Rapid Deprotection of O - and N -Benzyl Groups by Catalytic Transfer Hydrogenation with Industrially Viable Silane Reagents

Abstract

A practical and scalable deprotection protocol for O- and N-benzyl protecting groups has been developed using wet Pd/C and organosilanes, notably 1,1,3,3-tetramethyldisiloxane (TMDS) and poly(methylhydrosiloxane) (PMHS), as hydrogen-donor reagents. The use of these cost-effective hydrogen sources eliminates the need for molecular hydrogen, significantly improving process safety while providing a rapid and efficient approach to debenzylation. Operating under mild reaction conditions and ambient pressure, this methodology is designed for pharmaceutical applications where avoiding hazardous gas handling is a priority. The developed system efficiently cleaves benzyl esters, benzyl ethers, and N-benzyl amines, affording the corresponding deprotected products in short reaction times and consistently high yields (82–98%). Importantly, the reaction byproducts can be readily removed by standard industrial unit operations, including extraction, distillation, and crystallization, eliminating the need for labor-intensive purification techniques such as column chromatography. Additionally, the utility of the catalytic system was extended to the efficient, gram-scale reductive cleavage of aromatic azo compounds into primary aromatic amines. This operationally simple approach offers a sustainable alternative for both laboratory and large-scale industrial syntheses.