α-Hydroxylation of enolizable ketones under continuous flow conditions

Abstract

α-hydroxyketone derivatives are organic scaffolds widely encountered in natural or pharmaceutical active compounds. Many synthetic routes were reported in the literature but within the actual context of developing greener chemical processes, strategies involving transition-metal free synthesis using widely available molecular oxygen as the oxidizing source will be considered. Procedures for the hydroxylation of ketones with molecular oxygen have been already reported in batch but left with quite unresolved safety issues. This work aimed at developing a continuous-flow system allowing the safe hydroxylation of ketone-substrates using the intrinsic properties of flow chemistry. Herein, we report a green and safe continuous flow procedure towards the synthesis of α-hydroxylated ketones. Conditions were first developed on a model substrate, namely, isobutyrophenone. The reaction conditions involved FDA class 3 and Chem21 green solvents, including ethanol and DMSO, as well as reactants presenting a low toxicity profile. Once all parameters were optimized, the conditions were applied to a small library of substrates to assess its efficiency. Enolizable ketones or esters were selected as potential substrates. Our procedure was then used for the synthesis of an important α-hydroxylated ketone intermediate for the preparation of active pharmaceutical ingredient ketamine. This synthesis worked efficiently under our conditions since total conversion and selectivity was achieved. The reaction conditions were next transposed to a larger mesofluidic pilot scale reactor, thus enabling the preparation of 1.3 kg per day with high conversions and selectivity.