Direct activation of Csp3–H bonds of alkylbenzenes using palladium catalysis has been investigated. The direct coupling of alkylbenzenes, such as toluene, with a variety of stabilized nucleophiles, including α-aryl-azlactones, α-aryl-malononitriles, and α-aryl-cyanoesters, leads to chemoselective dual-Csp3–H oxidative cross-coupling. The scope of the transformation was found to include electronically and structurally different alkylbenzenes, including methyl-naphthalenes, and methyl-anisoles, among others. Importantly, the use of longer chain alkylbenzenes, such as propylbenzene, yielded functionalization of the terminal Csp3–H bond in a nucleophile dependent manner. The mechanism of this transformation was studied using both experimental and computational approaches to begin elucidating the role of the nucleophile and the palladium catalyst in this unusual Csp3–H selective functionalization of alkylbenzenes. Continuing efforts in this area will utilize rigorous mechanistic investigation to provide a rational and general approach to harnessing palladium catalysis and abundant alkylbenzenes as building blocks for complex small molecule synthesis.

Chemoselective Csp3–H functionalization of alkylbenzenes via palladium catalysis

256th National Meeting (2018)

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