Defluoroalkylation of Trifluoromethylarenes with Hydrazones: Rapid Access to Benzylic Difluoroarylethylamines

Here, we report an efficient and modular approach toward the formation of difluorinated arylethylamines from simple aldehyde-derived N,N-dialkylhydrazones and trifluoromethylarenes (CF3-arenes). This method relies on selective C–F bond cleavage via reduction of the CF3-arene. We show that a diverse set of CF3-arenes and CF3-heteroarenes react smoothly with a range of aryl and alkyl hydrazones. The β-difluorobenzylic hydrazine product can be selectively cleaved to form the corresponding benzylic difluoroarylethylamines.


I-D. General Photoredox Reaction Setup
The reactions were ran in a shallow oil bath at elevated temperatures (Photo 1). A 15 W LED array lamp was used as the light source. It was positioned approximately 6 inches above the reaction vials (Photo 2).

II. Optimization Details Optimization Procedure
An 8 mL oven-dried screw-top test tube was charged with 4CzIPN (1 mol%, 0.001 mol), sodium formate (4.0 equiv, 0.4 mmol), mesna (20 mol%, 0.02 mol), and (E)-3-phenyl-N-(piperidin-1yl)propan-1-imine S6 (1.0 equiv, 0.1 mmol). The tube was equipped with an oven-dried stir bar and sealed with a PTFE/silicon septum. Under nitrogen atmosphere, separately degassed DMSO (1 mL) was added via syringe, followed by 1,3-bis(trifluoromethyl)benzene (3.0 equiv, 0.3 mmol). The resulting mixture was heated to 80 °C in an oil bath and stirred at 700 RPM for 16 h under irradiation by blue LEDs. The reaction was cooled to room temperature and 2-(trifluoromethyl)pyridine (0.1 mmol) was added as the internal standard. A small aliquot of the reaction mixture was diluted in d6-DMSO and the sample was analyzed by 19 F NMR and the integral values were used to calculate the data given in Table S1.

III-A. Preparation of CF3-Arenes
methyl 2-(3,5-bis(trifluoromethyl)phenyl)acetate (S1): To a solution of 2-(3,5bis(trifluoromethyl)phenyl)acetic acid (5.00 mmol, 1.36 g, 1.0 equiv) dissolved in MeOH (12 mL) was added a few drops of conc. HCl. The reaction was stirred overnight under reflux using a heating mantle. The reaction was allowed to cool to temperature. The reaction was concentrated in vacuo, washed with sat. NaHCO3 (3x) and extracted with EtOAc (2x), dried over Na2SO4 and concentrated in vacuo. The reaction was passed with through a plug of silica gel (20-30% EtOAc/hexanes as eluent) to afford the title compound as a clear oil (1.22 g, 85% yield). The physical properties and spectral data were consistent with reported values.

General Procedure SA
In a screw-top test tube equipped with a stirbar was added a solution of aldehyde (1 equiv) dissolved in DCM. The hydrazine (1.1 equiv) was added to the reaction dropwise followed by the addition of sodium sulfate and stirred overnight. The reaction was filtered and concentrated in vacuo. The crude reaction mixture was purified by silica chromatography to afford the corresponding hydrazone product.

General Procedure A
A 15 mL oven-dried screw-top test tube was charged with 4CzIPN (1 mol%), sodium formate (4.0 equiv), mesna (20 mol%) hydrazone (1.0 equiv, if solid or oil) and CF3-arene (3.0 equiv, if solid or oil). The tube was equipped with a stir bar and was sealed with a PTFE/silicon septum. The atmosphere was exchanged by applying vacuum and backfilling with nitrogen (this process was conducted a total of three times). Under nitrogen atmosphere, the degassed solvent (DMSO, 0.1 M) was added via syringe followed by hydrazone (1.0 equiv, if liquid) and CF3-arene (3.0 equiv, if liquid) The resulting mixture was stirred for 16 h under irradiation by blue LEDs at 80 °C in an oil bath. Upon completion, the reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were passed through silica to remove excess DMSO and concentrated in vacuo. The residue was then purified by silica chromatography using the indicated solvent mixture as the eluent to afford the title compound.

