Photocatalyzed Dual-Oxidative Trifluoromethylthio-Trifluoromethylation of Alkenes with CF 3 SO 2 Na

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Dec 2021Photocatalyzed Dual-Oxidative Trifluoromethylthio-Trifluoromethylation of Alkenes with CF3SO2Na Shuaishuai Liang, Jingjing Wei, Lvqi Jiang, Jie Liu, Yasir Mumtaz and Wenbin Yi Shuaishuai Liang School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094 Google Scholar More articles by this author , Jingjing Wei School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094 Google Scholar More articles by this author , Lvqi Jiang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094 Google Scholar More articles by this author , Jie Liu School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094 Google Scholar More articles by this author , Yasir Mumtaz School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094 Google Scholar More articles by this author and Wenbin Yi *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094 Key Laboratory of Organofluorine Chemistry, Shanghai Institute Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.020.202000577 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail A novel photocatalyzed trifluoromethylthio-trifluoromethylation of alkenes has been developed, using CF3SO2Na as both CF3 and SCF3 source. This photocatalyzed dual-oxidative strategy, which combines two parallel oxidative events, provides a facile method to synthesize a series of vicinal trifluoromethylthio-trifluoromethylated compounds. This reaction is operationally simple, proceeds under mild conditions and exhibits exceptional substrate generality and functional group compatibility. Furthermore, mechanistic investigations indicated that a photocatalyzed dual-oxidative process was involved in the reaction. Download figure Download PowerPoint Introduction Organofluorine compounds are frequently found in the areas of pharmaceuticals and agrochemicals, as well as in materials science.1–6 Increasing interest of fluorinated compounds has prompted the development of various methods to introduce fluorine atoms or fluorinated functional groups into organic frameworks.7,8 Among the prevalent fluorine-containing moieties, introducing a trifluoromethyl group (CF3) or trifluoromethylthio group (SCF3) into organic compounds with potential use could lead to significant changes in their lipophilicity, bioavailability, and metabolic stability.9–11 Consequently, it is still highly desirable to develop practical synthetic methods for the preparation of trifluoromethylthiolated or trifluoromethylated compounds.12–16 Due to the prevalence of C=C bonds in biomedically and synthetically relevant molecules,17 catalytic difunctionalization of alkenes has attracted great attention from synthetic methodology.18–21 Due to the unique properties of fluorine-containing moieties, fluoroalkylation-involved difunctionalization of alkenes has been widely investigated, resulting in diverse tools to generate complex molecules with various functional groups.22,23 In particular, difunctionalizations of alkenes with two fluorinated functional groups are highly attractive and potentially useful in many research areas, so methods for the bis(trifluoromethylation), bis(trifluoromethoxylation), and fluoroalkylfluoroalkylselenolation of alkenes have been developed.24–26 In view of the widespread dissemination of both CF3 and SCF3 groups in drugs, pesticides, and bioactive compounds, new strategies for the trifluoromethylthio-trifluoromethylation of alkenes would attract considerable attention and may enable numerous avenues in chemical and biomedical research. As shown in Figure 1, our calculations of selected drug-like molecules indicate increased logP values for trifluoromethylthio-trifluoromethylated molecules versus other difluoroalkyl-substituted molecules.a To the best of our knowledge, there have only been two reports regarding the construction of vicinal trifluoromethylthio-trifluoromethylated compounds until now.27,28 Both of these two approaches require different CF3 and SCF3 reagents (Scheme 1a), and the SCF3 reagents employed (NMe4SCF3 and N-trifluoromethylthiosaccharin) must be synthesized in multiple steps. Thus, new approaches that can easily and directly incorporate both CF3 and SCF3 groups using cheap and easy-to-handle reagents with a wide range of substrates under mild conditions are urgently needed and remain a significant challenge. Figure 1 | Comparison of logP values. Download figure Download PowerPoint Langlois’ reagent (CF3SO2Na), a frequently used trifluoromethylation