The incorporation of a trifluoromethyl (CF₃) group into bioactive molecules is a widely employed strategy to improve key properties such as biological activity, metabolic stability, and lipophilicity.^[1] Given its importance, the development of trifluoromethylation methods has attracted considerable attention over the past decades.^[2]

The CF₃ radical, a key intermediate in many trifluoromethylation reactions, has been extensively studied.^[3] Beyond this role, it can also serve as a hydrogen atom transfer (HAT) reagent to promote other radical transformations (Scheme 1, A).^[4] However, compared with other HAT catalysts or reagents employed in radical-mediated C(sp³)—H functionalization,^[5] the use of the CF₃ radical as a HAT reagent remains relatively underexplored.

In 2019, Studer and coworkers^[4a] developed an elegant protocol for the boron-retaining coupling of boronates with organolithium reagents, enabled by a CF₃ radical-promoted HAT process. Subsequently, using a similar strategy, the same group^[4b] achieved radical boron migration in diboronates complexes to form valuable gem-diboronates with good yields (Scheme 1, B). Nevertheless, methods that employ the CF₃ radical primarily as a HAT reagent remain scarce.

1-Phenylethan-1-one (acetophenone) motifs are privileged structural units, frequently found in bioactive natural products and pharmaceuticals due to their unique properties (Scheme 1, C).^[6] Direct C(sp³)—H alkylation represents one of the most straightforward routes to access functionalized acetophenone derivatives. However, existing methods typically require stoichiometric external oxidants^[7] or harsh reaction conditions,^[8] highlighting a need for milder, oxidant-free alternatives.

Building on our ongoing interest in photoinduced C(sp³)—H functionalization,^[9] herein we report an efficient, external oxidant-free method for CF₃ radical- mediated C(sp³)—H alkylation with arylvinyl trifluoromethanesulfonates. This operationally simple, thioxanthone-catalyzed protocol proceeds under mild conditions, and accommodates a variety of C(sp³)—H feedstocks and arylvinyl trifluoromethanesulfonates to deliver diverse acetophenone derivatives in good yields. This strategy thus provides a practical and sustainable complement to existing methods (Scheme 1, D).

The C(sp³)—H alkylation reaction was initially investigated using 1-phenylvinyl trifluoromethanesulfonate (1a)^[10] and tetrahydrofuran (THF, 2a) as model substrates under blue LED irradiation (430 nm) for 24 h. The reaction was conducted with Ir(dFCF₃ppy)₂(dtbbpy)PF₆ (PC1) as the photocatalyst and KOH as the base in THF as the solvent. Under these conditions, the desired product, 1-phenyl- 2-(tetrahydrofuran-2-yl)ethan-1-one (3a), was obtained in 74% yield (Table 1, Entry 1). Analysis by ¹⁹F NMR spectra confirmed the formation of trifluoromethane as a byproduct,^[11] while the detection of potassium sulfite byproduct indicated that sulfur dioxide released during the reaction was trapped by KOH.^[10b] Further screening of photocatalysts revealed that Ir(ppy)₂(dtbbpy)PF₆ (PC2) was ineffective (Entry 2), whereas 2-isopropylthioxanthone (ⁱPr-TXT, PC3) proved optimal, affording 3a in 82% yield (Entry 3). Evaluation of bases identified KOH was superior to other inorganic bases such as KOAc and K₂CO₃ (Entries 4~6). The optimal amount of KOH was found to be 2.5 equiv. (Entries 7, 8). The yield of 3a increased to 87% upon the addition of 50 μL of water (Entry 9). Solvent screening showed that the reaction proceeded smoothly in ethyl acetate (Entry 10), but was ineffective in acetonitrile or dichloromethane (Entries 11, 12). The transformation could be successfully scaled to the mmol-level without significant loss in efficiency (Entry 13). Control experiments established that KOH, light, and the photocatalyst were all essential for this transformation (Entries 14~16). Interest-ingly, under 365 nm irradiation, the alkylation occurred even in the absence of a photocatalyst, yielding 3a in 50% (Entry 17). This result suggests that the reaction possibly proceed via an energy-transfer pathway.

