Metal-free hydroxylation of tertiary ketones under intensified and scalable continuous flow conditions

An intensified and scalable continuous flow process is presented for the hydroxylation of enolizable tertiary ketones. The procedure relies on molecular oxygen, metal-free conditions and a low toxicity solvent (DMSO). The reaction is optimized on the microfluidic scale with a model ketone substrate (isobutyrophenone) and next extended to a small library of structurally diverse enolizable ketones. High conversion and selectivity are achieved under extremely short residence time. A DFT computational study provides insights on the mechanism and selectivity on various substrates. The scalability of the hydroxylation step is next assessed in a commercial pilot scale continuous flow SiC reactor, hence providing up to 12.5 kg per day of industrially relevant α-ketols with applications ranging from Type I radical photoinitiators to intermediates for the preparation of active pharmaceutical ingredients.