2-(4-Iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: While under an atmosphere of argon, a solution of tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate (7.00 g, 20.06 mmol) in freshly distilled (THF 50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (60 mL, 1.0 M in THF). After stirring for 10 min 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.4 g, 40.0 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. Next, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave tert-butyl 2-(diphenylmethyleneamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (8.50 g, 80%). Rf 0.55 (30% ethyl acetate in heptane). ESI MS found for C33H46BNO4 m/z [532.5 (M+1)]. was added the reaction was warmed to room temperature Next, the reaction mixture was cooled to 0° C. washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl dried over MgSO4 filtered concentrated Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: While under an atmosphere of argon, a solution of tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate (7.00 g, 20.06 mmol) in freshly distilled (THF 50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (60 mL, 1.0 M in THF). After stirring for 10 min 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.4 g, 40.0 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. Next, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave tert-butyl 2-(diphenylmethyleneamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (8.50 g, 80%). Rf 0.55 (30% ethyl acetate in heptane). ESI MS found for C33H46BNO4 m/z [532.5 (M+1)]. was added the reaction was warmed to room temperature Next, the reaction mixture was cooled to 0° C. washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl dried over MgSO4 filtered concentrated Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV)

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

Procedure: While under a nitrogen atmosphere, a solution of tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate (450 mg, 1.0 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.0 mL, 1.0 M in tetrahydrofuran, 2.0 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (931 mg, 3.0 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, and then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane) gave tert-butyl 2-(2-(4-chlorophenoxy)ethyl)-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (486 mg. 77%); 1H NMR (CDCl3, 300 MHz) δH 7.54 (d, J=7 Hz, 2H), 7.36 (m, 4H), 7.18-7.32 (m, 6H), 6.82 (d, J=9 Hz, 2H), 4.19 (m, 1H), 4.04 (m, 1H), 2.39 (ddd, J=14 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 2.22 (ddd, J1=13.5 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 1.73 (m, 2H), 1.14-1.46 (m, 4H), 1.34 (s, 9H), 1.18 (s, 12H) and 0.76 (t, J=7 Hz, 2H); MS (+CI): m/z for C37H47BClNO5: expected 631.3. found 632.3 (M+H)+, 576.3 (M+H-isobutene)+. After the addition Stirring extracted with ethyl acetate (3×) The combined organic phase was washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate filtered concentrated Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane)

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

Procedure: A solution of (2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate (4.69 g, 13.27 mmol) and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (d 1.38, 5.96 mL, 8.23 g, 26.5 mmol, 2 equiv) in THF (66 mL, 0.2 M) and HMPA (6.6 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (14.6 mL, 1.0 M, 1.1 equiv) drop wise over 5 min and stirred for 1 h. After warming to room temperature and stirring for an additional 2 h, the solution was cooled to 0° C. and quenched with 0.5 NHC (2-3 equiv). The resulting solution was diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as a white solid (6.66 g, 94%); ESI-LCMS m/z calcd for C31H42BNO2: expected 535.3. found 536.4 (M+H)+. stirring for an additional 2 h the solution was cooled to 0° C. quenched with 0.5 NHC (2-3 equiv) The resulting solution was diluted with heptane washed successively with water and saturated aqueous NaCl dried over MgSO4 filtered concentrated Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV)

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

Procedure: While under a nitrogen atmosphere, a solution of 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.2 g, 0.176 mol, 1.0 equiv) and sodium iodide (52.8 g, 0.35 mol, 2 equiv) in acetone (176 mL, 1.0 M) was heated to 50° C. for 4 h. After cooling to room temperature the solution was concentrated under reduced pressure. The resulting residue was diluted with heptane (200 mL) and filtered through a short pad of silica gel (300 g) wetted with heptane. After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated to give 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (53.5 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.18 (t, J=7.2 Hz, 2H), 1.90-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.24 (s, 12H), 0.79 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C10H20BIO2: expected 310.1. found 311.1 (M+H)+. was concentrated under reduced pressure The resulting residue was diluted with heptane (200 mL) filtered through a short pad of silica gel (300 g) After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated

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

Procedure: While under a nitrogen atmosphere, a solution of 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.2 g, 0.176 mol, 1.0 equiv) and sodium iodide (52.8 g, 0.35 mol, 2 equiv) in acetone (176 mL, 1.0 M) was heated to 50° C. for 4 h. After cooling to room temperature the solution was concentrated under reduced pressure. The resulting residue was diluted with heptane (200 mL) and filtered through a short pad of silica gel (300 g) wetted with heptane. After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated to give 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (53.5 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.18 (t, J=7.2 Hz, 2H), 1.90-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.24 (s, 12H), 0.79 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C10H20BIO2: expected 310.1. found 311.1 (M+H)+. was concentrated under reduced pressure The resulting residue was diluted with heptane (200 mL) filtered through a short pad of silica gel (300 g) After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: While under an atmosphere of argon, a solution of tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate (7.00 g, 20.06 mmol) in freshly distilled (THF 50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (60 mL, 1.0 M in THF). After stirring for 10 min 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.4 g, 40.0 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. Next, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave tert-butyl 2-(diphenylmethyleneamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (8.50 g, 80%). Rf 0.55 (30% ethyl acetate in heptane). ESI MS found for C33H46BNO4 m/z [532.5 (M+1)]. was added the reaction was warmed to room temperature Next, the reaction mixture was cooled to 0° C. washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl dried over MgSO4 filtered concentrated Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV)

