Carbenes are valuable reactive intermediates in organic synthesis capable of selectively targeting non- polar ?-systems and element?hydrogen bonds in the presence of common polar functional groups. The advent of transition metal catalysis has greatly expanded the utility of carbene transfer reactions, tempering the reactivity of free carbenes and enabling high levels of chemo-, regio-, and stereoselectivity to be achieved under catalyst control. Current methods for catalytic carbene transfer have predominately relied on the extrusion of N2 from diazoalkanes as a central strategy for generating metal carbenoid intermediates. Despite the synthetic utility of these approaches, many state-of-the-art methods are restricted to a relatively narrow scope of diazoacetates, and their derivatives, due to the requirement for stabilizing electron-withdrawing substituents. The overarching goal of this proposed research program is to design a new class of reductive carbene transfer reactions that use readily available and indefinitely stable 1,1-dichloroalkanes as carbene precursors. The primary impact of this work will be to enable catalytic transfer reactions of non-stabilized carbene equivalents, providing direct access to novel synthetic building blocks and facilitating challenging bond constructions. Our central hypothesis is that the elementary steps of transition metal-catalyzed cross-coupling reactions can be re-purposed to enable carbene-type reactivity. Specifically, the oxidative addition of a 1,1-dihaloalkane at a low-valent nickel catalyst is proposed to generate catalyst-bound carbenoid equivalents that can be used in broad range of transformations. Under this general catalytic manifold, we will pursue reductive cyclopropanations, methylene cyclopropanations, multicomponent cycloadditions, cyclooligomerization reactions, C(sp2)?H bonds insertion reactions, and heteroatom?H insertion reactions. In tandem with the development of synthetic methods, mechanistic studies will be conducted to highlight the unique properties of nickel-bound carbenoids. Collectively, the methods described in this proposal will enable the synthesis of novel biologically active compounds by providing rapid access to privileged substructures.
Carbenes are versatile reactive intermediates that have found extensive utility in the synthesis of biologically active compounds relevant to human health. This proposal describes a new catalytic reductive carbene transfer strategy that provides access to powerful cycloaddition and bond insertion methods.
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| Werth, Jacob; Uyeda, Christopher (2018) Regioselective Simmons-Smith-type cyclopropanations of polyalkenes enabled by transition metal catalysis. Chem Sci 9:1604-1609 |
