[4-(bromomethyl)phenyl]methanol

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

Procedure: To a stirred solution of 2,3-dihydrospiro[indene-1,4′-piperidine] (0.4 g, 1.78 mmol) in DMF (12 mL) is added Cs2CO3 (1.4 g, 4.4 mmol) and [4-(bromomethyl)phenyl]methanol (0.36 g, 1.78 mmol) and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into cold water and extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine solution, dried over Na2SO4, and concentrated under vacuum. The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2) to give the title compound (0.6 g, 98%). ESI/MS m/z 308.40 (M+H)+. extracted with EtOAc (3×50 mL) The combined organic layer is washed with brine solution dried over Na2SO4 concentrated under vacuum The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2)

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

Procedure: To a solution of 4-bromomethyl-benzoic acid methyl ester (5 g, 21.82 mmol) in DCM (200 mL) is added DIBAL-H (1.0 M in hexane, 54.56 mL, 54.56 mmol) drop wise at −78° C. The reaction mixture is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture is quenched with sodium potassium tartrate (10% solution, 8 mL) and diluted with DCM (100 mL). The combined organic layer is washed with water (50 mL), brine (25 mL), dried over sodium sulfate, and evaporated to give the title compound as an off white solid (3.5 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.23-7.21 (m, 2H), 7.4-7.3 (m, 2H), 4.5-4.3 (bs, 2H), 4.68 (s, 2H). The reaction mixture is quenched with sodium potassium tartrate (10% solution, 8 mL) diluted with DCM (100 mL) The combined organic layer is washed with water (50 mL), brine (25 mL) dried over sodium sulfate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to −78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at −78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100%) as a white solid: 1H NMR (CDCl3) δ 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz). Stirring quenched with H2O The organic layer was separated the aqueous was extracted with CH2Cl2 (2×100 mL) The combined organic extracts were dried (MgSO4) evaporated

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

Procedure: The 4-bromomethylbenzyl alcohol (57.91 g, 288.0 mmol) was then converted to the corresponding aldehyde by dissolving the intermediate in 350 ml of dichloromethane and then adding this solution to a flask containing pyridinium chlorochromate (93.0 g, 431 mmol) suspended in 750 ml of dichloromethane. The dark-brown reaction mixture was then stirred at room temperature under nitrogen atmosphere. After 70 minutes of stirring most of the starting material had been consumed as determined by thin layer chromatography. adding this solution to a flask After 70 minutes of stirring most of the starting material had been consumed

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

Procedure: The 4-bromomethylbenzyl alcohol (9.0 g, 43 mmol) was reduced to the corresponding aldehyde by dissolving the above-synthesized intermediate in methylene chloride and then adding pyridinium chlorochromate (14.1 g, 6.5 mmol). The reaction mixture was then allowed to stir at room temperature under a nitrogen atmosphere for about oone hour. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then filtered through a CELITE® pad, concentrated in vacuo, and then partitioned between equal volumes of diethyl ether and water. The organic fraction was washed with water, then with brine, and dried over magnesium sulfate. The solvents were removed in vacuo to yield a white crystalline solid. Recrystallization from hot diethyl ether yielded 4.9 grams of 4-(bromomethyl)benzaldehyde as needle-like crystals. The reaction mixture was then filtered through a CELITE® pad concentrated in vacuo partitioned between equal volumes of diethyl ether and water The organic fraction was washed with water with brine, and dried over magnesium sulfate The solvents were removed in vacuo to yield a white crystalline solid Recrystallization from hot diethyl ether

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to −78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at −78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100%) as a white solid: 1H NMR (CDCl3) δ 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz). Stirring quenched with H2O The organic layer was separated the aqueous was extracted with CH2Cl2 (2×100 mL) The combined organic extracts were dried (MgSO4) evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to −78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at −78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100%) as a white solid: 1H NMR (CDCl3) δ 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz). Stirring quenched with H2O The organic layer was separated the aqueous was extracted with CH2Cl2 (2×100 mL) The combined organic extracts were dried (MgSO4) evaporated

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

Procedure: To a stirred solution of 2,3-dihydrospiro[indene-1,4′-piperidine] (0.4 g, 1.78 mmol) in DMF (12 mL) is added Cs2CO3 (1.4 g, 4.4 mmol) and [4-(bromomethyl)phenyl]methanol (0.36 g, 1.78 mmol) and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into cold water and extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine solution, dried over Na2SO4, and concentrated under vacuum. The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2) to give the title compound (0.6 g, 98%). ESI/MS m/z 308.40 (M+H)+. extracted with EtOAc (3×50 mL) The combined organic layer is washed with brine solution dried over Na2SO4 concentrated under vacuum The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2)

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

Procedure: To a solution of 4-bromomethyl-benzoic acid methyl ester (5 g, 21.82 mmol) in DCM (200 mL) is added DIBAL-H (1.0 M in hexane, 54.56 mL, 54.56 mmol) drop wise at −78° C. The reaction mixture is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture is quenched with sodium potassium tartrate (10% solution, 8 mL) and diluted with DCM (100 mL). The combined organic layer is washed with water (50 mL), brine (25 mL), dried over sodium sulfate, and evaporated to give the title compound as an off white solid (3.5 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.23-7.21 (m, 2H), 7.4-7.3 (m, 2H), 4.5-4.3 (bs, 2H), 4.68 (s, 2H). The reaction mixture is quenched with sodium potassium tartrate (10% solution, 8 mL) diluted with DCM (100 mL) The combined organic layer is washed with water (50 mL), brine (25 mL) dried over sodium sulfate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to −78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at −78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100%) as a white solid: 1H NMR (CDCl3) δ 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz). Stirring quenched with H2O The organic layer was separated the aqueous was extracted with CH2Cl2 (2×100 mL) The combined organic extracts were dried (MgSO4) evaporated

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

Procedure: To a solution of the product of Example 4 Step A, (4.44 g, 22.1 mmol) in CH2Cl2 was added N,N-diisopropylethyl amine (1.2 eq.) and 4-dimethylaminopyridine (0.1 eq.), and t-butyldimethylsilyl chloride (1.2 eq.). The mixture was stirred for 1.5 hours at room temperature, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica (ethyl acetate/hexanes (2.5/97.5)) to afford 5.0 g (71%) of the title compound. concentrated in vacuo The residue was dissolved in ethyl acetate washed with water, brine dried (MgSO4) filtered concentrated in vacuo The residue was chromatographed on silica (ethyl acetate/hexanes (2.5/97.5))

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 4-bromomethylbenzoic acid (5.04; 23.3 mmol) in THF (30 ml) was cooled to 0° C. and treated with borane/THF (35 mmol). The ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The excess borane was quenched with MeOH, and then with water, and the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 4% HCl, water NaHCO3, brine, dried (MgSO4), filtered, concentrated in vacuo to afford 4.44 g (94%) of the title compound. The ice bath was removed to warm to room temperature The excess borane was quenched with MeOH with water, and the reaction mixture was concentrated in vacuo The residue was dissolved in ethyl acetate washed with 4% HCl, water NaHCO3, brine dried (MgSO4) filtered concentrated in vacuo