6,7,8,9-tetrahydrobenzo[7]annulen-5-one

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: 5.2 g 6,7,8,9-tetrahydro-benzocyclohepten-5-one, 0.96 g paraformaldehyde and 10.0 g allyl-methylamine hydrochloride in 60 ml glacial acetic acid were reacted as in example 1, step 1. After analogous work-up, 6.7 g (84.8% of theoretical) 6-[(allyl-methyl-amino)-methyl]-6,7,8,9-tetrahydro-benzocyclohepten-5-one were obtained as a yellowish oil.

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

Procedure: 2-amino-1-cyano-benzene (2.0 g, 16.9 mmol), 1-benzosuberone (6, 7, 8, 9-tetrahydrobenzocyclohepten-5-one) (3.0 g, 18.7 mmol) and boron trifluoride diethyl etherate(1M, 2.6 ml, 18.7 mmol) were treated according to the general procedure described herein to give the title compound.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of sodium hydride (60%, 2.25 g) in anhydrous benzene (100 ml) was slowly added with a solution of diethyl phosphonoacetate (14.0 g) in anhydrous benzene (20 ml) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. The mixture was added with a solution of 1-benzosuberone (5.00 g) in anhydrous benzene (30 ml), and the mixture was stirred at 0° C. for 15 minutes, and then refluxed overnight by heating. The reaction mixture was left to cool and then added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:200) to quantitatively obtain the title compound. the mixture was stirred at 0° C. for 15 minutes refluxed overnight by heating The reaction mixture was left to cool the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:200)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of sodium hydride (60%, 2.25 g) in anhydrous benzene (100 ml) was slowly added with a solution of diethyl phosphonoacetate (14.0 g) in anhydrous benzene (20 ml) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. The mixture was added with a solution of 1-benzosuberone (5.00 g) in anhydrous benzene (30 ml), and the mixture was stirred at 0° C. for 15 minutes, and then refluxed overnight by heating. The reaction mixture was left to cool and then added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:200) to quantitatively obtain the title compound. the mixture was stirred at 0° C. for 15 minutes refluxed overnight by heating The reaction mixture was left to cool the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:200)

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

Procedure: To a solution of anthranilonitrile (0.69 g, 5.8 mmol) and 1-benzosuberone (1.03 g, 0.96 mL, 6.4 mmol) in 25 mL anhydrous toluene was added boron trifluoride etherate (0.91 g, 0.81 mL, 6.4 mmol) slowly via syringe under a nitrogen atmosphere. The reaction was heated to reflux for 22 h. After cooling, sodium hydroxide solution (25 mL, 2 M, 50 mmol) was added. The reaction was heated to reflux for 23 h. After cooling, the reaction was diluted with ethyl acetate, washed with water (3×50 mL), brine (20 mL), dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue (1.46 g) was dissolved in ethyl acetate:diethyl ether (1:1; 100 mL) with a trace of methanol (3 mL). To the solution was added 7 mL of a 1 N solution of HCl in diethyl ether. A resulting precipitate was collected by vacuum filtration and air-dried to provide the hydrochloride salt of the title compound as an off-white solid (1.30 g, 75%). MS (API+): M+1: 261 (100%); 1H NMR (300 MHz, DMSO-d6/TFA-d) d 2.13-2.29 (br m, 2H), 2.51-2.56 (br m, 2H), 2.56-2.75 (br m, 2H), 7.49 (d, J=7.0 Hz, 1H), 7.55-7.65 (m, 2H), 7.67-7.74 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.91-7.98 (m, 1H), 8.05 (d,J=8.7 Hz, 1H), 8.57 (d, J=8.7 Hz, 1H). The reaction was heated to reflux for 22 h After cooling The reaction was heated to reflux for 23 h After cooling washed with water (3×50 mL), brine (20 mL) dried over Na2SO4 filtered the solvent removed in vacuo The residue (1.46 g) was dissolved in ethyl acetate:diethyl ether (1:1; 100 mL) with a trace of methanol (3 mL) To the solution was added 7 mL of a 1 N solution of HCl in diethyl ether A resulting precipitate was collected by vacuum filtration air-dried

