Photoredox-Mediated, Nickel-Catalyzed Trifluoromethylthiolation of Aryl and Heteroaryl Iodides

Abstract

While trifluoromethylthiolation of aryl halides has been extensively explored, the current methods require complex and/or air-sensitive catalysts. Reported here is a method employing a bench-stable Ni(II) salt and an iridium photocatalyst that can mediate the trifluoromethylthiolation of a wide range of electronically diverse aryl and heteroaryl iodides, likely via a Ni(I)/Ni(III) catalytic cycle. The reaction has broad functional group tolerance and potential for application in medicinal chemistry, as demonstrated by a late-stage functionalization approach to access (racemic)-Monepantel.

Halide Noninnocence and Direct Photoreduction of Ni(II) Enables Coupling of Aryl Chlorides in Dual Catalytic, Carbon–Heteroatom Bond-Forming Reactions

“…6 In addition, with a small change in reaction conditions, SCF 3 nucleophiles became effective, with 60 examples demonstrated. 7 This universality of a single method is highly desirable for synthetic organic chemistry, especially in medicinal chemistry where these reactions are used at a high frequency. 8,9 In the former system, we proposed a mechanistic hypothesis involving an energy transfer quenching event, supported by literature precedent and a stoichiometric nickel study demonstrating that no added sacrificial oxidant/reductant is needed to promote reactivity� something necessary for photocatalytic cycle turnover in many reductive/oxidative quenching mechanisms.…”

Trifluoromethylthiolation of Tryptophan and Tyrosine Derivatives: A Tool for Enhancing the Local Hydrophobicity of Peptides

“…Very recently, the synthesis of p-SCF 3 phenylalanine (Phe) through a photoredox-mediated Ni-catalyzed trifluoromethylthiolation pathway was reported. 22 To the best of our knowledge, CF 3 S incorporation into tyrosine derivatives has not been reported so far. As the demand for original fluorinated compounds continues to increase, the development of robust methods that allow efficient access to aromatic CF 3 S-AAs on a gram scale is of great importance.…”

“…Nevertheless, the reaction conditions proved to be sensitive to the nature of the aromatic ring and are mainly limited to electron-rich aromatic compounds. Very recently, the synthesis of p -SCF 3 phenylalanine (Phe) through a photoredox-mediated Ni-catalyzed trifluoromethylthiolation pathway was reported . To the best of our knowledge, CF 3 S incorporation into tyrosine derivatives has not been reported so far.…”

Assembly of (hetero)aryl thioethers via simple nucleophilic aromatic substitution and Cu-catalyzed coupling reactions with (hetero)aryl chlorides and bromides under mild conditions

“…During the past two decades, great efforts have been directed to the development of catalytic systems for coupling of (hetero)aryl halides with thiols and their equivalents 1–15 to assemble (hetero)aryl thioethers of high prevalence in bioactive molecules 16 and synthetic intermediates. 17 Because of their abundance, relatively low cost but low reactivity, the utilization of (hetero)aryl chlorides as coupling partners has become a reference point to assess the efficiency of newly developed catalytic systems.…”