Organophotocatalytic Late-stage N-CH3 Oxidation of Trialkylamines with O2 in Continuous Flow

Abstract

We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for processing in flow which allowed harnessing of O2 as a benign reagent for late-stage photocatalytic N-CH3 oxidation of natural products and active pharmaceutical ingredients. These substrates bear functional groups which are not tolerated by previous methods. The organophotocatalytic process benefited from the flow parameters, affording cleaner reactions in short residence time of 13.5 mins and productivities of up to 0.65 g / day. Mechanistic studies found that catalyst derivatization not only enhanced solubility of the new catalyst compared to DCA, it profoundly diverted the photocatalytic reaction mechanism from singlet electron transfer (SET) reductive quenching with amines to energy transfer (EnT) with O2.

Mechanisms and Synthetic Strategies in Visible Light‐Driven [2+2]‐Heterocycloadditions

“…Mechanistic investigations, carried out by light-excitation of the benzophenone 47 a showed that the indole derivative 46 quenches its emission, and the reactivity is greatly decreased in presence of DABCO or oxygen as tripletexcited-state quencher. [44] The absorbance and emission profiles of the benzophenone solution remained unchanged upon adding indole 46, thus excluding any ground-state or excited-state association. Moreover, ΔG PET calculations showed that a PET pathway was not feasible for benzophe-none (ΔG PET = + 28.83 kcal mol À 1 ).…”

Mechanisms and Synthetic Strategies in Visible Light‐Driven [2+2]‐Heterocycloadditions

“…Benzils were also tested using Mechanistic investigations, carried out by light-excitation of the benzophenone 47 a showed that the indole derivative 46 quenches its emission, and the reactivity is greatly decreased in presence of DABCO or oxygen as tripletexcited-state quencher. [44] The absorbance and emission profiles of the benzophenone solution remained unchanged upon adding indole 46, thus excluding any ground-state or excited-state association. Moreover, ΔG PET calculations showed that a PET pathway was not feasible for benzophe-none (ΔG PET = + 28.83 kcal mol À 1 ).…”