Functionalization of 2‐Trifluoromethyl‐1H‐pyrrole: A Convenient Entry into Advanced Fluorinated Building Blocks Including all Isomeric 2‐(Trifluoromethyl)prolines

Abstract

The synthetic utility of 2‐trifluoromethyl‐1H‐pyrrole as a pharmaceutically relevant platform was demonstrated by the preparation of mono‐ and bifunctional C‐2(5)‐ or C‐3‐substituted derivatives, i.e. regioisomeric sulfonyl halides, carboxylic acids, aldehydes, and nitriles. A series of modifications relied on lithiation or electrophilic substitution, which proceeded regioselectively on multigram scale, mostly in protecting‐group‐free mode. Subsequent catalytic hydrogenation of the pyrrole ring was also performed for synthesis of all isomeric 2‐trifluoromethyl α‐ and β‐prolines. These derivatives were considered as promising low‐molecular‐weight building blocks for synthesis, drug discovery, and agrochemistry.