reagent,29–33 has been reported as a popular trifluoromethylthiolation reagent due to its low cost and stable properties.34,35 Exploring new potential applications of CF3SO2Na, we have set out to develop a novel method to achieve two functions of CF3SO2Na in parallel: trifluoromethylation and trifluoromethylthiolation, realizing the direct trifluoromethylthio-trifluoromethylation of alkenes using only CF3SO2Na (Scheme 1b). However, this hypothesis still faces several challenges, including the integration of multiple redox events, regulation of the rate of multistep, and the selection of suitable catalysts. Scheme 1 | (a and b) Some related previous work and this work. Download figure Download PowerPoint Owing to the general mildness, capacity to integrate multiple redox events concurrently, and high functional group tolerance, a visible light photocatalyzed approach initially appears to be ideal. Over the past few decades, photoredox catalysis, a process that integrates an oxidative and a reductive events concurrently (Scheme 2a), has provided a broad range of useful transformations and substantially improved the scope of synthetic chemistry.36–41 However, as we expected in Scheme 1b, both CF3 and SCF3 species in this transformation must be oxidized to activate. Despite extensive studies on redox-neutral transformations, photochemical net oxidation reactions have remained largely unexplored.42–47 As such, we envision that a new photochemical net oxidative strategy might offer a solution to the redox problem via the combination of multiple oxidative events (Scheme 2b). The proposed photocatalyzed dual-oxidative method, combining reactive intermediates generated by two distinct and parallel oxidative events prior to cross-coupling, can potentially also provide a platform for the development of new synthetic strategy in reaction discovery and organic synthesis. Herein, we present an example of photocatalyzed dual-oxidative trifluoromethylthio-trifluoromethylation of alkenes with CF3SO2Na. This protocol distinguishes itself by its operational simplicity and mild reaction conditions and can be applied to direct trifluoromethylthio-trifluoromethylation of C=C bonds in complex small molecules. Scheme 2 | (a and b) New strategies for photochemical multiredox organic transformations. Download figure Download PowerPoint Results and Discussion Based on our assumptions, we began our investigations on the trifluoromethylthio-trifluoromethylation of 4-bromostyrene 1a in the presence of a photocatalyst with CF3SO2Na under visible-light irradiation (Table 1). Oxidant, reductant, and metal catalyst were added to oxidize the photocatalyst,48–51 deoxygenatively reduce CF3SO2Na,52–54 and catalyze the trifluoromethylthiolation,25,55–58 respectively. After extensive evaluation of the reaction conditions, we found that a combination of [Ir(dF(CF3)ppy)2(dtbbpy)](PF6), Cu(MeCN)4PF6 as the catalyst, and K2S2O8, PPh3 as the additive in acetonitrile at room temperature gave the best results after a reaction time of 6 h (see Supporting Information Tables S1–S5 and Figure S1). Under these conditions, the desired product 3a was isolated in 82% yield (entry 1). Replacing the photocatalyst with fac-Ir(ppy)3, [Ir(ppy)2(dtbbpy)](PF6)2, or other organic photocatalysts, gave a lower yield of the desired product (entries 2–5). Other metal catalysts and copper salts of different valence states were also evaluated, and Cu(MeCN)4PF6 was found to give the highest yield (entries 6–8). Although K2S2O8 is an oxidizing agent and PPh3 is a reducing agent, the reaction between them at ambient temperature is quite slow. Since it is presumed that the reaction proceeds via two oxidation processes and one reduction process, the ratio and amounts of K2S2O8 and PPh3 must match to avoid accumulation of one reaction intermediate. Decreasing the amount of K2S2O8 or PPh3 can lead to reduced conversion (entries 9 and 10). The choice of the reaction solvent was found to be crucial, where MeCN proved to be the best while tetrahydrofuran (THF) and toluene were inferior (entries 11 and 12), and were attributed to their low dissolution capacity of CF3SO2Na. Importantly, light (entry 13), photoredox catalyst (entry 14), copper salts (entry 15), and K2S2O8 (entry 16) were all critical for this transformation, and control reactions in the absence of any of these elements showed none of the trifluoromethylthio-trifluoromethylated product. Performing the reaction in air provided a diminished yield (62%) compared with the reaction conducted under inert conditions (entry 17). Table 1 | Reaction Condition