1-ethenyl-3-fluorobenzene

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: By a procedure analogous to that described in Example 1h, 2-chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one was coupled with 3-fluorostyrene in the presence of bis(triphenylphosphine)palladium(II) chloride and triethylamine. The product was hydrogenated by a procedure analogous to that described in Example 15 to give 16 mg of the title compound, m.p. 130°-131° C. (ethyl acetate/hexanes).

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

Procedure: By a procedure analogous to that described in Example 1h, 2-chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one was coupled with 3-fluorostyrene in the presence of bis(triphenylphosphine)palladium(II) chloride and triethylamine. The product was hydrogenated by a procedure analogous to that described in Example 15 to give 16 mg of the title compound, m.p. 130°-131° C. (ethyl acetate/hexanes).

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

Procedure: 3-Fluorostyrene (9.7 mL, 82 mmol) and ethyl diazoacetate (8.6 mL, 82 mmol) were reacted by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. The product was purified on silica. 9.4 g of ethyl 2-(3-fluorophenyl)cyclopropane carboxylate (45 mmol, 55%) was obtained. MS (GC/MS, EI) 208 (M+). (b) The trans ester was selectively hydrolyzed from the cis/trans mixture by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. Recrystallize from hexane to yield 2.5 g (13.9 mmol, 89% of the trans) of trans-2-(3-fluorophenyl)cyclopropane carboxylic acid. (c) The trans-2-(3-fluorophenyl)cyclopropane carboxylic acid (400 mg, 2.2 mmol) and (R)-3-methoxyphenyl ethylamine (280 mg, 1.9 mmol) were converted to the diastereomeric amides by the method reported in Aust. J. Chem. 1984, 37, 1709. 446 mg (1.4 mmol, 75%) of trans-2-(3-fluorophenyl)-N-(1(R))-(3-methoxyphenyl)ethyl)cyclopropane carboxamide was obtained. MS (GC/MS, EI) 313 (M+). (d) The mixture of diastereomeric amides (550 mg, 1.8 mmol) were reduced to the amines with BH3.THF (7 mL, 7.0 mmol) in 10 mL THF. Upon complete addition, the solution was heated to reflux, overnight. The solution was cooled to 0° C. and 7 mL of 6 N HCl was carefully added. This was stirred open to air for two hours, THF was removed in vacuo. The aqueous residue was basified to pH 9 with Na2CO3 solution and extracted with 3×20 mL CH2Cl2. The combined extracts were washed with 20 mL water and 20 mL of 1:1 water/brine. The organics were dried (Na2SO4), filtered, and solvent was removed. 520 mg of N-(trans-2-(3-fluorophenyl)cyclopropanylmethyl)-1-(R)-(3-methoxyphenyl)ethylamine (1.8 mmol, 99%) was obtained as an oil. MS (CI) m/z 300 (MH+). The product was purified on silica

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

Procedure: 3-Fluorostyrene (9.7 mL, 82 mmol) and ethyl diazoacetate (8.6 mL, 82 mmol) were reacted by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. The product was purified on silica. 9.4 g of ethyl 2-(3-fluorophenyl)cyclopropane carboxylate (45 mmol, 55%) was obtained. MS (GC/MS, EI) 208 (M+). (b) The trans ester was selectively hydrolyzed from the cis/trans mixture by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. Recrystallize from hexane to yield 2.5 g (13.9 mmol, 89% of the trans) of trans-2-(3-fluorophenyl)cyclopropane carboxylic acid. (c) The trans-2-(3-fluorophenyl)cyclopropane carboxylic acid (400 mg, 2.2 mmol) and (R)-3-methoxyphenyl ethylamine (280 mg, 1.9 mmol) were converted to the diastereomeric amides by the method reported in Aust. J. Chem. 1984, 37, 1709. 446 mg (1.4 mmol, 75%) of trans-2-(3-fluorophenyl)-N-(1(R))-(3-methoxyphenyl)ethyl)cyclopropane carboxamide was obtained. MS (GC/MS, EI) 313 (M+). (d) The mixture of diastereomeric amides (550 mg, 1.8 mmol) were reduced to the amines with BH3.THF (7 mL, 7.0 mmol) in 10 mL THF. Upon complete addition, the solution was heated to reflux, overnight. The solution was cooled to 0° C. and 7 mL of 6 N HCl was carefully added. This was stirred open to air for two hours, THF was removed in vacuo. The aqueous residue was basified to pH 9 with Na2CO3 solution and extracted with 3×20 mL CH2Cl2. The combined extracts were washed with 20 mL water and 20 mL of 1:1 water/brine. The organics were dried (Na2SO4), filtered, and solvent was removed. 520 mg of N-(trans-2-(3-fluorophenyl)cyclopropanylmethyl)-1-(R)-(3-methoxyphenyl)ethylamine (1.8 mmol, 99%) was obtained as an oil. MS (CI) m/z 300 (MH+). The product was purified on silica

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

Procedure: To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 ml) was added and the reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.30 g of the title compound as a slightly tinted oil which was used without further purification. the reaction was left The reaction mixture was partitioned between water and EtOAc the aqueous phase was extracted with EtOAc The combined organic phases were washed with brine dried (Na2SO4) filtered evaporated in vacuo

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

Procedure: To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 ml) was added and the reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.30 g of the title compound as a slightly tinted oil which was used without further purification. the reaction was left The reaction mixture was partitioned between water and EtOAc the aqueous phase was extracted with EtOAc The combined organic phases were washed with brine dried (Na2SO4) filtered evaporated in vacuo

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

Procedure: Compound 50 was prepared by the basic process from 5.0 mmol 4-chloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile.

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

Procedure: Compound 29 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.

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

Procedure: Compound 28 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile.

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

Procedure: Compound 8 was prepared in a yield of 44% by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile.