of perfluorocarboxylic acids and their metal salts can generate a perfluoroalkyl radical by anodic reaction, which was inspired by Kolbe electrosynthesis (Scheme 2.1) [3, 4]. The perfluoroalkyl radical can be electrophilically added to alkenes, alkynes, and aromatic compounds, and some examples are described below.
Scheme 2.1 Electrochemical generation of perfluoroalkyl radical.
2.2.1.1 Reactions of Alkenes and Alkynes
In 1973, Renaud and Sullivan found that electrochemical oxidation of a mixture of sodium trifluoroacetate and propionate gave a mixture of 3,3,3‐trifluoropropene, 1,2‐bis(trifluoromethyl)ethane, 1,1,2‐tris(trifluoromethyl)ethane, and 1,2,4‐tris(trifluoromethyl)butane (Scheme 2.2) [5]. These products were considered to be produced by addition of the CF3 radical to ethylene formed in situ from propionic acid under electrolysis conditions; this was confirmed by the reaction of ethylene gas with trifluoroacetate [6].
Scheme 2.2 Anodic trifluoromethylation of ethylene formed in situ.
The group of Brookes, Coe, Pedler, and Tatlow reported perfluoroalkylation of alkenes with perfluorocarboxylic acids [7, 8]. They determined the structures of several products obtained by the reaction of alkenes such as non‐substituted terminal alkenes, methyl acrylate, acrylonitrile, and methyl 3‐butenoate with perfluorocarboxylic acid. For example, methyl acrylate gave dimethyl succinate derivatives as major products in most cases via homocoupling of alkyl radicals generated by the reaction of alkene and perfluoroalkyl radical (Scheme 2.3). Notably, β‐perfluoroalkylated methyl acrylate was also isolated as a major product when pentafluorobutanoic acid was used.
On the other hand, cyclopentene did not give the trifluoromethylated product, but instead trifluoroacetoxylation occurred. Furthermore, they also examined the reactivity of 1‐hexyne, but obtained a complex mixture containing 1,1,1‐trifluoro‐2‐heptene (E/Z = 1 : 4) and a vicinal double trifluoromethylated product, 1,1,1‐trifluoro‐3‐(trifluoromethyl)‐2‐heptene. In 1975, Renaud and Champagne independently reported a similar reaction of trifluoroacetic acid with alkenes possessing an ester group, affording the corresponding trifluoromethylated meso‐dimers and vicinal bis‐trifluoromethylated products [9]. They also synthesized ethyl 3,3,3‐trifluoropropionate by decarboxylative electrochemical oxidation of malonic acid monoethyl ester in the presence of trifluoroacetic acid. Dmowski et al. reported the dimer‐forming electrochemical trifluoromethylation of acrylonitrile and crotonitrile in 1997 [10].
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
