5-chloropent-1-yne

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 14.85 Parts of 5-chloropent-1-yne is dissolved in 250 parts by volume of toluene and the resulting solution is cooled to approximately -40°. To that solution is then added 62.8 parts by volume of 2.31 M ethereal butyl lithium and stirring is continued for approximately 15 minutes. 6.87 Parts of boron trifluoride etherate is added and the reaction mixture is stirred for about 2 hours, then allowed to stand for about 16 hours at -5° to -10°. At the end of that time 10.14 parts of methyl vinyl ketone is added at -40° and the reaction mixture is stirred for about 4 hours, then is quenched with water. 50 Parts by volume of 3 N hydro=chloric acid is added and the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers are separated. The aqueous layer is extracted with toluene and the organic layer with water. The organic solutions are combined, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure, thus affording the crude product. This material is purified by distillation under reduced pressure to afford 9-chloro-5-nonyn-2-one, boiling at about 80°-92° at a pressure of 0.11-0.06 mm. the resulting solution is cooled to approximately -40° the reaction mixture is stirred for about 2 hours to stand for about 16 hours at -5° to -10° the reaction mixture is stirred for about 4 hours is quenched with water 50 Parts by volume of 3 N hydro=chloric acid is added the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers are separated The aqueous layer is extracted with toluene washed successively with aqueous sodium hydroxide and water dried over anhydrous sodium sulfate thus affording the crude product This material is purified by distillation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 3.350 g (0.0048 mol) bis-(triphenylphosphine)-palladium(II)dichloride and 1.90 g (0.010 mol) copper(I)iodide in 500 mL triethylamine was heated to reflux for 30 min. The mixture was cooled to room temperature and 190 g (0.534 mol) (4-bromo-2-iodo-phenyl)-carbamic acid methyl ester and 66.462 mL 5-chloro-1-pentyne (65 g, 0.634 mol) were added. The mixture was heated to reflux. When a temperature of 70° C. was reached, a strong exothermic reaction was observed leading to vigorous reflux! A thick suspension formed. Refluxing was continued for 15 min. The mixture was cooled to room temperature and diluted with 500 mL ethyl acetate. The solids were removed by filtration and the filter cake was washed with ca. 200 mL ethyl acetate. The filtrate was concentrated under aspirator vacuum, taken up in 500 mL ethyl acetate and washed successively with 10% citric acid solution, 10% sodium thiosulfate solution, 10% sodium bicarbonate solution and brine. The aqueous phases were re-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate. To the solution was added 200 mL dimethylsulfoxide and the mixture concentrated under aspirator vacuum. Remaining ethyl acetate was removed under high vacuum. The resulting dimethylsulfoxide solution was added to a suspension of 70 g lithium hydroxide monohydrate in 120 mL water and 1000 mL dimethylsulfoxide. The resulting suspension was heated to 80° C. for 2 h. The mixture was cooled to room temperature and 1500 mL of ice water and 600 mL dichloromethane were added. The pH was adjusted to 6 by addition of 25% hydrochloric acid. The phases were separated and the organic phase was washed with half concentrated brine. The aqueous phases were extracted with 200 mL dichloromethane. The combined organic phases were diluted to a volume of 2000 mL with n-hexane. The resulting solution was filtered over 1 kg silica gel with hexane: dichloromethane=2: 1. The product fractions were combined and concentrated under aspirator vacuum, whereby crystallisation occurred to yield 95 g white crystals. (HPLC 100%). The mother liquor was evaporated to afford a second crop [7.2 g, 87% purity by HPLC) which was recrystallised to furnish a further 6 g (100% purity by HPLC) Total yield: 101 g (80%) of the title compound as white crystals, m.p.: 78.7-79.4° C. was heated to reflux for 30 min The mixture was heated to reflux a temperature of 70° C. a strong exothermic reaction A thick suspension formed Refluxing The mixture was cooled to room temperature The solids were removed by filtration the filter cake was washed with ca. 200 mL ethyl acetate The filtrate was concentrated under aspirator vacuum washed successively with 10% citric acid solution, 10% sodium thiosulfate solution, 10% sodium bicarbonate solution and brine The aqueous phases were re-extracted with ethyl acetate The combined organic phases were dried over magnesium sulfate To the solution was added 200 mL dimethylsulfoxide the mixture concentrated under aspirator vacuum Remaining ethyl acetate was removed under high vacuum The resulting dimethylsulfoxide solution was added to a suspension of 70 g lithium hydroxide monohydrate in 120 mL water and 1000 mL dimethylsulfoxide The resulting suspension was heated to 80° C. for 2 h The mixture was cooled to room temperature 1500 mL of ice water and 600 mL dichloromethane were added The pH was adjusted to 6 by addition of 25% hydrochloric acid The phases were separated the organic phase was washed with half concentrated brine The aqueous phases were extracted with 200 mL dichloromethane The combined organic phases were diluted to a volume of 2000 mL with n-hexane The resulting solution was filtered over 1 kg silica gel with hexane concentrated under aspirator vacuum, whereby crystallisation

