Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer
Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer
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DOI：
10.1038/s41929-021-00652-8
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发表时间：
2021-07-12
期刊：
影响因子：
37.8
通讯作者：
Leonori, Daniele
中科院分区：
文献类型：
--
作者：
Gorski, Bartosz;Barthelemy, Anne-Laure;Leonori, Daniele
尽管卤代烷与氮亲核试剂的亲核取代（S（N）2）是有机化学教学中引入的第一个反应之一，但其实际应用在很大程度上限于无阻碍的（初级）或活化的（α-羰基，苄基）底物。在这里，我们展示了一种替代胺化策略，其中烷基碘被用作自由基前体，而不是亲电试剂。使用α-氨基烷基能够通过卤素原子转移将碘有效转化为相应的烷基，而铜催化在室温下组装sp3 C-N键。该方法提供了S（N）2-样的可编程性，并在几种密集官能化药物的后期官能化中的应用证明了其在制备有价值的N-烷基化药物类似物中的实用性。
Despite the fact that nucleophilic displacement (S(N)2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (alpha-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of alpha-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C-N bonds at room temperature. The process provides S(N)2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues.