1-chloro-4-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:

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

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

Procedure: 2.0 mmol of 4-chlorofluorobenzene, 2.4 mmol of piperidine, 2.8 mmol of potassium tert-butoxide, 0.4 mmol of lithium bromide, 1.0 mol-% (9.4 mg) of palladacycle (trans-di(μ-aceto)-bis[o[di-o-tolylphosphino)benzyl]dipalladium(II) in 10 ml of toluene are reacted according to the GWI to give 4-fluorophenylpiperidine and 3-fluorophenylpiperidine in the ratio 2:1 in 75% yield.

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.3 g, 0.020 mole) in dry DMF is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (1.6 g, 0.033 mole), previously washed with hexane, in 40 ml dry DMF, at 65° C. After the evolution of gas ceases, a solution of p-chlorofluorobenzene (3.6 g, 0.028 mole) in 15 ml dry DMF is added slowly, and the resulting mixture is allowed to stir at 75° C. for 16 hours. After cooling to room temperature the solution is poured into water (110 ml), extracted with chloroform, the chloroform phase is washed twice with water, dried (saturated NaCl, anhydrous MgSO4) and removed via reduced pressure to yield an oil which is purified by dry column chromatography, over silica gel using ethyl acetate as the eluent. The desired product is crystallized from ether as the hydrochloride salt, yielding 1.9 g (31%) of a solid of 4-(p-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, d@92° C. previously washed with hexane, in 40 ml dry DMF, at 65° C After cooling to room temperature the solution extracted with chloroform the chloroform phase is washed twice with water dried (saturated NaCl, anhydrous MgSO4) removed via reduced pressure to yield an oil which is purified by dry column chromatography The desired product is crystallized from ether as the hydrochloride salt

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

Procedure: To a solution of sodium hydride (60%, 254 mg, 6.35 mmol) in 15 mL tetrahydrofuran (THF) was added 5-allyloxyindole (Step A; 1.0 g, 5.77 mmol) in 5 mL THF and the mixture was stirred for 1 hour at ambient temperature. 4-fluorochlorobenzene (0.69 mL, 6.35 mmol) was added and the reaction heated to reflux for 21 hours. After cooling, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue purified by flash chromatography on silica gel (15% ethyl acetate/hexane) to provide the title compound. the reaction heated to reflux for 21 hours After cooling the reaction was quenched with saturated aqueous ammonium chloride extracted with ethyl acetate The organic layer was washed with water, brine dried over magnesium sulfate filtered concentrated in vacuo the crude residue purified by flash chromatography on silica gel (15% ethyl acetate/hexane)

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

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

Procedure: Finely pulverized maleic anhydride (3.0 g) is added portionwise to a mixture of 1-chloro-4-fluorobenzene (24.6 g) and anhydrous aluminium chloride (11.56 g). A gas bubbler is attached to the top of the condenser and the mixture is heated in an oil bath at 80°-85° C. for 2 hours at which time little hydrogen chloride gas evolution is evident. The mixture is cooled and the excess 1-chloro-4-fluorobenzene is recovered by distillation at water aspirator pressure. The resultant mixture is quenched with ice and then steam distilled to remove the last traces of the 1-chloro-4-fluorobenzene. Concentrated hydrochloric acid (10 mL) is added to the cooled mixture and the resultant solid collected by filtration (9.2 g). This material is taken up in boiling benzene (50 mL), treated with decolorizing charcoal and filtered through a celite bed. On standing overnight, the yellow solid is collected by filtration (2.45 g). A second recrystallization from benzene (40 mL) leads to 4-(2'-fluoro-5'-chlorophenyl)-4-oxo-2E-butenoic acid (2.1 g) as pure regioisomer. The mixture is cooled the excess 1-chloro-4-fluorobenzene is recovered by distillation at water aspirator pressure The resultant mixture is quenched with ice steam distilled to remove the last traces of the 1-chloro-4-fluorobenzene Concentrated hydrochloric acid (10 mL) is added to the cooled mixture the resultant solid collected by filtration (9.2 g) treated with decolorizing charcoal filtered through a celite bed the yellow solid is collected by filtration (2.45 g) A second recrystallization from benzene (40 mL)

