Trifluoroethoxy-Coated Phthalocyanine Catalyzes Perfluoroalkylation of Alkenes under Visible-Light Irradiation †

We disclose herein the perfluoroalkylation of alkenes catalyzed by trifluoroethoxy-coated zinc phthalocyanine under irradiation of visible light. Perfluoroalkyl iodides were nicely incorporated into unsaturated substrates, including alkyne, to provide perfluoroalkyl and iodide adducts in moderate to good yields. Trifluoromethylation is also possible by trifluoromethyl iodide under the same reaction conditions. The mechanistic study is discussed.

Phthalocyanines, which are man-made blue color dyes with nearly a century of history [32,33], are 18 π-electron macro-heterocycles consisting of four isoindoline units with a planar structure. Their large conjugated system induces good absorption bands of spectra at 620-700 nm, and their chemical, thermal, and photo stabilities, low-cost and non-toxicity makes them promising photosensitizers for dye-sensitized solar cell (DSSC) applications [34][35][36]. From the viewpoint of the successful application of phthalocyanines for DSSC, they should also be very attractive alternative catalysts to Ru(II) polypyridyl complexes for photoredox perfluoroalkylation reactions. In spite of their potential performance as photoredox materials, as mentioned above, research on phthalocyanines for photoredox radical perfluoroalkylation is rarely reported [37,38]. This is presumably due to the notorious low solubility of phthalocyanines in organic solvents [32,33]. In the last several years, we have reported the design and synthesis of a series of trifluoroethoxy-coated phthalocyanines, and revealed their extraordinary non-aggregation property allowing them to become highly soluble in a wide variety of organic solvents [39][40][41][42][43][44][45]. We recently reported that trifluoroethoxy-coated boron subphthalocyanine is a very effective catalyst for the radical fluoroalkylation of alkenes and alkynes under energetically lower red light irradiation [46]. However, apart from the advantages of its reactivity following red-light activation (λ = 600-700 nm), boron subphthalocyanine might have a problem, its long-term photo-stability [47][48][49]. That is, if the reaction requires very long time, catalytic activity would disappear. We disclose herein the radical perfluoroalkylation of alkenes, including alkyne, catalyzed by trifluoroethoxy-coated zinc phthalocyanine under visible light irradiation.

Results and Discussion
Initially, perfluorooctylation of 1-hexenol (1a) with perfluorooctyl iodide (nC 8 F 17 I) in the presence of a catalytic amount of trifluoroethoxy-coated zinc phthalocyanine (TFEO-ZnPc, 1 mol %) under LED light (white LED, 10 W) irradiation was attempted. The solvent system and additive were selected according to our previous report [46]. The desired perfluorooctylated product 2aa was obtained after 1 h in 88% yield (Table 1, Entry 1). Control experiments showed the reaction no longer proceeded without light irradiation, catalyst, or additive (Entries 2-4). The uses of tBu-functionalized zinc phthalocyanine (tBuZnPc) or trifluoroethoxy-coated subphthalocyanine (TFEO-SubPc) instead of TFEO-ZnPc decreased product yields (Entries 5, 6). Next, additives were screened and the use of ascorbic acid or Hantzsch ester resulted in a decrease in yields ( Entries 7,8). Finally, study of solvent effect revealed that single solvents such as MeOH, MeCN, or DMSO showed no improvement in yields (Entries 9-11), but an increase in concentration gave higher product yield (Entry 12). successful application of phthalocyanines for DSSC, they should also be very attractive alternative catalysts to Ru(II) polypyridyl complexes for photoredox perfluoroalkylation reactions. In spite of their potential performance as photoredox materials, as mentioned above, research on phthalocyanines for photoredox radical perfluoroalkylation is rarely reported [37,38]. This is presumably due to the notorious low solubility of phthalocyanines in organic solvents [32,33]. In the last several years, we have reported the design and synthesis of a series of trifluoroethoxy-coated phthalocyanines, and revealed their extraordinary non-aggregation property allowing them to become highly soluble in a wide variety of organic solvents [39][40][41][42][43][44][45]. We recently reported that trifluoroethoxy-coated boron subphthalocyanine is a very effective catalyst for the radical fluoroalkylation of alkenes and alkynes under energetically lower red light irradiation [46]. However, apart from the advantages of its reactivity following red-light activation (λ = 600-700 nm), boron subphthalocyanine might have a problem, its long-term photo-stability [47][48][49]. That is, if the reaction requires very long time, catalytic activity would disappear. We disclose herein the radical perfluoroalkylation of alkenes, including alkyne, catalyzed by trifluoroethoxy-coated zinc phthalocyanine under visible light irradiation.

