Carbonyl Alkylative Amination

叔烷基胺在医药和农用化学品、天然产物和小分子生物探针中的普遍存在，继续激发了人们对其流线型合成的巨大努力。可以说，叔烷基胺合成最可靠的方法是羰基还原胺化：包括两个基本步骤，仲烷基胺与脂肪醛缩合形成全烷基-亚胺离子，由氢化物试剂还原。在这方面，科学家们试图通过将烷基片段与原位生成的烷基-铝离子结合，为该反应的“高阶”变体开发直接策略。然而，尽管经过了70多年的研究，这种“羰基烷基化胺化”的成功实现仍然是难以捉摸的。我们的目标是开发一个实用的和一般的解决方案，这一长期的合成挑战，完成添加烷基自由基到所有的烷基-铝离子。羰基烷基化胺化过程将通过可见光和硅烷还原剂的作用介导，建立一个允许醛和仲胺与烷基卤化物结合的链式过程。这种模块化转化的一个特别显著的特点将是叔胺产品的无偏性，这些产品是由醛和烷基卤化物与各种仲胺的无痕迹结合而产生的。因此，这些种类丰富的原料中固有的结构和功能多样性将促进复杂叔胺产品的流线型合成的通用策略，其中许多产品将通过目前建立的方法生产。

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes continues to stimulate enormous efforts towards their streamlined synthesis. Arguably, the most robust method for tertiary alkylamine synthesis is carbonyl reductive amination: comprising two elementary steps, condensation of a secondary alkylamine with an aliphatic aldehyde forms an all alkyl-iminium ion, which is reduced by a hydride reagent. In this regard, scientists have sought to develop direct strategies for a 'higher order' variant of this reaction via the union of an alkyl fragment with an in-situ generated alkyl-iminium ion. However, despite more than 70 years of research, the successful realization of such a 'carbonyl alkylative amination' has remained elusive. We aim to develop a practical and general solution to this long-standing synthetic challenge, accomplished by addition of alkyl radicals to all alkyl-iminium ions. The carbonyl alkylative amination process will be mediated by the action of visible light and a silane reducing agent, establishing a chain process that permits the combination of aldehydes and secondary amines with alkyl halides. A particularly distinctive feature of this modular transformation will be the unbiased nature of tertiary amine products that arise from the traceless union of aldehyde and alkyl halide building blocks with a wide range of secondary amines. As such, the structural and functional diversity inherent within these classes of abundant feedstocks will facilitate a versatile strategy for the streamlined synthesis of complex tertiary amine products, many of which would be non-trivial to produce via currently established methods.