3,3,3-trifluoropropyl trifluoromethanesulfonate

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

Procedure: To a cold (−25° C.) stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330 g ISCO) and the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m). After 2 hr stirred for 1 hr The reaction mixture was concentrated to half its volume purified the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil

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

Procedure: To a cold (−25° C.) stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330 g ISCO) and the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m). After 2 hr stirred for 1 hr The reaction mixture was concentrated to half its volume purified the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil

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

Procedure: To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in CH2Cl2 (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was then concentrated to half its volume and was then purified by loading directly on a silica gel column (330 g ISCO) and eluting with CH2Cl2. Obtained Preparation A-1M (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m). After 2 hr stirred for 1 hr The reaction mixture was then concentrated to half its volume was then purified eluting with CH2Cl2 Obtained Preparation A-1M (13.74 g, 53%) as a colorless oil

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

Procedure: To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C The reaction mixture was then extracted with ethyl acetate (3×10 mL) The combined organic extracts were washed with water and brine dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography

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

Procedure: To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C The reaction mixture was then extracted with ethyl acetate (3×10 mL) The combined organic extracts were washed with water and brine dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography

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

Procedure: To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in CH2Cl2 (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half volume, then purified by loading directly on silica gel column (330 g Isco) and eluted with CH2Cl2. Obtained Intermediate S-1F (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m). After 2 hr stirred for 1 hr The reaction mixture was concentrated to half volume purified eluted with CH2Cl2

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

Procedure: To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330 g ISCO) and the product was eluted with DCM to afford Intermediate S-5D (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2 H, t, J=6.15 Hz), 2.49-2.86 (2 H, m). After 2 hr stirred for 1 hr The reaction mixture was concentrated to half its volume purified the product was eluted with DCM to afford Intermediate S-5D (13.74 g, 53%) as a colorless oil

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

Procedure: To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330 g ISCO) and the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2 H, t, J=6.15 Hz), 2.49-2.86 (2 H, m). After 2 hr stirred for 1 hr The reaction mixture was concentrated to half its volume purified the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil

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

Procedure: To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in CH2Cl2 (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half volume, then purified by loading directly on silica gel column (330 g ISCO) and eluted with CH2Cl2. Obtained Preparation 1M (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m). After 2 hr stirred for 1 hr The reaction mixture was concentrated to half volume purified eluted with CH2Cl2 Obtained Preparation 1M (13.74 g, 53%) as a colorless oil

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

Procedure: To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C The reaction mixture was then extracted with ethyl acetate (3×10 mL) The combined organic extracts were washed with water and brine dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography

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

Procedure: To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C The reaction mixture was then extracted with ethyl acetate (3×10 mL) The combined organic extracts were washed with water and brine dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography

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

Procedure: To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C The reaction mixture was then extracted with ethyl acetate (3×10 mL) The combined organic extracts were washed with water and brine dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography