Benzyl Bromide → 3-(Benzyloxy)-4-iodobenzaldehyde

Participants

Reaction Steps

To a stirred solution of 3-hydroxy-4-iodobenzaldehyde (4.0 g, 16.2 mmol) in acetone (50 ml) was added benzyl bromide (2.76 g, 16.2 mmol) and potassium carbonate (2.23 g, 16.2 mmol). The reaction mixture was heated under reflux for 16 h. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 3-benzyloxy-4-iodo-benzaldehyde (5.1 g) as orange oil. A mixture of 3-benzyloxy-4-iodobenzaldehyde (1.05 g, 3.24 mmol), 5-fluoro-2-methoxyphenyl boronic acid (1.12 g 6.6 mmol), potassium carbonate (1.22 g, 8.8 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.40 g, 0.35 mmol) in tetrahydrofuran (12.0 ml) and dimethylformamide (4 ml) was heated in a microwave oven at 120° C. for 30 min. The reaction mixture was diluted with diethyl ether, washed with 2M sodium hydroxide and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue flash chromatographed over silica gel eluting with 5:1 heptane/ethyl acetate to give 2-benzyloxy-5′-fluoro-2′-methoxy-biphenyl-4-carbaldehyde. To a stirred solution of 2-benzyloxy-5′-fluoro-2′-methoxy-biphenyl-4-carbaldehyde (0.50 g, 1.5 mmol) was added 2-methyl-2-propane sulfinamide (0.183 g, 1.51 mmol) and titanium(IV) isopropoxide (3 ml, 7.5 mmol) in tetrahydrofuran (10 ml). The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 16 h. Brine was added to reaction mixture which was then filtered through dicalite and extracted with dichloromethane The extract was dried over anhydrous sodium sulfate, the solvent evaporated and the residue flash chromatographed over silica gel eluting with 8:2 heptane/ethyl acetate to give 2-methyl-propane-2-sulfininic acid-2-benzyloxy-5′-fluoro-2′-methoxy-biphenyl-4-ylmethylene amide (0.3 g). To a stirred solution of 2-methyl-propane-2-sulfininic acid-2-benzyloxy-5′-fluoro-2′-methoxy-biphenyl-4-ylmethylene amide (0.3 g, 0.7 mmol) in dichloromethane (20 ml) was added diisobutylaluminium hydride (1M in tetrahydrofuran, 6 ml, 4.2 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture warmed to ambient temperature over 16 h. Potassium sodium L-tartrate tetrahydrate was added and the mixture stirred for 30 min then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent evaporated to give 2-methyl-propane-2-sulfininic acid-(2-benzyloxy-5′-fluoro-2′-methoxy-biphenyl-4-ylmethylene) amide (0.250 g). To a stirred solution of 2-methyl-propane-2-sulfininic acid-(2-benzyloxy-5′-fluoro-2′-methoxy-biphenyl-4-ylmethylene) amide (0.25 g, 0.57 mmol) in methanol (5 ml) was added Hydrogen chloride (1M in diethyl ether). The solution was left to stir at ambient temperature for 10 min and the solvent evaporated. The residue was dissolved in dichloromethane and purified on a SCX column (eluted with 2M ammonia in methanol) to give C-(2-Benzyloxy-5′-methoxy-biphenyl-4-yl)-methylamine (0.12 g). The title compound was then prepared in a similar manner to N-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-ylmethyl)-4-methoxy-benzenesulfonamide (Example 6) using C-(2-benzyloxy-5′-methoxy-biphenyl-4-yl)-methylamine and 2-trifluromethoxybenzene sulfonyl chloride. MS (ESI) m/z: 562.2 [M+H]+.

Provenance & Evidence