1-bromo-4-hexoxybenzene

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

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

Procedure: To a suspension of magnesium turnings (0.48 g) in tetrahydrofuran (10 ml) was added dropwise a solution of 4-hexyloxybromobenzene (5 g) in tetrahydrofuran (70 ml) and stirred for 1 hour at ambient temperature. Then to the reaction mixture was added 1-benzyloxycarbonyl-4-piperidone (4.12 g) and stirred for 2 hours under ice-cooling. The reaction was quenched with saturated NH4Cl aq. and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the object compound were collected and evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (3.44 g). stirred for 2 hours under ice- cooling The reaction was quenched with saturated NH4Cl aq. extracted with ethyl acetate dried over magnesium sulfate The magnesium sulfate was filtered off filtrate was evaporated under reduced pressure eluted with (hexane/ethyl acetate)=(3/1) The fractions containing the object compound were collected evaporated under reduced pressure

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

Procedure: A solution of the Grignard Reagent prepared from 1A (72 g) and Mg (7.75 g) in dry THF 250 ml) is added dropwise to a stirred, cooled (-78° C.) solution of tri-isopropyl borate (109.1 g) in dry THF 40 ml) under dry N2. The stirred mixture is allowed to warm to room temperature overnight and stirred with 10% HCl (320 ml) at room temperature for 1 hr. The product is extracted into ether twice, and the combined etheral extracts are washed with water and dried (MgSO4). Solvent is removed in vacuo to yield a colourless solid, mp =80°-85° C. is added dropwise to a stirred The product is extracted into ether twice the combined etheral extracts are washed with water dried (MgSO4) Solvent is removed in vacuo to yield a colourless solid, mp =80°-85° C.

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

Procedure: A solution of 1-bromohexane (60 g) in acetone (150 ml) is added dropwise to a stirred mixture of 4-bromphenol (71 g) and K2CO3 (120 g) in acetone 600 ml) at room temperature. The stirred mixture is heated under reflux for 43 hrs (i.e. until glc revealed complete reaction). The product is extracted into ether twice, and the combined ethereal extracts are washed with water, 5% NaOH water and dried (MgSO4). The solvent is removed in vacuo and the residue was distilled (bp=100°-110° C. at 0.1 mm Hg) to yield a colourless liquid. The stirred mixture is heated under reflux for 43 hrs (i.e. until glc revealed complete reaction) The product is extracted into ether twice the combined ethereal extracts are washed with water, 5% NaOH water dried (MgSO4) The solvent is removed in vacuo the residue was distilled (bp=100°-110° C. at 0.1 mm Hg) to yield a colourless liquid

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

Procedure: In a baked-out apparatus filled with argon, magnesium turnings (1.89 g; 78 mmol) were treated with a crystal of iodine and covered with dried THF. Subsequently, a few drops of 4-hexyloxybromobenzene were added to the static solution. The Grignard reaction commenced very quickly and the 4-hexyloxybromobenzene (total amount: 20 g; 78 mmol) was subsequently added dropwise while stirring at such a rate that the mixture boiled gently; during this addition, the mixture was diluted with THF (total of about 100 ml). The mixture was refluxed for 3 hours (only a few flakes of magnesium remaining in the solution) and was subsequently allowed to cool. The Grignard soltuion was transferred in a countercurrent of protective gas to a 250 ml dropping funnel and added dropwise at −70° C. to a solution of trimethyl borate (8.9 g; 9.6 ml; 86 mmol) in 50 ml of dry THF while stirring, with a precipitate being formed. The mixture was allowed to warm to RT overnight and the reaction mixture was poured into a mixture of 100 g of ice and 3 ml of concentrated sulfuric acid while stirring. The organic phase was separated off and the aqueous phase was extracted with 3×100 ml of chloroform, the combined organic phases were evaporated. The crude product was subsequently recrystallized from hexane. The Grignard reaction during this addition to cool while stirring, with a precipitate being formed while stirring The organic phase was separated off the aqueous phase was extracted with 3×100 ml of chloroform the combined organic phases were evaporated The crude product was subsequently recrystallized from hexane

