1-(4-bromophenyl)butane-1,3-dione

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

Procedure: 4.23 g (20.74 mmol) N-[3-(trifluoromethyl)phenyl]urea, 2.72 g (20.74 mmol) 4-cyanobenzaldehyde, 5.00 g (20.74 mmol) 1-(4-bromophenyl)butane-1,3-dione and 6.5 g polyphosphoric acid ethyl ester are suspended in 50 ml of tetrahydrofuran. The mixture is stirred at reflux for 20 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent. at reflux for 20 hours the solvent is removed in vacuo the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate

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

Procedure: The intermediate 3-(4-bromophenyl)-1-methyl-3-oxo-1-propenamine, m.p. 126°-128° C., 56.8 g, was prepared following the procedure described in Example A-2 using 83 g of 1-(4-bromophenyl)-1,3-butanedione, 750 ml of methanol and 100 ml of concentrated aqueous ammonium hydroxide solution. The solid residue after stripping the reaction mixture to dryness on a rotary evaporator was treated with 500 ml of boiling n-hexane, the mixture allowed to stand at room temperature overnight, and, the product collected and dried at room temperature. on a rotary evaporator was treated with 500 ml of boiling n-hexane the product collected dried at room temperature

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

Procedure: The intermediate 3-(4-bromophenyl)-1-methyl-3-oxo-1-propenamine, m.p. 126°-128° C., 56.8 g, was prepared following the procedure described in Example A-2 using 83 g of 1-(4-bromophenyl)-1,3-butanedione, 750 ml of methanol and 100 ml of concentrated aqueous ammonium hydroxide solution. The solid residue after stripping the reaction mixture to dryness on a rotary evaporator was treated with 500 ml of boiling n-hexane, the mixture allowed to stand at room temperature overnight, and, the product collected and dried at room temperature. on a rotary evaporator was treated with 500 ml of boiling n-hexane the product collected dried at room temperature

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

Procedure: 4.23 g (20.74 mmol) N-[3-(trifluoromethyl)phenyl]urea, 2.72 g (20.74 mmol) 4-cyanobenzaldehyde, 5.00 g (20.74 mmol) 1-(4-bromophenyl)butane-1,3-dione and 6.5 g polyphosphoric acid ethyl ester are suspended in 50 ml of tetrahydrofuran. The mixture is stirred at reflux for 20 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent. at reflux for 20 hours the solvent is removed in vacuo the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate

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

Procedure: 4.23 g (20.74 mmol) N-[3-(trifluoromethyl)phenyl]urea, 2.72 g (20.74 mmol) 4-cyanobenzaldehyde, 5.00 g (20.74 mmol) 1-(4-bromophenyl)butane-1,3-dione and 6.5 g polyphosphoric acid ethyl ester are suspended in 50 ml of tetrahydrofuran. The mixture is stirred at reflux for 20 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent. at reflux for 20 hours the solvent is removed in vacuo the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate

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

Procedure: To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(4-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warming slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (5.07 g, 85%); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.10 (s, 1H, H-3), 7.36 (s, 1H, H-5), 7.69 (d, 2H, J=8.6 Hz, Arom), 7.76 (d, 2H, J=8.6 Hz, Arom); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584. After addition This temperature was maintained for 2 hours before warming slowly to ambient temperature stirred for 18 hours mixture was heated to 60° C. with good stirring for 3 hours The volatiles were removed in vacuo the aqueous solution was washed with diethyl ether (2×100 mL) the orange precipitate was filtered from the acid washed with water dried by vacuum desiccation

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

Procedure: To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(4-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warming slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (5.07 g, 85%); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.10 (s, 1H, H-3), 7.36 (s, 1H, H-5), 7.69 (d, 2H, J=8.6 Hz, Arom), 7.76 (d, 2H, J=8.6 Hz, Arom); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584. After addition This temperature was maintained for 2 hours before warming slowly to ambient temperature stirred for 18 hours mixture was heated to 60° C. with good stirring for 3 hours The volatiles were removed in vacuo the aqueous solution was washed with diethyl ether (2×100 mL) the orange precipitate was filtered from the acid washed with water dried by vacuum desiccation

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

Procedure: To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(4-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warming slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (5.07 g, 85%); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.10 (s, 1H, H-3), 7.36 (s, 1H, H-5), 7.69 (d, 2H, J=8.6 Hz, Arom), 7.76 (d, 2H, J=8.6 Hz, Arom); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584. After addition This temperature was maintained for 2 hours before warming slowly to ambient temperature stirred for 18 hours mixture was heated to 60° C. with good stirring for 3 hours The volatiles were removed in vacuo the aqueous solution was washed with diethyl ether (2×100 mL) the orange precipitate was filtered from the acid washed with water dried by vacuum desiccation

