1-(4-fluorophenyl)butan-1-one

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aluminum chloride (139 g, 1.04 mol) was added to a solution of butyryl chloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml) stirring under a nitrogen atmosphere at 25° C. A solution of fluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was added and stirring was continued for 18 h. The reaction solution was poured over ice and extracted with dichloromethane (3×400 ml) . The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo. This material was combined with material from a similar preparation (using 0.26 mol of fluorobenzene) for distillation. Distillation at reduced pressure gave 69.27 g (53%) of 4'-fluorobutyrophenone as a pale yellow liquid which later partially crystallized, b.p. 108°-112° C. at 30 millitorr: NMR (DMSO-d6): d 8.03 (q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0 Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). stirring The reaction solution was poured over ice extracted with dichloromethane (3×400 ml) The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo Distillation at reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aluminum chloride (139 g, 1.04 mol) was added to a solution of butyryl chloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml) stirring under a nitrogen atmosphere at 25° C. A solution of fluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was added and stirring was continued for 18 h. The reaction solution was poured over ice and extracted with dichloromethane (3×400 ml) . The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo. This material was combined with material from a similar preparation (using 0.26 mol of fluorobenzene) for distillation. Distillation at reduced pressure gave 69.27 g (53%) of 4'-fluorobutyrophenone as a pale yellow liquid which later partially crystallized, b.p. 108°-112° C. at 30 millitorr: NMR (DMSO-d6): d 8.03 (q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0 Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). stirring The reaction solution was poured over ice extracted with dichloromethane (3×400 ml) The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo Distillation at reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aluminum chloride (139 g, 1.04 mol) was added to a solution of butyryl chloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml) stirring under a nitrogen atmosphere at 25° C. A solution of fluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was added and stirring was continued for 18 h. The reaction solution was poured over ice and extracted with dichloromethane (3×400 ml) . The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo. This material was combined with material from a similar preparation (using 0.26 mol of fluorobenzene) for distillation. Distillation at reduced pressure gave 69.27 g (53%) of 4'-fluorobutyrophenone as a pale yellow liquid which later partially crystallized, b.p. 108°-112° C. at 30 millitorr: NMR (DMSO-d6): d 8.03 (q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0 Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). stirring The reaction solution was poured over ice extracted with dichloromethane (3×400 ml) The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo Distillation at reduced pressure

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

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

Procedure: A solution of butyllithium, 2.5M in hexanes (166 ml, 0.416 mol, Aldrich) was added dropwise over 0.5 hr, with rapid mechanical stirring, to a solution of triethyl phosphonoacetate (93.2 g, 0.416 mol, Aldrich) in tetrahydrofuran (700 ml, anhydrous, Aldrich) at <5° C. while blanketed with a nitrogen atmosphere. This solution was stirred for an additional 0.25 hr and cooled to -5° C. with a methanol:ice bath and a solution of 4'-fluorobutyrophenone (69 g, 0.416 mol, Aldrich) in tetrahydrofuran (150 ml) was then added in one portion. Stirring was continued for 18 hr without additional cooling. The solution was concentrated to a dark camel sludge by spin evaporation in vacuo and diluted to 600 ml with deionized water. The aqueous solution was extracted with dichloromethane (5×500 ml) and the dichloromethane was concentrated by spin evaporation in vacuo. Distillation at reduced pressure gave 58.5 g (60%) of ethyl 3-(4-fluorophenyl)hexenoate as a mixture of (E) and (Z) isomers (ratio 1:1) as clear liquid b.p. 140-150° C. at aspirator pressure: Stirring was continued for 18 hr without additional cooling The solution was concentrated to a dark camel sludge by spin evaporation in vacuo diluted to 600 ml with deionized water The aqueous solution was extracted with dichloromethane (5×500 ml) the dichloromethane was concentrated by spin evaporation in vacuo Distillation at reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aluminum chloride (1.39 g, 1.04 mol) was added to a solution of butyryl chloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml) stirring under a nitrogen atmosphere at 25° C. A solution of fluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was added and stirring was continued for 18 h. The reaction solution was poured over ice and extracted with dichloromethane (3×400 ml). The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml), concentrated by spin evaporation in vacuo. This material was combined with material from a similar preparation (using 0.26 mol of fluorobenzene) for distillation. Distillation at reduced pressure gave 69.27 g (53%) of 4'-fluorobutyrophenone as a pale yellow liquid which later partially crystallized, b.p. 108-112° C. at 30 millitorr: NMR (DMSO-d6): d 8.03 (q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0 Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). stirring The reaction solution was poured over ice extracted with dichloromethane (3×400 ml) The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml) concentrated by spin evaporation in vacuo Distillation at reduced pressure

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

Procedure: When the procedure of Example 37, 4-[4-((4-chloro-1-naphthyl)methyl)-1-piperidyl]-1-phenyl-1-butanone hydrochloride is substituted for 4-[4-(2-naphthyl)hydroxymethyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone, α-phenyl-4-[(4-chloro-1-naphthyl)methyl]-1-piperidinebutanol is obtained.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aluminum chloride (139 g, 1.04 mol) was added to a solution of butyryl chloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml) stirring under a nitrogen atmosphere at 25° C. A solution of fluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was added and stirring was continued for 18 h. The reaction solution was poured over ice and extracted with dichloromethane (3×400 ml) . The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo. This material was combined with material from a similar preparation (using 0.26 mol of fluorobenzene) for distillation. Distillation at reduced pressure gave 69.27 g (53%) of 4'-fluorobutyrophenone as a pale yellow liquid which later partially crystallized, b.p. 108°-112° C. at 30 millitorr: NMR (DMSO-d6): d 8.03 (q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0 Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). stirring The reaction solution was poured over ice extracted with dichloromethane (3×400 ml) The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo Distillation at reduced pressure