Optimizationa Entry Deviation from Standard Conditions Yield (%)b 1 None 86 (82) 2 fac-Ir(ppy)3 (photocatalyst) 41 3 Ru(bpy)3 (photocatalyst) 23 4 [Ir(dtbbpy)(ppy)2]PF6 (photocatalyst) 73 5 Mes-Acr (photocatalyst) 12 6 PPh3AuCl instead of Cu(MeCN)4PF6 15 7 CuOTf instead of Cu(MeCN)4PF6 19 8 Cu(OTf)2 instead of Cu(MeCN)4PF6 <5 9 1.5 equiv K2S2O8 49 10 1.5 equiv PPh3 37 11 THF was used as solvent <5 12 Toluene was used as solvent 0 13 No light 0 14 No photocatalyst 0 15 No Cu(MeCN)4PF6 0 16 No persulfate 0 17 Under air 62 aReaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), K2S2O8 (0.9 mmol), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (0.5 mol %) [dF(CF3)ppy=2-(2,4-difluorophenyl)-5-(trifluoromethyl)-pyridine, dtbbpy=4,4′-di-tert-butyl-2,2’-bipyridine], PPh3 (0.9 mmol), Cu(MeCN)4PF6 (0.09 mmol), MeCN (5 mL), r.t. for 6 h. bYield determined by 19F NMR using (trifluoromethoxy)benzene as an internal standard and isolated yields in parentheses. Having established optimal reaction conditions, we next investigated the substrate scope with structurally diverse alkenes (Table 2). First, para-substituted styrenes with different electronic properties were tested. Styrenes bearing various substituents on the phenyl rings were all compatible in this photoreaction, including bromine ( 3a, 82%), tert-butyl ( 3c, 87%), phenyl ( 3d, 78%), nitro ( 3e, 81%), ester ( 3g, 89%), carboxylic acid ( 3h, 81%), and boric acid ( 3i, 55%). This transformation is not particularly sensitive to steric effects, as proven by the good yields of 3f. 2-Vinylnaphthalene and heterocyclic alkene (2-vinylpyridine and 2-vinylthiophene) were also applied in the reaction to afford products with satisfactory results ( 3j– 3l). Next, the scope of this methodology was extended to a series of unactivated alkenes. Electron-deficient alkenes, for example, α,β-unsaturated amide and carbonyl ester, also proved to be good candidates for the reaction to generate compounds ( 3n– 3p) in good yields. The precise configuration was unambiguously confirmed by single-crystal X-ray analysis of 3o.b Chain alkenes, such as methyl 10-undecenoate ( 3v) or 1,2-epoxy-9-decene ( 3w), could also afford the desired products. Then, cyclic alkenes were also proven to be suitable substrates, predominantly producing the trans products in moderate yields with good diastereoselectivity ( 3x– 3cc). Electron-rich heterocycle-benzofuran dearomatized to form desired products with high diastereomeric ratios ( 3aa). Afterward, 1,1-disubstituted, 1,2-disubstituted ( 3dd– 3jj), and trisubstituted ( 3kk and 3ll) alkenes were surveyed, and the corresponding products were observed in moderate to good yields. Both (E)- and (Z)-β-methylstyrene provided 3hh in moderate yields with identical diastereomeric ratios, which indicated the intermediacy of radical adduct in this reaction. Crotamiton, which has scabicidal activity against sarcoptes scabiei, yielded the desired product 3ii in 47% yield with excellent regioselectivity, albeit in low stereoselectivities. Finally, to further demonstrate the practicality and applicability of this transformation, we turned our attention to more challenging complex alkenes. Late-stage trifluoromethylthio-trifluoromethylation of sertraline ( 3mm), rotenone ( 3nn), estrone ( 3oo), and dehydropregnenoloneacetate ( 3pp) were conducted. The reactions proceeded smoothly to afford the corresponding products, which demonstrates the potential use of this methodology to modify bio-active compounds. A limitation of this method is that no desired products were observed with tetrasubstituted alkenes ( 3qq and 3rr), which may be ascribed to the large steric hindrance. Table 2 | Substrate Scope for the Trifluoromethylthio-Trifluoromethylation of Alkenesa aReaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), K2S2O8 (0.9 mmol), PPh3 (0.9 mmol), Cu(MeCN)4PF6 (0.09 mmol), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (0.5 mol %), MeCN (5 mL), r.t. for 6 h. bVolatile compounds, yield determined by 19F NMR using (trifluoromethoxy)benzene as an internal standard. c[Ir(ppy)2(dtbbpy)](PF6)2 (0.5 mol %) was used as photocatalyst. dE-β-methylstyrene was used. eZ-β-methylstyrene was used. To gain some insight into the mechanism, some control experiments were conducted (Scheme 3). Simply by stirring a mixture of CF3SO2Na/PPh3/Cu(MeCN)4PF6 in MeCN would produce CuSCF3 with high yield (Scheme 3a). Moreover, when triphenylphosphine, copper salt, and part of the sodium trifluoromethylsulfinate in the reaction are replaced by CuSCF3, the desired trifluoromethylthio-trifluoromethylated