A Guide for Mono-Selective N-Methylation, N-Ethylation, and N-n-Propylation of Primary Amines, Amides, and Sulfonamides and Their Applicability in Late-Stage Modification.

This review provides a comprehensive overview of mono-alkylation methodologies targeting crucial nitrogen moieties - amines, amides, and sulfonamides - found in organic building blocks and pharmaceuticals. Emphasizing the intersection of chemical precision with drug discovery, the central challenge addressed is achieving one-pot mono-selective short-chain N-alkylations (methylations, ethylations, and n-propylations), preventing undesired overalkylation. Additionally, sustainable, safe, and benign alternatives to traditional alkylating agents, including alcohols, carbon dioxide, carboxylic acids, nitriles, alkyl phosphates, quaternary ammonium salts, and alkyl carbonates, are explored. This review, categorized by the nature of the alkylating agent, aids researchers in selecting suitable methods for mono-selective N-alkylation.