Photo-driven redox-neutral decarboxylative carbon-hydrogen trifluoromethylation of (hetero)arenes with trifluoroacetic acid

Catalytic oxidative C–H bond functionalization reactions that proceed without requiring stoichiometric amounts of external oxidants or pre-functionalized oxidizing reagents could maximize the atom- and step-economy in chemical syntheses. However, such a transformation remains elusive. Here, we report that a photo-driven catalytic process enables decarboxylative C–H trifluoromethylation of (hetero)arenes with trifluoroacetic acid as a trifluoromethyl source in good yields in the presence of an external oxidant in far lower than stoichiometric amounts (for example, 0.2 equivalents of Na2S2O8) using Rh-modified TiO2 nanoparticles as a photocatalyst, in which H2 release is an important driving force for the reaction. Our findings not only provide an approach to accessing valuable decarboxylative C–H trifluoromethylations via activation of abundant but inert trifluoroacetic acid towards oxidative decarboxylation and trifluoromethyl radical formation, but also demonstrate that a photo-driven catalytic process is a promising way to achieve external oxidant-free C–H functionalization reactions.


Instrument.
The 365 nm ultra-violet irradiation was obtained by using high pressure mercury lamp (100 W/250 W/400 W/1 kW). The visible light irradiation was provided by 300 W Xe lamp (PLS-SXE300C, Beijing Perfect Light Co.) equipped with a 420 nm cutoff filter. XPS analysis was carried out on a Thermofisher ESCALAB 250 X-ray photoelectron spectrometer with a chromatized Al Kα source (15 kV, 150W). XRD measurements were carried out on Rigaku MiniFlexⅡ using Cu Kα as radiation source (λ = 0.15064 nm) at 30 kV and 15 mA. TEM and SEAD observation was made on JEOL JEM-2010. The preparations of TEM samples were carried out by depositing a drop of the nanoparticle suspension, which was redispersed by ultrasonics, onto a continuous carbon-coated copper grid and dried at room temperature under atmospheric pressure. Gas chromatographic (GC) analysis for H2 determination was conducted using an Agilent 7820A gas chromatography equipped with a thermal conductivity detector (TCD) and a TD-01 packed column, using Ar as the carrier gas. 1 H, 13 C, and 19 F NMR spectra were recorded on Burker Avance 400 NMR spectrometer. Data for 1 H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (Hz), integration. Data for 13 C NMR are reported in terms of chemical shift (δ, ppm). 19 F NMR spectra are reported in terms of chemical shift (δ, ppm).
Preparation of 0.1 wt% Rh-modified anatase TiO2 nanopaticles. In a 30 mL quartz round bottom flask, a mixture of 60 nm anatase TiO2 (3.0 g) and RhCl3•xH2O (0.023 g, Rh content of 39 %) was deoxygenated and filled with N2, followed by addition of deoxygenated methanol (30 mL). The suspension was stirred with an irradiation of 250 W high pressure Hg lamp (365 nm UV) for 48 h. After illumination, nanocatalysts were separated from the solution by centrifugation (8000 rpm, 2 min, 298 K). The separated nanocatalysts were washed for three times by ethanol and three times by water, dried in vacuum at 298 K for 8 h. The Rh content of as-prepared nanocatalyst was 0.1 wt% by the inductively coupled plasma (ICP) analysis.

Typical reaction A (trifluoromethylation reaction of caffeine was used as an example).
photocatalyst (0.016 g, 0.2 mmol), caffeine (0.0971 g, 0.5 mmol) and Na2S2O8 (0.0238 g, 0.1 mmol) were introduced into a Schlenk tube. Then, the tube was fitted with a rubber septum. After evacuation and N2 backfill for three times, distilled trifluoroacetic acid (15 mL) was added to the Schlenk tube through the rubber septum using syringes, and the rubber septum was replaced by a Teflon cap under N2 flow. The reaction was performed under illumination of 250 W high pressure Hg lamp (365 nm UV) at room temperature for 48 hours. After reaction, the trifluoroacetic acid was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: EtOAc/hexanes) to provide the corresponding product. The yield were also determined by 19 F NMR spectrum using 1-methoxy-4-(trifluoromethoxy)benzene (76 μL, 0.5 mmol, δ -58.4 ppm) as an internal reference.

Typical reaction B (trifluoromethylation reaction of caffeine was used as an example).
Typical reaction B is identical to typical reaction A except that Na2SO4 was used instead of Na2S2O8.
Typical gram scale reaction (trifluoromethylation reaction of caffeine was used as an example). 0.1 wt% Rh/anatase TiO2 nanocatalysts of (0.04 g, 0.5 mmol), caffeine (1 g, 5 mmol) and Na2S2O8 (0.119 g, 0.5 mmol) were introduced into a Schlenk tube. Then, the tube was fitted with a rubber septum. After evacuation and N2 backfill for three times, distilled trifluoroacetic acid (60 mL) was added to the Schlenk tube through the rubber septum using syringes, and the rubber septum was replaced by a Teflon cap under N2 flow. The reaction was performed under illumination of 250 W high pressure Hg lamp (365 nm UV) at room temperature for 120 hours. After reaction, the trifluoroacetic acid was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: EtOAc/hexanes) to provide the corresponding product.
Radical trapping experiment with TEMPO. 0.1 wt% Rh/anatase TiO2 nanocatalysts (0.008 g, 0.1 mmol), TEMPO (0.0781 g, 0.5 mmol) and Na2SO4 (0.14 g, 1 mmol), were introduced into a Schlenk tube. Then, the tube was fitted with a rubber septum. After evacuation and N2 backfill for three times, benzene (46 μL, 0.5 mmol) and 2 mL distilled trifluoroacetic acid was added to the Schlenk tube through the rubber septum using syringes, and the rubber septum was replaced by a Teflon cap under N2 flow. The reaction was performed under illumination of 100 W high pressure Hg lamp (365 nm UV) at room temperature for 2 hours. The resultant mixture was analyzed by 19 F NMR spectroscopy using 1-methoxy-4-(trifluoromethoxy)benzene (76 μL, 0.5 mmol, δ -58.4 ppm) as the internal standard.
Detection of H2 and CO2 formed in the control experiment of trifluoroacetic acid. 0.1 wt% Rh/anatase TiO2 nanocatalysts (0.016 g, 0.2 mmol) and Na2SO4 (0.14 g, 1 mmol) were introduced into a Schlenk tube. Then, the tube was fitted with a rubber septum. After evacuation and N2 backfill for three times, distilled trifluoroacetic acid (15 mL) was added to the Schlenk tube through the rubber septum using syringes, and the rubber septum was replaced by a Teflon cap under N2 flow. The reaction was performed under illumination of 250 W high pressure Hg lamp (365 nm UV) at room temperature for 24 hours. After reaction, the atmosphere of reaction (1 mL) in schlenk tube was injected into GC instrument. The oven temperature was held constant at 40 °C for 20 min, then it was raised to 250 °C with 15°C/min. Inlet and detector temperature were set at 120 °C and 200 °C, respectively. Synthesis of CF3I. 0.1 wt% Rh/anatase TiO2 nanocatalysts (0.016 g, 0.1 mmol) and I2 (0.127 g, 1 mmol) were introduced to a Schlenk tube. Then, the tube was fitted with a rubber septum. After evacuation and N2 backfill for three times, distilled trifluoroacetic acid (15 mL) was added to the Schlenk tube through the rubber septum using syringes, and the rubber septum was replaced by a Teflon cap under N2 flow. The reaction was performed under illumination of 250 W high pressure Hg lamp (365 nm UV) at room temperature for 24 hours. The yield was determined by 19 F NMR spectrum using 1-methoxy-4-(trifluoromethoxy)benzene (76 μL, 0.5 mmol, δ -58.4 ppm) as the internal standard..

Characterization of photocatalysts.
The characterization of as-prepared photocatalysts was carried out using XPS, XRD, TEM, HRTEM, and ICP. After catalytic reaction, the suspension was centrifuged (8000 rpm, 2 min, 298 K) for separating nanocatalysts from the solution. And then the separated nanocatalysts were washed for 3 times with ethanol and 3 times with water, dried in vacuum at 298 k for 10 h. The measurements of separated nanocatalysts for XPS, XRD, TEM and ICP were performed.
The typical reaction B was followed with fluorobenzene (47 μL, 0.5 mmol), 0.1wt% Rh/anatase TiO2 (0.008 g, 0.1 mmol), Na2SO4 (0.14 g, 1 mmol) and a reaction time of 72 hours. The reaction mixture was analyzed directly by 19 F NMR (47 %, o/m/p = 1/1.3/1). Due to the availability of the products, no purification was attempted on this reaction mixture. The fluorine signals of the products were identical to those of the commercial samples.
Due to the availability of the products, no purification was attempted on this reaction mixture. The fluorine signals of the products were identical to those of the commercial samples.
Due to the availability of the products, no purification was attempted on this reaction mixture. The fluorine signals of the products were identical to those of the commercial samples.
The identities of trifluoromethylated products of 2m were verified by synthesis of authentic samples from their corresponding phenols in analogy to a literature procedure. 1