Results and Discussion
Initially, perfluorooctylation of 1-hexenol (1a) with perfluorooctyl iodide (nC8F17I) in the presence of a catalytic amount of trifluoroethoxy-coated zinc phthalocyanine (TFEO-ZnPc, 1 mol %) under LED light (white LED, 10 W) irradiation was attempted. The solvent system and additive were selected according to our previous report [46]. The desired perfluorooctylated product 2aa was obtained after 1 h in 88% yield (Table 1, Entry 1). Control experiments showed the reaction no longer proceeded without light irradiation, catalyst, or additive (Entries 2-4). The uses of tBu-functionalized zinc phthalocyanine (tBuZnPc) or trifluoroethoxy-coated subphthalocyanine (TFEO-SubPc) instead of TFEO-ZnPc decreased product yields (Entries 5, 6). Next, additives were screened and the use of ascorbic acid or Hantzsch ester resulted in a decrease in yields (Entries 7, 8). Finally, study of solvent effect revealed that single solvents such as MeOH, MeCN, or DMSO showed no improvement in yields (Entries 9-11), but an increase in concentration gave higher product yield (Entry 12). With optimized reaction conditions in hand, perfluoroalkylation of a variety of alkenes 1 in the presence of a catalytic amount of TFEO-ZnPc under visible light irradiation was attempted ( Figure 1). Varied functionalized alkenes (1) having tosylate, halogens, carbamate, and ketone showed good reactivity to furnish perfluoroalkylated compounds (2) after 1 h irradiation. The reaction could be applied to inner-alkene substrates 1j and 1k, including alkyne 1g, in comparable yields, and to electron-deficient alkene 1l in acceptable yield. Other perfluoroalkyl iodides, including C4 and C6 perfluoroalkyl chains, were successfully used under the optimized reaction conditions and desired products 2ab and 2ac were afforded in 1 h. The trifluoromethylation reaction using trifluoromethyl iodide required a longer reaction time to furnish comparable product 2ad in 87% yield. With optimized reaction conditions in hand, perfluoroalkylation of a variety of alkenes 1 in the presence of a catalytic amount of TFEO-ZnPc under visible light irradiation was attempted ( Figure  1). Varied functionalized alkenes (1) having tosylate, halogens, carbamate, and ketone showed good reactivity to furnish perfluoroalkylated compounds (2) after 1 h irradiation. The reaction could be applied to inner-alkene substrates 1j and 1k, including alkyne 1g, in comparable yields, and to electron-deficient alkene 1l in acceptable yield. Other perfluoroalkyl iodides, including C4 and C6 perfluoroalkyl chains, were successfully used under the optimized reaction conditions and desired products 2ab and 2ac were afforded in 1 h. The trifluoromethylation reaction using trifluoromethyl iodide required a longer reaction time to furnish comparable product 2ad in 87% yield. To confirm the reaction mechanism, the time profile of the reaction was investigated. The trifluoromethylation was selected for this purpose due to its longer reaction time ( Figure 2). First, trifluoromethylation of 1a was carried out with optimized conditions for only 1 h and 65% isolated yield of product 2ad was obtained, even though an excess amount of CF3I was used (Figure 2a). This result indicates the difficulty of trifluoromethylation compared with other perfluoroalkylations. Next, the time profile was further studied by checking the yields of each reaction time with PhCF3 as an To confirm the reaction mechanism, the time profile of the reaction was investigated. The trifluoromethylation was selected for this purpose due to its longer reaction time ( Figure 2). First, trifluoromethylation of 1a was carried out with optimized conditions for only 1 h and 65% isolated yield of product 2ad was obtained, even though an excess amount of CF 3 I was used (Figure 2a). This result indicates the difficulty of trifluoromethylation compared with other perfluoroalkylations. Next, the time profile was further studied by checking the yields of each reaction time with PhCF 3 as an internal standard with a pause in light irradiation (Figure 2b). The reaction gradually proceeded and gave comparable yields after a 5 h reaction time, while the reaction did not proceed in the dark. These results show good agreement with our previous results [46] and with other reports [19] on the photo-induced radical trifluoromethylation of alkenes with photoredox catalysts. internal standard with a pause in light irradiation (Figure 2b). The reaction gradually proceeded and gave comparable yields after a 5 h reaction time, while the reaction did not proceed in the dark. These results show good agreement with our previous results [46] and with other reports [19] on the photoinduced radical trifluoromethylation of alkenes with photoredox catalysts. A plausible reaction mechanism shown in Scheme 1 is supported by previous reports [9] and by the light/dark experiment mentioned above. The reaction starts with the electron transfer from Na ascorbate to excited TFEO-ZnPc (Pc*) by visible light to form the TFEO-ZnPc anion radical (Pc − ) and the anion radical reduces the perfluoroalkyliodide (RFI) to produce the perfluoroalkyl radical (RF). The radical reacts with an unsaturated moiety of the substrate to form an alkyl radical intermediate. Then, the alkyl radical may donate the electron to excited TFEO-ZnPc to reproduce the TFEO-ZnPc anion radical (Path A; Closed reaction cycle). Another possibility of this reaction is radical propagation of the perfluoroalkyl radical intermediate with RFI (Path B; Chain propagation cycle). The control experiment shows that both plausible reaction passes need an initial electron-transfer between Na ascorbate and TFEO-ZnPc and the experiment in Figure 1b shows that continuous light irradiation is essential for the production of a perfluoroalkylated product. From the previous study A plausible reaction mechanism shown in Scheme 1 is supported by previous reports [9] and by the light/dark experiment mentioned above. The reaction starts with the electron transfer from Na ascorbate to excited TFEO-ZnPc (Pc*) by visible light to form the TFEO-ZnPc anion radical (Pc − ) and the anion radical reduces the perfluoroalkyliodide (R F I) to produce the perfluoroalkyl radical (R F ). The radical reacts with an unsaturated moiety of the substrate to form an alkyl radical intermediate. Then, the alkyl radical may donate the electron to excited TFEO-ZnPc to reproduce the TFEO-ZnPc anion radical (Path A; Closed reaction cycle). Another possibility of this reaction is radical propagation of the perfluoroalkyl radical intermediate with R F I (Path B; Chain propagation cycle). The control experiment shows that both plausible reaction passes need an initial electron-transfer between Na ascorbate and TFEO-ZnPc and the experiment in Figure 1b shows that continuous light irradiation is essential for the production of a perfluoroalkylated product. From the previous study [46] and these results in this reaction, Path A and B may work concertedly in this transformation. Further studies are required to disclose the details of this mechanism.

