Catalytic Generation of α-CF₃ Enolate: Direct Catalytic Asymmetric Mannich-Type Reaction of α-CF₃ Amide

Abstract

The introduction of the CF3 unit is a common strategy for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity. To date, α-CF3 enolates have been a less explored class of nucleophiles because of rapid defluorination. The present study reveals that a designed α-CF3 amide enables a direct asymmetric Mannich-type reaction in a cooperative catalytic system.

The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations

“…Although the strong electron-withdrawing a-trifluoromethyl group is more effective than a-fluorine atom for the stabilization of a carbanion electronically, a-CF 3 carbanions with ''hard'' metal countercations usually readily eliminate a b-fluoride to form gem-difluoroolefins due to the strong metal-fluorine interaction (Scheme 12). 35 This undesired b-fluoride elimination reaction is a main obstacle for effective synthetic application of a-CF 3 carbanions. a-Trifluoromethyl enolates are active nucleophiles for synthesizing CF 3 -bearing functionalized organic molecules.…”

Nucleophilic and Electrophilic Activation of Non‐Heteroaromatic Amides in Atom‐Economical Asymmetric Catalysis

“…Although fluoro‐functionalized carbonyl compounds can be conceived as starting materials to build fluorinated carbon frameworks in the context of enolate‐based carbon–carbon bond‐forming reactions, β‐fluorinated enolates are highly unstable due to rapid defluorination and have met with only partial success when stoichiometric amounts were used to suppress undesired reaction pathways. α‐Trifluoromethyl 7‐azaindoline acetamide 32 c containing β‐fluorine atoms, was particularly effective to catalytically generate its enolate without defluorination by similar Cu I catalysis, which was amenable to coupling with N ‐carbamoylimines in a stereoselective manner . X‐ray analysis of the Cu I /binap complex 43 / 32 c suggested that the fluorine atoms were untouched by Cu I even after the generation of enolates, and the defluorination pathway was significantly retarded.…”

Structural and Computational Investigation of Intramolecular N···H Interactions in α‐ and β‐Fluorinated 7‐Azaindoline Amides

“…Our investigation of the direct catalytic asymmetric Mannich‐type reaction of fluorinated 7‐azaindoline amides 1 – 3 with N ‐Boc‐imines revealed an unanticipated downfield shift of the 1 H NMR signals of the amide α‐protons (H α ) compared with their indoline analogues lacking the 7‐nitrogen (N 7py ) . X‐ray analysis of single crystals revealed unusually short intramolecular N 7py ··· H α distances (Figure )[6b] that are shorter than the sum of the van der Waals (vdW) radii of the individual atoms . Hence, it was proposed that a stabilizing intramolecular N 7py ··· H α interaction locks the conformations of amides 1 – 3 and their corresponding Mannich adducts.…”

“…Fluorinated 7‐azaindoline amides 1 – 3 displaying short intramolecular N 7py ··· H α distances. [6b]…”