Regioselective access to polycyclic N-heterocycles via homogeneous copper-catalyzed cascade cyclization of allenynes

Abstract

Polycyclic N-heterocycles are important structural motifs commonly found in bioactive compounds, however, their selective construction via the cyclization of allenynes remains challenging yet highly desirable. Here we show a homogeneous copper-catalyzed hetero Diels−Alder (HDA) reaction of allenynes with cis-diazenes (PTAD, 4-phenyl-1,2,4-triazoline-3,5-dione), allowing the practical and efficient synthesis of a diverse array of valuable polycyclic N-heterocycles. A temperature-controlled and stereocontrolled chemoselectivity of the reaction was observed, leading to the chemodivergent synthesis of tetracyclic pyrrolidines, pentacyclic triazepanes and tricyclic pyrrolidines. Compared with related Au-catalyzed cyclization of allenynes, this copper catalysis achieves cyclization of allenynes terminating in C–N bond formation via the HDA reaction.

Copper(I)-Catalyzed Indolyl Ynamide Oxidation/Dearomatization: Divergent and Regioselective Synthesis of Valuable Indoline Scaffolds

“…In 2020, we have disclosed the first example of generation of α-oxo copper carbenes via intermolecular alkyne oxidation, providing regioselectively the cyclopentadiene frameworks and 2-aminofurans . In line with our continuous interest in alkyne transformation, we realized the copper-catalyzed oxidation-initiated cyclopropanation of arene-ynamide, providing a direct way to dearomatized cyclopropane-fused indolines, which is a challenging task since the formation of cyclopropanes via dearomatization of indoles and the controlling of the diastereoselectivity are both difficult (Scheme c). Added to that, this copper-catalyzed arene-ynamide cyclization could also be expanded to the convenient construction of worthy pentacyclic spiroindolines.…”

Copper-Catalyzed Directed Hydroindolation/Annulation Sequence of Alkynes with Indoles via Copper Carbenes

“…Inspired by the results presented above and by our recent study of developing alkyne chemistry for heterocycle synthesis, we envisioned that the catalytic indolylcupration-initiated 6π-electrocyclization reaction of allene-ynamides with indoles might be practicable, thus providing the formation of the expected indole-fused spirobenzo­[ f ]­indole-cyclohexanes (Scheme b). However, achieving this indolylcupration-initiated 6π-electrocyclization, especially with high regio- and stereoselectivity, is highly challenging due to two competing reactions.…”