General Procedure B
A 15 mL oven-dried screw-top test tube was charged with 4CzIPN (1 mol%), sodium formate (4.0 equiv), mesna (20 mol%), hydrazone (1.0 equiv, if solid or oil) and CF3-arene (3.0 equiv, if solid or oil). The tube was equipped with a stir bar and was sealed with a PTFE/silicon septum. The atmosphere was exchanged by applying vacuum and backfilling with nitrogen (this process was conducted a total of three times). Under nitrogen atmosphere, the degassed solvent (DMSO, 0.1 M) was added via syringe followed by hydrazone (1.0 equiv, if liquid), CF3-arene (3.0 equiv, if liquid) and formic acid (3.0 equiv). The resulting mixture was stirred for 16 h under irradiation by blue LEDs at 80 °C in an oil bath. Upon completion, the reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were passed through silica to remove excess DMSO and concentrated in vacuo. The residue was then purified by silica chromatography using the indicated solvent mixture as the eluent to afford the title compound.
The residue was then purified by silica chromatography (5-20% EtOAc/hexanes as the eluent) to afford the title compound as a yellow oil (316 mg, 77% yield).

N-(1,1-difluoro-4-phenyl-1-(3-(trifluoromethyl)phenyl)butan-2-yl)piperidin-1-amine (3):
A 15 mL screw-top test tube was charged with 4CzIPN (5.00 µmol, 3.93 mg, 1 mol%), sodium formate (2.00 mmol, 136 mg, 4.0 equiv), mesna (0.100 mmol, 0.0164 g, 20 mol%). The tube was equipped with a stir bar and was sealed with a PTFE/silicon septum. The atmosphere was exchanged by applying vacuum and backfilling with nitrogen (this process was conducted a total of three times). Under nitrogen atmosphere, the degassed DMSO (5 mL) was added via syringe followed by 3-phenylpropanal (0.500 mmol, 65.8 µL, 1 equiv), N-aminopiperidine (0.500 mmol, 54.0 µL, 1.0 equiv) and 1,3-bis(trifluoromethyl)benzene (1.50 mmol, 0.233 mL, 3.0 equiv). The reaction was allowed to stir for 5 minutes before placing under lamps. The resulting mixture was stirred for 16 h under irradiation by blue LEDs at 80 °C in an oil bath. Upon completion, the reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were passed through silica to remove excess DMSO and concentrated in vacuo. The residue was purified by silica chromatography (3-12% EtOAc/hexanes as the eluent) to afford the title compound as a yellow oil (107 mg, 52% yield). Raney nickel (0.310 g). The atmosphere was exchanged for N2 (3x) and freshly degassed MeOH (2.5 mL) was added via syringe. The reactions atmosphere was sparged with H2 gas. The reaction was heated to 55 °C using a heating mantle and stirred under a balloon of H2 for 16 hours. The reaction was cooled to room temperature, filtered through celite and concentrated. The crude material was purified via silica chromatography (5-30% EtOAc/hexanes as the eluent) to afford the title compound as a clear oil (25.9 mg, 79% yield  The tube was equipped with a stir bar and sealed with a PTFE/silicon septum. Under nitrogen atmosphere, separately degassed DMSO (1 mL) was added via syringe, followed by 1,3bis(trifluoromethyl)benzene (0.300 mmol, 47.0 µL, 3.0 equiv) and dimethyl disulfide (0.020 mmol, 1.80 µL, 20 mol%). The resulting mixture was heated to 80 °C and stirred at 700 RPM for 16 h under irradiation by blue LEDs. The reaction was cooled to room temperature and 2-(trifluoromethyl)pyridine (0.1 mmol) was added as the internal standard. A small aliquot of the reaction mixture was diluted in d6-DMSO and the sample was analyzed by 19 F NMR. The integral values were used to calculate the yield of the product (59% yield).