Direct C–H trifluoromethylation of di- and trisubstituted alkenes by photoredox catalysis

Summary Background: Trifluoromethylated alkene scaffolds are known as useful structural motifs in pharmaceuticals and agrochemicals as well as functional organic materials. But reported synthetic methods usually require multiple synthetic steps and/or exhibit limitation with respect to access to tri- and tetrasubstituted CF3-alkenes. Thus development of new methodologies for facile construction of Calkenyl–CF3 bonds is highly demanded. Results: The photoredox reaction of alkenes with 5-(trifluoromethyl)dibenzo[b,d]thiophenium tetrafluoroborate, Umemoto’s reagent, as a CF3 source in the presence of [Ru(bpy)3]2+ catalyst (bpy = 2,2’-bipyridine) under visible light irradiation without any additive afforded CF3-substituted alkenes via direct Calkenyl–H trifluoromethylation. 1,1-Di- and trisubstituted alkenes were applicable to this photocatalytic system, providing the corresponding multisubstituted CF3-alkenes. In addition, use of an excess amount of the CF3 source induced double C–H trifluoromethylation to afford geminal bis(trifluoromethyl)alkenes. Conclusion: A range of multisubstituted CF3-alkenes are easily accessible by photoredox-catalyzed direct C–H trifluoromethylation of alkenes under mild reaction conditions. In particular, trifluoromethylation of triphenylethene derivatives, from which synthetically valuable tetrasubstituted CF3-alkenes are obtained, have never been reported so far. Remarkably, the present facile and straightforward protocol is extended to double trifluoromethylation of alkenes.


Scheme 3:
Our strategies for synthesis of CF 3 -alkenes.

Results and Discussion
The results of investigations on the reaction conditions are summarized in Table 1. We commenced examination of photo- Other solvent systems gave substantial amounts of the hydroxytrifluoromethylated byproduct, which we reported previously [37]. In addition, the present C-H trifluoromethylation proceeds even in the absence of a base ( Notably, product 3a was obtained neither in the dark nor in the absence of photocatalyst (Table 1, entries 9 and 10), strongly supporting that the photoexcited species of the photoredox catalyst play key roles in the reaction.
In the reactions of unsymmetrically substituted substrates (2e-h), products were obtained in good to moderate yields but consisted of mixtures of E and Z-isomers. Based on the experimental results, the E/Z ratios are susceptible to the electronic structure of the aryl substituent. Reactions afforded the major isomers, in which the CF 3 group and the electron-rich aryl substituent are arranged in E-fashion. In addition, the present photocatalytic reaction can be tolerant of the Boc-protected amino group (2f) or pyridine (2h). Moreover, a substrate with an alkyl substituent, 2,4-diphenyl-4-methyl-1-pentene (2i), was also applicable to this transformation, whereas the reaction of 1,2-disubsituted alkenes such as trans-stilbene provided complicated mixtures of products.
Next, we extended the present C-H trifluoromethylation to trisubstituted alkenes. The reactions of 1,1-diphenylpropene derivatives 2j and 2k (E/Z = 1/1) afforded the corresponding tetrasubstituted CF 3 -alkenes 3j and 3k in 82% and 59% (E/Z = 74/26) yields, respectively. Triphenylethenes 2l and 2m (only E-isomer) are also applicable to this photocatalytic C-H trifluoromethylation. Remarkably, the E-isomer of 3m is a key intermediate for the synthesis of panomifene, which is known as an antiestrogen drug [71,72]. These results show that the present protocol enables the efficient construction of a C alkenyl -CF 3 bond through direct C-H trifluoromethylation of 1,1-disubstituted and trisubstituted aryl alkenes.
During the course of our study on the C-H trifluoromethylation of 1,1-diarylethenes 2, we found that a detectable amount of bis(trifluoromethyl)alkenes 4 was formed through double C-H trifluoromethylation. In fact, the photocatalytic trifluoromethylation of 2a,b and d with 4 equivalents of Umemoto's reagent 1a in the presence of 5 mol % of [Ru(bpy) 3 ](PF 6 ) 2 with irradiation from blue LEDs for 3 h gave geminal bis(trifluoromethyl)ethene (4a,b and d) in 45, 80 and 24% NMR yields, respectively (Scheme 4). Substituents on the benzene ring significantly affect the present double trifluoromethylation. Reaction of the electron-rich alkene 2b afforded 1,1-anisyl-2,2bis(trifluoromethyl)ethene (4b) in a better yield than other alkenes 2a and 2d. Additionally, we found that photocatalytic trifluoromethylation of CF 3 -alkene 3d in the presence of an excess amount of Umemoto's reagent 1a produced bis(trifluoromethyl)alkenes 4d in a better yield (56% yield) compared to the above-mentioned one-pot double trifluoromethylation of 2d.

