175. “Scope and Mechanism of Asymmetric C(sp³)-H/C(Ar)-X Coupling Reactions: Computational and Experimental Study”
     E. Larionov, M. Nakanishi, D. Katayev, C. Besnard, E.P. Kündig,
     Chem. Sci. 2013, 4, 1995-2005.

Advances in the efficient palladium–NHC catalysed synthesis of highly enantioenriched 2,3-trans-fused and 2-alkyl indolines via asymmetric C(sp³)–H activation of an unactivated methylene/methyl group are reported. Very high asymmetric inductions (up to 99% ee) were achieved at reaction temperatures ranging from 120 to 160 °C. Factors influencing the efficiency of the reaction (halide, pseudohalide, N-protecting group) were investigated. The reaction pathway and enantioselection were probed by detailed density functional theory (DFT) calculations (M06-L functional). The combined theoretical and experimental study shows that the Pd–NHC catalysed C(sp³)–H arylation proceeds via a concerted metalation–deprotonation (CMD) mechanism. The CMD step is shown by DFT calculations and kinetic isotope effect measurements to be selectivity-determining. A good agreement between experimental enantioselectivities and calculated differences amongst diastereomeric activation barriers is observed.

DOI : 10.1039/C3SC00098B 

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