Cesium Carbonate Promoted Direct Amidation of Unactivated Esters with Amino Alcohol Derivatives

Cesium carbonate is a white hygroscopic powder that is readily soluble in water. Many of the properties of cesium carbonate are due to the softness of the cesium cation. The softness makes cesium carbonate rather soluble in organic solvents such as alcohol, DMF and diethyl ether. Because of the solubility in polar solvents it not only promotes successful carbonylation of alcohols and carbonation of amine but also suppresses common side reactions traditionally encountered with other protocols.

Cesium carbonate promoted direct amidation of unactivated esters with amino alcohols was developed without the use of transition-metal catalysts and coupling reagents. This method enabled the synthesis of several serine-containing oligopeptides and benzamide derivatives with yields up to 90%. The methodology proceeds under mild reaction conditions and exhibits no racemization for most naturally occurring amino acid substrates. The reaction demonstrates good compatibility with primary alkyl and benzyl esters and broad tolerance for a range of amino acid substrates with nonpolar and protected side chains. The hydroxy group on the amine nucleophile was found to be critical for the reaction to be successful. A likely mechanism involving cesium coordination to the substrates enabling the subsequent proximity-driven acyl transfer was proposed. The practicality of this approach was demonstrated in the preparation of a biologically active nicotinamide derivative in a reasonable yield.

References:

[1] CHIH-HUNG KUO, YUYA A. LIN* Cesium Carbonate Promoted Direct Amidation of Unactivated Esters with Amino Alcohol Derivatives[J]. The Journal of Organic Chemistry, 2024. DOI:10.1021/acs.joc.4c00162.