Materials and Methods
All reactions were performed in oven-dried glassware under the positive pressure of argon unless otherwise mentioned. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All reactions were monitored by thin-layer chromatography (TLC) carried out on a 0.25 mm Merck silica gel (60-F254). TLC plates were visualized with UV light and KMnO4 in water/heat. Column chromatography was carried out on columns packed with silica gel (60N spherical neutral size 63-210 μm, Kanto Chemical Co., Inc., Tokyo, Japan). The 1 H-NMR (300 MHz), 19 F-NMR (282 MHz), and 13 C-NMR (125 MHz) spectra for solution in CDCl3 were recorded on a Varian 300 (Agilent Technologies, Palo Alto, CA, USA) and a Bruker Avance 500 (Bruker, Billerica, MA, USA). Chemical shifts (δ) are expressed in ppm downfield from TMS (δ = 0.00) or C6F6 (δ = −162.2 (CDCl3)) as an internal standard. Mass spectra were recorded on a Shimadzu GCMS-QP5050A (EI-MS) and Shimadzu LCMS-2020 (ESI-MS) (Shimadzu Corporation, Kyoto, Japan). Melting points were recorded on a Buchi M-565 (Büchi Labortechnik AG, Flawil, Switzerland). Infrared spectra were recorded on a JASCO FT/IR-4100 spectrometer (Jasco Corporation, Tokyo, Japan). Chemicals were purchased and used without further purification unless otherwise noted. MeOH was dried and distilled before use.
All reactions were performed under irradiation by commercially available 10 W white LED (Panasonic Corporation, Osaka, Japan, DA10DGK60W, 810 lumens). The LEDs were placed at a distance of 3-4 cm.

