The carbon–fluorine (C−F) bond transformation in perfluoroalkyl compounds not only is an important synthetic method in organic chemistry,¹ but also is an urgent issue to solve PFAS (polyfluoroalkyl substances) environmental problems.² Numerous C−F bond activation protocols have been reported for single C−F bond transformations of perfluoroalkyl group.^{3, 4} However, a sequential C−F bond transformation of a difluoromethylene unit (−CF₂−) into two different functional groups remains underdeveloped (Figure 1A) despite being an important clue to the solution of PFAS problems. This is because the harsh reaction conditions needed to cleave robust C−F bonds cause the undesired installation of the same functional group. In fact, dialkoxylation,⁵ dimethylation⁶ and dichlorination⁶ of a CF₂ moiety have been reported. To avoid installing the same groups, amino alcohols were used in the aminoalkoxylation of α-perfluoroalkyl ketones in a three-component tandem reaction (Figure 1B, a).⁷ Recently, two distinguished reactions were reported: a sequential defluorinative alkylation of trifluoroacetyl compounds by a radical mechanism (Figure 1B, b)⁸ and a coupling reaction of 1,1-difluoroalkyl compounds (RCF₂R’) with Grignard reagents and chlorosilanes or alkyl tosylates by CrCl₂ catalysis via chromium carbenoid species (Figure 1B, c).⁹ Neither method is applicable to the transformation of longer perfluoroalkyl compounds (RCF₂(CF₂)_nR’). Herein we propose a reaction design based on a sequential process via radical and ionic paths (Figure 1C). The primary substitution of F with RO groups involves C−F bond activation by photocatalysis^4g and capture of the perfluoroalkyl radical by an oxyl radical.¹⁰ Then the second transformation employs a Lewis acid and nucleophiles. Because the reaction mechanism includes an oxonium intermediate, diverse nucleophiles can be introduced. Based on our proposed design using a dual activation system, in this study we achieved a sequential C−F bond transformation of perfluoroalkylarenes via aminoxylation with a fine-tuned phenothiazine photocatalyst and aminoxyl radical reagent followed by AlCl₃-mediated nucleophilic substitution with organosilicon reagents (Figure 1D).

Firstly, we investigated reaction conditions for the photo-catalyzed aminoxylation using 4-phenyl(perfluorobutyl)benzene 1 a (E_red=−2.06 V vs SCE) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) (2) under visible light irradiation (370 nm) (Table 1). The use of Ir(ppy)₃ resulted in no reaction due to the low reducing ability of excited Ir(ppy)₃ (Entry 1).^4g We focused on phenothiazines exhibiting higher reducing abilities than Ir(ppy)₃. Their photocatalytic activities can be tuned by a substituent effect.¹¹ N-Phenylphenothiazine PC1 exhibited a catalytic activity to mediate the aminoxylation, giving product 3 a (Entry 2). To access more negative redox potentials, phenothiazine PC2 was used, leading to an improved yield (Entry 3). It should be noted that newly developed phenothiazine PC3 bearing diisopropylamino and two methyl groups showed the best catalytic activity (Entry 4), suggesting the effect of the two Me groups is crucial to the aminoxylation. N-Dimethylphenylphenothiazine PC4 was less effective, which indicates the increase of reducing ability by an amino group is significant (Entry 5). Next, to utilize much lower reduction potential of photocatalysts, we applied thiolate catalysis¹² and consecutive photo-induced electron transfer (conPET) system¹³ to this reaction. Thiolate catalysis resulted in no reaction, and 1 a was hardly converted (Entry 6). In the conPET system, 1 a was completely consumed, but only a trace amount of 3 a was obtained according to complicated products (Entry 7). In this case, the high reducing ability of the active catalytic species generated by conPET would cause the undesired overreduction or side-reactions. Both photocatalyst and photo-irradiation were essential for the reaction progress (Entries 8 and 9). Finally, under the optimized conditions using the 5 mol % amount of PC3, 3 a was obtained in 82 % yield (Entry 10). Further optimization for addition amount of TEMPO 2 and solvent screening is described in the Supporting Information.¹⁴