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

Procedure: To a solution of anthranilonitrile (0.69 g, 5.8 mmol) and 1-benzosuberone (1.03 g, 0.96 mL, 6.4 mmol) in 25 mL anhydrous toluene was added boron trifluoride etherate (0.91 g, 0.81 mL, 6.4 mmol) slowly via syringe under a nitrogen atmosphere. The reaction was heated to reflux for 22 h. After cooling, sodium hydroxide solution (25 mL, 2 M, 50 mmol) was added. The reaction was heated to reflux for 23 h. After cooling, the reaction was diluted with ethyl acetate, washed with water (3×50 mL), brine (20 mL), dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue (1.46 g) was dissolved in ethyl acetate:diethyl ether (1:1; 100 mL) with a trace of methanol (3 mL). To the solution was added 7 mL of a 1 N solution of HCl in diethyl ether. A resulting precipitate was collected by vacuum filtration and air-dried to provide the hydrochloride salt of the title compound as an off-white solid (1.30 g, 75%). MS (API+): M+1: 261 (100%); 1H NMR (300 MHz, DMSO-d6/TFA-d) d 2.13-2.29 (br m, 2H), 2.51-2.56 (br m, 2H), 2.56-2.75 (br m, 2H), 7.49 (d, J=7.0 Hz, 1H), 7.55-7.65 (m, 2H), 7.67-7.74 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.91-7.98 (m, 1H), 8.05 (d,J=8.7 Hz, 1H), 8.57 (d, J=8.7 Hz, 1H). The reaction was heated to reflux for 22 h After cooling The reaction was heated to reflux for 23 h After cooling washed with water (3×50 mL), brine (20 mL) dried over Na2SO4 filtered the solvent removed in vacuo The residue (1.46 g) was dissolved in ethyl acetate:diethyl ether (1:1; 100 mL) with a trace of methanol (3 mL) To the solution was added 7 mL of a 1 N solution of HCl in diethyl ether A resulting precipitate was collected by vacuum filtration air-dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of benzosuberone (8 g, 50 mmol) and neat dimethyl carbonate (45 mL) at ambient temperature under N2 was treated with NaH (60% in mineral oil, 4 g, 100 mmol) in 0.1 mL of dry MeOH, heated at 80° C. for 3 hours, cooled to ambient temperature, treated with 2 N HCl (55 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated to provide the title compound as an oil, as a 3:1 mixture of enol and keto forms of product by NMR spectroscopy. The NMR of the main enol form was: 1H NMR (CDCl3) δ 2.03-2.16 (m, 4H), 2.64 (m, 2H), 3.82 (s, 3H), 7.23 (m, 1H), 7.33 (m, 2H), 7.62 (m, 1H), 12.6 (bs, 1H). MS (M+H)+ m/z 219. cooled to ambient temperature extracted with ethyl acetate The organic layer was washed with brine dried (MgSO4) concentrated

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

Procedure: A solution of dimethyl carbonate (20 mL) was treated with NaH (3 g, 60% dispersed in oil, 75 mmol) and heated to 85° C. To the mixture was dropwise added a solution of bezosuberone (3 g, 18.75 mmol) in dimethyl carbonate (10 mL). The resulting mixture was refluxed for 3 hours, cooled to 0° C., quenched with HCl (1N) (100 mL) and extracted with ether. The organic layer was washed with NaHCO3 and brine, dried (MgSO4) and concentrated to provide the title compound as a brownish oil. The resulting mixture was refluxed for 3 hours cooled to 0° C. quenched with HCl (1N) (100 mL) extracted with ether The organic layer was washed with NaHCO3 and brine dried (MgSO4) concentrated

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

Procedure: Following the procedure described in Example 4, using 6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.10 g, 6.87 mmoL) and 4-methoxy-phenylhydrazine HCl salt (1.20 g, 6.87 mmoL) as the starting material, the title compound was prepared as a brown solid.

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

Procedure: Following the procedure described in Example 4, using 6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.10 g, 6.87 mmoL) and 4-methoxy-phenylhydrazine HCl salt (1.20 g, 6.87 mmoL) as the starting material, the title compound was prepared as a brown solid.