2-phenylbenzaldehyde

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: To a solution of biphenyl-2-carbaldehyde (5.01 g, 27.5 mmol) in dichloromethane (150 ml) at rt under nitrogen was added piperazine-1-carboxylic acid tert-butyl ester (5.63 g, 30.2 mmol) followed by glacial acetic acid (1.90 ml, 33.2 mmol). The reaction was stirred for 1 h before sodium triacetoxyborohydride (11.65 g, 55.0 mmol) was introduced. After 3 h, a solution of 5% NaOH (˜15 ml) was added and the mixture was extracted with dichloromethane. The organic layer was separated, washed with H2O (×2), brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 4-biphenyl-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester as an oil (9.9 g, 100%) which was used without further purification. HPLC-MS 353 [M+1]+. was introduced the mixture was extracted with dichloromethane The organic layer was separated washed with H2O (×2), brine dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: 3-(4-Phenyl-benzyl)-7-trifluoromethylsulfonyloxy-4-chromanone (35.0 g, 91.0 mmole, prepared from the product of Example 2C with biphenyl aldehyde using the procedures of Example 2D and Example 2E, was dissolved in a mixture of dimethylformamide (230 mL) and dimethoxyethane (230 mL). To this solution was added in the following order, tris(2-methylphenyl)phosphine (7.48 g, 24.6 mmole), bis(benzonitrile)palladium (II) chloride (2.44 g, 6.37 mmole), the trimethylsilyl ketene acetal of ethyl cyclopentanecarboxylate (29.26 g, 136.5 mmole), and a 1.0M ethereal solution of zinc chloride (25 mL, 25 mmole). The resulting clear yellow solution was refluxed for about 1 hour. Additional trimethylsilyl ketene acetal (9.75 g, 45.5 mmole) was added at this point and the reflux continued for about another 1 hour. The cooled mixture was diluted with water (1 L) and extracted with ether. The combined ether extracts were washed with water (1 L) and then dried over magnesium sulfate. Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane). This yielded 22.13 g (64%) of the title compound of this Example 5A as a white solid; m.p. 50-56 ° C.; 1H NMR (CDCl3): 1.23 (3H, t, J=7.0), 1.75 (4H, m), 1.9 (2H, m), 2.6 (2H, m), 2.70 (1H, dd, J=10.5, 13.8), 2.9 (1H, m), 3.26 (1H, dd, J=4.3, 13.8), 4.08 (2H, d, J=7.0), 4.15 (1H, dd, J=8.2, 11.5), 4.35 (dd, J=4.3, 11.5), 6.95 (1H, d, J=1.7), 7.02 (1H, dd, J=1.7, 8.3), 7.2-7.4 (5H, m) 7.84 (1H, d, J=8.3). The resulting clear yellow solution was refluxed for about 1 hour continued for about another 1 hour extracted with ether The combined ether extracts were washed with water (1 L) dried over magnesium sulfate Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane)

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

Procedure: 19.2 mg of the target compound (0.05 mmol, 5.6%) was obtained using 1-(3-trifluoromethylphenyl)piperazine hydrochloride (437 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 148 mg of the target compound (0.37 mmol, 66.5%) was obtained using 1-(biphenyl-2-yl)piperazine (260 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.

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

Procedure: 100 mg of the target compound (0.27 mmol, 49.1%) was obtained using 1-(2-isopropylphenyl)piperazine (223 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.

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

Procedure: 58 mg of the target compound (0.16 mmol, 19.5%) was obtained using 1-(3,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 35.8 mg of the target compound (0.10 mmol, 12.2%) was obtained using 1-(2,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 201.6 mg of the target compound (0.57 mmol, 69.0%) was obtained using 1-(2,4-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.

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

Procedure: 52.7 mg of the target compound (0.15 mmol, 18.3%) was obtained using 1-(2,3-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.