3.1. General

All reagents and organic solvents were ACS grade or higher and used without further purification. Unless otherwise noted, all chemicals were purchased from J&K Scientific (Shanghai, China). Reactions were performed under argon atmosphere with standard Schlenk techniques. Thin layer chromatography was performed on HAIYANG silica gel F254 plate, and compounds were visualized under UV light (λ = 254 nm). Column chromatography was carried out using HAIYANG silica gel (type: 200–300 mesh ZCX-2). 1H (500 MHz), 13C-NMR (126 MHz) and 19F-NMR (470 MHz) spectra were recorded on an Avance 500 spectrometer (Bruker; Billerica, MA, USA). Chemical shifts are reported in δ units (ppm) downfield relative to the chemical shift for tetramethylsilane.

4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid (10b). Entry 2. The 4-bromo-2,2-diphenylbutanoic acid 8 (200 mg, 0.6266 mmol) was dissolved in THF (10 mL), followed by addition of 4-(4-chlorophenyl)-piperidin-4-ol (133 mg, 0.6266 mmol, 1 eq.) and DIPEA (0.242 mL, 1.8798 mmol, 3 eq.) to the solution. The mixture was refluxed for 2 days. No new product was found via TLC. Entry 5 . The 4-bromo-2,2-diphenylbutanoic acid 8 (400 mg, 1.253 mmol) was suspended in acetonitrile (10 mL) and DIPEA (0.675 mL, 3.75 mmol) was added. The mixture was stirred at 105 °C for 30 h. After the solvent was removed under vacuum, the crude was dissolved in CH 2 Cl 2 and was introduced onto a silica gel column. The product was eluted with 3% MeOH in dichloromethane to give 10b as a pale-orange solid (20 mg, 6% yield). TLC (silica gel; MeOH–CH 2 Cl 2 (5:95 v:v); R f = 0.40). LC-MS (M++1): found 449.88; calcd for C 27 H 29 ClNO 3 , 450.18.

4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (12b). 4-(4-Chlorophenyl)-4-hydroxypiperidine (2.1 g, 10.0 mmol) was suspended in acetonitrile (15 mL) and DIPEA (3.5 mL, 30 mmol) was added. 4-Bromo-2,2-diphenylbutanenitrile (3.00 g, 10 mmol) in acetonitrile (15 mL) was then added. The reaction mixture was stirred at 70 °C for 30 h. After the solvent was removed under vacuum, the crude material was redissolved in CH 2 Cl 2 and introduced onto a silica gel column. The product was eluted with 5% MeOH in dichloromethane to yield 12b as a pale-orange solid (2.8 g, 66% yield). TLC (silica gel; MeOH–CH 2 Cl 2 (5:95 v:v); R f = 0.50). 1H-NMR (CDCl 3 ): δ 7.37 (m, 14H), 2.80 (d, 2H, J = 11.25 Hz), 2.67 (m, 2H), 2.55 (m, 2H), 2.47 (t, 2H, J = 11.3 Hz), 2.105 (m, 2H), 1.73 (d, 2H, J = 11.9 Hz). 13C-NMR (CDCl3): δ 140.16, 132.95, 129.09, 128.57, 128.10, 126.95, 126.23, 122.27, 71.11, 54.93, 50.17, 49.71, 38.52, 36.80ppm. LC-MS (M++1) found 431.20; calcd for C 27 H 28 ClN 2 O, 431.19.

4-(4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (12a). Compound 12a was synthesized using the same procedure that was followed the synthesis of the compound 12b, and was obtained in 35% yield as a pale-orange solid. 1H-NMR (CDCl 3 ): δ 7.45 (m, 2H), 7.39 (d, 4H, J = 10 Hz), 7.35 (t, 4H, J = 5Hz ), 7.29 (t, 2H, J = 10 Hz ), 7.00 (t, 2H, J = 10 Hz), 2.75 (d, 2H, J = 10 Hz), 2.63 (m, 2H), 2.52 (m, 2H), 2.47 (t, 2H, J = 10 Hz), 2.08 (m, 2H), 1.71 (d, 2H, J = 15 Hz).13C-NMR: δ 162.89, 160.93, 144.27, 140.16, 129.03, 128.05, 126.91, 126.45, 126.39, 122.23, 115.18, 115.01, 70.91, 54.88, 50.19, 49.72, 38.56, 36.74. 19F-NMR: δ 116.12. LC-MS (M++1): Found: 415.06; Calcd: C 27 H 28 FN 2 O: 415.22.

