Fast-Synthesis of alpha-Phosphonyloxy Ketones as Drug Scaffolds in a Capillary Microreactor

Abstract

A simple, room temperature approach for the fast single-step synthesis of alpha-phosphonyloxy ketone, a drug scaffold, has been developed which involves highly reactive species i.e., 1,2-dicarbonyls that readily react with trialkyl phosphites and formic acids in batch as well as in continuous-flow with the flow rate of 3 ml/min (t (R) = similar to 4 s). The present approach reduced the synthesis time from hours to minutes in batch, which was further lowered to a few seconds precisely controlled by single capillary microfluidics. A wide range of 1,2-dicarbonyl derivatives were smoothly transformed to their corresponding alpha-phosphonyloxy ketones in moderate to good yields (50-82 %) under optimized flow-reaction conditions. Further, the alpha-phosphonyloxy ketones produced can be utilized in batch process to form benzoin, oxazole core, and alpha,alpha '-diarylated carbonyl compounds in 82 %, 50 %, and 54 % yields, respectively, which are alternative key precursors/scaffolds of natural products and active pharmaceutical ingredients (APIs).