Zhang Zhenhua, Poletti Lorenzo, Leonori Daniele
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, Aachen 52056, Germany.
J Am Chem Soc. 2024 Aug 14;146(32):22424-22430. doi: 10.1021/jacs.4c05487. Epub 2024 Aug 1.
Amide alkylation is a fundamental process in organic chemistry. However, the low nucleophilicity of amides means that divergent coupling with alkyl electrophiles is often not achievable. To circumvent this reactivity challenge, individual amine synthesis followed by amidation with standard coupling agents is generally required. Herein, we demonstrate a radical solution to this challenge by using an amine-borane complex and copper catalysis under oxidative conditions. While borohydride reagents are generally used as reducing agents in ionic chemistry, their conversion into amine-ligated boryl radicals diverts their reactivity toward halogen-atom transfer. This enables the conversion of alkyl halides into the corresponding alkyl radicals for amide functionalization via copper catalysis. The process is applicable to the -alkylation of primary amides employing unactivated alkyl iodides and bromides, and it was also showcased in the late-state functionalization of both complex amide- and halide-containing drugs.
酰胺烷基化是有机化学中的一个基本过程。然而，酰胺的亲核性较低，这意味着与烷基亲电试剂的发散偶联通常难以实现。为了克服这一反应性挑战，通常需要先单独合成胺，然后用标准偶联剂进行酰胺化反应。在此，我们展示了一种通过在氧化条件下使用胺-硼烷配合物和铜催化来应对这一挑战的自由基解决方案。虽然硼氢化物试剂在离子化学中通常用作还原剂，但它们转化为胺连接的硼基自由基会使其反应性转向卤原子转移。这使得卤代烷能够通过铜催化转化为相应的烷基自由基，用于酰胺官能化。该方法适用于使用未活化的烷基碘化物和溴化物对伯酰胺进行α-烷基化反应，并且在含有复杂酰胺和卤化物的药物的后期官能化中也得到了展示。
