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

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.

Automated summary

A robust synthesis of Soai-type pyrimidine aldehydes was achieved by controlled formation and quenching of a lithiated pyrimidine intermediate. The optimized rate of n-BuLi addition synchronized with the addition to ethyl formate, resulting in consistently high yields of 2-alkylpyrimidinecarboxaldehydes, which can be used in autocatalysis or as functionalized synthons.