Atom-economic catalytic amide synthesis from amines and carboxylic acids activated in situ with acetylenes.

Thilo Krause,Benjamin Erb,Lukas J Gooßen,Sabrina Baader

doi:10.1038/ncomms11732

Abstract

Amide bond-forming reactions are of tremendous significance in synthetic chemistry. Methodological research has, in the past, focused on efficiency and selectivity, and these have reached impressive levels. However, the unacceptable amounts of waste produced have led the ACS GCI Roundtable to label ‘amide bond formation avoiding poor atom economy' as the most pressing target for sustainable synthetic method development. In response to this acute demand, we herein disclose an efficient one-pot amide coupling protocol that is based on simple alkynes as coupling reagents: in the presence of a dichloro[(2,6,10-dodecatriene)-1,12-diyl]ruthenium catalyst, carboxylate salts of primary or secondary amines react with acetylene or ethoxyacetylene to vinyl ester intermediates, which undergo aminolysis to give the corresponding amides along only with volatile acetaldehyde or ethyl acetate, respectively. The new amide synthesis is broadly applicable to the synthesis of structurally diverse amides, including dipeptides.

Highlights

Amide bond-forming reactions are of tremendous significance in synthetic chemistry
The thermal amide bond formation from the ammonium carboxylate salts requires high temperatures[5,6,7], which can be lowered by Lewis acids or boronic acid derivatives
Amides are usually synthesized by aminolysis of activated carboxylic acid derivatives, such as halides, anhydrides, azides, or activated esters, that are mostly generated in an extra step with aggressive, expensive or waste-intensive reagents[14,15,16,17,18,19,20]

Summary

Introduction

Amide bond-forming reactions are of tremendous significance in synthetic chemistry. Methodological research has, in the past, focused on efficiency and selectivity, and these have reached impressive levels. The most desirable amide synthesis, a direct condensation of carboxylic acids with amines, is hindered by the intrinsic acid–base reactivity of the starting materials. Some elegant strategies for waste-minimized amide synthesis have been devised (Fig. 1), for example, dehydrogenative couplings of alcohols, aldehydes or alkynes with amines, or additions of alcohols to nitriles[39,40,41,42,43,44,45,46,47,48,49,50,51].

Results

Conclusion