<i>syn</i>-Selective Construction of Fused Heterocycles by Catalytic Reductive Tandem Functionalization of N‑Heteroarenes

To date, numerous methods have been successfully developed to functionalize N-heteroaryl C–H bonds. In contrast, dearomative tandem functionalization of N-heteroarenes is still a subject to be explored. Reported herein is an example on reductive dearomatization-induced tandem functionalization of N-heteroarenes by ruthenium catalysis, which offers a general method for diastereoselective construction of fused heterocycles featuring a cyclic syn-N, O-acetal motif from N-heteroarenes, phenols, and paraformaldehyde. Mechanistic study reveals that the products are formed via a tandem sequence of pyridyl C3-benzylation and hydroxymethylation followed by C2-aryloxylation of N-heteroarenium salts, proceeding with broad substrate scope, good functional group tolerance, high atom efficiency, and applicability for postfunctionalization of some biomedical molecules.迄今为止，学界已成功开发出多种可实现氮杂芳基C-H键（N-heteroaryl C–H bonds）官能化的方法。相较而言，氮杂芳烃（N-heteroarenes）的去芳构化串联官能化仍有待深入探索。本文报道一例钌催化（ruthenium catalysis）下基于还原去芳构化（reductive dearomatization）诱导的氮杂芳烃串联官能化反应，该方法可从氮杂芳烃、苯酚（phenols）与多聚甲醛（paraformaldehyde）出发，非对映选择性构建带有环状syn-N,O-缩醛骨架的稠合杂环（fused heterocycles），具备良好的普适性。机理研究表明，目标产物通过氮杂芳烃鎓盐（N-heteroarenium salts）的吡啶基C3位苄基化、羟甲基化，继而发生C2位芳氧基化的串联过程生成；该反应底物适用范围广、官能团兼容性优异、原子经济性高，且可用于部分生物医学分子的后功能化。