Nickel-catalyzed intermolecular oxidative Heck arylation driven by transfer hydrogenation

Abstract

The conventional oxidative Heck reaction between aryl boronic acids and alkenes typically involved the Pd^II/Pd⁰/Pd^II catalytic cycle incorporating an external oxidant and often suffered C=C bond isomerization for internal alkyl-substituted alkenes via chain-walking. Herein, we demonstrate that the regioselectivity (γ-selectivity vs. δ-selectivity) and pathway selectivity (hydroarylation vs. oxidative Heck coupling) of a directed Ni-catalyzed alkene arylation can be controlled by judicious tuning of the coordination environment around the nickel catalyst via optimization of an appropriate phosphine ligand and directing group. In this way, the Ni(0)-catalyzed oxidative Heck arylation that relies on transfer hydrogenation of an acceptor olefin is developed with excellent E/Z selectivity and regioselectivity. Mechanistic investigations suggest that the addition of the acceptor is crucial for lowering the energy for carbometalation and for enabling catalytic turnover.

Fig. 1

Inspiration and motivation for the present study. a Catalytic cycle for previously reported Ni-catalyzed hydroarylation reaction. b Envisioned oxidative Heck reaction. c Relevant biologically active compounds containing γ-aryl carboxylic acid substructure

Fig. 2

Synthesis of key intermediates towards natural products. a The application of hydroarylation to approach the key intermediates in the synthesis of the natural products. b The application of oxidative Heck coupling toward the key intermediate in the synthesis of the natural product curcudiol

Fig. 3

Experiments to elucidate Heck coupling mechanism. a Control experiments establishing the need for the AQ-directing group in both hydroarylation and Heck coupling. b The role of the compound A18. c The importance of aryl boronic acid in alkene insertion. d The reaction with δ,δ-di-deuterated alkene 1a-d₂. e Deuteration experiments in t-BuOD

Fig. 4

A series of experiments to study the mechanism of the γ-selective hydroarylation. a The control experiment in the absence of arylboronic acid. b The monitoring of the alkene substrate in hydroarylation for 5 h. c Deuterium incorporation into isomerized alkene. d The hydroarylation reaction in the presence of the compound A18 for 5 h. e The reaction by use of PnBu₃ as the ligand for 5 h

Fig. 5

DFT calculations for reaction mechanism. a Proposed catalytic cycle with free energies computed by DFT (kcal mol⁻¹). b Structures of transition states TS1A, TS1B, TS2A, and TS2B