4-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (12c). Compound 12c was synthesized using the same procedure that was followed the synthesis of the compound 12b, and was obtained in 58% yield as a pale-orange solid. 1H-NMR (CDCl 3 ): δ 7.48 (d, 2H, J = 10 Hz), 7.41 (d, 4H, J = 10 Hz), 7.37 (m, 6H), 7.31 (t, 2H, J = 5 Hz), 2.76 (d, 2H, J = 10 Hz), 2.65 (m, 2H), 2.54 (m, 2H), 2.45 (t, 2H, J = 10 Hz), 2.08 (m, 2H), 1.68 (m, 3H). 13C-NMR: δ 147.64, 140.11, 131.47, 129.07, 128.09, 126.91, 126.66, 122.25, 121.00, 70.97, 54.90, 50.18, 49.64, 38.35, 36.67. LC-MS (M++1): Found: 476.92; Calcd: C 27 H 28 BrN 2 O: 477.13.

4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide (13b). 4-(4-(4-Chloro-phenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (2.5 g, 6.0 mmol) was dissolved in BuOH (40 mL) and potassium hydroxide (1.2 g, 21.3 mmol) was added. The reaction mixture was stirred at 100 °C for 3d. After concentration under vacuum, the crude material was redissolved in dichloromethane and filtered through a pad of Celite. Chromatography of the sample on a silica gel column eluted with ammonium hydroxide (2 M) solution in MeOH-CH 2 Cl 2 (5:95 v/v) gave 13b as a pale-yellow solid (1.58 g, 55% yield). TLC (silica gel; MeOH–CH 2 Cl 2 (5:95 v:v); R f = 0.40). 1H-NMR (CDCl 3 ): δ 7.36 (m, 14H), 6.58 (s, 1H), 5.46 (s, 1H), 3.91 (s, 1H), 2.83 (m, 2H), 2.69 (s, 2H), 2.39 (m, 3H), 2.10 (m, 2H), 1.74 (d, 2H, J = 12.85 Hz). 13C-NMR: 176.56, 167.25, 158.96, 146.67, 143.26, 132.82, 128.69, 128.41, 127.06, 126.10, 59.91, 54.92, 49.48, 38.28, 35.87. LC-MS (M++1): Found: 449.3; Calcd: C 27 H 30 ClN 2 O 2 : 449.20.

4-(4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide (6). Compound 6 was synthesized using the same procedure that was followed the synthesis of the compound 13b, and was obtained in 40% yield as a pale-orange solid. 1H-NMR (CDCl 3 ): δ 7.45 (m, 2H), 7.31 (m, 10H), 6.99 (t, 2H, J = 10 Hz), 5.07 (s, 1H), 2.89 (m, 2H), 2.64 (m, 2H), 2.35 (m, 2H), 2.04 (m, 2H), 1.59 (d, 2H, J = 5 Hz), 6.22 (s, 1H), 5.82 (s, 1H), 3.02 (m, 2H), 2.82 (m, 4H), 2.63 (m, 2H), 2.36 (m, 2H), 1.76 (d, 2H, J = 10 Hz). 13C-NMR: δ 175.53, 162.43, 160.51, 145.88, 143.83, 129.27, 128.46, 127.29, 127.24, 127.07, 115.15, 114.98, 69.28, 59.54, 54.73, 49.44, 37.33, 29.55. 19F-NMR: δ 117.01.

4-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide (7). Compound 7 was synthesized using the same procedure that was followed the synthesis of the compound 13b, and was obtained in 57% yield as a pale-orange solid.1H-NMR (CDCl 3 ): δ 7.41 (t, 2H, J = 5 Hz), 7.31 (m, 12H), 6.45 (s, 1H), 5.87 (s, 1H), 2.82 (m, 12H), 2.31 (m, 12H), 2.50 (m, 12H), 2.42 (m, 12H), 2.11 (m, 12H), 1.69 (m, 12H). 13C-NMR: δ 176.79, 147.17, 143.14, 131.46, 128.75, 128.57, 127.26, 126.64, 121.06, 70.67, 59.88, 55.00, 49.48, 37.79, 35.46. LC-MS (M++1): Found: 494.93; Calcd: C 27 H 30 BrN 2 O 2 +: 495.14.

