The Acyl Effect on Intramolecular Palladium-Catalyzed Trimethylenemethane Cycloadditions

Article abstract of DOI:10.1021/jo00028a052

Enhancing the generality of the intramolecular palladium-catalyzed <3 + 2> cycloaddition involving trimethylenemethane complexes as reactive intermediates is possible by incorporation of acyl substituents on the TMM unit.Such substituted TMM-PdL2 species greatly expand the scope such that bicyclo<3.3.0>octyl, bicyclo<4.3.0>nonyl, and bicyclo<5.3.0>decyl ring systems all can be created.Furthermore, the acyl-TMM chemistry permits incorporation of a bridgehead methyl substituent - the first example of a TMM-PdL2 cycloaddition in synthetically useful yields initiated byattack of a tertiary carbon in the first step to give a quaternary center.The requisite substrates are readily available using nucleophilic acylations via lithiated thioacetals.A general lynchpin strategy derives from bis(methylthio)methane onto which can be attached both the donor and acceptor partners of the cycloaddition. 2-((Trimethylsilyl)methyl)propenal serves as a convenient conjunctive reagent to introduce the donor partner.Alternatively 2-acyldithianes serve as a lynchpin to build substrates leading to bicycles bearing bridgehead substituents.In this case, 2-bromo-3-(trimethylsilyl)propene serves as a convenient conjunctive reagent to create the donor partner.The beneficial effect of acyl substitution derives from a combination of inhibiting side reactions derived from protodesilylation processes and facilitating the initial step of this nonconcerted cycloaddition.In addition to improving the generality of the intramolecular process, the ketone group that results in the product is a powerful functionality for further structural elaboration.