N‑Heterocyclic Carbene Mediated Microfluidic Oxidative Electrosynthesis of Amides from Aldehydes – Syrris in Publications

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Organic Letters, 2016, 18 (5), pp 1198–1201

Robert A. Green†, Derek Pletcher†, Stuart G. Leach‡, and Richard C. D. Brown*†

†Department of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, U.K. ‡ GlaxoSmithKline, Stevenage, Herts SG1 2NY, U.K.

Using a Syrris Asia flow system and the FLUX continuous electrochemistry module, researchers at the University of Southampton and GlaxoSmithKline have demonstrated a flow process for the N-Heterocyclic carbene-mediated continuous oxidative electrosynthesis of amides from aldehydes.

The use of N-Heterocyclic carbenes (NHCs) as organic catalysts for a range of reactions including the oxidative conversion from aldehydes to amides is well known but requires a stoichiometric amount of chemical oxidant. The electrochemical oxidation of the Breslow intermediate offers an attractive, greener alternative.

After electrochemical oxidation, the reaction of the intermediate N-acylated thiazolium cation with primary amines is carried out in a heated micro reactor to achieve a high conversion in a single pass. Using this methodology high yields (71–99%), productivities (up to 2.6 g h–1), and current efficiencies (65–91%) were realized for 19 amides.

N‑Heterocyclic Carbene-Mediated Microfluidic Oxidative Electrosynthesis of Amides from Aldehydes

A flow process for N-Heterocyclic Carbene (NHC)-mediated anodic oxidative amidation of aldehydes is described, employing an undivided microfluidic electrolysis cell to oxidize Breslow intermediates. After electrochemical oxidation, the reaction of the intermediate N-acylated thiazolium cation with primary amines is completed by passage through a heating cell to achieve high conversion in a single pass. The flow mixing regimen circumvented the issue of competing for imine formation between the aldehyde and amine substrates, which otherwise prevented the formation of the desired product. High yields (71–99%), productivities (up to 2.6 g h–1), and current efficiencies (65–91%) were realized for 19 amides.

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