methyl 3-(2-bromophenyl)propanoate

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: To a solution of methyl 3-(2-bromophenyl)propionate (35.77 g) in ethanol (80.7 ml) was added at room temperature dropwise a solution of sodium hydroxide (11.77 g) in water (40 ml). After the reaction mixture was stirred under reflux for 2.5 hrs. and left standing for cooling, methanol was removed by distillation under reduced pressure, the residue was poured into ice-hydrochloric acid and stirred for 20 minutes. Crystalline precipitates were filtered, washed well with water, dried under reduced pressure to give the title compound (32.4 g). under reflux for 2.5 hrs and left standing for cooling methanol was removed by distillation under reduced pressure the residue was poured into ice-hydrochloric acid stirred for 20 minutes Crystalline precipitates were filtered washed well with water dried under reduced pressure

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl 2-(2-bromobenzyl)malonate (54.25 g) was dissolved in a mixture of dimethylsulfoxide (220 ml) and water (3.24 ml), and lithium chloride (15.27 g) was added. The mixture was stirred at 160° C. of a bath temperature for 7.5 hours. After the reaction mixture was left standing for cooling, the solvent was removed by distillation under reduced pressure. The residual concentrate was poured into water, extracted with toluene. The organic layer obtained was washed twice with water and once with a saturated aqueous saline, dried over sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residual concentrate was distilled under reduced pressure (96°-98° C./0.5 mmHg) to give the title compound (30.05 g). was added After the reaction mixture was left for cooling the solvent was removed by distillation under reduced pressure The residual concentrate was poured into water extracted with toluene The organic layer obtained was washed twice with water and once with a saturated aqueous saline dried over sodium sulfate the solvent was removed by distillation under reduced pressure the residual concentrate was distilled under reduced pressure (96°-98° C./0.5 mmHg)

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

Procedure: Palladium acetate (60 mg) was added to a deaerated solution of methyl 3-(2-bromophenyl)propanoate (11.10 g, 25 mmole), 1-tridecyne (6.75 g) and triphenylphosphine (200 mg) in anhydrous triethylamine (100 ml) and the mixture was stirred at reflux under nitrogen for 24 hrs. After cooling, the precipitated triethylamine hydrobromide was filtered off and the filtrate was evaporated to a red oil. Chromatography on silica eluting with 1:1 dichloromethane-petrol (bp 60°-80° C.) gave the title product, 1.91 g (22%) as an oil, νmax (film) 2920, 2850, 1745 cm-1, δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.39 (2H, t, J 7 Hz; C=C--CH2), 2.62 (2H, m, ArCH2), 3.04 (2H, m, CH2CO2), 3.62 (3H, s, ester CH3), 7.12 (3H, m, arom), 7.31 (1H, m, arom). at reflux under nitrogen for 24 hrs After cooling the precipitated triethylamine hydrobromide was filtered off the filtrate was evaporated to a red oil

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

Procedure: Methyl iodide (51 g, 22.4 ml, 0.24 mole) was added to a stirred mixture of 3-(2-bromophenyl)propanoic acid (36.7 g, 0.16 mole, prepared as described by F. G. Holliman and F. G. Mann J Chem. Soc. 9, 1960) and anhydrous potassium carbonate (33 g, 0.24 mole) in dry N,N-dimethylformamide (250 ml) and the mixture was stirred at ambient temperature overnight. After removal of the solvent in vacuo the residue was partitioned between ether and water and the ethereal phase washed with aqueous sodium thiosulphate and then brine and dried (MgSO4). Evaporation gave a pale yellow oil which distilled at 116°-118° C. (0.2 mm) to give 36.91 g (95%) of the title ester as a colourless oil, νmax 2950, 1740, 1570, 1470, 1440 cm-1, δ(CDCl3), 2.63 (2H, m, ArCH2), 3.07 (2H, m, CH2CO2), 3.70 (3H, s, CH3), 7.12 (3H, m, arom), 7.50 (1H, d, arom). After removal of the solvent in vacuo the residue was partitioned between ether and water the ethereal phase washed with aqueous sodium thiosulphate brine and dried (MgSO4) Evaporation gave a pale yellow oil which distilled at 116°-118° C. (0.2 mm)

