Rapid, One-Step Synthesis of α-Ketoacetals via Electrophilic Etherification

Herein, we report a rapid, one-step synthesis of α-ketoacetals via electrophilic etherification of α-alkoxy enolates and monoperoxyacetals. Methyl, primary, and secondary α-ketoacetals were obtained in 44-63% yields from tetrahydropyranyl substrates; using methyl tetrahydropyranyl, alkyl tetrahydropyranyl, or methyl tetrahydrofuranyl peroxyacetals, however, methyl and primary products were isolated in 66-90% yields. The present method is applied to C-O bond formation at tertiary carbons, via alkyl and methyl peroxyacetals, with yields of 25-65%. Intermolecular "alkoxyl" transfer, from peroxyacetal to α-alkoxy enolate, relies heavily on decreased steric bulk surrounding the peroxide bond and site of etherification; additionally, we found the α-OCH₃ group to be critical in ensuring product formation. α-Ketoacetals demonstrated excellent reactivity, as selective, nucleophilic attack at the unprotected carbonyl furnished α-hydroxy acetals in 80-100% yields; subsequent hydrolysis of the foregoing compounds provided α-hydroxy aldehydes in yields of 58-90%.