Advances in photocatalytic research on decarboxylative trifluoromethylation of trifluoroacetic acid and derivatives

Abstract

Trifluoromethylation stands as a pivotal technology in modern synthetic chemistry, playing an indispensable role in drug design, functional material development, and agrochemical innovation. With the growing emphasis on green chemistry principles, the pursuit of environmentally benign trifluoromethylation strategies has emerged as a critical research frontier. Trifluoroacetic acid (TFA), characterized by its cost-effectiveness, stability, and low toxicity, has become a promising alternative to conventional trifluoromethylation reagents. This review systematically summarizes advancements in photocatalytic decarboxylative trifluoromethylation using TFA and its derivatives over the past decade, focusing on three key activation mechanisms: single-electron transfer (SET), electron donor-acceptor (EDA) complex-mediated pathways, and ligand-to-metal charge transfer (LMCT). This paradigm shift is driven by the intrinsic limitations of conventional thermal decarboxylation, particularly its reliance on harsh conditions and significant environmental burdens. In contrast, photocatalytic strategies enable efficient C-CF₃ bond construction under mild conditions, offering a modular platform for synthesizing fluorinated functional molecules. Strategic research priorities should focus on overcoming fundamental challenges, including but not limited to optimizing photosensitizer catalytic efficiency, establishing regioselective manipulation strategies, and engineering multicomponent tandem reaction systems to achieve trifluoromethylation methodologies under mild conditions. Furthermore, the integration of mechanistic investigations with artificial intelligence-driven reaction prediction will accelerate the advancement of precision trifluoromethylation technologies. This progress is anticipated to provide sustainable synthetic solutions for next-generation fluorinated pharmaceuticals and advanced functional materials, effectively bridging the innovation gap between academic research and industrial implementation.

Keywords: decarboxylation; photocatalysis; radical; trifluoroacetic acid (TFA); trifluoromethylation.

SCHEME 1

Three main routes for photocatalytic production of trifluoromethyl from trifluoroacetic acid and its derivatives.

SCHEME 2

Photocatalytic decarboxylative trifluoromethylation of TFA and trifluoroacetates. (A) TiO₂-catalyzed C–H trifluoromethylation of (hetero)arenes via CF₃CO₂Ag decarboxylation; (B) Rh@TiO₂-catalyzed C–H trifluoromethylation of (hetero)arenes via TFA decarboxylation; (C) Au@ZnO-catalyzed trifluoromethylation of (hetero)arenes via CF₃CO₂Na decarboxylation; (D) Ru(bpy)₃Cl₂-catalyzed trifluoromethylation of (hetero)arenes via TFA decarboxylation.

SCHEME 3

Photoelectrocatalytic decarboxylative trifluoromethylation of TFA and CF₃CO₂K. (A) Graphite anode-mediated oxidative TFA decarboxylation for (hetero)arene trifluoromethylation; (B) Mo-doped WO₃ anode-mediated oxidative CF₃CO₂K decarboxylation for (hetero)arene trifluoromethylation.

SCHEME 4

Photocatalytic decarboxylative trifluoromethylation of TFAA. (A) Trifluoromethylation of 1-hydroxypyridine-2-thione in the early phase using TFAA as a trifluoromethyl source; (B) fac-Ir(ppy)₃-catalyzed trifluoromethylation using TFAA as the trifluoromethyl source.

SCHEME 5

Photocatalytic single-electron oxidation of TFA derivatives. (A) Ru(bpy)₃(PF₆)₂-catalyzed trifluoromethylation using FPIFA as the trifluoromethyl source; (B) based-Ir-catalyzed trifluoromethylation using NHBC as the trifluoromethyl source.

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Photocatalytic ET-mediated decarboxylative trifluoromethylation of alkenes via TFAOx activation.

SCHEME 7

Stephenson’s pioneering work on EDA-mediated trifluoromethylation.

SCHEME 8

Photocatalytic generation of CF₃• radicals from TFA and derivatives via the EDA process. (A) Leibfarth’s expansion to industrial applications; (B) Advancements in tandem trifluoromethylation and cyclization; (C) Stephenson’s redesign of the EDA platform; (D) Application of Os(tpy)₂(PF₆)₂ as a near-infrared photocatalyst in EDA processes; (E) Tandem trifluoromethylation-cyclization reaction.

SCHEME 9

Photocatalytic generation of •CF₃ from TFA and derivatives via the LMCT process. (A) Fe(AcO)₂-catalyzed generation of •CF₃ from CF₃CO₂Na via LMCT process; (B) Ag(bpy)₂(OTf)₂ -catalyzed generation of •CF₃ from CF₃CO₂Na via LMCT process.

SCHEME 10

Photocatalytic generation of •CF₃ from TFA and derivatives via the LMCT process. (A) Ag(OTf)₂-catalyzed generation of •CF₃ from TFA via LMCT process; (B) Fe(acac)₃-catalyzed generation of •CF₃ from TFAA via LMCT process.