5-bromo-3-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-1H-indole

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

Procedure: A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), phenylvinylsulphone (0.19 g), tri-o-tolylphosphine (0.075 g), palladium (II) acetate (0.0125 g), triethylamine (0.25 mL) and acetonitrile (2.5 mL) was heated under reflux for 42 hours in an atmosphere of nitrogen. The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a foam (0.24 g): Anal. Calcd for C22H24N2O2S. HBr. 1/3 CH2Cl2 : C,54,77; H,5,29; N,5.72. Found: C,55.00; H,4.85; N,5.58. was heated under reflux for 42 hours in an atmosphere of nitrogen The solvent was evaporated the residue was chromatographed on silica gel Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1)

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

Procedure: A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), phenylvinylsulphone (0.19 g), tri-o-tolylphosphine (0.075 g), palladium (II) acetate (0.0125 g), triethylamine (0.25 mL) and acetonitrile (2.5 mL) was heated under reflux for 42 hours in an atmosphere of nitrogen. The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a foam (0.24 g): Anal. Calcd for C22H24N2O2S. HBr. 1/3 CH2Cl2 : C,54,77; H,5,29; N,5.72. Found: C,55.00; H,4.85; N,5.58. was heated under reflux for 42 hours in an atmosphere of nitrogen The solvent was evaporated the residue was chromatographed on silica gel Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1)

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

Procedure: A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), ethyl vinyl sulphone (0.14 g), tri-o-tolylphosphine (0.075 g), palladium (II) acetate (0.013 g), triethylamine (0.25 mL) and acetonitrile (3 mL) was heated under reflux for 17 hours in an atmosphere of nitrogen. The mixture was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1) gave the title compound as a foam (0. 185 g): TLC (dichloromethane/-ethanol/concentrated aqueous ammonia, 90:10:1): Rf =0.5. Anal. Calcd for C18H24N2O2S. 0.2 CH2Cl2 : C,62.55; H,7.04; N,8.02. Found: C,62.65; H,6.94; N,7.92. was heated under reflux for 17 hours in an atmosphere of nitrogen The mixture was evaporated the residue was chromatographed on silica gel Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1)

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

Procedure: A solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (1.04 g) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran (15 mL) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled. Additional lithium aluminium hydride (50 mg) was added and refluxing was continued for an additional 3 hours. The mixture was again cooled, lithium aluminium hydride (40 mg) was added, and refluxing was continued for a further 18 hours. The mixture was cooled and water (0.44 mL) was carefully added with stirring, followed by 20% aqueous sodium hydroxide (0.44 mL), followed by more water (1.33 mL). The mixture was diluted with ethyl acetate and filtered through Celite (trademark) filter aid. The filtrate was washed with water, brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gave the title compound as a solid (0.51 g), m.p. 137°-140° C. (from dichloromethane/hexane); IR (KBr) 1620, 1595, 1570, 1480, 1450, 1435 cm-1 ; 1H NMR (DMSO-d6) δ11.05 (br s, 1H), 7.65 (br d, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.21 (br d, 1H), 7.16 (dd, J=1.8 and 8.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.47 (dd, J=9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H), 2.33 (s, 3H), 2.09 (dd, J=8.7 and 17.3 Hz, 1H), 1.73-1.38 (m, 4H); 13C NMR (DMSO-d6) δ134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9, 66.1, 57.0, 40.5, 30.9, 29.1, 21.6; LRMS, m/z (relative intensity) 294 (M+ with 81Br, 1), 293 (2), 292 (M+ with 79Br, 1), 210 (14), 208 (15), 154 (8), 129 (42), 128 (19), 01 (26) 85 (57), 84 (100), 83 (30); [α]25D =+62° (methanol, c=0.10). Anal Calcd for C14H17N2Br. 0.25H2O: C, 56.48; H, 5.93; N, 9.41. Found: C, 56.65; H, 5.69; N,9.23. The mixture was heated under reflux cooled refluxing was continued for an additional 3 hours The mixture was again cooled refluxing was continued for a further 18 hours The mixture was cooled with stirring filtered through Celite (trademark) filter aid The filtrate was washed with water, brine dried (Na2SO4) Evaporation of the solvent gave an oil which was chromatographed on silica gel Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5)

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

Procedure: A solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (1.04 g) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran (15 mL) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled. Additional lithium aluminium hydride (50 mg) was added and refluxing was continued for an additional 3 hours. The mixture was again cooled, lithium aluminium hydride (40 mg) was added, and refluxing was continued for a further 18 hours. The mixture was cooled and water (0.44 mL) was carefully added with stirring, followed by 20% aqueous sodium hydroxide (0.44 mL), followed by more water (1.33 mL). The mixture was diluted with ethyl acetate and filtered through Celite (trademark) filter aid. The filtrate was washed with water, brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gave the title compound as a solid (0.51 g), m.p. 137°-140° C. (from dichloromethane/hexane); IR (KBr) 1620, 1595, 1570, 1480, 1450, 1435 cm-1 ; 1H NMR (DMSO-d6) δ11.05 (br s, 1H), 7.65 (br d, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.21 (br d, 1H), 7.16 (dd, J=1.8 and 8.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.47 (dd, J=9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H), 2.33 (s, 3H), 2.09 (dd, J=8.7 and 17.3 Hz, 1H), 1.73-1.38 (m, 4H); 13C NMR (DMSO-d6) δ134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9, 66.1, 57.0, 40.5, 30.9, 29.1, 21.6; LRMS, m/z (relative intensity) 294 (M+ with 81Br, 1), 293 (2), 292 (M+ with 79Br, 1), 210 (14), 208 (15), 154 (8), 129 (42), 128 (19), 01 (26) 85 (57), 84 (100), 83 (30); [α]25D =+62° (methanol, c=0.10). Anal Calcd for C14H17N2Br. 0.25H2O: C, 56.48; H, 5.93; N, 9.41. Found: C, 56.65; H, 5.69; N,9.23. The mixture was heated under reflux cooled refluxing was continued for an additional 3 hours The mixture was again cooled refluxing was continued for a further 18 hours The mixture was cooled with stirring filtered through Celite (trademark) filter aid The filtrate was washed with water, brine dried (Na2SO4) Evaporation of the solvent gave an oil which was chromatographed on silica gel Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5)

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

Procedure: (R)-5-Bromo-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole (60 mg, 0.2 mmol) was dissolved in ethanol (1 mL) and hydrogenated over 10% palladium on carbon (45 mg) at 60 p.s.i. of hydrogen pressure at room temperature for 16 hours. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried (Na2SO4), and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2 :MeOH:NH4OH) to give the title compound (28 mg). Anal. Calcd for C14H18N2 ·1/8 CH2Cl2C,75.42; H,8.18; N,12 46 Found: C,75 50; H,8 51; N,12 09. [α]25D =+60.2° (c=0.088, CHCl3). The reaction mixture was evaporated to dryness the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate The organic phase was dried (Na2SO4) evaporated in vacuo The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2 :MeOH:NH4OH)

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

Procedure: A stirred solution of 5-bromo-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole (WO-A-92/06973; 879 mg, 3.0 mmol), 2-methylbut-3-en-2-ol (0.408 ml, 3.9 mmol), tri-o-tolylphosphine (273 mg, 0.90 mmol), palladium(II) acetate (45 mg, 0.20 mmol), triethylamine (0.84 ml, 6.0 mmol) and acetonitrile (50 ml), under nitrogen, was heated under reflux for 24 hours, allowed to cool, then partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic phase was separated, washed sequentially with 2M aqueous sodium carbonate solution (×2) and brine (×1), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95), to afford the title compound as a solid (226 mg), m.p. 155°-158° C. Rf 0.10 (SS 1). [α]D25 +81° (c=0.1, CH3OH). Found: C,75.27; H,8.96; N,8.99. C19H26N2O; 0.25 H2O requires C,75.33; H,8.82; N,9.25%. under reflux for 24 hours to cool partitioned between ethyl acetate and 2M aqueous sodium carbonate solution The organic phase was separated washed sequentially with 2M aqueous sodium carbonate solution (×2) and brine (×1) dried (Na2SO4) evaporated under reduced pressure The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95)

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

Procedure: A stirred solution of 5-bromo-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole (WO-A-92/06973; 879 mg, 3.0 mmol), 2-methylbut-3-en-2-ol (0.408 ml, 3.9 mmol), tri-o-tolylphosphine (273 mg, 0.90 mmol), palladium(II) acetate (45 mg, 0.20 mmol), triethylamine (0.84 ml, 6.0 mmol) and acetonitrile (50 ml), under nitrogen, was heated under reflux for 24 hours, allowed to cool, then partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic phase was separated, washed sequentially with 2M aqueous sodium carbonate solution (×2) and brine (×1), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95), to afford the title compound as a solid (226 mg), m.p. 155°-158° C. Rf 0.10 (SS 1). [α]D25 +81° (c=0.1, CH3OH). Found: C,75.27; H,8.96; N,8.99. C19H26N2O; 0.25 H2O requires C,75.33; H,8.82; N,9.25%. under reflux for 24 hours to cool partitioned between ethyl acetate and 2M aqueous sodium carbonate solution The organic phase was separated washed sequentially with 2M aqueous sodium carbonate solution (×2) and brine (×1) dried (Na2SO4) evaporated under reduced pressure The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95)

