In this paper, a NaOtBu-mediated synthesis approach was developed for direct amidation of unactivated esters with amines under transition-metal-free and solvent-free conditions, affording a series of amides in good to excellent yields at room temperature. In particular, an environmentally friendly and practical workup procedure, which circumvents the use of organic solvents and chromatography in most cases, was disclosed. Moreover, the gram-scale production of representative products 3a, 3w and 3au was efficiently realized by applying operationally simple, sustainable and practical procedures. Furthermore, this approach was also applicable to the synthesis of valuable molecules such as moclobemide (a powerful antidepressant), benodanil and fenfuram (two commercial agricultural fungicides). These results demonstrate that this protocol has the potential to streamline amide synthesis in industry. Meanwhile, quantitative green metrics of all the target products were evaluated, implying that the present protocol is advantageous over the reported ones in terms of environmental friendliness and sustainability. Finally, additional experiments and computational calculations were carried out to elucidate the mechanistic insight of this transformation, and one plausible mechanism was provided on the basis of these results and the related literature reports.

This paper is dedicated to Professor Youyou Tu, the 2015 Nobel Prize Laureate of Physiology or Medicine, on the occasion of her 90^th birthday A practical sodium tert-butoxide (NaOtBu)-mediated protocol is disclosed for the transamidation of various N,N-dimethyl amides with primary amines to afford the corresponding amides in moderate to good yields at room temperature under solvent-free conditions. This protocol features a facile work-up procedure and good functional group compatibility, especially for N,N-dimethyl amides with long-chain alkyl groups and heteroatom-containing amines. Notably, a few representative gram-scale reactions proceed smoothly to furnish the desired amides in high yields, which demonstrates the potential of this process for further practical applications. Several control experiments are carried out and a plausible mechanism is provided. Received: 29 May 2020 Accepted after revision: 22 July 2020 Publication Date: 08 September 2020 (online) © 2020. Thieme. All rights reserved Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany