Transition Metal Catalyzed Reductive Carbene Transfer Reactions

摘要 卡宾是有机合成中有价值的活性中间体，能够选择性地针对非 具有共同极性官能团的极性π体系和元素-氢键。《降临》 过渡金属催化，极大地扩展了卡宾转移反应的用途，回火了 游离卡宾的反应性和实现高水平的化学、区域和立体选择性 在催化剂的控制下。目前催化卡宾转移的方法主要依赖于 从重氮烷中挤出氮气作为生成金属卡宾中间体的中心策略。尽管 这些方法的综合效用，许多最先进的方法被限制在相对狭窄的 重氮乙酸酯及其衍生物的范围，由于稳定电子引出的要求 取代基。这个被提议的研究计划的首要目标是设计一类新的约化 以易得且稳定的1，1-二氯烷烃为卡宾的卡宾转移反应 先驱物。这项工作的主要影响将是使非稳定的催化转移反应成为可能 卡宾的等价物，提供直接访问新的合成构建块并促进具有挑战性的键 建筑。 我们的中心假设是过渡金属催化的交叉偶联反应的基本步骤 可以改变用途以实现卡宾类型的反应性。具体地说，1，1-二卤代烷的氧化加成 提出了一种低价镍催化剂，以产生可使用的催化剂结合的卡宾等效物 在大范围的转变中。在这个一般的催化流形下，我们将追求还原 环丙烷、亚甲基环丙烷、多组分环加成、环齐聚 反应、C(Sp2)-H键插入反应和杂原子-H插入反应。与 开发合成方法，进行机理研究，以突出其独特的性质 镍结合的卡宾。总的来说，本提案中描述的方法将使小说的合成成为可能 通过提供对特权亚结构的快速访问，获得具有生物活性的化合物。

Abstract Carbenes are valuable reactive intermediates in organic synthesis capable of selectively targeting non- polar π-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.