Scheme 4: Synthesis of geminal bis(trifluoromethyl)alkenes.
A possible reaction mechanism based on SET photoredox processes is illustrated in Scheme 5. According to our previous photocatalytic trifluoromethylation [37][38][39][40][41], the trifluoromethyl radical (·CF 3 ) is generated from an one-electron-reduction of electrophilic Umemoto's reagent 1a by the photoactivated Ru catalyst, *[Ru(bpy) 3 ] 2+ . ·CF 3 reacts with alkene 2 to give the benzyl radical-type intermediate 3' in a regioselective manner. Subsequent one-electron-oxidation by highly oxidizing Ru species, [Ru III (bpy) 3 ] 3+ , produces β-CF 3 carbocation intermediate 3 + . Finally, smooth elimination of the olefinic proton, which is made acidic by the strongly electron-withdrawing CF 3 substituent, provides trifluoromethylated alkene 3. Preferential formation of one isomer in the reaction of unsymmetrical substrates is attributed to the population of the rotational conformers of the β-CF 3 carbocation intermediate 3 + . Our experimental result is consistent with the previous report [71], which described E-selective formation of the tetrasubstituted CF 3 -alkene 3m via a β-CF 3 carbocation intermediate. In the presence of an excess amount of CF 3 reagent 1a, further C-H trifluoromethylation of CF 3 -alkene 3 proceeds to give bis(trifluoromethyl)alkene 4.

Scheme 5: A possible reaction mechanism.
We cannot rule out a radical chain propagation mechanism, but the present transformation requires continuous irradiation of visible light (Figure 1), thus suggesting that chain propagation is not a main mechanistic component.

Conclusion
We have developed highly efficient C-H trifluoromethylation of alkenes using Umemoto's reagent as a CF 3 source by visiblelight-driven photoredox catalysis. This reaction can be applied to multi-substituted alkenes, especially, 1,1-disubstituted and trisubstituted aryl alkenes, leading to tri-and tetrasubstituted CF 3 -alkenes. The present straightforward method for the synthesis of multisubstituted CF 3 -alkenes from simple aryl alkenes is the first report. In addition, we can extend the present photocatalytic system to double trifluoromethylation. Further development of this protocol in the synthesis of bioactive organofluorine molecules and fluorescent molecules is a continuing effort in our laboratory.

Experimental
Typical NMR experimental procedure (reaction conditions in Table 1 General procedure for the photocatalytic C−H trifluoromethylation of alkenes (reaction conditions in Table 2) A 20 mL Schlenk tube was charged with Umemoto's reagent 1a (102 mg, 0.3 mmol, 1.2 equiv), [Ru(bpy) 3 ](PF 6 ) 2 (4.3 mg, 2 mol %), alkene 2 (0.25 mmol), and DMSO (2.5 mL) under N 2 . The tube was irradiated for 2 h at room temperature (water bath) with stirring by 3 W blue LED lamps (hν = 425 ± 15 nm) placed at a distance of 2-3 cm. After the reaction, H 2 O was added. The resulting mixture was extracted with Et 2 O, washed with H 2 O, dried (Na 2 SO 4 ), and filtered. The filtrate was concentrated in vacuo. The product was purified by the two methods described below.
For products 3b, 3e, 3f, 3g, 3h, 3k and 3m, the residue was purified by column chromatography on silica gel (eluent: hexane and diethyl ether) to afford the corresponding product 3. Further purification of 3f by GPC provided pure 3f. For products 3a, 3c, 3d, 3i, 3j, and 3l, the residue was treated by mCPBA (74 mg, ca. 0.3 mmol) in CH 2 Cl 2 to convert the dibenzothiophene to sulfoxide, which was more easily separated from the products. After the solution was stirred at room temperature for 2 h, an aqueous solution of Na 2 S 2 O 3 ·5H 2 O was added to the solution, which was extracted with CH 2 Cl 2 . The organic layer was washed with H 2 O, dried (Na 2 SO 4 ), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluent: hexane) to afford the corresponding product 3. Further purification of 3c and 3d by GPC provided pure 3c and 3d.
Procedures for the photocatalytic double C−H trifluoromethylation of 1,1-bis(4methoxyphenyl)ethylene (2b) A 20 mL Schlenk tube was charged with Umemoto's reagent 1a (340 mg, 1.0 mmol, 4 equiv), [Ru(bpy) 3 ](PF 6 ) 2 (10.7 mg, 5 mol %), 2b (60 mg, 0.25 mmol), and DMSO (5 mL) under N 2 . The tube was irradiated for 3 h at room temperature (water bath) with stirring by 3 W blue LED lamps (hν = 425 ± 15 nm) placed at a distance of 2-3 cm. After reaction, H 2 O was added. The resulting mixture was extracted with Et 2 O, washed with H 2 O, dried (Na 2 SO 4 ), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (hexane→hexane/Et 2 O = 29:1) to afford 4b as a product mixture with 3b. Further purification by GPC provided pure 4b in 44% isolated yield (42 mg, 0.11 mmol). Isolated yield was much lower than the NMR yield because of the difficulty of separation of 3b and 4b.

Supporting Information File 1
Experimental procedures and NMR spectra.