1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol

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

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

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

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

Procedure: A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to 8° C. while stirring overnight (18 h) The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (500 mg, 2.19 mmol), (S)-3-isocyanato-2,2-dimethyl-butane (845 mg, 5.58 mmol), and DBU (681 mg, 5.9 mmol) in THF (10 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column to give 6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (80 mg, crude). was heated to reflux for 25 h washed with 1 N aq HCl The aqueous phase was extracted with EtOAc (3×) The combined organic phase was dried over Na2SO4 After the solvents were evaporated the crude product was purified by column

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

Procedure: A 1000-mL flask was charged with anhydrous CeCl3 (50 g, 0.2 mol) and THF (360 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C., and a solution of allylmagnesium bromide (1.0 M in THF, 188.2 mL, 188 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (22.6 g, 120 mmol) in THF (269 mL) was added dropwise. The reaction mixture was allowed to slowly warm to rt while stirring overnight. The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (23.8 g, 87%) as an oil. 1H NMR (CDCl3): 2.27 (m, 1H), 2.31 (m, 2H), 2.50 (m, 1H), 2.69 (m, 1H), 3.19 (m, 1H), 3.52 (m, 1H), 5.16 (m, 2H), 5.51 (m, 1H), 7.04 (m, 2H), 7.35 (m, 2H). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to rt while stirring overnight The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to 8° C. while stirring overnight (18 h) The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M−OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to 8° C. while stirring overnight (18 h) The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M−OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m). The suspension was then cooled to −78° C. After stirring for 2 h at −78° C. to slowly warm to 8° C. while stirring overnight (18 h) The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc

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

Procedure: A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (760 mg, 3.3 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5 mmol), KI (1.1 g, 6.7 mmol) and K2CO3 (920 mg, 6.7 mmol) in acetonitrile (33 mL) was heated to reflux overnight. The reaction mixture was filtered. The filtrate was condensed to give the crude product, which was purified by preparative TLC to afford (3S)-tert-butyl-3-(3-(4-fluorophenyl) -3-hydroxyhex-5-enylamino)piperidine-1-carboxylate (500 mg, 38%). 1H NMR: (CDCl3): 1.23 (m, 1H), 1.38 (d, 9H), 1.57 (m, 1H), 1.75 (broad, 1H), 1.94 (m, 2H), 2.37 (m, 1H), 2.43 (m, 2H), 2.56 (m, 1H), 2.80 (broad, 3H), 3.49 (broad, 1H), 3.71 (broad, 3H), 4.95 (d, 2H), 5.56 (m, 1H), 6.95 (t, 2H), 7.32 (m, 2H). was heated to reflux overnight The reaction mixture was filtered condensed to give the crude product, which was purified by preparative TLC

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

Procedure: A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (760 mg, 3.3 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5 mmol), KI (1.1 g, 6.7 mmol) and K2CO3 (920 mg, 6.7 mmol) in acetonitrile (33 mL) was heated to reflux overnight. The reaction mixture was filtered. The filtrate was condensed to give the crude product, which was purified by preparative TLC to afford (3S)-tert-butyl-3-(3-(4-fluorophenyl) -3-hydroxyhex-5-enylamino)piperidine-1-carboxylate (500 mg, 38%). 1H NMR: (CDCl3): 1.23 (m, 1H), 1.38 (d, 9H), 1.57 (m, 1H), 1.75 (broad, 1H), 1.94 (m, 2H), 2.37 (m, 1H), 2.43 (m, 2H), 2.56 (m, 1H), 2.80 (broad, 3H), 3.49 (broad, 1H), 3.71 (broad, 3H), 4.95 (d, 2H), 5.56 (m, 1H), 6.95 (t, 2H), 7.32 (m, 2H). was heated to reflux overnight The reaction mixture was filtered condensed to give the crude product, which was purified by preparative TLC

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

Procedure: A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78 ° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78 ° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ-116.52 (m). The suspension was then cooled to −78 ° C. After stirring for 2 h at −78 ° C. to slowly warm to 8° C. while stirring overnight (18 h) The reaction was then quenched with satd aq NaHCO3 extracted with EtOAc dried over Na2SO4 After the solvents were evaporated the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc