(R)-Benzyl 2-((5-bromo-1H-indol-3-yl)methyl)pyrrolidine-1-carboxylate

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

Procedure: (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole(0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2. warmed to reflux for 16 hours After cooling to room temperature 2NHCl (10 mL) was added dropwise the reaction mixture partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×) dried (Na2SO4) evaporated in vacuo to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: 3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylcarbonyl)-5-bromo-1H-indole (WO-A-92/06973; 0.67 g, 1.57 mmol) was dissolved in dry tetrahydrofuran (20 ml) and, at room temperature under nitrogen, lithium borohydride (2M solution in tetrahydrofuran; 1.2 ml, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, heated under reflux for 16 hours, then allowed to cool to room temperature. 2M Hydrochloric acid (10 ml) was added dropwise and the reaction mixture then partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (×2) and brine (×1), dried (Na2SO4), and evaporated under reduced pressure to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane, gave the title compound as an oil (0.32 g). Rf 0.20 (SS 16). Found: C,59.94; H,5.07; N,6.58. C21H21BrN2O2 ; 0.10 CH2Cl2 requires C,60.08; H,5.07; N,6.64%. δ(CDCl3)--mixture of rotamers: 1.63-1.90 (4H, m), 2.60-2.82 (1H, m), 3.10-3.28 (1H, m), 3.30-3.54 (2H, m), 4.18 (1H, m), 5.15-5.25 (2H, m), 5.30 (0.2H, s, CH2Cl2), 6.90 and 6.95 (1H, 2×s), 7.05-7.50 (7H, m), 7.70 and 7.85 (1H, 2×s), 8.25 (1H, br s). heated under reflux for 16 hours to cool to room temperature the reaction mixture then partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (×2) and brine (×1) dried (Na2SO4) evaporated under reduced pressure to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and 3-ethylpent-1-en-3-ol (Example 9(a)), as a foam. Rf 0.66 (SS 7). [α]D25 -27° (c=0.1, CH3OH). Found: C,75.33; H,+.29; N,5.65. C28H34N2O3 requires C,75.30; H,7.67; N,6.26%. Obtained by a procedure similar to

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

Procedure: Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and methyl vinyl ketone, as a foam. Rf 0.60 (SS 7). [α]D25 -51° (c=0.1, CH3OH). Found: C,74.16; H,6.39; N,6.92. C25H26N2O3 requires C,74.60; H,6.51; N,6.96%. Obtained by a procedure similar to

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

Procedure: Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and methyl vinyl ketone, as a foam. Rf 0.60 (SS 7). [α]D25 -51° (c=0.1, CH3OH). Found: C,74.16; H,6.39; N,6.92. C25H26N2O3 requires C,74.60; H,6.51; N,6.96%. Obtained by a procedure similar to

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

Procedure: Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and 1-vinylcyclopentanol (Example 5(a)), as a foam. Rf 0.40 (SS 10). [α]D25 -31° (c=0.1, CH3OH). Found: C,75.58; H,7.24; N,6.22. C28H32N2O3 requires C,75.64; H,7.26; N,6.30%. Obtained by a procedure similar to

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

Procedure: 3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylcarbonyl)-5-bromo-1H-indole (WO-A-92/06973; 0.67 g, 1.57 mmol) was dissolved in dry tetrahydrofuran (20 ml) and, at room temperature under nitrogen, lithium borohydride (2M solution in tetrahydrofuran; 1.2 ml, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, heated under reflux for 16 hours, then allowed to cool to room temperature. 2M Hydrochloric acid (10 ml) was added dropwise and the reaction mixture then partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (x2) and brine (x1), dried (Na2SO4), and evaporated under reduced pressure to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane, gave the title compound as an oil (0.32 g). Rf 0.20 (SS 16). Found: C,59.94; H,5.07; N,6.58. C21H21 BrN2O2 ; 0.10 CH2Cl2 requires C,60.08; H,5.07; N,6.64%. heated under reflux for 16 hours to cool to room temperature the reaction mixture then partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (x2) and brine (x1) dried (Na2SO4) evaporated under reduced pressure to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole (0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2x), brine (1x), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2. warmed to reflux for 16 hours After cooling to room temperature 2NHCl (10 mL) was added dropwise the reaction mixture partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2x), brine (1x) dried (Na2SO4) evaporated in vacuo to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole (0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2x), brine (1x), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2. warmed to reflux for 16 hours After cooling to room temperature 2NHCl (10 mL) was added dropwise the reaction mixture partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2x), brine (1x) dried (Na2SO4) evaporated in vacuo to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole(0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2. warmed to reflux for 16 hours After cooling to room temperature 2NHCl (10 mL) was added dropwise the reaction mixture partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×) dried (Na2SO4) evaporated in vacuo to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole (0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2. warmed to reflux for 16 hours After cooling to room temperature 2NHCl (10 mL) was added dropwise the reaction mixture partitioned between ethyl acetate and water The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2×), brine (1×) dried (Na2SO4) evaporated in vacuo to give a colourless oil Purification by column chromatography on silica gel eluting with dichloromethane

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

Procedure: A stirred mixture of 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 2; 0.43 g, 1.04 mmol), ethyl vinyl sulphone (0.17 g, 1.4 mmol), tri-o-tolylphosphine (91 mg), palladium(II) acetate (16 mg), triethylamine (0.31 ml) and acetonitrile (4 ml), under nitrogen, was heated under reflux for 18 hours, allowed to cool, then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a dichloromethane to dichloromethane:ethanol (99:1) gradient, to afford the title compound as a foam (0.34 g). Rf 0.80 (SS 2). [α]D25 -50° (c=0.1, CH3OH). Found: C,65.16; H,6.17; N,5.97. C25H28N2O4S; 0.125 CH2Cl2 requires C,65.15; H,6.15; N,6.05%. δ(CDCl3)--mixture of rotamers: 1.42(3H,t), 1.70-1.88(4H,m), 2.78(1H,m), 3.05-3.48(5H,m), 4.20(1H,m), 5.16-5.28(2H, br q), 5.30(0.25H,s,CH2Cl2), 6.64-7.82(1H,m), 6.96 and 7.05(1H, 2×s), 7.30-7.45(7H,m), 7.55-7.80 and 8.00(2H, m and s), 8.32(1H,br s). under nitrogen, was heated under reflux for 18 hours to cool evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with a dichloromethane to dichloromethane:ethanol (99:1) gradient