Scheme 2.3 Perfluoroalkylation of methyl acrylate.
Renaud extensively studied the electrochemical trifluoromethylation of alkenes, using mono‐ and disubstituted alkenes and heterocyclic alkenes [11]. In contrast to acyclic alkenes such as methyl vinyl ketone, vinyl acetate, diethyl fumarate, and diethyl maleate, which gave the dimer as the major product, heterocyclic alkenes such as N‐ethylmaleimide and 2,5‐dihydrothiophene 1,1‐dioxide efficiently afforded the vicinal bis‐trifluoromethylated products (Scheme 2.4a). They also succeeded in demonstrating an intramolecular carbo‐trifluoromethylation via radical cyclization of bis‐alkenes bearing ester groups (Scheme 2.4b) [12]. Grinberg's group performed electrolysis of sodium trifluoroacetate in the presence of the dimethyl ester of maleic acid, obtaining the corresponding bis‐trifluoromethylated product and the trifluoromethylated dimer [13]. They also examined the influence of the current density on the product yields and selectivity, finding that an increase of the current density reduced the yields of the trifluoromethylated products without significantly changing the product ratio and facilitated the formation of hexafluoroethane (C2F6).
Scheme 2.4 (a) Vicinal bis‐trifluoromethylation and (b) carbo‐trifluoromethylation.
From the viewpoint of synthesizing new trifluoromethylated molecules, bis‐trifluoromethylated products could be a good building block; for example, Muller reported the derivatization of a bis‐trifluoromethylated product, 2‐(trifluoromethyl)‐4,4,4‐trifluorobutyric acid, obtained by the anodic trifluoromethylation of acrylic acid (Scheme 2.5) [14]. The trifluoromethyl group at the α‐position of the carboxylic acid was hydrolyzed selectively to a carboxyl group under basic conditions, and the obtained malonic acid was transformed into a barbital analog in several steps.
Scheme 2.5 Synthesis of a barbital analog using a bis‐trifluoromethylated product.
Uneyama et al. demonstrated the synthetic utility of a bis‐trifluoromethylated amide prepared by anodic trifluoromethylation of acrylamide with trifluoroacetic acid, successfully generating cyanoester, amino acid, and β‐lactam analogs (Scheme 2.6) [15, 16]. In the above early reports, the products of electrochemical trifluoromethylation of alkenes using trifluoroacetic acid were usually limited to bis‐trifluoromethylated products or trifluoromethylated dimeric products. Muller overcame this limitation, achieving the synthesis of mono‐trifluoromethylated products by means of anodic trifluoromethylation (Scheme 2.7) [17]. When isopropenyl acetate was employed in electrochemical trifluoromethylation with trifluoroacetic acid in the presence of sodium hydroxide, 4,4,4‐trifluoro‐2‐butanone was efficiently obtained [17a]. In addition, 12,12,12‐trifluorododecanoic acid [17b] and 4,4,4‐trifluorobutanal [17c] were synthesized from undecylenic acid and allyl alcohol, respectively.
Scheme 2.6 Utility of bis‐trifluoromethylated amide. as a synthetic building block
Uneyama greatly advanced the electrochemical perfluoroalkylation reaction of alkenes using carboxylic acids [18]. In 1988, he applied enolate chemistry to anodic electrophilic trifluoromethylation; electrochemically generated trifluoromethyl radical was added to an enol formed in situ from β‐ketoester (Scheme 2.8a) [19]. While the reaction at 60 °C gave α‐trifluoromethylated β‐ketoester in 31% yield as the sole product, interestingly, the α‐trifluoromethylated ester was generated via elimination of acetic acid at −40 °C. In addition, the use of enol acetate instead of the ketoester substrate was found to give trifluoromethylated β‐ketoester exclusively in better yield (Scheme 2.8b), which suggests that the acetate group is a better leaving group to facilitate the C—O bond cleavage. Uneyama also reported pioneering work on bifunctionalization‐type perfluoroalkylation reactions [20]. In 1988, amino‐trifluoromethylation of methyl methacrylate with trifluoroacetic acid under basic conditions was developed (Scheme 2.9a) [20a], in which trifluoromethyl and acetamide groups were installed simultaneously in an acetonitrile–H2O cosolvent system. Notably, the dimeric product was not obtained under these conditions.
Scheme 2.7 Mono‐trifluoromethylations of alkenes.
Scheme 2.8 Application of enolate chemistry; reactions of (a) β‐ketoester (b) enol acetate.
Scheme 2.9 Bifunctionalization‐type trifluoromethylations.
He then reported hydro‐trifluoromethylation of fumaronitrile [20b] and dialkyl fumarates [20c] (Scheme 2.9b). The hydrogen atom was proposed to come from the water cosolvent via protonation of an anionic intermediate. Furthermore oxy‐trifluoromethylations affording alcohol [20d] and ketone [20e] products were developed (Scheme 2.9c). In the reaction, water and oxygen were utilized as oxygen sources for the bifunctionalization‐type trifluoromethylation. These conditions of electrochemical trifluoromethylation could be applied to perfluoroalkylations of electron‐deficient alkenes with perfluoroalkanoic acids (RfCO2H: Rf = CF3, C3F7, C7F15, CHF2, and CH2F) [20d].
In 1996, Dmowski and Biernacki found that electrochemical trifluoromethylation of 2,5‐dihydrothiophene 1,1‐dioxide in H2O