Robust and Scalable Synthesis of Soai Aldehydes via Improved Barbier‐type Halogen−lithium Exchange

Abstract

A robust synthesis of Soai‐type pyrimidine aldehydes proceeds in good to high yields by controlled formation and quenching of a lithiated pyrimidine intermediate. The alkyne‐substituted bromopyrimidine, furnished by Sonogashira cross‐coupling, underwent a Barbier‐type halogen‐lithium exchange to form a transient pyrimidinyl lithium species. The rate of n‐BuLi addition was optimized to better synchronize with the addition to ethyl formate, in order to achieve consistently high yields of 2‐alkylpyrimdinecarboxaldehydes for use in autocatalysis or as functionalized synthons.