Large scale synthesis of N-benzyl-4-formylpiperidine through partial reduction of esters using aluminum hydride reagents modified with pyrrolidine

The modification of sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) wit h pyrrolidine provided a highly selective reducing agent to transform N-ben zyl-4-ethoxycarbonylpiperidine into N-benzyl-4-formylpiperidine 1 under mil d conditions. However, this simple modification led to a significant amount of N-benzyl-4-(pyrrolidin-1-ylmethyl)piperidine 4 due to overreduction of an intermediate. Our extensive research revealed that an alkaline base such as potassium tert butoxide could suppress the formation of the by-product to give the desired aldehyde, enabling us to establish a viable synthetic p rocess for a key intermediate of donepezil hydrochloride. The potential app lications of this reagent are also described. (C) 2001 Elsevier Science Ltd . All rights reserved.