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，能够选择性地靶向非- 极性π-系统和元素-氢键在共同的极性官能团的存在下。问世 过渡金属催化剂的应用极大地扩展了卡宾转移反应的应用， 自由卡宾的反应性，并能够实现高水平的化学选择性、区域选择性和立体选择性 在催化剂控制下。目前用于催化卡宾转移的方法主要依赖于 从重氮烷烃中挤出N2作为产生金属类卡宾中间体的中心策略。尽管 由于这些方法的综合效用，许多现有技术的方法限于相对狭窄的 重氮乙酸酯及其衍生物的范围，由于需要稳定吸电子 取代基。这项研究计划的总体目标是设计一种新的还原类 使用容易获得且无限期稳定的1，1-二氯烷烃作为卡宾的卡宾转移反应 前体这项工作的主要影响将是使非稳定的催化转移反应， 卡宾等价物，提供直接获得新型合成结构单元的途径，并促进具有挑战性的键合 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 可以被重新利用以实现卡宾型反应性。具体地，1，1-二卤代烷烃的氧化加成 在低价镍催化剂被提出来产生催化剂结合的类卡宾等价物， 在广泛的转变。在这个一般的催化流形下，我们将追求还原 环丙烷化，亚甲基环丙烷化，多组分环加成，环低聚 反应、C（sp2）-H键插入反应和杂原子-H插入反应。的同时 开发合成方法，将进行机理研究，以突出的独特性能， 镍结合类卡宾。总的来说，本提案中描述的方法将使得能够合成新颖的化合物。 生物活性化合物通过提供快速访问特权的子结构。

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.