Fine Design of Photoredox Systems for Catalytic Fluoromethylation of Carbon–Carbon Multiple Bonds

• Published in: Accounts of chemical research Vol. 49; no. 9; pp. 1937 - 1945
• Main Authors: Koike, Takashi, Akita, Munetaka
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20.09.2016
• DOI: 10.1021/acs.accounts.6b00268
• ISSN: 0001-4842

Trifluoromethyl (CF3) and difluoromethyl (CF2H) groups are versatile structural motifs, especially in the fields of pharmaceuticals and agrochemicals. Thus, the development of new protocols for tri- and difluoromethylation of various skeletons has become a vital subject to be studied in the field of synthetic organic chemistry. For the past decades, a variety of fluoromethylating reagents have been developed. In particular, bench-stable and easy-to-use electrophilic fluoromethylating reagents such as the Umemoto, Yagupolskii–Umemoto, Togni, and Hu reagents serve as excellent fluoromethyl sources for ionic and carbenoid reactions. Importantly, the action of catalysis has become a promising strategy for developing new fluoromethylations. For the past several years, photoredox catalysis has emerged as a useful tool for radical reactions through visible-light-induced single-electron-transfer (SET) processes. Commonly used photocatalysts such as [Ru­(bpy)3]2+ and fac-[Ir­(ppy)3] (bpy = 2,2′-bipyridine; ppy = 2-pyridylphenyl) have potential as one-electron reductants strong enough to reduce those fluoromethylating reagents, resulting in facile generation of the corresponding fluoromethyl radicals. Therefore, if we can design proper reaction systems, efficient and selective radical fluoromethylation would proceed without any sacrificial redox agents, i.e., via a redox-neutral process under mild reaction conditions: irradiation with visible light, including sunlight, below room temperature. It should be noted that examples of catalytic fluoromethylation of compounds with carbon–carbon multiple bonds have been limited until recent years. In this Account, we will focus on our recent research on photoredox-catalyzed fluoromethylation of carbon–carbon multiple bonds. First, choices of the photocatalyst and the fluoromethylating reagent and the basic concept involving a redox-neutral oxidative quenching cycle are explained. Then photocatalytic trifluoromethylation of olefins is discussed mainly. Trifluoromethylative difunctionalization reactions, i.e., simultaneous introduction of the CF3 group and a different functional group across carbon–carbon double bonds, are in the middle of the discussion. Oxy-, amino-, and ketotrifluoromethylation allow us to synthesize various organofluorine compounds bearing C­(sp3)–CF3 bonds. In addition, the synthesis of valuable trifluoromethylated alkenes is also viable when the olefins have an appropriate leaving group or undergo deprotonation. The present reaction system features high functional group compatibility and high regioselectivity. Furthermore, future prospects, especially trifluoromethylative difunctionalization of alkynes and difluoromethylation of alkenes, are also discussed.