Organofluorine compounds, especially polyfluorinated compounds, have been exploited in pharmaceutical, agrochemical, and material sciences owing to the unique physical and biological properties of fluorine atoms1–8. The primary methods for synthesizing these molecules largely rely on specialized fluorinated functional groups and/or stoichiometric use of fluorinating reagents9–17. Alternatively, selective C-F bond functionalization of easily accessible multifluorinated compounds also shows massive potential for atom- and step-economic access to complex fluorine-containing molecules18–24. Although significant progress has been made, selective functionalization of sp3 C-F bonds under mild conditions remains less explored due to the high bond dissociation energy of the C(sp3)-F bond and the stepwise decreased C-F bond strength during defluorination processes25–29.
Visible-light-driven photoredox catalysis avoids harsh reaction conditions and enables the generation of strong reducing intermediates for inert C-F bond activation30–31. Several visible-light-absorbing photocatalysts with high reducing capability have been successfully explored to realize defluorinated functionalization of multifluorinated compounds containing aroyls or electron-withdrawing aryls32–34. In another inventively-designed strategy, carbon dioxide radical anion, a powerful single electron reductant in situ generated in photoredox cycles, was elegantly designed for activating C(sp3)-F bonds in trifluoromethyl (hetero)arenes, trifluoroacetamides, and trifluoroacetates35–40. So far, most of the π-systems situated next to fluoroalkyl groups focus on arenes and carbonyl groups, and the commonly explored defluorinated products contain the starting π-systems (Fig. 1a). The electron geometries of the defluorinated products are highly similar to those of the starting polyfluorinated compounds, leading to a narrow redox window between the substrates and the defluorination products. Although selective defluorination proceeds predominantly because electron-transfer events for the polyfluorinated substrates are slightly more exergonic than those for the corresponding mono-defluorinated products41, the narrow redox window between the substrates and the defluorination products still gives rise to undesirable side-products. As such, an extension of reaction types for the visible-light-driven defluorination of C(sp3)-F bonds and ultimately toward the exclusive formation of mono-defluorinated products is deemed worthy of pursuit.
In seeking a solution to circumvent these challenges, we were drawn to readily accessible imines which have shown abundant chemical properties in photoredox catalysis. Conceptually, the installation of an imine next to the polyfluoroalkyl chain could facilitate the defluorinative spin-center shift (SCS) process42. We anticipate that polyfluorinated imine will provide the defluorinated products with diverse molecular scaffolds43, which can thoroughly exclude exhaustive defluorinations due to the distinct redox window (Scheme 1A). Herein, a photoredox-neutral single C(sp3)–F bond activation method was developed for the radical cycloaddition of perfluoroalkyl imines with alkenes and water. By tuning the perfluoroalkyl imines structure, we achieved multifluorinated γ-lactams via an imine-involved 5-endo-trig radical cyclization, which is generally considered to be kinetically unfavorable according to Baldwin’s rules.
γ-Lactams are basic structural elements found in many complex natural products and pharmaceutical compounds (Fig. 1b) 44. In particular, 3-alkyl-γ-lactams are core structural motifs in anti-fungi agents and prostacyclin receptors. The introduction of a CF2 group into γ-lactams with interesting biological profiles has been intensively studied45. Nevertheless, the synthesis of 3-polyfluoroalkyl-γ-lactams remains challenging and has never been explored until now. With a wide range of polyfluorinated imines being easily prepared from polyfluorocarboxylic acids, the present approach allows access to a variety of multifluorinated γ-lactams with rapid modification.