Perfluoroalkylation of Alkenes and Alkynes with TFEOZnPc
A Schlenk tube equipped with a rubber septum and magnetic stir bar was charged with TFEO-ZnPc (5.4 mg, 0.0025 mmol, 1 mol %) and Na ascorbate (17.3 mg, 0.0875 mmol, 0.35 equiv). The tube was degassed by vacuum evacuation and argon backfill (×3) before MeCN (1.0 mL), MeOH (0.75 mL), substrate (0.25 mmol, 1.0 equiv) and perfluoroalkyliodide (0.375 mmol, 1.5 equiv) were added. The mixture was degassed by the freeze-pump-thaw method (×3). The mixture was stirred for 1 h under irradiation by 10 W white LEDs. After the reaction was complete, the mixture was diluted by Et2O and filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give the desired product.

Materials and Methods
All reactions were performed in oven-dried glassware under the positive pressure of argon unless otherwise mentioned. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All reactions were monitored by thin-layer chromatography (TLC) carried out on a 0.25 mm Merck silica gel (60-F 254 ). TLC plates were visualized with UV light and KMnO 4 in water/heat. Column chromatography was carried out on columns packed with silica gel (60N spherical neutral size 63-210 µm, Kanto Chemical Co., Inc., Tokyo, Japan). The 1 H-NMR (300 MHz), 19 F-NMR (282 MHz), and 13 C-NMR (125 MHz) spectra for solution in CDCl 3 were recorded on a Varian 300 (Agilent Technologies, Palo Alto, CA, USA) and a Bruker Avance 500 (Bruker, Billerica, MA, USA). Chemical shifts (δ) are expressed in ppm downfield from TMS (δ = 0.00) or C 6 F 6 (δ = −162.2 (CDCl 3 )) as an internal standard. Mass spectra were recorded on a Shimadzu GCMS-QP5050A (EI-MS) and Shimadzu LCMS-2020 (ESI-MS) (Shimadzu Corporation, Kyoto, Japan). Melting points were recorded on a Buchi M-565 (Büchi Labortechnik AG, Flawil, Switzerland). Infrared spectra were recorded on a JASCO FT/IR-4100 spectrometer (Jasco Corporation, Tokyo, Japan). Chemicals were purchased and used without further purification unless otherwise noted. MeOH was dried and distilled before use.
All reactions were performed under irradiation by commercially available 10 W white LED (Panasonic Corporation, Osaka, Japan, DA10DGK60W, 810 lumens). The LEDs were placed at a distance of 3-4 cm.

Perfluoroalkylation of Alkenes and Alkynes with TFEOZnPc
A Schlenk tube equipped with a rubber septum and magnetic stir bar was charged with TFEO-ZnPc (5.4 mg, 0.0025 mmol, 1 mol %) and Na ascorbate (17.3 mg, 0.0875 mmol, 0.35 equiv). The tube was degassed by vacuum evacuation and argon backfill (×3) before MeCN (1.0 mL), MeOH (0.75 mL), substrate (0.25 mmol, 1.0 equiv) and perfluoroalkyliodide (0.375 mmol, 1.5 equiv) were added. The mixture was degassed by the freeze-pump-thaw method (×3). The mixture was stirred for 1 h under irradiation by 10 W white LEDs. After the reaction was complete, the mixture was diluted by Et 2 O and filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give the desired product.

5-Iodo-6-trifluoromethylhexanol (2ad)
A Schlenk tube equipped with a rubber septum and a magnetic stir bar was charged with TFEO-ZnPc (5.4 mg, 0.0025 mmol, 1 mol %) and Na ascorbate (17.3 mg, 0.0875 mmol, 0.35 equiv). The tube was degassed by vacuum evacuation and argon backfill (×3) before MeCN (1.0 mL), MeOH (0.75 mL) and alkene 1a (29.5 µL, 0.25 mmol, 1.0 equiv) were added. The mixture was degassed by the freeze-pump-thaw method (×3). CF 3 I (1.45 g, 7.32 mmol, 29.3 equiv) in a balloon was then added to the tube via a needle then cooled to −78 • C in an ethanol bath. The mixture was warmed to room temperature and stirred for 5 h under irradiation by 10 W white LEDs. After the reaction was complete, the mixture was diluted by Et 2 O and filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane/EtOAc = 8:2) to give desired product 2ad (64.2 mg, 87% yield) as a white solid.

Conclusions
In summary, we disclose the first photo-induced radical perfluoroalkylation of alkenes and alkyne induced by trifluoroethoxy-coated zinc phthalocyanine as a catalyst. From the view of the ease of availability, lower cost, and the substantiality of phthalocyanines, this study will be a monumental work of phthalocyanines as photocatalysts. Further studies to reveal the new potential of phthalocyanines are under investigation by our group [54].