Metal-free cascade O–H double insertion between I(III)/S(VI)-ylides, carboxylic acids, and alcohols: modular access to unsymmetrical α,α-O,O-substituted ketones

Abstract

The synthesis of unsymmetrical α,α-O,O-substituted ketones via O–H double insertion is appealing but remains constrained due to the lack of compatible coupling partners or uncontrollable selectivity. Herein, we present a cascade O–H double insertion reaction between I^(III)/S^(VI)-ylides, carboxylic acids, and alcohols under metal-free conditions, enabling the modular synthesis of unsymmetrical α,α-O,O-substituted ketones with up to 97% yield and broad scope. Furthermore, cascade double α-acyloxylation of I^(III)/S^(VI)-ylides with two molecular carboxylic acids was established to access an array of symmetrical α,α-diacyloxy ketones. Notably, the synthetic utility of this protocol is demonstrated in a gram-scale reaction and diverse late-stage modification of bioactive molecules and drugs.