With the optimized conditions established, the scope of arylvinyl trifluoromethanesulfonates 1 was next evaluated (Table 2). The reaction proved tolerant of various electron-withdrawing substituents on the phenyl ring of 1-phen- ylvinyl trifluoromethanesulfonates. Substrates bearing ester (3b), cyano (3c), trifluoromethyl (3d), and halogen atoms (3e~3h) all reacted smoothly, providing the corresponding 1-phenylethan-1-one derivatives in good yields. 1-(3-Meth- oxyphenyl)vinyl trifluoromethanesulfonate (3i) was a feasible substrate in this C(sp³)—H alkylation reaction with 83% yield. Furthermore, the reaction was successfully extended to 3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate, giving the desired product 3j in 55% yield.

Next, the generality of C(sp³)—H feedstocks was investigated (Table 3). Under the standard conditions, tetrahydropyran, diethyl ether, and tetrahydrothiophene, performed well to provide the desired α-heteroatom site functionalized products 3k~3m in good yields. Isopropanol was also a viable substrate, furnishing product 3n in reasonable yield. However, the benzylic C—H bonds of 1,3,5-trimethyl- benzene proved unreactive under these initial parameters. Further optimization revealed that employing 5,7,12,14- pentacenetetrone (PC4) as the photocatalyst under 400 nm LED irradiation enabled the desired transformation. Under these modified conditions, the benzylic alkylation proceeded to give product 3o in 45% yield. Moreover, cycloalkanes such as cyclopentane and cyclohexane were also found to be suitable substrates when using PC4 as the photocatalyst.

To gain insight into the reaction mechanism, several control experiments were conducted. Light on/off experiments demonstrated that after an initial irradiation period, the C(sp³)—H alkylation continued to proceed under dark conditions (Figure 1). A quantum yield of Φ=1.62 indicated that the transformation follows a chain-reaction pathway (Scheme 2, A). Kinetic isotope effects (KIEs) were evaluated through both competition and parallel reactions. The results suggested that C(sp³)—H bond cleavage is likely the rate-determining step (Scheme 2, B). When 2,2, 6,6-tetramethylpiperidinyloxyl (TEMPO) was employed as a radical scavenger, the trifluoromethyl adduct 4 was detected by HR-MS. Performing the reaction in the absence of KOH led to the trapping by TEMPO of both the acetophenone-derived alkyl radical 5 and the trifluoromethanesulfonyl radical 6 (Scheme 2, C).

Based on the above results and previous reports,^[12] two plausible mechanisms are proposed (Scheme 3). Upon light irradiation, 1-phenylvinyl trifluoromethanesulfonate (1a) reaches an excited state via a thioxanthone-catalyzed energy transfer process.^[13] Homolysis of excited 1a generates the acetophenone-derived alkyl radical (I) and a trifluoromethanesulfonyl radical (II). In the presence of KOH, intermediate II releases sulfur dioxide to form a CF₃ radical (III),^[10b] which abstracts a hydrogen atom from the α- oxygen atom position of THF to afford alkyl radical IV.^[14] Radical IV adds to 1a to form intermediate V, which then undergoes desulfonylation delivers product 3a and regenerates radical II (Scheme 3, A).^[15] Alternatively, the formation of 3a via direct radical-radical coupling between intermediates I and IV cannot be excluded.

Additionally, thioxantone PC3 may serve as a HAT photocatalyst.^[9e,16] Thus, an alternative pathway for the generation of THF radical IV involves direct photoinduced HAT catalysis (Scheme 3, B).^[5b]

In conclusion, we have developed an oxidant-free C(sp³)—H alkylation with arylvinyl trifluoromethanesulfonates, enabled by photoinduced energy transfer catalysis. This method provides direct access to a diverse range of acetophenone-derived products from readily available C(sp³)—H feedstocks. Mechanistic studies support a reaction pathway in which a trifluoromethyl radical acts as a HAT reagent, with the transformation proceeding via a radical chain mechanism.