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

Procedure: 4-Bromophenol (173 g, 1 mol) was dissolved in about 500 ml of freshly distilled THF under protective gas and, after passing argon through the solution, NaH (33 g, (80% in oil), 1.1 mol) was added a little at a time. During this addition the clear solution became turbid and gray and the temperature rose by 20°. The suspension was stirred for about 1 hour at room temperature under a blanket of protective gas. Hexyl bromide (181 g; 149 ml; 1.1 mol) was placed in a dropping funnel and N2 was briefly passed through it; the hexyl bromide was then added to the reaction mixture over a period of 25 minutes while stirring. The mixture, which was still gray, was refluxed at 75° C. After 3 days, (the suspension had now become paler), the salt formed was filtered off with suction and the filtrate was admixed with 20 ml of EtOH to destroy any remaining NaH (no gas evolution). The yellowish solution was evaporated and the product was isolated from the (turbid) solution by means of fractional vacuum distillation: product: 95° C./1 mbar; 172.5 g (67%); (d˜1.17). was added a little at a time During this addition the clear solution rose by 20° while stirring was refluxed at 75° C After 3 days formed was filtered off with suction to destroy any remaining NaH (no gas evolution) The yellowish solution was evaporated the product was isolated from the (turbid) solution by means of fractional vacuum distillation 95° C./1 mbar

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

Procedure: 4-Bromophenol (173 g, 1 mol) was dissolved in about 500 ml of freshly distilled THF under protective gas and, after passing argon through the solution, NaH (33 g, (80% in oil), 1.1 mol) was added a little at a time. During this addition the clear solution became turbid and gray and the temperature rose by 20°. The suspension was stirred for about 1 hour at room temperature under a blanket of protective gas. Hexyl bromide (181 g; 149 ml; 1.1 mol) was placed in a dropping funnel and N2 was briefly passed through it; the hexyl bromide was then added to the reaction mixture over a period of 25 minutes while stirring. The mixture, which was still gray, was refluxed at 75° C. After 3 days, (the suspension had now become paler), the salt formed was filtered off with suction and the filtrate was admixed with 20 ml of EtOH to destroy any remaining NaH (no gas evolution). The yellowish solution was evaporated and the product was isolated from the (turbid) solution by means of fractional vacuum distillation: product: 95° C./1 mbar; 172.5 g (67%); (d˜1.17). was added a little at a time During this addition the clear solution rose by 20° while stirring was refluxed at 75° C After 3 days formed was filtered off with suction to destroy any remaining NaH (no gas evolution) The yellowish solution was evaporated the product was isolated from the (turbid) solution by means of fractional vacuum distillation 95° C./1 mbar

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 mL N2 filled round bottom flask was added 1-bromo-4-(hexyloxy)benzene (20.5 g, 80.0 mmol, 1 equiv.) and DMF (160 mL, 0.5 M). The mixture was then sparged with bubbling N2. To this mixture was added N2-sparged triethylamine (39.0 mL, 280 mmol, 3.5 equiv.) via syringe. Finally, copper (I) iodide (254.0 mg, 1.33 mmol, 1.7%), triphenylphosphine (603.0 mg, 2.67 mmol, 3.3%) and PdCl2(PPh3)2 (933.0 mg, 1.33 mmol, 1.7%) were added as a single portion and the head space was flushed with N2. Ethynyltrimethylsilane (16.9 mL, 120.0 mmol, 1.5 equiv.) was added via syringe to the mixture. The flask was sealed with a ground glass stopper, Teflon tape, and then electrical tape and heated to 90° C. for 48 hours. After 48 hours the mixture was diluted with hexanes and extracted with 10% H3PO4 then 5% K2CO3. The organic layer was then dried with MgSO4 and filtered through a plug of SiO2 with 100% hexanes. Upon evaporation, ((4-(hexyloxy)phenyl)ethynyl)trimethylsilane was isolated as a clear oil (16.45 g, 60.2 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ7.42 (d, J=9.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 1.85-1.73 (m, 2H), 1.52-1.42 (m, 2H), 1.41-1.26 (m, 4H), 0.94 (t, J=7.6 Hz, 3H), 0.27 (s, 9H). The mixture was then sparged with bubbling N2 To this mixture was added N2- the head space was flushed with N2 extracted with 10% H3PO4 The organic layer was then dried with MgSO4 filtered through a plug of SiO2 with 100% hexanes Upon evaporation

