Palladium–N‐Heterocyclic Carbene (NHC)‐Catalyzed Asymmetric Synthesis of Indolines through Regiodivergent C(sp³)H Activation: Scope and DFT Study

Abstract

Two bulky, chiral, monodentate N‐heterocyclic carbene ligands were applied to palladium‐catalyzed asymmetric CH arylation to incorporate C(sp3)H bond activation. Racemic mixtures of the carbamate starting materials underwent regiodivergent reactions to afford different trans‐2,3‐substituted indolines. Although this CArCalkyl coupling requires high temperatures (140–160 °C), chiral induction is high. This regiodivergent reaction, when carried out with enantiopure starting materials, can lead to single structurally different enantiopure products, depending on the catalyst chirality. The CH activation at a tertiary center was realized only in the case of a cyclopropyl group. No CH activation takes place alpha to a tertiary center. A detailed DFT study is included and analyses of methyl versus methylene versus methine CH activation is used to rationalize experimentally observed regio‐ and enantioselectivities.

Chiral N‐Heterocyclic Carbene Ligands Enable Asymmetric C−H Bond Functionalization

“…Later, the same group reported a regiodivergent synthetic approach to indolines using a similar catalytic system (Scheme 2). [28,29] The asymmetric CÀH annulation of racemic carbamate substrates led to the formation of two different indolines with high enantio-induction. Enantiomers interacted with the chiral catalyst differently, providing for each a regioselective product accordingly (Scheme 2).…”

“…Later, the same group reported a regiodivergent synthetic approach to indolines using a similar catalytic system (Scheme ) . The asymmetric C−H annulation of racemic carbamate substrates led to the formation of two different indolines with high enantio‐induction.…”

Balzan Prize: R. Jahn / Honorary Membership of the Swiss Chemical Society: E. P. Kündig / KNCV Van Marumpenning: J. van Maarseveen / Emil Kirschbaum Medal: A. Seidel‐Morgenstern

“…Kündig's research interests are focused on organic synthesis and catalysis with transition metals. His report on the synthesis of indoles catalyzed by palladium–N‐heterocyclic carbenes was featured on the cover of Chemistry—A European Journal , and he is co‐author of a report in Angewandte Chemie on arene–ruthenium complexes . Kündig was on the International Advisory Board of Chemistry—An Asian Journal from its launch in 2006 until 2013, and is on the International Advisory Board of Helvetica Chimica Acta , which was founded by the SCS and is published by Wiley‐VHCA AG.…”

Recent advances in the application of group-10 transition metal based catalysts in C–H activation and functionalization

“…With the help of this method, pinamine derivatives with a range of functionalities can be arylated easily.N-heterocyclic carbene (NHC)-containing catalytic systems have been thoroughly exploited for activation and functionalization. The use of NHC ligands with different metal partners often produces valuable enantio-enriched substituted indolines and azaindolines[48,49]. Kündig et al[49] studied the detailed scope and limitations of Pd-NHC-catalyzed complexes in asymmetric C(sp 3 )−H activation (Scheme 23).…”

“…The use of NHC ligands with different metal partners often produces valuable enantio-enriched substituted indolines and azaindolines[48,49]. Kündig et al[49] studied the detailed scope and limitations of Pd-NHC-catalyzed complexes in asymmetric C(sp 3 )−H activation (Scheme 23). The authors used racemic mixtures of the carbamate which underwent regiodivergent reactions to afford single regioisomeric, enantiopure trans-2,3-substituted indolines with high chiral induction.…”