Using the optimized protocols, numerous unactivated alkyl and aryl esters are converted into amides in one step. (iii) Functional groups reactive towards anilines such as alkyl halide and ketones can be tolerated. Nitroarenes offer several advantages over anilines as nitrogen sources: (i) nitroarenes are generally cheaper and more stable (ii) as anilines are often prepared by hydrogenation of nitroarenes 16, direct use of nitroarenes is more step-economical further, substrates containing reducible groups, such as alkenes and nitriles, can be tolerated. Here, we describe a nickel-catalysed reductive coupling method for the direct amidation of esters with nitroarenes ( Fig. While density functional theory computations suggested that these amidation reactions proceeded via an unusual oxidative addition of the acyl carbon-oxygen bonds of esters, the scope of esters is largely limited to those containing a naphthyl group, which are specialized and activated substrates compared to conventional dialkyl and alkyl aryl esters. A stoichiometric amount of aluminum tert-butoxide (Al(O t-Bu) 3) was needed to shift the thermodynamic equilibrium towards amide formation and to facilitate the kinetics by carbonyl activation. Garg and co-workers recently reported nickel-catalysed direct amidation of esters with secondary aryl amines to furnish tertiary anilides 15 ( Fig. These reactions proceed via nucleophilic substitution at the acyl carbon and mostly work with strongly nucleophilic alkyl amines, while anilines are often not suitable reaction partners. Catalytic methods are rare 11, 12 and notable examples include a Zr(O t-Bu) 4-HOAt system developed by Porco and co-workers (HOAt=1-hydroxy-7-azabenzotriazole) 13 and a Ru-pincer system developed by Milstein and co-workers 14. Direct amidation of esters with amines typically requires stoichiometric amounts of promoters or metal mediators 7, 8, 9, 10 ( Fig. A particularly important conversion is the transformation of esters into amides 3, 4, which are key components of peptides and proteins, as well as privileged molecules in medicinal chemistry 5, as exemplified in some top-selling drugs such as Harvoni, Januiva, Glivec and Symbicort 6. Compared to other carbonyl groups such as ketones, aldehydes and carboxylic acids, esters are more stable, which leads to applications as solvents and as protecting groups for carboxylic acids.īecause esters are ubiquitous synthetic intermediates, bio-active molecules and materials, direct conversion of the ester group into other functional groups is attractive in organic synthesis. Fragrance additives applied in flavor and perfume industries, such as citronellyl formate and geranyl acetate, also contain ester groups. Ester linkages can be found in top-selling drugs, such as Tamiflu, Lovaza, Methylphenidate and Fenofibrate 2. Esters are important compounds in medicine, pharmacology, and flagrance as well. In industry, polyesters, such as polyethylene terephthalate and cellulose acetate, are produced in millions-tons scale every year. In nature, esters are responsible for the aroma of many flowers and fruits, and fats are generally triesters. The work provides a novel and efficient method for amide synthesis.Įsters are common in nature and have found widespread applications in industry 1. Preliminary mechanistic study indicates a reaction pathway distinct from conventional amidation methods using anilines as nitrogen sources. The method has been used to expedite the syntheses of bio-active molecules and natural products, as well as their post-synthetic modifications. Here we report nickel-catalysed reductive coupling of unactivated esters with nitroarenes to furnish in one step a wide range of amides bearing functional groups relevant to the development of drugs and agrochemicals. However, efficient methods for direct amidation of unactivated esters are still lacking. Direct amidation of esters is particularly appealing due to the omnipresence of the amide moiety in biomolecules, fine chemicals, and drug candidates. Esters are one of the most common functional groups in natural and synthetic products, and the one-step conversion of the ester group into other functional groups is an attractive strategy in organic synthesis.

Ester functional group