In situ generation and reactions of p-(trifluoromethyl)benzyl electrophiles: an efficient access to p-(trifluoromethyl)benzyl compounds

Abstract

A new three-component reaction, namely condensation-anti-Michael addition-aromatization, enabling the construction of benzylic compounds is disclosed. This reaction can not only act as an alternative approach to regioselective Csp-H trifluoromethylation of arenes through an "aromatic to be" strategy, but also provides a simple, convenient, step-economic, and practical strategy for the in situ generation of electrophilic p-(trifluoromethyl)benzyl species under extremely mild conditions.

Calcium(II)‐Catalyzed Intermolecular Hydroarylation of Deactivated Styrenes in Hexafluoroisopropanol

“…As a result, the synthesis of diaryl alkanes incorporating strongly electron withdrawing groups is difficult, thus denying access to potentially useful compounds. Only a handful of methods to generate these types of frameworks have been developed, all of which bear their own limitations . For example, McCubbin, Hall, and co‐workers reported an elegant Friedel–Crafts alkylation of deactivated benzylic alcohols featuring the use of a ferroceniumboronic acid as a catalyst (Scheme a), while focusing mainly on the preparation of diaryl methanes.…”

“…However, their transformation could not be conducted in the presence of heteroaromatic and anisole derivatives. Another variant based on the preactivation of a quinone derivative was disclosed by Liu, Pan, and co‐workers (Scheme c), but the reaction is limited to a trifluoromethyl substituent and requires a large amount of a Lewis acid as a promoter.…”

“…[2] However,t hese approaches have am ajor drawback:T he presence of electron-donating groups or, at best, moderately electron withdrawing groups on the aromatic ring is usually necessary to trigger the reaction, although in some cases this limitation can be overcome with tailor-made transition-metalbased systems. [4][5][6][7][8] Fore xample,M cCubbin, Hall, and coworkers reported an elegant Friedel-Crafts alkylation of deactivated benzylic alcohols featuring the use of af erroceniumboronic acid as acatalyst (Scheme 1a), [4] while focusing mainly on the preparation of diaryl methanes.I nt erms of reactivity,amajor advance was made by the Moran group, who used TfOH (Tf = trifluoromethanesulfonyl) as acatalyst in hexafluoroisopropanol (HFIP), which enabled the Friedel-Crafts reaction of highly deactivated benzylic alcohols (Scheme 1b). Only ah andful of methods to generate these types of frameworks have been developed, all of which bear their own limitations.…”

“…[3] As ar esult, the synthesis of diaryl alkanes incorporating strongly electron withdrawing groups is difficult, thus denying access to potentially useful compounds. [5] However,t heir transformation could not be conducted in the presence of heteroaromatic and anisole derivatives.A nother variant based on the preactivation of aq uinone derivative was disclosed by Liu, Pan, and coworkers (Scheme 1c), [6] but the reaction is limited to at rifluoromethyl substituent and requires al arge amount of aLewis acid as apromoter. [4][5][6][7][8] Fore xample,M cCubbin, Hall, and coworkers reported an elegant Friedel-Crafts alkylation of deactivated benzylic alcohols featuring the use of af erroceniumboronic acid as acatalyst (Scheme 1a), [4] while focusing mainly on the preparation of diaryl methanes.I nt erms of reactivity,amajor advance was made by the Moran group, who used TfOH (Tf = trifluoromethanesulfonyl) as acatalyst in hexafluoroisopropanol (HFIP), which enabled the Friedel-Crafts reaction of highly deactivated benzylic alcohols (Scheme 1b).…”

“…Only ah andful of methods to generate these types of frameworks have been developed, all of which bear their own limitations. [4][5][6][7][8] Fore xample,M cCubbin, Hall, and coworkers reported an elegant Friedel-Crafts alkylation of deactivated benzylic alcohols featuring the use of af erroceniumboronic acid as acatalyst (Scheme 1a), [4] while focusing mainly on the preparation of diaryl methanes.I nt erms of reactivity,amajor advance was made by the Moran group, who used TfOH (Tf = trifluoromethanesulfonyl) as acatalyst in hexafluoroisopropanol (HFIP), which enabled the Friedel-Crafts reaction of highly deactivated benzylic alcohols (Scheme 1b). [5] However,t heir transformation could not be conducted in the presence of heteroaromatic and anisole derivatives.A nother variant based on the preactivation of aq uinone derivative was disclosed by Liu, Pan, and coworkers (Scheme 1c), [6] but the reaction is limited to at rifluoromethyl substituent and requires al arge amount of aLewis acid as apromoter.…”