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

Abstract

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.

Keywords: 1,2-Rearrangment; Desymmetrization; Strained Rings; Wacker Oxidation.

Scheme 1

Current scope and limitations of the Wacker oxidation. FG=functional group.

Scheme 2

Mechanistic hypothesis for the key rearrangement of the Wacker oxidation of 1,1‐disubstituted alkenes.

Scheme 3

Labelling experiments to probe the mechanistic hypothesis.

Scheme 4

Reactions were run in EtOH [0.1 M] on a 0.3 mmol scale using 5 mol % of catalyst, 1 equiv of tBuONO, and 30 equiv of H₂O. [a] Minor amounts of the respective aldehyde were formed for this substrate. [b] Reaction run at a 0.18 mmol scale. [c] Isolated as ketone:hemiketal mixture (66 : 34 ratio).

Scheme 5

Selectivity analysis of the Wacker oxidation including a) alkene‐tethered, b) α‐substituted, and c) prochiral methylenecyclobutanes. Yield of the crude reaction mixture is given in paranthesis and was determined by ¹H NMR using mesitylene as an internal standard. [a] regioisomeric ratio was determined from the crude reaction mixture by ¹H NMR spectroscopy. [b] Enantiomeric ratio was determined by HPLC using a chiral column.