3- BROMO-2-METHYL- BENZALDEHYDE

Intermediate 22-1Preparation of 3-(3-bromo-2-methylbenzylidene)indolin-2-one Step 1 A mixture of (3-bromo-2-methylphenyl)methanol (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 500 mg, 2.49 mmol) in THF (20 mL) was stirred at rt and treated with 1, 1, 1-tris(acetyloxy)-1, 1-dihydro-1, 2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 1.58 g, 3.73 mmol). After 2 h, the mixture was diluted with ether (ca. 100 mL) and washed with 5percent aqueous sodium bisulfite, NaHCO3 (aq) and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 55:45 hexane-EtOAc) to provide 3-bromo-2-methylbenzaldehyde as a colorless oil (343 mg, 70percent). (3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting material. Reaction mixture was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation. [00158] (3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting materia re was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation.1H NMR (600 MHz, CDCl3): 10.25 (s, 1H), 7.78 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 2.75 (s, 3H).13C NMR (150 MHz, CDCl3): 191.84, 137.72, 130.93, 130.20, 127.61, 127.37, 126.82, 18.13.To a solution of dimethylsulfoxide (2.99 mL, 41.8 mmol) in dichloromethane (55 mL) cooled to −78° C. under nitrogen, oxalyl chloride (2.0 M in dichloromethane, 10.4 mL, 20.8 mmol) was added slowly. The mixture was stirred at −78° C. for 30 minutes then a solution of 27-1 (2.79 g, 13.9 mmol) in dichloromethane (15 mL) was added dropwise by cannula. The mixture was stirred for 1 hour, triethylamine (5.8 mL, 41.8 mmol) was added slowly, and the reaction was allowed to warm to room temperature. The mixture was washed with saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 3-bromo-2-methylbenzaldehyde (27-2, 2.76 g).n-BuLi (1.6M in hexanes, 28.5 mL, 45.6 mmol) was added dropwise to a solution of 1, 3-dibromo-2-methylbenzene (9.50 g, 38.0 mmol) in THF (119 mL) at -78° C. and the reaction was maintained at this temperature for 30 minutes. N, N-Dimethylformamide (4.41 mL, 57.0 mmol) was added and the reaction was stirred for a further 30 min, before being allowed to warm to 0° C. over 1 hour. Preparation of 3-bromo-2-methylbenzaldehvde w-BuLi in hexanes (1.6M; 28.5 mL, 45.6 mmol) was added dropwise to a solution of 1, 3- dibromo-2-methylbenzene (9.50 g, 38.0 mmol) in THF (119 mL) at -78 °C and the reaction was maintained at this temperature for 30 minutes. N, N-Dimethylformamide (4.41 mL, 57.0 mmol) was added and the reaction was stirred for a further 30 minutes before being allowed to warm to 0 °C over 1 hour. The reaction was quenched by addition of water and then was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to afford 3-bromo-2-methylbenzaldehyde (7.19 g, 95percent) as a light yellow oil. b Lithium aluminum hydride (201 mg, 5.31 mmol) was added in one portion to a-78 oC solution of 3-bromo-N-methoxy-2, N-dimethyl-benzamide ( (EXAMPLE 6: step b) 1.1 g, 4.24 mmol) in THF (25 mL). After stirring for 1 h AT-78 oC, the hydride reagent was quenched with EtOAc (10 mL), and the solution was slowly poured into a vigorously stirred mixture of citric acid (10percent, 30 mL) and EtOAc (50 mL). After separating the layers, the organic layer was washed with NAHCO3 (3 x 20 mL), water (20 mL), and brine (30 mL). The solution was dried (sodium sulfate) and the solvent was removed IRA vacuo, giving the title compound (813 mg, 96percent) as a colorless oil which was used without further PURIFICATION. 1H-NMR (CDCl3) : δ 10.28 (s, 1H), 7.80 (m, 2H), 7.25 (m, 1H), 2.78 (s, 3H).

Molecular Weight:199.04
XLogP3:2.4
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:197.96803
Monoisotopic Mass:197.96803
Topological Polar Surface Area:17.1
Heavy Atom Count:10
Complexity:124
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes