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

• Published in: Chemical science (Cambridge) Vol. 4; no. 5; pp. 1995 - 2005
• Main Authors: Larionov, Evgeny, Nakanishi, Masafumi, Katayev, Dmitry, Besnard, Celine, Kuendig, EPeter
• Format: Journal Article
• Language: English
• Published: 01.01.2013
• Subjects: Activation; Asymmetry; Computational efficiency; Density functional theory; Isotope effect; Joining; Mathematical analysis; Synthesis
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c3sc00098b

Advances in the efficient palladium-NHC catalysed synthesis of highly enantioenriched 2,3-trans-fused and 2-alkyl indolines viaasymmetric C(sp super(3))-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 degree 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(sp super(3))-H arylation proceeds viaa 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.