ethyl 2,2-difluoro-2-iodoacetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.5 g, 2.092 mmol) in DMSO (10 mL) was added ethyl 2,2-difluoro-2-iodoacetate (0.410 mL, 2.000 mmol) and copper (0.439 g, 6.90 mmol) at rt. The mixture was stirred at 20° C. for 10 h. The mixture was extracted with EA, washed with brine, and the organic layer was concentrated to give ethyl 2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate (320 mg, 0.981 mmol, 46.9% yield): 1H NMR (400 MHz, CD3OD-d4) δ 7.72 (d, J=7.8 Hz, 1H), 7.60-7.45 (m, 3H), 4.26 (d, J=7.1 Hz, 2H), 3.63 (t, J=16.9 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H). The mixture was extracted with EA washed with brine the organic layer was concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound: After 20 h the mixture was transferred to a separatory funnel extracted with ethyl acetate (2×50 mL) The organic extracts were washed with saturated aq. brine dried (sodium sulfate) decanted evaporated Purification by flash column chromatography on silica gel eluting with 70:30 v/v hexanes/ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound: After 20 h the mixture was transferred to a separatory funnel extracted with ethyl acetate (2×50 mL) The organic extracts were washed with saturated aq. brine dried (sodium sulfate) decanted evaporated Purification by flash column chromatography on silica gel eluting with 70:30 v/v hexanes/ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound: After 20 h the mixture was transferred to a separatory funnel extracted with ethyl acetate (2×50 mL) The organic extracts were washed with saturated aq. brine dried (sodium sulfate) decanted evaporated Purification by flash column chromatography on silica gel eluting with 70:30 v/v hexanes/ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound: After 20 h the mixture was transferred to a separatory funnel extracted with ethyl acetate (2×50 mL) The organic extracts were washed with saturated aq. brine dried (sodium sulfate) decanted evaporated Purification by flash column chromatography on silica gel eluting with 70:30 v/v hexanes/ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986,27,6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at RT. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with EtOAc (2×50 mL). The organic extracts were washed with saturated aq. NaCl, dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/EtOAc, gave 363 mg of the title compound as an amber liquid. For the title compound: 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J=9, 1H), 7.53 (d, J=9, 1H), 4.43 (q, J=7, 2H), 2.82 (s, 3H), 1.38 (t, J=7, 3H). After 20 h the mixture was transferred to a separatory funnel extracted with EtOAc (2×50 mL) The organic extracts were washed with saturated aq. NaCl dried (Na2SO4) decanted evaporated Purification by flash column chromatography on silica gel eluting with 70:30 v/v hexanes/EtOAc

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (32 mg, 0.06 mmol, prepared as described in Procedure 14) in DMF (0.5 mL) was added Cs2CO3 (39 mg, 0.12) and ICF2CO2Et (28 mg, 0.12 mmol). The mixture was heated at 60° C. for 3 days. NaHCO3 was added. It was extracted with CH2Cl2. The organic layer was washed with 10% citric acid, brine, dried over MgSO4, concentrated and the crude mixture was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5 μ) using MeOH/H2O (0.1% TFA) to give two products, (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-ethoxy-5-fluorophenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (2.5 mg, 7% yield) as a pale yellow solid, LCMS: 4.38 min [M+1] 561.44 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 1.33-1.40 (m, J=6.88, Hz, 3 H), 3.61 (d, J=12.88 Hz, 1 H), 3.93-4.00 (m, 2 H), 4.54 (d, J=12.88 Hz, 1 H), 6.49-6.56 (m, 3 H), 6.76 (dt, J=9.85, 1.89 Hz, 1 H), 6.84 (s, 1 H), 7.02 (t, J=7.45 Hz, 2 H), 7.11 (t, J=7.33 Hz, 1 H), 7.22-7.31 (m, 3 H), 7.70 (dd, J=8.59, 2.27 Hz, 1 H), 7.85-7.90 (m, 1 H), 8.03 (dd, J=6.82, 2.02 Hz, 1 H), 8.32 (d, J=2.53 Hz, 1 H), 9.11 (s, 1 H), and (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-(difluoromethoxy)-5-fluorophenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (3 mg, 7% yield) as a pale yellow foam, LCMS: 4.28 min [M+1] 583.32 (4 min gradient, MeOH/H2O 0.1% TFA); 1 H NMR (400 MHz, CDCl3) δ ppm 3.61 (d, J=12.88 Hz, 1 H), 4.54 (d, J=12.88 Hz, 1 H), 6.51 (m, 3 H), 6.76-6.83 (m, 1 H), 7.00-7.08 (m, 4 H), 7.13 (t, J=7.45 Hz, 1 H), 7.20-7.29 (m, 2 H), 7.74 (dd, J=8.59, 2.27 Hz, 1 H), 7.87 (ddd, J=8.46, 4.67, 2.27 Hz, 1 H), 8.02 (dd, J=6.69, 1.89 Hz, 1 H), 8.35 (d, J=2.27 Hz, 1 H), 9.11 (s, 1 H). It was extracted with CH2Cl2 The organic layer was washed with 10% citric acid, brine dried over MgSO4 concentrated the crude mixture was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5 μ)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound: After 20 h the mixture was transferred to a separatory funnel extracted with ethyl acetate (2×50 mL) The organic extracts were washed with saturated aq. brine dried (sodium sulfate) decanted evaporated Purification by flash column chromatography on silica gel eluting with 70:30 v/v hexanes/ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl iododifluoroacetate (73.4 g, 74% yield) could also be prepared from 2-iodo-1,1,2,2-tetrafluoroethyl fluorosulfate (130.4 g, 0.4 mol), potassium fluoride (23.2 g, 0.4 mol) and ethanol (150 mL) according to the procedure described in Experiment (3a).

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.5 g, 2.092 mmol) in DMSO (10 mL) was added ethyl 2,2-difluoro-2-iodoacetate (0.410 mL, 2.000 mmol) and copper (0.439 g, 6.90 mmol) at rt. The mixture was stirred at 20° C. for 10 h. The mixture was extracted with EA, washed with brine, and the organic layer was concentrated to give ethyl 2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate (320 mg, 0.981 mmol, 46.9% yield): 1H NMR (400 MHz, CD3OD-d4) δ 7.72 (d, J=7.8 Hz, 1H), 7.60-7.45 (m, 3H), 4.26 (d, J=7.1 Hz, 2H), 3.63 (t, J=16.9 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H). The mixture was extracted with EA washed with brine the organic layer was concentrated