4-(bromomethyl)benzaldehyde

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

Procedure: To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.96 g, 3.36 mmol) in 2-butanone (50 ml) was added 4-bromomethyl benzaldehyde (1.0 g, 5.03 mmol). The reaction was heated to reflux where it was maintained for 48 h. After this time, the suspension was cooled to rt and filtered. The collected solid was washed with additional 2-butanone and then dried to provide 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde hydrobromide salt (0.80 g, 49%) as a yellow solid which was used without further purification. HPLC-MS 404 [M+1]+. The reaction was heated to reflux where it was maintained for 48 h filtered The collected solid was washed with additional 2-butanone dried

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

Procedure: To a THF-toluene (2.4 L -0.24 L) solution of α bromo p tolunitrile (266.4 g, 1.36 mol) maintained at an internal temperature below 0° C. was added DIBAL-H in hexane (1.0 M) (1.49 L, 1.49 mol) over a period of 2 h. After a period of 1.5 h, the reaction mixture was transferred via canula to a 3N HCl solution (8 L) at 0° C. To the resulting suspension EtOAc (4 L) and THF (0.8 L) were added. After stirring, the organic phase was separated and evaporated to give a yellow solid. The solid was stirred, in 20% EtOAc in hexane (1.3 L) for 3 hours. After filtration and drying, the title compound was obtained (210 g). the organic phase was separated evaporated to give a yellow solid After filtration drying

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

Procedure: To a THF-toluene (2.4 L -0.24 L) solution of α bromo p tolunitrile (266.4 g, 1.36 mol) maintained at an internal temperature below 0° C. was added DIBAL-H in hexane (1.0 M) (1.49 L, 1.49 mol) over a period of 2 h. After a period of 1.5 h, the reaction mixture was transferred via canula to a 3N HCl solution (8 L) at 0° C. To the resulting suspension EtOAc (4 L) and THF (0.8 L) were added. After stirring, the organic phase was separated and evaporated to give a yellow solid. The solid was stirred, in 20% EtOAc in hexane (1.3 L) for 3 hours. After filtration and drying, the title compound was obtained (210 g). the organic phase was separated evaporated to give a yellow solid After filtration drying

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

Procedure: To a solution of 4-(bromomethyl)-benzaldehyde (0.940 g, 4.72 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (2.40 g, 6.4 mmol) and sodium triacetoxyborohydride (2.53 g, 11.9 mmol). The reaction mixture was stirred for 1 hour then poured into ethyl acetate (300 mL). The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane) to yield the desired product (1.504 g, 83% yield). LC/MS: m/z 382/384 [M+H]+ The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4) concentrated purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane)

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

Procedure: To a solution of 4-(bromomethyl)-benzaldehyde (0.940 g, 4.72 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (2.40 g, 6.4 mmol) and sodium triacetoxyborohydride (2.53 g, 11.9 mmol). The reaction mixture was stirred for 1 hour then poured into ethyl acetate (300 mL). The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane) to yield the desired product (1.504 g, 83% yield). LC/MS: m/z 382/384 [M+H]+ The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4) concentrated purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane)

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

Procedure: Hydantoin (0.80 g, 8.00 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 88 mg, 2.20 mmol) was added. The mixture was stirred at room temperature for 3 hours. 4-(Bromomethyl)benzaldehyde (0.40 g, 2.00 mmol) was added. The mixture was stirred at room temperature for 2.5 days. Saturated aqueous NH4Cl (1 mL) was added. The mixture was concentrated to dryness. Water (10 mL) was added, extracted with dichloromethane, and the organic phase was dried over anhydrous Na2SO4. Solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde as a white solid. Yield: 0.28 g (64%). The mixture was stirred at room temperature for 2.5 days The mixture was concentrated to dryness Water (10 mL) was added extracted with dichloromethane the organic phase was dried over anhydrous Na2SO4 Solvent was removed the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent)

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

Procedure: To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.96 g, 3.36 mmol) in 2-butanone (50 ml) was added 4-bromomethyl benzaldehyde (1.0 g, 5.03 mmol). The reaction was heated to reflux where it was maintained for 48 h. After this time, the suspension was cooled to rt and filtered. The collected solid was washed with additional 2-butanone and then dried to provide 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde hydrobromide salt (0.80 g, 49%) as a yellow solid which was used without further purification. HPLC-MS 404 [M+1]+. The reaction was heated to reflux where it was maintained for 48 h filtered The collected solid was washed with additional 2-butanone dried

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

Procedure: (3,5-Dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (1 g, 6.0 mmol), 4-(bromomethyl)-benzaldehyde (1.18 g, 6.0 mmol) and K2CO3 (1.73 g, 12.5 mmol) were refluxed in 5 ml acetonitrile for 12 h. After cooling, the mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1). After cooling the mixture was filtered the solvent was removed under reduced pressure The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1)

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

Procedure: A solution of the 4-bromomethyltoluoyl chloride (3.48 g. 15 mmol) in dry tetrahydrofuran (15 ml) was added dropwise to a solution of lithium tri-t-butoxyaluminium hydride (3.81 g, 15 mmol) in dry tetrahydrofuran (50 ml) at -70° C., stirred for 2 h, allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured into water, filtered, extracted with ethyl acetate, dried (magnesium sulphate), and evaporated in vacuo to yield 4-bromomethylbenzaldehyde (1.31 g, 44%). stirred for a further 1 h filtered extracted with ethyl acetate dried (magnesium sulphate) evaporated in vacuo

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

Procedure: To a solution of 4-(bromomethyl)-benzaldehyde (Hsung et al. (1995) Organometallics, 14: 4808-4815; Bookser and Bruice (1991) Am. Chem. Soc. 113: 4208-4218; Wagner et al. (1997) Tetrahedron 53: 6755-6790 for the synthesis of 3-(bromomethyl)benzaldehyde) (0.43 g, 2.2 mmol) in acetone (10 mL) was added potassium thioacetate (280 mg, 2.5 mmol) under stirring at rt, then the mixture was refluxed. A precipitate formed after a few minutes. The reaction was monitored by TLC and cooled to rt when no starting material was detectable (3.5 h). Water (25 mL) was added, the mixture was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried (Na2SO4) and evaporated. Column chromatography over flash silica gel (ethyl ether/hexanes, 1:1) gave 359 mg (85% yield) of a brown oil which darkened upon standing (nonetheless elementary analysis four weeks after exposure to air at rt indicated a high level of purity as listed below). IR (neat): {tilde over (v)} 3052, 2923, 2830, 2737, 1694, 1606, 1576; 1H NMR δ 2.36 (s, 3H), 4.15 (s, 2H), 7.45, 7.81 (AA′BB′, 2×2H), 9.97 (s, 1H); 13C NMR (APT) δ 30.1 (−), 32.9 (+), 129.3 (−), 129.9 (−), 135.2 (+), 144.7 (+), 191.5 (−), 194.3 (+); GC-MS (EI) obsd 194, 152, 119, 91, 43; Anal. Calcd for C10H10O2S: C, 61.83; H, 5.19; S, 16.51. Found: C, 61.97; H, 5.20; S, 16.60. the mixture was refluxed A precipitate formed after a few minutes cooled to rt when no starting material (3.5 h) the mixture was extracted with ethyl acetate (3×30 mL) the combined organic phases were dried (Na2SO4) evaporated