products reaction can also be obtained in 94% yield (Scheme 3b). These results provide substantial evidence that CuSCF3 was generated in situ and participated in the trifluoromethylthiolation process. In addition, CuSCF3 could also convert to bis(trifluoromethyl)disulfane by K2S2O8, indicating that disulfides may also be intermediates in the reaction (Scheme 3c). The cyclization product 5a and ring-opened product 5b were obtained when diene substrate and α-cyclopropylstyrene were subjected to the standard conditions (Scheme 3d). Afterward, light/dark experiments were performed to verify the effect of photoirradiation (Scheme 3e), and it was observed that the reaction completely ceased once the light source was removed, which suggested that visible light was essential. Furthermore, we performed Stern–Volmer fluorescence-quenching experiments to gain an insight into the electron transfer between catalyst and substrates (Scheme 3f), and the results indicated that the CF3SO2Na and CuSCF3 quenched the excited photocatalyst. Scheme 3 | (a–f) Control experiments. Download figure Download PowerPoint To acquire a better understanding of the reaction mechanism, density functional theory (DFT) calculations were also performed to study C–S formation (see Supporting Information for details, Figure S2). Based on the above investigations, a plausible pathway for the present reaction is illustrated in Scheme 4. First, under visible-light irradiation, the photocatalyst IrIII would generate a long-lived triplet excited-state species IrIII*. Then, single-electron transfer (SET) between IrIII* complex and CF3SO2Na results in the trifluoromethyl radical CF3• and IrII species.59–61 The trifluoromethyl radical then subsequently reacts with alkene to generate a radical intermediate 6. Concurrently, CuSCF3, which is generated in situ via CuI and CF3SO2Na in the presence of PPh3, is also oxidized to a CuII species 7 by the IrIII* through SET. Both of the IrII complexes generated through reductive quenching were converted to ground-state photocatalyst IrIII by potassium persulfate to complete the photoredox catalytic cyclic. The intermediate 6 then undergoes single-electron oxidative addition to CuII–SCF3 to form species 8, a formally CuIII intermediate.58,62 Finally, reductive elimination from intermediate 8 would yield the desired product 3 and regenerate the CuI species. Scheme 4 | Proposed mechanism. Download figure Download PowerPoint Conclusions We have developed the first example of a photocatalyzed dual-oxidative trifluoromethylthio-trifluoromethylation of alkenes with CF3SO2Na as the trifluoromethylation and trifluoromethylthiolation reagent in parallel. This new method takes advantage of visible-light photocatalysis to generate the trifluoromethyl radical, combined with copper-promoted trifluoromethylthiolating process. Various useful trifluoromethylthio-trifluoromethylated alkenes were prepared with good tolerance of functional groups under mild conditions. More importantly, late-stage modification based on this new method also proved to be feasible. In light of the promising properties of vicinal trifluoromethylthio-trifluoromethylated compounds as well as the original photocatalyzed dual-oxidative strategy, we believe that the presented methodology could enable wide applications in pharmaceutical and agrochemical research and open new avenues to innovation in organic photocatalytic synthesis. Footnotes a LogP was calculated by the methodology developed by Molinspiration (v2018.10) as a sum of fragment-based contributions and correction factors. b CCDC-2014294 contains the supplementary crystallographic data for compound 3o. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. Supporting Information Supporting Information is available and includes experimental procedures, characterization data, and 1H NMR, 13C NMR, and 19F NMR for products. Conflict of Interest There is no conflict of interest to report. Funding Information This research was made possible as a result of a generous grant from XYZ Foundation (grant no. 123567). Acknowledgments The authors gratefully acknowledge the National Natural Science Foundation of China (nos. 21776138 and 22078161), the Fundamental Research Funds for the Central Universities (nos. 30920021124 and 30918011314), the Natural Science Foundation of Jiangsu (no. BK20180476), the Postdoctoral Science Foundation Funded Project (no. 2019M661848), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Center for Advanced Materials and Technology in Nanjing University of Science and Technology for their financial support.