Abstract
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 imine formation between the aldehyde and amine substrates, which otherwise prevented 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.
Highlights
The amide functional group is of fundamental importance as a structural and functional motif present in a vast array of natural and synthetic substances, from small molecule drugs to biopolymers and materials.[1]
Approaches to the Synthesis of Amides from Aldehydes Mediated by N-Heterocyclic Carbene (NHC) us, using a microfluidic electrolysis cell (Figure 1).[10]
We describe a flow process for NHC-mediated synthesis of amides from aldehydes using an electrochemical microflow cell in sequence with a heating chip, where high conversions and yields can be achieved in a single pass
Summary
A significant benefit of performing reactions in flow is the ability to control reactant and reagent mixing, which enabled formation of the NHC and Breslow intermediate in flow prior to mixing with the amine and before the reaction mixture entered the electrolysis cell (see Table 1) This in-flow mixing regimen led to encouraging isolated yields of amide 11a of 30−40% in a THF/DMSO solvent mixture with a total flow rate of 0.12 mL min−1 at rt An in-flow process for NHC-mediated anodic oxidative amidation of aldehydes has been described, employing an undivided microfluidic electrolysis cell in series with a heater chip to achieve high conversion in a single pass. Experimental details and procedures, compound characterization data, current efficiencies, and copies of 1H and 13C NMR spectra for all new compounds (PDF)
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