Development and Mechanistic Studies of Ni-Catalyzed Asymmetric Reductive Cross-Coupling Reactions

Citation

Hofstra, Julie Lyn (2019) Development and Mechanistic Studies of Ni-Catalyzed Asymmetric Reductive Cross-Coupling Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/G8M3-CQ05. https://resolver.caltech.edu/CaltechTHESIS:06012019-034543690

Abstract

Cross-coupling reactions have emerged as powerful methods to form carbon-carbon and carbon-heteroatom bonds in a vast array of synthetic contexts. Nickel-catalyzed reductive cross-coupling reactions have opened up a new mode of reactivity, allowing for the cross-coupling of bench-stable electrophiles as both coupling partners. Asymmetric variants, which use a chiral ligand, increase molecular complexity by introducing stereocenters with high levels of enantioselectivity. Application of this methodology to an array of electrophiles has led to the development of a number of transformations incorporating both C(sp²)-hybridized electrophiles (aryl iodides, alkenyl bromides, and acyl chlorides) and C(sp³)-hybridized electrophiles (benzyl chlorides and α-chloronitriles).

Herein we discuss our most recent efforts in the development and application of Ni-catalyzed asymmetric cross-coupling reactions with alkenyl electrophiles. First, the expansion of our previously developed methodology has allowed for bulky trimethylsilyl groups on the benzyl chloride electrophile, providing chiral allylic silane products in good yield and enantioselectivity. The utility of these products with both traditional and newly developed methodology is highlighted. Following this, we describe the development of reaction conditions that proceed with benzyl N-hydroxyphthalimide esters. This approach proceeds through a decarboxylative strategy, generates previously accessible radical intermediates, and proceeds with the use of a homogenous reductant. Our investigations into the mechanism on the cross-coupling of alkenyl bromides and benzyl chlorides is also disclosed, where we first identified the formation of alkenyl chloride and alkenyl iodide intermediates under the reaction conditions. This inspired us to develop a Ni-catalyzed alkenyl triflate halogenation in order to prepare alkenyl halide synthetic intermediates.

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