and washed with H₂O. The organic portion was extracted with EtOAc, dried (Na₂SO₄), and purified by column chromatography (silica gel, EtOAc–hexane). 2,6-Difluoro-N-[2-(2-thienyl)ethyl]benzamide (4x) White solid; yield: 521 mg (78%); mp 152–153 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.28 (m, 1 H), 7.15 (dt, J = 5.1, 1.2 Hz, 1 H), 6.96–6.83 (m, 4 H), 6.19 (br s, 1 H), 3.71 (q, J = 6.3 Hz, 2 H), 3.14 (t, J = 6.7 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 161.32, 160.55, 141.04, 131.65, 127.22, 125.75, 124.20, 114.36, 111.95, 41.51, 29.85. LC-MS: m/z [M + H]⁺ calcd for C₁₃H₁₂F₂NOS: 268.0512; found: 268.0509.