A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst Enables Highly Enantioselective Suzuki-Miyaura Cross-Coupling Reactions for the Synthesis of Biaryl Atropisomers.

Research paper by Di D Shen, Youjun Y Xu, Shi-Liang SL Shi

Indexed on: 05 Oct '20Published on: 29 Aug '19Published in: Journal of the American Chemical Society


Axially chiral biaryl scaffolds are essential structural units in chemistry. The asymmetric Pd-catalyzed Suzuki-Miyaura cross-coupling reaction has been widely recognized as one of the most practical methods for constructing atropisomers of biaryls. However, longstanding challenges remain in this field. For example, substrate scope is often narrow and specialized, functional groups and heterocycles can lead to reduced reactivity and selectivity, bulky ortho-substituents are usually needed, and reported methods are generally inapplicable to tetra-ortho-substituted biaryls. We have developed an unprecedented highly enantioselective N-heterocyclic carbene (NHC)-Pd catalyzed Suzuki-Miyaura cross-coupling reaction for the synthesis of atropisomeric biaryls. These reactions enable efficient coupling of aryl halides (Br, Cl) or aryl triflates and various types of aryl boron compounds (B(OH)2, Bpin, Bneo, BF3K), tolerate a remarkably broad scope of functional groups and heterocycles (>41 examples), employ low loading of catalyst (0.2-2 mol%), and proceed under mild conditions. The protocol provided general and efficient access to various atropisomeric biaryls and heterobiaryls in excellent enantioselectivities (up to >99% ee) with no need of using bulky ortho-substituted substrates and was effective for the synthesis of tetra-ortho-substituent biaryls. Moreover, the method was successfully applied to the diastereo- and enantioselective synthesis of atropisomeric ternaphthalenes. Critical to the success of the reaction is the development and application of an extremely bulky C2-symmetric chiral NHC, (R,R,R,R)-DTB-SIPE, as the ligand for palladium. To the best of our knowledge, this is the first highly enantioselective (>90% ee) example of a chiral NHC-metal catalyzed C(sp2)-C(sp2) cross-coupling reaction.

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