Herein, we report an efficient one-pot chemoselective methylation of carboxylic acids using N-methyl-N-nitrosourea (MNU) as an economical and safe precursor for diazomethane. This strategy enables the methylating agent to be generated and consumed in situ, thereby effectively avoiding the hazardous separation and transfer processes. The reaction proceeds under mild conditions with excellent functional group tolerance, accommodating a broad range of substrates including amino acids, peptides, and drug-like molecules to deliver the corresponding methyl esters in moderate to excellent yields. Furthermore, the methodology was successfully applied to the N-methylation of phenyltetrazole, a common carboxylic acid bioisostere, highlighting its utility for late-stage functionalization in pharmaceutical synthesis.

Key words: N-Methyl-N-Nitrosourea, Diazomethane, One-pot reaction, Chemoselective methylation