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

Procedure: A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), phenylvinylsulphone (0.19 g), tri-o-tolylphosphine (0. 075 g), palladium (II) acetate (0. 0125 g), triethylamine (0.25 mL) and acetonitrile (2.5 mL) was heated under reflux for 42 hours in an atmosphere of nitrogen. The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a foam (0.24 g): Anal. Calcd for C22H24N2O2S. HBr. 1/3 CH2Cl2 : C, 54.77; H, 5.29; N, 5.72. Found: C, 55.00; H, 4.85; N, 5.58. was heated under reflux for 42 hours in an atmosphere of nitrogen The solvent was evaporated the residue was chromatographed on silica gel Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1)

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

Procedure: A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), ethyl vinyl sulphone (0.14 g), tri-o-tolylphosphine (0. 075 g), palladium (II) acetate (0. 013 g), triethylamine (0.25 mL) and acetonitrile (3 mL) was heated under reflux for 17 hours in an atmosphere of nitrogen. The mixture was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1) gave the title compound as a foam (0.185 g): TLC (dichloromethane/-ethanol/concentrated aqueous ammonia, 90:10:1): Rf =0.5. Anal. Calcd for C18H24N2O2S. 0.2 CH2Cl2 : C, 62.55; H, 7.04; N, 8.02. Found: C, 62.65; H, 6.94; N, 7.92. was heated under reflux for 17 hours in an atmosphere of nitrogen The mixture was evaporated the residue was chromatographed on silica gel Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1)

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

Procedure: A solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (1.04 g) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran (15 mL) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled. Additional lithium aluminium hydride (50 mg) was added and refluxing was continued for an additional 3 hours. The mixture was again cooled, lithium aluminium hydride (40 mg) was added, and refluxing was continued for a further 18 hours. The mixture was cooled and water (0.44 mL) was carefully added with stirring, followed by 20% aqueous sodium hydroxide (0.44 mL), followed by more water (1.33 mL). The mixture was diluted with ethyl acetate and filtered through Celite (trademark) filter aid. The filtrate was washed with water, brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gave the title compound as a solid (0.51 g), m.p. 137°-140° C. (from dichloromethane/hexane); IR (KBr) 1620, 1595, 1570, 1480, 1450, 1435 cm-1 ; 1H NMR (DMSO-d6) δ11.05 (br s, 1H), 7.65 (br d, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.21 (br d, 1H), 7.16 (dd, J=1.8 and 8.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.47 (dd, J=9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H), 2.33 (s, 3H), 2.09 (dd, J=8.7 and 17.3 Hz, 1H), 1.73-1.38 (m,4H); 13C NMR (DMSO-d6) δ134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9, 66.1, 57.0, 40.5, 30.9, 29.1, 21.6; LRMS, m/z (relative intensity) 294 (M+ with 81Br, 1) 293 (2) 292 (M+ with 79Br, 1), 210 (14), 208 (15), 154 (8), 129 (42), 128 (19), 101 (26) 85 (57) 84 (100), 83 (30); [α]25D =+62° (methanol, c=0.10). Anal Calcd for C14H17N2Br. 0.25 H2O: C, 56.48; H, 5.93; N, 9.41. Found: C, 56.65; H, 5.69; N, 9.23. The mixture was heated under reflux cooled refluxing was continued for an additional 3 hours The mixture was again cooled refluxing was continued for a further 18 hours The mixture was cooled with stirring filtered through Celite (trademark) filter aid The filtrate was washed with water, brine dried (Na2SO4) Evaporation of the solvent gave an oil which was chromatographed on silica gel Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5)

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

Procedure: (R)-5-Bromo-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole (60 mg, 0.2 mmol) was dissolved in ethanol (1 mL) and hydrogenated over 10% palladium on carbon (45 mg) at 60 p.s.i. of hydrogen pressure at room temperature for 16 hours. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried (Na2SO4), and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2:MeOH:NH4OH) to give the title compound (28 mg). Anal. Calcd for C14H18N2. 1/8 CH2Cl2C, 75.42; H, 8.18; N, 12.46 Found: C, 75.50; H, 8.51; N, 12.09⟦alpha⟧sup.25D =+60.2° (c=0.088, CHCl3). The reaction mixture was evaporated to dryness the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate The organic phase was dried (Na2SO4) evaporated in vacuo The resulting residue was purified by column chromatography on silica gel (eluting with 89:10:1 CH2Cl2:MeOH:NH4OH)