Synthesis of Tri‐ and Difluoromethoxylated Compounds by Visible‐Light Photoredox Catalysis

Abstract

Trifluoromethoxy (OCF3) and difluoromethoxy (OCF2H) groups are fluorinated structural motifs that exhibit unique physicochemical characteristics. Incorporation of these substituents into organic molecules is a highly desirable approach used in medicinal chemistry and drug discovery processes to alter the properties of a parent compound. Recently, tri‐ and difluoromethyl ethers have received increasing attention and several innovative strategies to access these valuable functional groups have been developed. The focus of this Minireview is the use of visible‐light photoredox catalysis in the synthesis of tri‐ and difluoromethyl ethers. Recent photocatalytic strategies for the formation of O−CF3, C−OCF3, O−CF2H, and C−OCF2H bonds as well as other transformations leading to the construction of ORF groups are discussed herein.

Direct Trifluoromethylation of Alcohols Using a Hypervalent Iodosulfoximine Reagent

“…In the field of organofluorine chemistry, research efforts towards accessing trifluoromethyl ethers (OCF 3 ) have never moved faster or more relentlessly than in the last decade. This is evidenced by the emergence of five new trifluoromethoxylating reagents in the past three years alone, [1–5] with several review articles appearing alongside to keep up with the ever‐growing body of synthetic methodologies [6–10] . The pronounced interest in this group is due to its high lipophilicity (Hansch parameter: π =+1.04) [11] relative to CF 3 and F, high electronegativity (Pauling's electronegativity scale: χ =3.7), [12] good metabolic stability and unique conformational properties [13] .…”

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

“…The introduction of a trifluoromethoxy (OCF 3 ) group into a molecule can improve its metabolic stability and membrane permeability. Some strategies for the synthesis of trifluoromethoxylated compounds have been reviewed: Poisson [209] and Billard [210] discussed the recent advances toward the synthesis of OCF 3 -containing molecules; Hopkinson [211] depicted a radical revolution for trifluoromethoxylation; recently, Ngai [212] summarized some photoredox-based approaches to form tri- and difluoromethoxylated compounds. Despite the great interest in this functional group, only a few transition-metal-catalyzed methods have been developed for the synthesis of trifluoromethoxylated compounds over the past decade.…”

Progress in Photoinduced Radical Reactions using Electron Donor‐Acceptor Complexes

“…[11][12][13][14][15] These photochemical transformations were successfully accomplished via an oxidative quenching cycle or a reductive quenching cycle. [16][17][18][19][20] On the other hand, if the ground state substrates contain an electron donor (D) and an acceptor (A), which can form an electron donor-acceptor (EDA) complex via the diffusion event. [21,22] The EDA complex can harvest the energy of light.…”