4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid (10b). 4-(4-(4-Chloro-phenyl)-4-hydroxycyclohexyl)-2,2-diphenylbutanamide (1.2 g, 2.6 mmol) was added to 40%H 2 SO 4 (50 mL) and the mixture was stirred at 100 °C for 2 days. The crude material was extracted with ethyl acetate (60 mL×3). The ethyl acetate was removed by reduced pressure distillation. After drying with MgSO 4 and dissolving in CH 2 Cl 2 (2 mL), the product was introduced onto a silica gel and eluted with 5% MeOH in CH 2 Cl 2 to give trance amount of 10b. TLC (silica gel; MeOH–CH 2 Cl 2 (5:95 v:v); R f = 0.30). 1H-NMR (CDCl 3 ): δ 7.3096(m, 14H), 5.9319 (s, 1H), 3.29 (m, 2H), 2.94 (m, 2H), 2.80 (m, 2H), 2.72 (m, 2H), 2.67 (m, 4H), 2.10 (m, 2H). LC-MS (M++1): found: 449.88; Calcd for C 27 H 28 ClNO 3 +, 450.18.

Procedure for Preparing 10b from 12b

Entry 3 . 4-(4-(4-Chlorophenyl)-4-hydroxypiperidine-1-yl)-2,2-diphenylbutanenitrile (400 mg, 0.928 mmol) was dissolved in 1,4-dioxane (10 mL) and 37% hydrochloric acid (5 mL) was then added. The reaction mixture was refluxed for 16 h. After concentration under vacuum, the crude was dissolved in trichloromethane (10 mL) and extracted with H 2 O (20 mL × 3). After the organic layer was dried by MgSO 4 , the solvent was removed under vacuum and redissolved in CH 2 Cl 2 . The mixture was introduced onto a silica gel column and the product was eluted with 50% EtOAc in hexane first and 5% MeOH in CH 2 Cl 2 later to give the product 14b as a yellow solid (250 mg, 66%). TLC (silica gel; EtOAc–hexane (1:1 v:v); R f = 0.70). Compound 14b: 1H-NMR (CDCl 3 ): δ 7.36 (m, 14H), 6.04 (m, 1H), 3.16 (m, 2H), 2.74 (m, 2H), 2.62 (m, 4H), 2.53 (m, 2H) ppm. 13C-NMR (CDCl 3 ): δ 141.44, 140.57, 135.56, 134.26, 130.53, 129.92, 129.55, 128.27, 127.72, 123.52, 55.96, 54.81, 51.93, 51.57, 38.48, 29.44 ppm. MS (M++1): found 412.99; Calcd C 27 H 25 ClN 2 +, 412.95.

1,4-bis(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutan-1-one (5). 4-(4-Chloro-phenyl)-4-hydroxypiperidinorophenyl)-4-hydroxypiperidine (28 mg, 0.12 mmol, 2 eq.) was dissolved in toluene (5 mL) and 4-(4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid (30 mg, 0.067 mmol) and TiCl 4 (1.5 mL) was then added. The mixture was refluxed for 20 h. After the solvent was removed under vacuum, the crude material was dissolved in CH 2 Cl 2 (10 mL). After the mixture was filtered and CH 2 Cl 2 was then removed to 2 mL, the product was introduced onto a silica gel with 5% MeOH in CH 2 Cl 2 to give 5 as a pale-orange solid (trace amount). TLC (silica gel column; MeOH–CH 2 Cl 2 (5:95 v:v); R f = 0.40).

Methyl 4-bromo-2,2-diphenylbutanoate (18). 4-Bromo-2,2-diphenylbutanoic acid (2.0 g, 6.266 mmol) was dissolved in dry CH 2 Cl 2 (20 mL) and thionyl chloride (2.27 mL, 31.33 mmol, 5 eq.) was then added slowly. A trace amount of DMF was added later. The reaction mixture was refluxed at N 2 for 3 h. Methyl alcohol (2 mL, excess) was added slowly and the mixture was stirred at 50 °C for 3 h. After the solvent was removed under vacuum, the crude material was redissolved in CH 2 Cl 2 and introduced onto a silica gel column. The product was eluted with 10% EA in hexane to give a pale-orange oil (900 mg, 43% yield).TLC (silica gel; EtAc–hexane (10:90 v:v); R f = 0.80). 1H-NMR (CDCl 3 ): δ 7.31 (m, 10H), 3.74 (s, 1H), 3.13 (m, 2H), 3.00 (m, 2H).13C-NMR (CDCl 3 ): δ 174.05, 141.70, 128.70, 128.42, 127.46, 60.84, 52.78, 42.0447, 29.18 ppm. GC-MS: found: 331.99; Calcd for C 17 H 17 BrO 2 , 332.04.