3-chloroprop-1-ynylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Sodium hydride (0.912 g, 23 mmol, 60% oil disp.) which had been rinsed with hexanes (3×10 mL), and dry N,N-dimethylformamide (50 mL) were cooled to 0° C. with stirring under a nitrogen atmosphere. A solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (4.3 g, 19 mmol) in dry DMF (15 mL) was added, and the mixture stirred for 1 hour. 3-Phenylpropargyl chloride (2.8 g, 19 mmol) was added, and the mixture was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure. The residue was u dissolved in ethyl acetate and extracted with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, and concentrated under reduced pressure to yield 1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine (1.02 g, 16% dark oil. 1H NMR (300 MHz, CDCl3 /TMS, δ): 7.5(m,2H), the mixture stirred for 1 hour the mixture was heated to reflux for 24 hours After cooling the solvent was removed by distillation under reduced pressure dissolved in ethyl acetate extracted with water (3×100 mL), brine (100 mL) dried (MgSO4) filtered concentrated under reduced pressure The crude product was purified by chromatography on silica gel eluting with 5% ethyl acetate in hexanes concentrated under reduced pressure

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

Procedure: 1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride and 20 ml of pyridine were stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2.54 g of 3-phenyl-2-propynyl chloride as a pale yellow, oily substance. extracted with ethyl acetate The oil layer was washed with 1N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate The solvent was distilled away The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5)

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

Procedure: 1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride and 20 ml of pyridine were stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was washed with 1 N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane 1:5) to give 2.54 g of 3-phenyl-2-propynyl chloride as a pale yellow, oily substance. extracted with ethyl acetate The oil layer was washed with 1 N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate The solvent was distilled away The residue was purified by silica gel column chromatography (ethyl acetate:hexane 1:5)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (3-chloro-l-propynyl)benzene (0.754 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4: 1) and the resulting solids were crystallized from diethyl ether-hexane to give 0.8 g of alpha-oxo-4-[(3-phenyl-2-propynyl)oxy]benzeneacetic acid methyl ester mp 57°-59° C. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4: 1) the resulting solids were crystallized from diethyl ether-hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (3-chloro-l-propynyl)benzene (0.754 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4: 1) and the resulting solids were crystallized from diethyl ether-hexane to give 0.8 g of alpha-oxo-4-[(3-phenyl-2-propynyl)oxy]benzeneacetic acid methyl ester mp 57°-59° C. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4: 1) the resulting solids were crystallized from diethyl ether-hexane

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

Procedure: The title compound was prepared in a manner similar to the preparation in Preparation 3 from (3-chloro-prop-1-ynyl)-benzene and (2S,3R,6S)4-(4-hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. Calculated for C23H25NO6S (M+H): 444.14. Found: 444.0.

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

Procedure: Sodium hydride (0.912 g, 23 mmol, 60% oil disp.) which had been rinsed with hexanes (3×10 mL), and dry N,N-dimethylformamide (50 mL) were cooled to 0° C. with stirring under a nitrogen atmosphere. A solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (4.3 g, 19 mmol) in dry DMF (15 mL) was added, and the mixture stirred for 1 hour. 3-Phenylpropargyl chloride (2.8 g, 19 mmol) was added, and the mixture was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and extracted with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, and concentrated under reduced pressure to yield 1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine (1.02 g, 16%) as a dark oil. 1H NMR (300 MHz, CDCl3 /TMS, δ): 7.5(m,2H), 7.3(m,3H), 4.4(s,2H), 4.1(m,2H), 3.6(t,2H), 2.7(br t,2H), 1.8-1.1(m,16H). MSCI: 344 (MH+, base). the mixture stirred for 1 hour the mixture was heated to reflux for 24 hours After cooling the solvent was removed by distillation under reduced pressure The residue was dissolved in ethyl acetate extracted with water (3×100 mL), brine (100 mL) dried (MgSO4) filtered concentrated under reduced pressure The crude product was purified by chromatography on silica gel eluting with 5% ethyl acetate in hexanes concentrated under reduced pressure

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

Procedure: 1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride and 20 ml of pyridine were stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2.54 g of 3-phenyl-2-propynyl chloride as a pale yellow, oily substance. extracted with ethyl acetate The oil layer was washed with 1N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate The solvent was distilled away The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5)

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

Procedure: Sodium hydride (0.912 g, 23 mmol, 60% oil disp.) which had been rinsed with hexanes (3×10 mL), and dry N,N-dimethylformamide (50 mL) were cooled to 0° C. with stirring under a nitrogen atmosphere. A solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (4.3 g, 19 mmol) in dry DMF (15 mL) was added, and the mixture stirred for 1 hour. 3-Phenylpropargyl chloride (2.8 g, 19 mmol) was added, and the mixture was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure. The residue was u dissolved in ethyl acetate and extracted with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, and concentrated under reduced pressure to yield 1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine (1.02 g, 16% dark oil. 1H NMR (300 MHz, CDCl3 /TMS, δ): 7.5(m,2H), the mixture stirred for 1 hour the mixture was heated to reflux for 24 hours After cooling the solvent was removed by distillation under reduced pressure dissolved in ethyl acetate extracted with water (3×100 mL), brine (100 mL) dried (MgSO4) filtered concentrated under reduced pressure The crude product was purified by chromatography on silica gel eluting with 5% ethyl acetate in hexanes concentrated under reduced pressure