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Carbonic acid 3-iodo-4-methoxycarbonylamino-phenyl ester methyl ester (28.0 g, 79.75 mmol) was dissolved in acetonitrile (350 mL). Triethylamine (22.2mL, 160 mmol), Copper (I) iodide (300 mg, 1.58 mmol), bis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.6 mmol) and 5-chloro-1-pentyne (10.0 mL, 95.54 mmol) were added and the mixture heated 3 h at 70° C. The reaction was cooled and partitioned between ethyl acetate (100 mL) and IM pH4 phosphate buffer (100 mL). The phases were separated, the aqueous phase extracted with ethyl acetate and the combined organic phases washed with 10% sodium thiosulfate solution, brine, dried over sodium sulfate and evaporated. The orange/brown residue (23.5 g, 90%) was used without further purification. (A small sample was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) for analytical purposes). ISP-MS: m/e=326.3 ([M−H]+) The reaction was cooled partitioned between ethyl acetate (100 mL) and IM pH4 phosphate buffer (100 mL) The phases were separated the aqueous phase extracted with ethyl acetate the combined organic phases washed with 10% sodium thiosulfate solution, brine dried over sodium sulfate evaporated The orange/brown residue (23.5 g, 90%) was used without further purification (A small sample was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) for analytical purposes)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2,2,2-trifluoro-N-(4-iodophenyl)acetamide (3.2 g, 10 mmol, prepared according to Melissaris, A. P. and Litt, M. H. J Org Chem 1994, 59, 5818-5821), dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.2 mmol), triphenylphosphine (19 mg, 0.07 mmol), and copper (I) iodide (0.019 g, 0.1 mmol) in triethylamine (50 mL) was degassed under Argon for 10 minutes while stirring in a 55° C. oil bath. The mixture was then treated with 5-chloropentyne (1.1 mL, 10 mmol). After four hours of heating, the mixture was allowed to cool to room temperature and was then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the crude title compound, which was carried forward without further purification. ES/MS calcd. for C14H14ClF3NO+ : 290.1. found m/z=290.1 (M+H)+ prepared After four hours of heating to cool to room temperature was then filtered through a pad of Celite diatomaceous earth The filtrate was concentrated under reduced pressure

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-iodonitrobenzene (25 g, 100 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.30 g, 0.43 mmol) and copper (I) iodide (0.18 g, 0.95 mmol) in tetrahydrofuran (300 mL) and triethylamine (150 mL) was degassed under Argon for 10 minutes. The mixture was then heated to 55° C. and treated with 5-chloropentyne (12 mL, 110 mmol) via syringe. After 30 minutes of stirring, additional quantities of dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and 5-chloropentyne (1 mL) were added. After another 30 minutes of stirring, the mixture was allowed to cool to room temperature and then was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was carried on without further purification. ES/MS calcd. for C11H11ClNO2+ 224.1. found m/z=224.2 (M+1-1)+. was degassed under Argon for 10 minutes After another 30 minutes of stirring to cool to room temperature was filtered through a pad of Celite diatomaceous earth The filtrate was concentrated to dryness under reduced pressure

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 14.85 Parts of 5-chloropent-1-yne is dissolved in 250 parts by volume of toluene and the resulting solution is cooled to approximately -40° C. To that solution is then added 62.8 parts by volume of 2.31 M ethereal n-butyl lithium and stirring is continued for approximately 15 minutes. 6.87 Parts of boron trifluoride etherate is added and the reaction mixture is stirred for about two hours, then is allowed to stand for about 16 hours at -5° to -10° C. At the end of that time, 10.14 parts of methyl vinyl ketone is added at -40° C. and the reaction mixture is stirred for about 4 hours, then is quenched with water. 50 Parts by volume of 3 N hydrochloric acid is added and the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers and separated. The aqueous layer is extracted with toluene and the organic layer with water. The organic solutions are combined, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure to afford the crude product. This material is purified by distillation under reduced pressure to give 9-chloro-5-nonyn-2-one, boiling at about 80° - 92° C. at a pressure of 0.11 - 0.06 mm. the reaction mixture is stirred for about two hours to stand for about 16 hours at -5° to -10° C the reaction mixture is stirred for about 4 hours is quenched with water 50 Parts by volume of 3 N hydrochloric acid is added the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers and separated The aqueous layer is extracted with toluene washed successively with aqueous sodium hydroxide and water dried over anhydrous sodium sulfate to afford the crude product This material is purified by distillation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5 M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to -20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1 N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (+/-)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125-126° C. 1H NMR (300 MHz, CDCl3) δ 7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H)102(s, 9H); 0.79-0.92(m, 4H)1; 0.27(s, 3H) 0.26(s, 3H). High resolution mass spec: calculated for C19H26NO2ClF3Si(M+H)+ : 420.1373, found: 420.1363. Over the course of the addition the internal temperature The reaction was cooled to -20° C. The dark solution was stirred an additional 30 min the cold bath was removed The reaction was stirred 5 min poured into 800 mL of 0° C The mixture was extracted twice with ether the combined organic extracts were washed with water brine, dried (MgSO4) concentrated under reduced pressure Chromatography on silica gel (elution with hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to -20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (±)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125°-126° C. 1H NMR (300 MHz, CDCl3) δ7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C19H26NO2ClF3Si(M+H)+ : 420.1373, found: 420.1363. Over the course of the addition the internal temperature The reaction was cooled to -20° C. The dark solution was stirred an additional 30 min. the cold bath was removed The reaction was stirred 5 min poured into 800 mL of 0° C The mixture was extracted twice with ether the combined organic extracts were washed with water brine, dried (MgSO4) concentrated under reduced pressure Chromatography on silica gel (elution with hexanes