Fluoro, Trifluoromethyl, and Trifluoroacetyl Substituent Effects on Cycloaddition Reactivities: Computations and Analysis

Abstract

The importance of fluoro and trifluoromethyl substituents in drug effectiveness prompted the computational exploration of fluorine-containing substituents in valuable synthetic cycloadditions. Diels–Alder or 1,3-dipolar cycloaddition reactions of typical reactants, cyclopentadiene, N-phenyldiazoacetamide, tetrazine, and N-phenylsydnone involving fluorine-containing substituents (F, CF3, and COCF3) were studied with M06-2X density functional theory. Inductive and conjugative effects influence normal and inverse electron-demand reactions differently. These results provide a guide to the design and use of cycloadditions for the introduction of fluoro and trifluoromethyl substituents in synthetic processes.

Pd-catalyzed oxa-[4 + n] dipolar cycloaddition using 1,4-O/C dipole synthons for the synthesis of O-heterocycles

“…The construction of medium-sized gem -difluoromethylene heterocycles is a formidable challenge due to the difficulties arising from medium-sized ring formation 35 and the unexpected properties induced by fluoro-containing functional groups. 36 In 2020, the Shibata group developed a Pd-catalyzed oxa-[4 + 5] dipolar cycloaddition of ADTMCs 1 with di-, mono-, and nonfluoro-oxindoles 60 to afford di-, mono-, and nonfluorinated nine-membered N-heterocyclic lactones 61 (Scheme 19). 37 The reaction proceeded via sequential amide C–N bond cleavage and ring expansion.…”