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.

Recent Advances in Functionalization of Pyrroles and their Translational Potential

“…Regardless of generation of a combination of α‐ and β‐regioisomers in ca . 1 : 2 ratio, easy separation of building blocks could be made via column chromatography with respective isolable yields of 24 % and 47 %, and, the observations could as well be extended up to 50 g scale [133] …”

“…The one pot preparation of sulfonylated pyrrole was proficiently investigated by Grygorenko and collaborators in 2020 (Scheme 131). [133] The synthetic prevalance of 2‐trifluoromethyl‐1H‐pyrrole as a chemically important entity was evidenced by the synthesis of regioisomeric sulfonyl halides, mono‐ and bifunctional C‐2(5)‐ or C‐3‐substituted pyrroles. A progression of changes laid on lithiation or electrophilic substitution continued regioselectively on multigram scale and for the most part in ensuring protecting group free manner.…”

“…For streamlined partition from the tar formed, the sequential quenching with aq K 2 CO 3 was experimented at 0 °C which gave sulfonylated potassium salt (24 % yield) having restricted dissolvability in non‐polar solvents. At last, the reaction of sulfonylated pyrrole with SOCl 2 in DMF brought about the objective subordinate in 86 % yield on extending up to 40 g scope after recrystallization from hexanes – EtOAc (4 : 1, v/v) [133] …”

Fluorine-Containing Prolines: Synthetic Strategies, Applications, and Opportunities

“…From the mechanistic standpoint, the redox-active complex 285 formed first, which In 2020, Grygorenko and co-workers from Enamine reported on a practical gram-scale synthesis of racemic cis-5-trifluoromethyl proline. 145 Reaction of pyrrole (288) with CF 3 I and Fenton's reagent (FeSO 4 /H 2 O 2 /H 2 SO 4 ) 146 gave the trifluoromethylated derivative 289 in 76% yield (Scheme 49). N-Boc protection, followed by treatment with butyl lithium and carbon dioxide, gave acid 290 in 57% yield.…”

Enantiopure 5-CF3–Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry

“…However, to control the trans / cis isomerization, the incorporation of a trifluoromethyl group in position 5 is clearly the most strategic position. In Scheme are presented several strategies reported in the literature for the synthesis of racemic cis -5-CF 3 -proline. − Although we already reported the syntheses of enantiopure cis - and trans -5-CF 3 -prolines, these syntheses were long and required several tedious diastereomers separations . We present herein a straightforward synthesis of enantiopure 5-CF 3 -proline, a methodological study of its unreported incorporation in a peptide chain in solution or by solid-phase peptide synthesis (SPPS), as well as a thermodynamic study of the trans / cis isomerization of the amide bond.…”