南昌大学曾小军/山西煤化所何鹏ACS Catal. :铜催化N-氯-N-环丙基酰胺的开环1,3-双官能团化反应

图1. TOC (图片来源于ACS Catal.)

摘要：

The selective functionalization of cyclopropylamines has long remained challenging due to their limited electronic bias and the difficulty of achieving efficient bond polarization. Here, we report a copper-catalyzed chloroamide-directed strategy that enables 1,3-difunctionalization of cyclopropylamides in a single step. This method leverages strain-driven single-electron reduction to generate nitrogen-centered radicals, which undergo rapid β-scission to produce versatile radical intermediates that can be efficiently intercepted by a broad range of nucleophiles. The approach provides modular access to α,γ-difunctionalized amines from simple precursors, features broad substrate scope including late-stage diversification of drug derivatives, and proceeds without the need for strong oxidants. By combining radical reactivity with a directing-group strategy, this atom-economical protocol establishes a general platform for constructing pharmaceutically relevant amine architectures and expands the synthetic utility of cyclopropylamines in synthetic and medicinal chemistry

研究背景：

图2. 研究背景及本策略 (图片来源于ACS Catal.)

研究内容：

图3. 条件优化 (图片来源于ACS Catal.)

图4. 酰胺底物范围 (图片来源于ACS Catal.)

图5. 炔烃、硅基及氰基底物范围 (图片来源于ACS Catal.)

图6. 合成应用 (图片来源于ACS Catal.)

图7. 机理研究 (图片来源于ACS Catal.)

总结：

In summary, we have developed a practical copper-catalyzed ring-opening difunctionalization of cyclopropylamides, providing streamlined access to α,γ-difunctionalized amines. The method exhibits high selectivity, broad substrate scope, and compatibility with diverse nucleophiles, such as amines, alkynes, silanes, and cyanides, under mild conditions. Its applicability to pharmaceuticals underscores its potential for late-stage diversification. By leveraging the dual reactivity of N–Cl bonds, this protocol achieves improved atom economy and expands the synthetic repertoire for constructing pharmaceutically relevant nitrogen scaffolds. We anticipate that this approach will inspire further applications in both synthetic methodology and medicinal chemistry.

文献信息：

DOI: https://doi.org/10.1021/acscatal.6c01703

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