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium ethoxide (4.49 g, 66 mmol) in EtOAc (10 mL) that was cooled to −5° C. was added a solution of 4-bromoacetophenone (11.94 g, 60 mmol) in EtOAc (10 mL) and THF (10 mL). The mixture was stirred at 0° C. for 4 hours before warming to ambient temperature and stirring for 48 hours. Water (20 mL) and dichloromethane (40 mL) were added and a white precipitate was filtered from the mixture. To the solid was added 2N HCl, with vigorous stirring, to pH 1. EtOAc (100 mL) was added and separated, and the water was washed with EtOAc (2×100 mL). The organic portions were combined, dried (Na2SO4) and concentrated in vacuo to yield the desired compound as a pale yellow, crystalline solid (11.09 g, 76%); 1H-NMR (CDCl3): 2.13 (s, 3H, CH3), 6.07 (s, 1H, ═CH), 7.52 (d, 2H, J=8.7 Hz, Ar-2, Ar-6), 7.67 (d, 2H, J=8.7 Hz, Ar-3, Ar-5). before warming to ambient temperature stirring for 48 hours a white precipitate was filtered from the mixture To the solid was added 2N HCl EtOAc (100 mL) was added separated the water was washed with EtOAc (2×100 mL) dried (Na2SO4) concentrated in vacuo

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium ethoxide (4.49 g, 66 mmol) in EtOAc (10 mL) that was cooled to −5° C. was added a solution of 4-bromoacetophenone (11.94 g, 60 mmol) in EtOAc (10 mL) and THF (10 mL). The mixture was stirred at 0° C. for 4 hours before warming to ambient temperature and stirring for 48 hours. Water (20 mL) and dichloromethane (40 mL) were added and a white precipitate was filtered from the mixture. To the solid was added 2N HCl, with vigorous stirring, to pH 1. EtOAc (100 mL) was added and separated, and the water was washed with EtOAc (2×100 mL). The organic portions were combined, dried (Na2SO4) and concentrated in vacuo to yield the desired compound as a pale yellow, crystalline solid (11.09 g, 76%); 1H-NMR (CDCl3): 2.13 (s, 3H, CH3), 6.07 (s, 1H, ═CH), 7.52 (d, 2H, J=8.7 Hz, Ar-2, Ar-6), 7.67 (d, 2H, J=8.7 Hz, Ar-3, Ar-5). before warming to ambient temperature stirring for 48 hours a white precipitate was filtered from the mixture To the solid was added 2N HCl EtOAc (100 mL) was added separated the water was washed with EtOAc (2×100 mL) dried (Na2SO4) concentrated in vacuo

Conditions: temp:-196.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl formamide (30 mL), palladium acetate (0.022 g, 0.1 mmol), tri-o-tolyl phosphine (0.060 g, 0.2 mmol), triethylamine (9.1 g, 90 mmol), 4-bromobenzoylacetone (2.41 g, 10 mmol) were added to a 100 mL Parr high pressure reactor with an inner glass liner. The solution was degassed with nitrogen for 10 minutes before the reactor was cooled to −196° C. and ethylene (1.7 g, 61 mmol) was condensed for 20 minutes. The reactor was allowed to warm to room temperature before heating to 100° C. in an oil bath. The pressure was bled off until 300 psi was achieved and the reaction was allowed to proceed for 12 hours. The reaction vessel was cooled to room temperature, the extra pressure bled, and the contents dissolved in water (50 mL) and ether (50 mL). The aqueous phase was made acidic by addition of concentrated hydrochloric acid followed by extraction with ether (2×50 mL). The combined organic phase was rinsed with saturated sodium chloride solution, and the organic phase was dried over magnesium sulfate overnight. The solution was filtered, the solvent was removed by vacuum, and the residue dissolved in chloroform (3 mL). The product was isolated by column chromatography from silica gel (Selecto, mesh size 63-200) with chloroform as eluent. The first band collected resulted in a yellow powder (1.03 g, 55% yield) upon solvent removal. 1H-NMR (200 MHz, 25° C., CDCl3): δ 16.12 (s, 1H), 7.83 (d, 2H), 7.45 (d, 2H), 6.70 (dd, 1H), 6.17 (s, 1H), 5.82 (d, 1H), 5.35 (d, 1H), 2.20 (s, 3H). The solution was degassed with nitrogen for 10 minutes before the reactor condensed for 20 minutes to warm to room temperature before heating to 100° C. in an oil bath The reaction vessel was cooled to room temperature followed by extraction with ether (2×50 mL) The combined organic phase was rinsed with saturated sodium chloride solution the organic phase was dried over magnesium sulfate overnight The solution was filtered the solvent was removed by vacuum the residue dissolved in chloroform (3 mL) The product was isolated by column chromatography from silica gel (Selecto, mesh size 63-200) with chloroform as eluent The first band collected

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

Procedure: The intermediate 3-(4-bromophenyl)-1-methyl-3-oxo-1-propenamine, m.p. 126°-128° C., 56.8 g, was prepared following the procedure described in Example A-2 using 83 g of 1-(4-bromophenyl)-1,3-butanedione, 750 ml of methanol and 100 ml of concentrated aqueous ammonium hydroxide solution. The solid residue after stripping the reaction mixture to dryness on a rotary evaporator was treated with 500 ml of boiling n-hexane, the mixture allowed to stand at room temperature overnight, and, the product collected and dried at room temperature. on a rotary evaporator was treated with 500 ml of boiling n-hexane the product collected dried at room temperature