Synthesis of Secondary N-Methylamines via Reductive Amination of Aldehydes with N-Boc-N-Methylamine Using Me₂SiHCl

A novel protocol for the synthesis of secondary N-methylamines via reductive amination of aldehydes with N-Boc-N-methylamine has been developed, using Me₂SiHCl as the reductant. The reaction proceeds through the formation of Boc-protected secondary N-methylamines, which undergo in situ Boc-deprotection facilitated by HCl generated during the initial reductive amination. This method features a broad substrate scope, efficiently accommodating a wide range of aldehydes and affording the desired secondary N-methylamines in excellent yields. Notably, the resulting N-methylamines are isolated as their HCl salts, which exhibit poor solubility in common organic solvents, enabling facile purification by simple filtration. The utility of this strategy was further demonstrated in the synthesis of vonoprazan, a marketed drug used to treat gastroduodenal ulcers and reflux esophagitis, where the N-methylamine moiety was introduced in the final step via the developed reductive amination.