Wacker Oxidation of Methylenecyclobutanes: Scope and Selectivity in an Unusual Setting

Methylenecyclobutanes are found to undergo Wacker oxidation via a semi-pinacol-type rearrangement. Key to a successful process is the use of tert-butyl nitrite as oxidant, which not only enables efficient catalyst turn-over but also ensures high Markovnikov-selectivity under mild conditions. Thus, cyclopentanones (26 examples) can be accessed in an overall good yield and excellent selectivity (up to 97 % yield, generally >99 : 1 ketone:aldehyde ratio). Stereochemical analysis of the reaction sequence reveals migration aptitudes in line with related 1,2-shifts. By introducing a pyox ligand to palladium, prochiral methylenecyclobutanes can be desymmetrized, thus realizing the first enantioselective Wacker oxidation.

Automated summary

Methylenecyclobutanes can undergo Wacker oxidation via a semi-pinacol-type rearrangement. The use of tert-butyl nitrite as oxidant ensures efficient catalyst turn-over and high Markovnikov-selectivity under mild conditions, leading to the synthesis of cyclopentanones in good yield and excellent selectivity. By introducing a pyox ligand to palladium, the first enantioselective Wacker oxidation of prochiral methylenecyclobutanes is achieved.