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 mL N2 filled round bottom flask was added 1-bromo-4-(hexyloxy)benzene (20.5 g, 80.0 mmol, 1 equiv.) and DMF (160 mL, 0.5 M). The mixture was then sparged with bubbling N2. To this mixture was added N2-sparged triethylamine (39.0 mL, 280 mmol, 3.5 equiv.) via syringe. Finally, copper (I) iodide (254.0 mg, 1.33 mmol, 1.7%), triphenylphosphine (603.0 mg, 2.67 mmol, 3.3%) and PdCl2(PPh3)2 (933.0 mg, 1.33 mmol, 1.7%) were added as a single portion and the head space was flushed with N2. Ethynyltrimethylsilane (16.9 mL, 120.0 mmol, 1.5 equiv.) was added via syringe to the mixture. The flask was sealed with a ground glass stopper, Teflon tape, and then electrical tape and heated to 90° C. for 48 hours. After 48 hours the mixture was diluted with hexanes and extracted with 10% H3PO4 then 5% K2CO3. The organic layer was then dried with MgSO4 and filtered through a plug of SiO2 with 100% hexanes. Upon evaporation, ((4-(hexyloxy)phenyl)ethynyl)trimethylsilane was isolated as a clear oil (16.45 g, 60.2 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ7.42 (d, J=9.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 1.85-1.73 (m, 2H), 1.52-1.42 (m, 2H), 1.41-1.26 (m, 4H), 0.94 (t, J=7.6 Hz, 3H), 0.27 (s, 9H). The mixture was then sparged with bubbling N2 To this mixture was added N2- the head space was flushed with N2 extracted with 10% H3PO4 The organic layer was then dried with MgSO4 filtered through a plug of SiO2 with 100% hexanes Upon evaporation

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

Procedure: In an apparatus which had been baked out and blanketed with argon, magnesium turnings (1.89 g; 78 mmol) were treated with a crystal of iodine and covered with dried THF. A few drops of 4-hexyloxybromobenzene were then added to the solution without stirring. The Grignard reaction began very quickly and, while stirring, the 4-hexyloxybromobenzene (total amount: 20 g; 78 mmol) was then added dropwise at such a rate that the mixture boiled gently. During this addition, the mixture was diluted with a little THF (total amount: about 100 ml). The mixture was refluxed for 3 hours (only a few flakes of magnesium remaining in the solution) and subsequently allowed to cool. The Grignard solution was transferred to a 250 ml dropping funnel in a countercurrent of protective gas and added dropwise to a solution of trimethyl borate (8.9 g; 9.6 ml; 86 mmol) in 50 ml of dry THF while stirring at −70° C., resulting in formation of a precipitate. The reaction mixture was allowed to warm to RT overnight and was then introduced while stirring into a mixture of 100 g of ice and 3 ml of concentrated sulfuric acid. The organic phase was separated off, the aqueous phase was extracted 3 times with 100 ml each time of chloroform and the combined organic phases were evaporated. The crude product was subsequently recrystallized from hexane. Product: colorless, wax-like solid (11.28 g; 66%); melting point: 84-87° C. The Grignard reaction while stirring During this addition to cool while stirring at −70° C. resulting in formation of a precipitate was then introduced The organic phase was separated off the aqueous phase was extracted 3 times with 100 ml each time of chloroform the combined organic phases were evaporated The crude product was subsequently recrystallized from hexane

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

Procedure: To a suspension of magnesium turnings (0.48 g) in tetrahydrofuran (10 ml) was added dropwise a solution of 4-hexyloxybromobenzene (5 g) in tetrahydrofuran (70 ml) and stirred for 1 hour at ambient temperature. Then to the reaction mixture was added 1-benzyloxycarbonyl-4-piperidone (4.12 g) and stirred for 2 hours under ice-cooling. The reaction was quenched with saturated NH4Cl aq. and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the object compound were collected and evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (3.44 g). stirred for 2 hours under ice- cooling The reaction was quenched with saturated NH4Cl aq. extracted with ethyl acetate dried over magnesium sulfate The magnesium sulfate was filtered off filtrate was evaporated under reduced pressure eluted with (hexane/ethyl acetate)=(3/1) The fractions containing the object compound were collected evaporated under reduced pressure

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

Procedure: A solution of the Grignard Reagent prepared from 1A (72 g) and Mg (7.75 g) in dry THF 250 ml) is added dropwise to a stirred, cooled (-78° C.) solution of tri-isopropyl borate (109.1 g) in dry THF 40 ml) under dry N2. The stirred mixture is allowed to warm to room temperature overnight and stirred with 10% HCl (320 ml) at room temperature for 1 hr. The product is extracted into ether twice, and the combined etheral extracts are washed with water and dried (MgSO4). Solvent is removed in vacuo to yield a colourless solid, mp =80°-85° C. is added dropwise to a stirred The product is extracted into ether twice the combined etheral extracts are washed with water dried (MgSO4) Solvent is removed in vacuo to yield a colourless solid, mp =80°-85° C.