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

Procedure: A suspension of 7.65 g of 1-methyl-3-phenyl-4-piperidinol (approximately a 50:50 mixture of isomers) of Example 1 in 100 ml of benzene is added to a suspension of 1.2 g of sodium hydride in 50 ml dry benzene. The mixture is heated to reflux, and 25 ml of dry DMF are added dropwise over a 10-minute period. After refluxing for 1 hour, the mixture is cooled to room temperature and a solution of 6.53 g of p-chlorofluorobenzene in 50 ml of benzene is added all at once. After stirring for 18 hours at room temperature, 100 ml of DMF are added and the mixture is refluxed for 5 hours, then stirred for 18 hours at room temperature and then refluxed an additional 4 hours. The mixture is partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether. The combined extracts are washed with water, saturated aqueous NaCl solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo affords an oil. This material is dissolved in dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed with saturated aqueous NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford an oil which crystallizes on standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. A pure product, trans-4-(4-chlorophenoxy)-1-methyl-3-phenylpiperidine, is thus obtained, m.p. s 83.5°, 84.5°-87° C. The mixture is heated to reflux After refluxing for 1 hour the mixture is refluxed for 5 hours stirred for 18 hours at room temperature refluxed an additional 4 hours The mixture is partitioned between ether and saturated aqueous NaCl solution The aqueous phase is extracted with ether The combined extracts are washed with water, saturated aqueous NaCl solution dried over anhydrous MgSO4 Removal of the solvent in vacuo affords an oil extracted with 2 N HCl solution The dichloromethane phase is washed with saturated aqueous NaHCO3 solution dried over anhydrous MgSO4 filtered concentrated in vacuo to afford an oil which crystallizes This material is chromatographed on silica gel

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

Procedure: A suspension of 7.65 g of 1-methyl-3-phenyl-4-piperidinol (approximately a 50:50 mixture of isomers) of Example 1 in 100 ml of benzene is added to a suspension of 1.2 g of sodium hydride in 50 ml dry benzene. The mixture is heated to reflux, and 25 ml of dry DMF are added dropwise over a 10-minute period. After refluxing for 1 hour, the mixture is cooled to room temperature and a solution of 6.53 g of p-chlorofluorobenzene in 50 ml of benzene is added all at once. After stirring for 18 hours at room temperature, 100 ml of DMF are added and the mixture is refluxed for 5 hours, then stirred for 18 hours at room temperature and then refluxed an additional 4 hours. The mixture is partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether. The combined extracts are washed with water, saturated aqueous NaCl solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo affords an oil. This material is dissolved in dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed with saturated aqueous NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford an oil which crystallizes on standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. A pure product, trans-4-(4-chlorophenoxy)-1-methyl-3-phenylpiperidine, is thus obtained, m.p. s 83.5°, 84.5°-87° C. The mixture is heated to reflux After refluxing for 1 hour the mixture is refluxed for 5 hours stirred for 18 hours at room temperature refluxed an additional 4 hours The mixture is partitioned between ether and saturated aqueous NaCl solution The aqueous phase is extracted with ether The combined extracts are washed with water, saturated aqueous NaCl solution dried over anhydrous MgSO4 Removal of the solvent in vacuo affords an oil extracted with 2 N HCl solution The dichloromethane phase is washed with saturated aqueous NaHCO3 solution dried over anhydrous MgSO4 filtered concentrated in vacuo to afford an oil which crystallizes This material is chromatographed on silica gel

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

Procedure: Under an argon atmosphere 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)propyl]-1H-indole (2.89 g, 5,61 mmol) was dissolved in about 11.2 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.247 g of a 60% suspension in mineral oil, 6.18 mmol) was added and the resulting mixture was stirred at room temperature for about 60 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.658 ml, 0.807 g, 6.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then heated to 80° C. and maintained at this temperature for about eight hours. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. Another half equivalence of sodium hydride was added and the reaction mixture was stirred at room temperature overnight again. Another half equivalence of 1-chloro-4-fluorobenzene was added and the reaction mixture was heated to 80° C. The resulting solution was then placed in an ice bath the resulting mixture was stirred at room temperature overnight The reaction mixture was then heated to 80° C. maintained at this temperature for about eight hours The reaction mixture was then cooled to room temperature stirred at this temperature overnight the reaction mixture was stirred at room temperature overnight again the reaction mixture was heated to 80° C.