A general carbonyl alkylative amination for tertiary amine synthesis
A general carbonyl alkylative amination for tertiary amine synthesis
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DOI：
10.1038/s41586-020-2213-0
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发表时间：
2020-04-08
期刊：
影响因子：
64.8
通讯作者：
Gaunt, Matthew J.
中科院分区：
文献类型：
--
作者：
Kumar, Roopender;Floden, Nils J.;Gaunt, Matthew J.
叔烷基胺在药物和农业化学试剂、天然产物和小分子生物探针（1，2）中的普遍存在刺激了对其简化合成的努力（3-9）。可以说，合成叔烷基胺的最稳健的方法是羰基还原胺化（3），其包括两个基本步骤：仲烷基胺与脂肪族醛缩合以形成全烷基亚胺离子，其随后被氢化物试剂还原。已经通过烷基片段与原位产生的烷基-亚胺离子的偶联来寻求该反应的“高阶”变体的直接策略（10-14）。然而，尽管进行了广泛的努力，但尚未成功实现“羰基烷基化胺化”。在这里，我们提出了一个实用的和一般的合成叔烷基胺通过加成烷基自由基的全烷基亚胺离子。可见光和硅烷还原剂促进了该过程，其触发了不同的自由基引发步骤以建立链过程。这种操作简单、无金属和模块化的转化通过醛和仲胺与烷基卤化物的偶联形成叔胺，而没有结构限制。这些易于获得的前体的结构和功能多样性为复杂叔胺的流线型合成提供了通用和灵活的策略。叔胺的合成通过可见光促进的羰基烷基化胺化反应来实现，其中醛和胺缩合形成亚胺离子，随后与烷基反应。
The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes(1,2) has stimulated efforts towards their streamlined synthesis(3-9). Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination(3), which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ(10-14). However, despite extensive efforts, the successful realization of a 'carbonyl alkylative amination' has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.The synthesis of tertiary amines is achieved through a carbonyl alkylative amination reaction facilitated by visible light, in which an aldehyde and an amine condense to form an iminium ion that subsequently reacts with alkyl radical.