gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu4NBF4 or electrogenerated acid

gem-Difluorination of carbon–carbon triple bonds was conducted using Brønsted acids, such as Tf2NH and TfOH, combined with Bu4NBF4 as the fluorine source. The electrochemical oxidation of a Bu4NBF4/CH2Cl2 solution containing alkyne substrates could also give the corresponding gem-difluorinated compounds (in-cell method). The ex-cell electrolysis method was also applicable for gem-difluorination of alkynes.

To the suspension of LiAlH4 (1.54 g, 40.6 mmol) in THF (100 mL) at 0 o C was slowly added a solution of 4-phenylbutanoic acid (6.58 g, 40.1 mmol)/THF (32 mL), and reaction temperature was increased to room temperature.Then, the solution was refluxed for 4 h.After the reaction, temperature was cooled to 0 o C, and H2O (1.5 mL), aqueous 15% NaOH (1.5 mL), and H2O (4.5 mL) were added to quench the reaction.After the celite filtration of the solution, the water in the solution was removed by MgSO4, which was filtered and concentrated under reduced pressure to give 4-phenylbutan-1ol (1a-I, 4.76 g, 31.7 mmol, 79% crude yield) as the crude material.This compound was identified by the comparison of the reported spectroscopic data. 2 Because the purity of the crude material was high, synthesized 4-phenylbutan-1-ol (1a-I) was used in the next step without the further purification.

Synthesis of 10-iododec-1-yne (1i).
To the solution of PPh3 (1.55 g, 5.9 mmol), I2 (1.52 g, 6.0 mmol), and imidazole (0.67 g, 9.8 mmol) in CH2Cl2 (30 mL), was slowly added dec-9-yn-1-ol (0.66 g, 4.3 mmol) at room temperature.The solution was stirred at room temperature for 2 h.Then, the solution was refluxed for 1 h.The reaction was quenched by the addition of the saturated aqueous Na2S2O3 (30 mL).CH2Cl2 (30 mL) was added to the solution and separated.The aqueous phase was extracted by CH2Cl2 (30 mL x 2), and the combined organic extract was washed by brine (30 mL), followed by dried over MgSO4.After the filtration and the concentration under reduced pressure, the crude product was purified by the flash chromatography (hexane/AcOEt = 30:1) to give 10-iododec-1-yne (1i, 0.94 g, 3.6 mmol, 84% yield).This compound was identified by the comparison of the reported spectroscopic data. 4

Typical procedure for the gem-difluorination in method A (Table 1, entry 2).
To the solution of Bu4NBF4 (823.0 mg, 2.5 mmol) in CH2Cl2 (4.0 mL), were added hex-5-yn-1ylbenzene (1a, 78.6 mg, 0.497 mmol) and Tf2NH (694.4 mg, 2.5 mmol).The reaction was stirred for 16 h at room temperature.Then, the reaction mixture was cooled to 0 o C and Et3N (1.0 mL) was added to quench the reaction.After the concentration of the solution under reduced pressure, the residue was quickly filtered through a short column (9.4 × 3.2 cm) of silica gel by Et2O to remove Bu4NBF4 and others.The silica gel was washed with Et2O.The crude product was evaluated by 19 F NMR using trifluorotoluene (CF3C6H5) (34.5 mg, 0.236 mmol) as an internal standard, indicating (5,5difluorohexyl)benzene (2a) was obtained in 83% yield.Then, the crude product was purified via the flash chromatography (hexane) to give (5,5-difluorohexyl)benzene (2a, 71.1 mg, 0.359 mmol, 72% yield).In this step, 19 F NMR was also measured to confirm the absence of trifluorotoluene.This compound was identified by the comparison of the reported spectroscopic data. 5her entries in Tables 1 and 2 were conducted according to the above procedure.If necessary, the preparative GPC separation was carried out for the crude products to purify and isolate the desired products.

Typical procedure for the gem-difluorination in method B (Scheme 1, 16 mA).
The electrochemical oxidation was carried out in an H-type divided cell (4G glass filter), which was equipped with a carbon felt anode and a platinum plate cathode (20 mm × 20 mm).In the cathodic and anodic chambers, 0.3 M Bu4NBF4/CH2Cl2 (8.0 mL × 2) was added.Then, hex-5-yn-1-ylbenzene (1a, 79.4 mg, 0.502 mmol) was added to the anodic solution.The constant current electrolysis (16 mA, 3.0 F/mol based on 1a) at room temperature was conducted.After the consumption of the electricity, Et3N (1.0 mL × 2) was added to both chambers to quench the reaction.After the concentration of the solution under reduced pressure, the residue was quickly filtered through a short column (9.4 × 3.2 cm) of silica gel by Et2O to remove Bu4NBF4 and others.The crude product was evaluated by 19 F NMR using trifluorotoluene (CF3C6H5) (33.4 mg, 0.229 mmol) as an internal standard, indicating (5,5difluorohexyl)benzene (2a) was obtained in 42% yield.Then, the obtained crude product was purified by the preparative GPC separation to give (5,5-difluorohexyl)benzene (2a, 29.0 mg, 0.146 mmol, 29% yield).In this step, 19 F NMR was also measured to confirm the absence of trifluorotoluene.This compound was identified by the comparison of the reported spectroscopic data. 5,3-Difluorobutyl)benzene (2b) 6 and 2-(4,4-difluoropentyl)isoindoline-1,3-dione (2h) 7 were fully identified by the comparison of the reported spectroscopic data.
, 43 (100).This compound was not detected by HRMS (ESI).The related aliphatic difluorinated compound such as 2,2difluorododecane was detected by GC-MS in the literature, 9 in which [M-HF] + was confirmed.Because of the reason, we also carried out the analysis of GC-MS for 2d, as described above.