A flow electrochemistry‐enabled synthesis of 2‐substituted N‐(methyl‐d)piperidines. (15th November 2022)

• Record Type: Journal Article
• Authors: AL‐Hadedi, Azzam A. M.; Sawyer, Stuart; Elliott, Stuart J.; Green, Robert A.; O'Leary, Daniel J.; Brown, Richard C. D.; Brown, Lynda J.
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 65:Number 14(2022)
• Page Start: 361
• Page End: 368
• Publication Date: 2022-11-15
• Subjects: flow electrosynthesis -- long‐lived nuclear spin -- monodeuterated -- NMR; Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.4006
• Languages: English
• ISSNs: 0362-4803

Abstract

Abstract : A synthesis of N ‐monodeuteriomethyl‐2‐substituted piperidines is described. An efficient and readily scalable anodic methoxylation of N ‐formylpiperidine in an undivided microfluidic electrolysis cell delivers methoxylated piperidine 3, which is a precursor to a N ‐formyliminium ion and enables C‐nucleophiles to be introduced at the 2‐position. The isotopically labelled N ‐deuteriomethyl group is installed using the Eschweiler–Clarke reaction with formic acid‐ d 2 and unlabelled formaldehyde. Monodeuterated N ‐methyl groups in these molecular systems possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long‐lived nuclear spin states in solution nuclear magnetic resonance. Abstract : Synthesis of N ‐monodeuteriomethyl‐2‐substituted piperidines by efficient and scalable methoxylation of N ‐formylpiperidine in an electrochemical flow cell, followed by an Eschweiler–Clarke reaction with formic acid‐ d 2 and unlabelled formaldehyde, is described. These monodeuterated N ‐methyl possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long‐lived nuclear spin states in solution NMR.