Abstract
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. Direct amidation of esters is particularly appealing due to the omnipresence of the amide moiety in biomolecules, fine chemicals, and drug candidates. However, efficient methods for direct amidation of unactivated esters are still lacking. 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. The method has been used to expedite the syntheses of bio-active molecules and natural products, as well as their post-synthetic modifications. Preliminary mechanistic study indicates a reaction pathway distinct from conventional amidation methods using anilines as nitrogen sources. The work provides a novel and efficient method for amide synthesis.
Highlights
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
Because esters are ubiquitous synthetic intermediates, bioactive molecules and materials, direct conversion of the ester group into other functional groups is attractive in organic synthesis
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. (iii) Functional groups reactive towards anilines such as alkyl halide and ketones can be tolerated
Summary
Silyl ether (TMS2O), and zinc(II) chlorides and siloxides are the expected by-products Such an amide formation reaction has yet to be reported, we were encouraged by the successful amine formation from alkyl halides and nitrosoarenes under Fe-catalysed reductive coupling conditions[17]. Previous method based on the amidation of ester with aniline required four steps and had a comparable yield[23] (Supplementary Fig. 2). The conventional amidation method, based on reactions of carboxylic acids and anilines using thionyl chloride as the coupling reagent, required two steps[24,25] (Fig. 6b). Tazarotene[27], a retinoid approved for the treatment of psoriasis, has an ester group This compound was converted into an amide derivative (6g) in one-step with a 62% yield using our method (Fig. 6d).
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