Issue 5, 2013

Scope and mechanism of asymmetric C(sp3)–H/C(Ar)–X coupling reactions: computational and experimental study

Abstract

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.

Graphical abstract: Scope and mechanism of asymmetric C(sp3)–H/C(Ar)–X coupling reactions: computational and experimental study

Supplementary files

Article information

Article type
Edge Article
Submitted
11 Jan 2013
Accepted
25 Feb 2013
First published
25 Feb 2013

Chem. Sci., 2013,4, 1995-2005

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 and E. P. Kündig, Chem. Sci., 2013, 4, 1995 DOI: 10.1039/C3SC00098B

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