Scheme 1 depicts a plausible mechanism for the aminoxylation of 1 with TEMPO 2 catalyzed by phenothiazine PC. The photoexcited PC* reduces 1 via single electron transfer (SET), affording radical anion A and radical cation PC⋅⁺. Mesolysis of a C−F bond affords benzyl radical B.^4g Then, B associates with 2 to give product 3. PC (E(PC3⋅⁺/PC3)=0.61 V vs SCE) is regenerated by single electron reduction with 2 (E(2⁺/2)=0.62 V vs SCE).¹⁵ A by-product, N-oxoammonium cation C captures F⁻, suppressing the retro-reaction from B to A.¹⁶ HRMS and ¹⁹F NMR confirmed N-oxoammonium fluoride D was generated.¹⁷ The appropriate reduction potential of PC3* achieves selective reduction of starting material 1 and not product 3, realizing a single C−F bond transformation without overreduction and side-reactions.¹⁸

We focused on the fact that our developed PC3 exhibited a more efficient catalytic activity than PC2 despite the lower reducing ability of PC3* than PC2* (Table 1).¹⁹ We conducted mechanistic studies to understand the origin of the high activity of PC3. First, the fluorescence quenching experiments of PC* with 4-trifluoromethyl(perfluorohexyl)benzene 1 e were performed. Stern–Volmer plots determined that the rate constants of the dynamic quenching of excited singlet species PC2* and PC3* were 5.3×10¹⁰ M⁻¹ s⁻¹ and 3.1×10¹⁰ M⁻¹ s⁻¹, respectively (Figures S2 and S4).^{20, 21} The 1st SET between 1 e and PC* is a diffusion-controlled process,²² which indicates that the catalytic turnover is independent of the reducing ability of PC*.²³ We then considered the 2nd SET between PC⋅⁺ and TEMPO for the catalyst regeneration. The sub-microsecond transient absorption spectroscopy using laser flash photolysis method at 355 nm (4 mJ/pulse, 4 ns pulse-width) was conducted for a mixture of PC, 4-phenyl(perfluoroethyl)benzene 1 n, and TEMPO to monitor the generation and quenching of PC^•+.²⁴ The quenching rate constant of PC3⋅⁺ (3.2×10⁴  M⁻¹ s⁻¹) was found to be much larger than that of PC2⋅⁺ (0.93×10²  M⁻¹ s⁻¹) (Figures S19 and S20).²⁵ Thus, the fast regeneration of PC3 dominates the catalytic turnover (Figure 2A). Next, Gibbs free energy changes (ΔG_r) and reorganization energies (λ) in the 2nd SET were obtained by DFT calculation to estimate activation energies (ΔG^ǂ) according to Marcus-Hush theory (Figure 2B).^{26, 27} While two ΔG_r values are almost identical (3.8 and 3.7 kcal/mol), λ value for PC3 (38.8 kcal/mol) is lower than that for PC2 (42.3 kcal/mol). Finally, ΔG^ǂ for PC3 (11.6 kcal/mol) is lower than that for PC2 (12.6 kcal/mol). This trend in ΔG^ǂ is consistent with that in the catalyst regeneration rate. Thus, we focused on the geometry change of PC because a smaller λ value leads to the decrease of ΔG^ǂ for SET. The planar structure of phenothiazine backbone in PC⋅⁺ changes to the bent one upon reduction (Figure 2B). This bending is the dominant geometry change and would be deeply related to λ values. We adopted the bent angle (θ) in Figure 2B right to represent the extent of a bent structure of PC. The smaller value of θ in PC3 (θ=14.5°) shows the smaller geometry change in the reduction of PC3⋅⁺ compared to PC2 (θ=18.0°). The steric repulsion of Me groups of PC3 suppresses bending of a phenothiazine backbone, eventually decreasing ΔG^ǂ. A catalyst design including both fast catalyst regeneration and effective photo-excited reduction potential is achieved by the rigidity of molecular structure and the introduction of an electron-donating group.

Using the determined optimal reaction conditions, we explored the substrate scope of this aminoxylation (Scheme 2). Electron withdrawing groups such as CN, CO₂Me, and CONMe₂ were available for the transformation (3 b, 3 c, 3 d). The CF₃-substituted perfluoroalkylarene selectively underwent the aminoxylation in the perfluoroalkyl group (3 e).²⁸ Silyl and boryl substituents were also tolerated (3 f and 3 g). It is noted that perfluoroalkylarenes with electron-donating groups smoothly underwent aminoxylation (3 h, 3 i, and 3 j). The development of PC3 with high reducing ability overcame the limitation of the substrate scope in our previous report for defluoroallylation.^4g Substrates including pyridine, benzofuran, or naphthalene moieties efficiently gave the corresponding products (3 k, 3 l, and 3 m). The reaction of perfluoroethylarene also gave 3 n in a moderate yield. Perfluoroalkyl-substituted pyridines were feasible substrates, and various functional groups such as OMe, OH, NH₂, and acetal groups were compatible with the present reaction (3 o, 3 p, 3 q, and 3 r). A quinoline-based substrate afforded desired product 3 s in 68 % yield. The substrate with two C₄F₉ groups underwent single aminoxylation to give product 3 t. Reactions of perfluoroalkylphenanthrene and -pyrene gave no products (3 u and 3 v).²⁹

