Copper-Catalyzed Aza-Sonogashira Cross-Coupling To Form Ynimines: Development and Application to the Synthesis of Heterocycles

Nitrogen-substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper-catalyzed synthesis of ynimines from readily available O-acetyl ketoximes and terminal alkynes. A wide range of O-acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross-coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.

Automated summary

A versatile copper-catalyzed synthesis of ynimines from readily available O-acetyl ketoximes and terminal alkynes has been developed, leading to the synthesis of medicinally important heterocycles.