The success of the proposed strategy requires suitable polyfluorinated imine derivatives that can readily undergo single-electron reduction and subsequent fluoride elimination under mild reaction conditions. Through initial exploration, we found that the selective defluorination of phenyl 2,2,3,3,3-pentafluoro-propanimidothioate (PFIT) 1a could indeed be realized under photoredox conditions (Table. S1). After extensive optimization, the reaction among PFIT 1a, water, and 2-vinylpyridine 2a efficiently afforded 3-polyfluorinated γ-lactam 3a (Table 1). The model reaction could be used to optimize the reaction conditions (Table 1 and also Table S2-S5). The optimized reaction conditions include 1 mol% of Ir(ppy)3 as a photocatalyst, and CH3CN as the solvent, with 2 equivalents of cesium carbonate under blue light irradiation (6 W, 450 nm). Under the standard conditions, the corresponding polyfluorinated γ-lactam 3a was obtained in 83% yield with high diastereoselectivity (Table 1, entry 1). Other reducing photocatalysts, such as 4-CzIPN, [Ir(ppy)2(dtbbpy)]+ and [Ru(bpy)3]2+ were unable to promote the reaction (entries 2–4). The evaluation of the solvent revealed that this transformation proceeds best in acetonitrile (entries 1 and 5–8). A lower yield of 3a was isolated when K2HPO4, NaHCO3, and KOH (entries 9–11) were used as bases. We conducted control experiments to confirm the essential role of light and photocatalyst in the success of this transformation (entries 12–13).
With the optimized conditions in hand, the scope of the alkenes was explored with the representative examples shown in Fig. 2. Due to the ubiquitous role of pyridyl motifs as aromatic heterocycles in ligand scaffolds, natural products, and medically relevant molecules, a wide range of structurally diverse 2-vinylpyridines possess different kinds of functional groups were subjected to this protocol. It was found that a variety of substituted 2-vinylpyridines reacted well under the conditions, giving rise to the corresponding products in moderate to high yields with high to excellent diastereoselectivities. Various functional groups, including methyl, bromo, chloro, ketone, ester, aldehyde, methoxyl, and cyano were well tolerated (3a − 3m). Although a pyridyl halide moiety has been known to be activated by strong reducing photocatalysts, we did not observe any decomposition in the defluorination46–47. The benign compatibility of halogen substituents further emphasized the potential synthetic applications. Subsequently, reactions of 4-vinylpyridine and styrene were examined, and the desired products (3n–3o) were produced as expected. Other heterocyclic substituted olefins such as quinoline, isoquinoline, benzothiazole, benzoxazole, and pyrimidine were also compatible under the standard conditions, and the corresponding polyfluorinated γ-lactams were generated efficiently (3p–3t). When a variety of 1,1-disubstituted vinylpyridines were employed, the desired products (3u–3ab) were obtained in 34–77% yields. Furthermore, the acrylamides were also accommodated and converted into the corresponding products with excellent diastereoselectivity (3ac–3ad). Additionally, a gram-scale experiment demonstrated that this protocol could be easily scaled up (See the Supporting Information for details).
To further explore the potential of this efficient defluoroalkylation reaction, a variety of polyfluorinated iminosulfides were investigated. As shown in Fig. 2, this method exhibits good substrate compatibility and excellent selectivity. Polyfluorinated iminosulfides bearing various substituents at the aromatic ring could be converted to the desired products 4b-4p in moderate to high yields with high to excellent diastereoselectivities. Notably, the reaction was well-compatible with a range of functional groups (e.g., F, Cl, Br, CF3, ether, ester, ketone) commonly encountered in organic synthesis. It should be noted that cleavage of the aryl C − F, C − Cl, C-Br, and even the benzylic C(sp3) − F bonds did not occur in these cases, indicating the excellent site-selectivity of the present C-F activation. In addition, N-naphthalen-2-yl-PFIT could also give the desired product 4q in 65% yield. To our delight, selective C–F bond functionalization of C3F7, C4F9, and C5F11 groups was also applicable to this method (4r − 4t). Unfortunately, when phenyl 2,2,2-trifluoro-N-phenylethanimidothioate was used, the desired cyclized product could not be obtained (4u), presumably owing to the stabilization of radical via fluoride elimination from the corresponding radical anion.
To further probe the mechanism, some control experiments were investigated. The 18O-labeling results proved that the oxygen atom in the amide group originates from water [Fig. 3a, Eq. (1)]. In the presence of a radical scavenger 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO), the reaction was completely shut down, suggesting the intermediacy of the radical formation in this transformation. Unfortunately, all efforts to the isolation of any TEMPO-adduct remained unsuccessful.
