CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

Abstract

“The extraordinary instability of such an “ion” accounts for many of the peculiarities of organic reactions” – Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations – carbocations substituted with electron-withdrawing groups – are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF3-substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations.

Controllable Single and Double Difluoromethylene Insertions into C–Cu Bonds: Copper-Mediated Tetrafluoroethylation and Hexafluoropropylation of Aryl Iodides with TMSCF2H and TMSCF2Br

“…Organofluorine compounds have been widely used in pharmaceuticals, agrochemicals, and advanced materials due to their unique physicochemical properties . In this context, the selective introduction of fluoromethyl groups into organic molecules has attracted much attention over the past decades, such as trifluoromethylation, difluoromethylation, and monofluoromethylation . In particular, the difluoromethyl functionality (CF 2 H) is known as a bioisostere of OH and SH groups and as a lipophilic hydrogen bond donor, which has been frequently used in the design of new pharmaceuticals , and agrochemicals .…”

Reactions of linear conjugated dienone structures with arenes under superelectrophilic activation conditions. An experimental and theoretical study of intermediate multicentered electrophilic species

“…Superelectrophilic activation of organic compounds by the action of strong Brønsted and Lewis acids or acidic zeolites is one of the efficient methods for the synthesis of various polyfunctional substances, carbo-and hetero-cycles. [1][2][3][4][5][6][7][8] The activation by protonation (or coordination) of basic centers of organic molecules in Brønsted (or Lewis) acids leads to an intermediate generation of highly reactive multicharged cationic species. Thus, the superelectrophilic activation of alkenes conjugated with electron withdrawing groups, such as carbonyl ones, affords O,C-diprotonated species, which take part in Friedel-Crafts reactions with aromatic nucleophiles (Scheme 1a).…”

Leveraging the Hydroarylation of α-(Trifluoromethyl)styrenes to Access Trifluoromethylated All-Carbon Quaternary Centers

“…15,16 Inspired by those results, our plan was to use such a combination to enable the first catalytic intermolecular hydroarylation of α-(trifluoromethyl)styrenes with readily available arenes as nucleophilic partners, thereby rapidly assembling trifluoromethylated diarylalkanes via the formation of a α-(trifluoromethyl) carbenium. 17 We began our optimization studies with 1,1,1-trifluoromethylstyrene 1a as a model substrate in the presence of TfOH as 1). By using anisole 2a as an arene nucleophile, the target product 3 was obtained in 84% yield in the form of a separable 92:8 mixture of para/ortho regioisomers (Table 1, entry 1).…”

“…While the hydroarylation of unactivated styrenes has been extensively investigated, the hydroarylation of highly electronically deactivated styrenes remains underdeveloped. However, we have recently demonstrated that the acidity of self-assembled hydrogen-bond clusters of hexafluoroisopropanol (HFIP) could be amplified through coordination to a Lewis acid (Ca­(NTf 2 ) 2 / n Bu 4 NPF 6 ) or a Brønsted acid (TfOH) to trigger cationic reactions using highly deactivated substrates. , Inspired by those results, our plan was to use such a combination to enable the first catalytic intermolecular hydroarylation of α-(trifluoromethyl)­styrenes with readily available arenes as nucleophilic partners, thereby rapidly assembling trifluoromethylated diarylalkanes via the formation of a α-(trifluoromethyl) carbenium …”