Iridium-Catalyzed Regio- and Diastereoselective Synthesis of C‑Substituted Piperazines

Piperazine rings
are essential motifs frequently found in commercial
drugs. However, synthetic methodologies are mainly limited to N-substituted piperazines, preventing structural diversity.
Disclosed herein is a straightforward catalytic method for the synthesis
of complex C-substituted piperazines based on an uncommon head-to-head
coupling of easily prepared imines. This 100% atom-economic process
allows the selective formation of a sole diastereoisomer, a broad
substrate scope, and a good functional group tolerance employing a
bench-stable iridium catalyst under mild reaction conditions. Key
to the success is the addition of N-oxides to the
reaction mixture, as they notably enhance the catalytic activity and
selectivity.

哌嗪环（piperazine ring）是一类广泛存在于商业化药物中的核心结构基序。然而，现有合成方法大多局限于N-取代哌嗪，极大限制了产物的结构多样性。本文报道了一种简便的催化合成策略，可通过易于制备的亚胺的非常规头对头偶联反应，构建结构复杂的C-取代哌嗪。该过程具备完全原子经济性，在温和反应条件下，使用常规实验条件下稳定的铱催化剂，可选择性生成单一非对映异构体，同时拥有宽泛的底物适用范围与良好的官能团耐受性。该方法成功的关键在于向反应体系中添加N-氧化物，其可显著提升催化活性与反应选择性。