Furthermore, the reaction was monitored by electron paramagnetic resonance spectroscopy with 5,5-dimethyl-1-pyrroline N-oxide as the radical trap [Fig. 3a, Eq. (2)] (Fig. S1). The result of this experiment is consistent with the radical nature of this defluorination process (Fig. 3a). Stern-Volmer fluorescence quenching experiments of the Ir(ppy)3 catalyst with reagents PFIT 1a and 2-vinylpyridine 2a were carried out. As shown in Fig. 3b-3c, excitation of the characteristic absorption of Ir(ppy)3 resulted in maximal photoluminescence at 519 nm in acetonitrile, which was quenched by PFIT 1a with a rate constant of 321 L mol-1. Although the luminescence of Ir(ppy)3 can also be quenched by 2-vinylpyridine 2a, the rate was lower(68 L mol− 1)(Fig. 3d). Such findings demonstrate that the SET reduction of 1a is likely the first step in the photo-catalytic cycle via oxidative quenching [*Ir(III)/Ir(IV)] pathway.
In order to get insight into the photoredox process, cyclic voltammetry experiments were further analyzed. The measured reduction potential of 1a is -1.63 V (peak potential vs SCE, see Fig. 3f), which is much higher than the reduction potential of 3a (-2.56 V vs SCE, see Fig. 3g). The wide redox window between the substrates and the defluorination products controls the chemoselectivity of the single C(sp3) − F bond cleavage.
Based on our mechanistic investigations and precedent literature48–49, we proposed a plausible reaction mechanism outlined in Fig. 4. Initially, irradiation of [Ir]Ⅲ gives rise to its excited state *[Ir]Ⅲ. Then 1a is reduced by *[Ir]Ⅲ via SET, affording the Ir(IV) species and radical anion A. Then, an SCS process occurs to generate the corresponding radical B with the cleavage of a C–F bond. The 2-vinylpyridine 2a captures B to form the alkyl radical intermediate C, which is intercepted by the C = N double bond of the imine group via a 5-endo-trig cyclization to give the C-centered radical intermediate D. Described by Baldwin’s rules, 5-endo-trig cyclizations are generally considered to be kinetically unfavorable. However, in our case, density functional theory using the (U)M06-2X/6-311 + G(d,p)/SMD(CH3CN) method revealed that such a 5-endo-trig cyclization of C requires an activation free energy (ΔG‡ = 12.7 kcal/mol) and is exergonic by 11.8 kcal/mol (Fig. 5). Thus, this route is considered feasible. The photoredox cycle is then closed by SET between D and [Ir]Ⅳ to afford the cationic intermediate E, which is trapped by the hydroxyl anion to afford the intermediate F. Finally, F undergoes elimination to give a polyfluorinated γ-lactam 3a and thiophenol.
In addition, DFT calculations (Fig. S7) suggest that radical anion A delocalizes in a π orbital on the benzene ring and also in the σ* orbitals of two C − F bonds (C1 − F1 and C1 − F2), and these C − F bonds of A are lengthened by comparison with those of neutral 1a (from 1.353 to 1.400 Å). These distinctive chemical characteristics ensure exquisite chemoselectivity during defluorination.
In summary, a direct and site-selective C(sp3) − F bond alkylation in polyfluorinated iminosulfides with alkenes and water was accomplished via photoredox catalysis, affording a diverse array of mutifluorinated γ-lactams with concomitant formation of one C(sp3)-C(sp3) bond, one C(sp3)-N bond and one C = O bond. This protocol allows for achieving more complex fluorine-containing molecules in a single step. The π-systems next to fluoroalkyl groups are functionalized simultaneously during defluorination, widening the redox window between the substrates and the defluorination products. These reactivity characteristics are crucial to control the single C(sp3) − F bond cleavage and avoid exhaustive defluorination. This novel methodology is anticipated to provide an efficient synthetic toolbox for further drug discovery and development. Further investigations on the development of photocatalytic C − F bond activation are currently ongoing in our laboratory.