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

Procedure: While under a nitrogen atmosphere, a solution of tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate (450 mg, 1.0 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.0 mL, 1.0 M in tetrahydrofuran, 2.0 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (931 mg, 3.0 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, and then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane) gave tert-butyl 2-(2-(4-chlorophenoxy)ethyl)-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (486 mg. 77%); 1H NMR (CDCl3, 300 MHz) δH 7.54 (d, J=7 Hz, 2H), 7.36 (m, 4H), 7.18-7.32 (m, 6H), 6.82 (d, J=9 Hz, 2H), 4.19 (m, 1H), 4.04 (m, 1H), 2.39 (ddd, J=14 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 2.22 (ddd, J1=13.5 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 1.73 (m, 2H), 1.14-1.46 (m, 4H), 1.34 (s, 9H), 1.18 (s, 12H) and 0.76 (t, J=7 Hz, 2H); MS (+CI): m/z for C37H47BClNO5: expected 631.3. found 632.3 (M+H)+, 576.3 (M+H-isobutene)+. After the addition Stirring extracted with ethyl acetate (3×) The combined organic phase was washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate filtered concentrated Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane)

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

Procedure: A solution of (2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate (4.69 g, 13.27 mmol) and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (d 1.38, 5.96 mL, 8.23 g, 26.5 mmol, 2 equiv) in THF (66 mL, 0.2 M) and HMPA (6.6 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (14.6 mL, 1.0 M, 1.1 equiv) drop wise over 5 min and stirred for 1 h. After warming to room temperature and stirring for an additional 2 h, the solution was cooled to 0° C. and quenched with 0.5 N HC (2-3 equiv). The resulting solution was diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as a white solid (6.66 g, 94%); ESI-LCMS m/z calcd for C31H42BNO2: expected 535.3. found 536.4 (M+H)+. stirring for an additional 2 h the solution was cooled to 0° C. quenched with 0.5 N HC (2-3 equiv) The resulting solution was diluted with heptane washed successively with water and saturated aqueous NaCl dried over MgSO4 filtered concentrated Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV)

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

Procedure: While under a nitrogen atmosphere, a solution of 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.2 g, 0.176 mol, 1.0 equiv) and sodium iodide (52.8 g, 0.35 mol, 2 equiv) in acetone (176 mL, 1.0 M) was heated to 50° C. for 4 h. After cooling to room temperature the solution was concentrated under reduced pressure. The resulting residue was diluted with heptane (200 mL) and filtered through a short pad of silica gel (300 g) wetted with heptane. After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated to give 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (53.5 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.18 (t, J=7.2 Hz, 2H), 1.90-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.24 (s, 12H), 0.79 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C10H20BIO2: expected 310.1. found 311.1 (M+H)+. was concentrated under reduced pressure The resulting residue was diluted with heptane (200 mL) filtered through a short pad of silica gel (300 g) After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated

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

Procedure: A solution of (2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate (4.69 g, 13.27 mmol) and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (d 1.38, 5.96 mL, 8.23 g, 26.5 mmol, 2 equiv) in THF (66 mL, 0.2 M) and HMPA (6.6 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (14.6 mL, 1.0 M, 1.1 equiv) drop wise over 5 min and stirred for 1 h. After warming to room temperature and stirring for an additional 2 h, the solution was cooled to 0° C. and quenched with 0.5 NHC (2-3 equiv). The resulting solution was diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as a white solid (6.66 g, 94%); ESI-LCMS m/z calcd for C31H42BNO2: expected 535.3. found 536.4 (M+H)+. stirring for an additional 2 h the solution was cooled to 0° C. quenched with 0.5 NHC (2-3 equiv) The resulting solution was diluted with heptane washed successively with water and saturated aqueous NaCl dried over MgSO4 filtered concentrated Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV)

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

Procedure: While under a nitrogen atmosphere, a solution of 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.2 g, 0.176 mol, 1.0 equiv) and sodium iodide (52.8 g, 0.35 mol, 2 equiv) in acetone (176 mL, 1.0 M) was heated to 50° C. for 4 h. After cooling to room temperature the solution was concentrated under reduced pressure. The resulting residue was diluted with heptane (200 mL) and filtered through a short pad of silica gel (300 g) wetted with heptane. After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated to give 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (53.5 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.18 (t, J=7.2 Hz, 2H), 1.90-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.24 (s, 12H), 0.79 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C10H20BIO2: expected 310.1. found 311.1 (M+H)+. was concentrated under reduced pressure The resulting residue was diluted with heptane (200 mL) filtered through a short pad of silica gel (300 g) After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated