Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis

The discovery of modern medicine relies on the sustainable development of synthetic methodologies to meet the needs associated with drug molecular design. Heterocycles containing difluoromethyl groups are an emerging but scarcely investigated class of organofluoro molecules with potential applications in pharmaceutical, agricultural and material science. Herein, we developed an organophotocatalytic direct difluoromethylation of heterocycles using O2 as a green oxidant. The C–H oxidative difluoromethylation obviates the need for pre-functionalization of the substrates, metals and additives. The operationally straightforward method enriches the efficient synthesis of many difluoromethylated heterocycles in moderate to excellent yields. The direct difluoromethylation of pharmaceutical moleculars demonstrates the practicability of this methodology to late-stage drug development. Moreover, 2′-deoxy-5-difluoromethyluridine (F2TDR) exhibits promising activity against some cancer cell lines, indicating that the difluoromethylation methodology might provide assistance for drug discovery.

multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br). 19 F NMR were recorded on a Varian NMR 400 spectrometer. Mass spectra were obtained using electrospray ionization (ESI) mass spectrometer. Substrates 1 was synthesized according to the literature method. 5 sodium difluoromethane sulfonate (CF 2 HSO 2 Na) was purchased from J&K without further purification.

General procedure for synthesis of quinoxalin-2(1H)-ones
To a 10 mL Schlenk tube equipped with a magnetic stir bar, added quinoxalin-2(1H)-ones 1 (0.2 mmol), CF 2 HSO 2 Na 2 (0.4 mmol) and rose bengal (0.004 mmol, 2 mol%) in DMSO (1.0 mL). Then the mixture was stirred and irradiated by the two 3W green LEDs at room temperature for 12 h. The residue was added water (10 mL) and extracted with ethyl acetate (5 mL  3). The combined organic phase was dried over Na 2 SO 4 . The resulting crude residue was purified via column chromatography on silica gel to afford the desired products.

Evaluation of anti-tumor activity
The in vitro anti-tumor activity of 6d against all cell lines was assessed using the For trifluridine, the same procedures were performed by varying the concentration of the specie in question to determine the cytotoxicity.
Eight standard reaction mixtures in 10 mL schlenk tube were equipped with a magnetic stir bar, added 1a (0.2 mmol, 1.0 equiv), CF 2 HSO 2 Na (0.4 mmol, 2.0 equiv) and rose bengal (0.004 mmol, 2 mol%) in DMSO (1.0 mL). Then the mixture was stirred and irradiated by two 3W green LEDs at room temperature. After 1.5 h, the green LEDs were turned off, and one schlenk tube was removed from the irradiation setup for analysis. The remaining seven schlenk tubes were stirred in the absence of light for an additional 1.5 h. Then, one schlenk tube was removed for analysis, and the green LEDs were turned back on to irradiate the remaining six reaction mixtures.
After an additional 1.5 h of irradiation, the green LEDs were turned off, and one schlenk tube was removed for analysis. The remaining five schlenk tubes were stirred in the absence of light for an additional 1.5 h. Then, schlenk tube was removed for analysis, and the green LED s were turned back on to irradiate the remaining four reaction mixtures. After 1.5 h, the green LEDs were turned off, and one schlenk tube was removed for analysis. The remaining three schlenk tubes were stirred in the absence of light for an additional 1.5 h, then, a schlenk tube was removed for analysis and the green LEDs were turned back on to 8 irradiate the remaining two reaction mixtures. After 1.5 h, the green LEDs were turned off, and one schlenk tube was removed for analysis. The last schlenk tube was stirred in the absence of light for an additional 1.5 h, and then it was analyzed. The yield was determined by 19 F NMR spectroscopy using benzotrifluoride as the internal standard. (1)