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

Procedure: Methyl iodide (51 g, 22.4 ml, 0.24 mole) was added to a stirred mixture of 3-(2-bromophenyl)propanoic acid (36.7 g, 0.16 mole, prepared as described by F. G. Holliman and F. G. Mann J Chem. Soc. 9, 1960) and anhydrous potassium carbonate (33 g, 0.24 mole) in dry N,N-dimethylformamide (250 ml) and the mixture was stirred at ambient temperature overnight. After removal of the solvent in vacuo the residue was partitioned between ether and water and the ethereal phase washed with aqueous sodium thiosulphate and then brine and dried (MgSO4). Evaporation gave a pale yellow oil which distilled at 116°-118° C. (0.2 mm) to give 36.91 g (95%) of the title ester as a colourless oil, νmax 2950, 1740, 1570, 1470, 1440 cm-1, δ(CDCl3), 2.63 (2H, m, ArCH2), 3.07 (2H, m, CH2CO2), 3.70 (3H, s, CH3), 7.12 (3H, m, arom), 7.50 (1H, d, arom). After removal of the solvent in vacuo the residue was partitioned between ether and water the ethereal phase washed with aqueous sodium thiosulphate brine and dried (MgSO4) Evaporation gave a pale yellow oil which distilled at 116°-118° C. (0.2 mm)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To Methyl 3-(2-bromophenyl)propanoate (715 mg, 2.94 mmol) and 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (1.0 g, 3.23 mmol) were added to a flask, followed by Pd(dppf)Cl2 (151 mg, 0.21 mmol) and K2CO3 (1.22 g, 8.82 mmol). The reaction flask was purged with Ar (3×). Dry DMF (22 mL) was added and the solution was degassed for 10 min. The reaction mixture was heated to 85° C. overnight. The mixture was filtered through Celite and was concentrated. The crude residue was purified by silica gel chromatography (gradient, 10% to 30% EtOAc/hexanes) to give tert-butyl 4-(2-(3-methoxy-3-oxopropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (23) as a pale yellow oil (970 mg, 96% yield). 1H NMR (400 MHz, CDCl3): δ 7.21-7.16 (m, 3H), 7.09-7.06 (m, 1H), 5.57-5.55 (m, 1H), 4.03 (q, 2H), 3.67 (s, 3H), 3.63 (t, 2H), 2.95-2.91 (m, 2H), 2.59-2.55 (m, 2H), 2.37-2.33 (m, 2H), 1.50 (s, 9H). LC/MS RT (5 min method)=2.10 min. Mass observed: 246.19 (M-Boc+H). The reaction flask was purged with Ar (3×) Dry DMF (22 mL) was added the solution was degassed for 10 min The mixture was filtered through Celite was concentrated The crude residue was purified by silica gel chromatography (gradient, 10% to 30% EtOAc/hexanes)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To Methyl 3-(2-bromophenyl)propanoate (715 mg, 2.94 mmol) and 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (1.0 g, 3.23 mmol) were added to a flask, followed by Pd(dppf)Cl2 (151 mg, 0.21 mmol) and K2CO3 (1.22 g, 8.82 mmol). The reaction flask was purged with Ar (3×). Dry DMF (22 mL) was added and the solution was degassed for 10 min. The reaction mixture was heated to 85° C. overnight. The mixture was filtered through Celite and was concentrated. The crude residue was purified by silica gel chromatography (gradient, 10% to 30% EtOAc/hexanes) to give tert-butyl 4-(2-(3-methoxy-3-oxopropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (23) as a pale yellow oil (970 mg, 96% yield). 1H NMR (400 MHz, CDCl3): δ 7.21-7.16 (m, 3H), 7.09-7.06 (m, 1H), 5.57-5.55 (m, 1H), 4.03 (q, 2H), 3.67 (s, 3H), 3.63 (t, 2H), 2.95-2.91 (m, 2H), 2.59-2.55 (m, 2H), 2.37-2.33 (m, 2H), 1.50 (s, 9H). LC/MS RT (5 min method)=2.10 min. Mass observed: 246.19 (M-Boc+H). The reaction flask was purged with Ar (3×) Dry DMF (22 mL) was added the solution was degassed for 10 min The mixture was filtered through Celite was concentrated The crude residue was purified by silica gel chromatography (gradient, 10% to 30% EtOAc/hexanes)

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

Procedure: In a manner similar to that described for Example YY, 3-(2-bromo-phenyl)-propionic acid methyl ester (243 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenyl phosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 3-[2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-propionic acid methyl ester, 92 mg (29%) as a beige solid: m.p. 201-201.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.43 (t, J=7.5 Hz, 2H), 2.68 (m, 2H), 2.86 (t, J=8.1 Hz, 2H) 3.38 (m, 2H), 3.47 (s, 3H), 7.20 (t, J=7.8 Hz, 1H), 7.37 (m, 4H), 7.52 (dd, J=7.8, 0.6 Hz, 1H), 7.70 (dd, J=7.5,0.6 Hz, 1H), 8.04 (br t, 1H), 11.41 (br s, 1H). MS (FAB, MH+): 349. Anal. (C21H20N2O.0.3 CHCl3) C, H, N.

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

Procedure: In a manner similar to that described for Example YY, 3-(2-bromo-phenyl)-propionic acid methyl ester (243 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenyl phosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 3-[2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-propionic acid methyl ester, 92 mg (29%) as a beige solid: m.p. 201-201.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.43 (t, J=7.5 Hz, 2H), 2.68 (m, 2H), 2.86 (t, J=8.1 Hz, 2H) 3.38 (m, 2H), 3.47 (s, 3H), 7.20 (t, J=7.8 Hz, 1H), 7.37 (m, 4H), 7.52 (dd, J=7.8, 0.6 Hz, 1H), 7.70 (dd, J=7.5,0.6 Hz, 1H), 8.04 (br t, 1H), 11.41 (br s, 1H). MS (FAB, MH+): 349. Anal. (C21H20N2O.0.3 CHCl3) C, H, N.

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

Procedure: To a solution of methyl 3-(2-bromophenyl)propionate (35.77 g) in ethanol (80.7 ml) was added at room temperature dropwise a solution of sodium hydroxide (11.77 g) in water (40 ml). After the reaction mixture was stirred under reflux for 2.5 hrs. and left standing for cooling, methanol was removed by distillation under reduced pressure, the residue was poured into ice-hydrochloric acid and stirred for 20 minutes. Crystalline precipitates were filtered, washed well with water, dried under reduced pressure to give the title compound (32.4 g). under reflux for 2.5 hrs and left standing for cooling methanol was removed by distillation under reduced pressure the residue was poured into ice-hydrochloric acid stirred for 20 minutes Crystalline precipitates were filtered washed well with water dried under reduced pressure