Next, Lewis acid mediators and nucleophilic coupling partners were surveyed for the selective C−F bond transformation of aminoxylated compounds 3 via an ionic path³⁰ (Tables S3 and S4). The combination of AlCl₃ and organosilicon reagents was found to be appropriate in the transformation (Scheme 3). After isolation of 3 a, which was provided by aminoxylation between 1 a and 2 (Table 1, Entry 10), 3 a was treated with allyltrimethylsilane (4 a) in the presence of AlCl₃. The reaction gave allylated alcohol 5 a in 74 % yield, in which the amino group was removed on the O atom (see below). The CN and CO₂Me groups were tolerated in this allylation (5 b and 5 c). Various organosilicon nucleophiles were applicable to this C−F bond transformation. Methallylsilane 4 b, silyl enol ethers 4 c and 4 d, silyl ketene acetal 4 e, and alkynylsilane 4 f provided functionalized perfluoroalkyl alcohols 5 d, 5 e, 5 f, 5 g, and 5 h, respectively. An organotin reagent, methallyltributyltin (4 g) also acted well as a nucleophile. Toluene (4 h) was a suitable nucleophile for the Friedel–Crafts reaction to give product 5 i. The reduction with HSiEt₃ smoothly proceeded to yield defluorinated product 5 j. On the other hand, vinylsilane 4 j and silyl ketene imine 4 k were not applicable.

Using the radical and ionic methods to realize two types of C−F bond activation, we demonstrated a one-pot transformation of a CF₂ unit via aminoxylation and allylation reactions (Scheme 4A). After aminoxylation of perfluoroalkylarene 1 a with 2 using PC3 and 370 nm LED light, the crude product was treated with 4 a and AlCl₃ to give product 5 a in high yield. The one-pot aminoxylation/alkylation was also successful using silyl ketene acetal 4 e (Scheme 4B).

Scheme 5 illustrates a proposed mechanism for AlCl₃-mediated C−F bond allylation of 3 with allylsilane 4 a. AlCl₃ abstracts F⁻ to give oxonium intermediate E. Then N-chloroamine and AlFCl₂ are eliminated to give ketone F. AlCl₃ activates F, and 4 a adds to a carbonyl group, affording G.³¹ Finally, hydrolysis of G yields product 5. The generation of F was confirmed when 3 was treated with AlCl₃ in the absence of nucleophiles (Scheme S4). Other typical Lewis acids³⁰ were not effective (Table S3). AlCl₃ can mediate abstraction of fluoride ion of 3 and activation of a less basic carbonyl group of F due to high Lewis acidity. In terms of the intermediacy of ketone F, our procedure has an impact on the synthesis of perfluoroalkyl ketones from PFAS via defluorination. Traditional methods such as defluorination of fully-perfluorinated alkylbenzenes,³² perfluoroalkyl-substituted anilines³³ and -enamines,³⁴ and α-hydroperfluoroalkanoic acid esters^{5, 35} have problems such as narrow substrate scopes. Especially for the synthesis of aryl ketones F, available substrates were extremely limited. In this report, compounds 3 can be synthesized and used as synthetic equivalents for F with the wide substrate scope and the high compatibility of functional groups. Our process is an efficient synthetic method of functionalized perfluoroalkyl alcohols like 5 from PFAS.

In summary, a combination of photoredox catalysis and Lewis acid activation realizes sequential C−F bond transformation of a CF₂ unit in perfluoroalkylarenes. Functionalized perfluoroalkyl alcohols were synthesized by phenothiazine-catalyzed photo-induced defluoroaminoxylation with TEMPO and subsequent AlCl₃ mediated substitution of a F atom with various carbon nucleophiles. Mechanistic studies revealed that the rigidity of molecular structure and the introduction of an electron-donating group is important in catalyst design to achieve fast catalyst regeneration and effective photo-excited reduction potential.