2-(Bromomethyl)-6-methylpyridine

Solid

A. To a stirred solution of (6-methylpyridin-2-yl)methanol (640 mg, 5.2 mmol) and carbon tetrabromide (2.77 g, 8.35 mmol) in dichloromethane (12 mL) at 0Reference Example 33 2-Bromomethyl-6-methyl-pyridine; To a solution of (6-methyl-pyridin-2-yl)-methanol (0.6 g, 4.872 mmol) in DCM (18 mL) were added triphenylphosphine (1.68 g, 6.405 mmol) and carbon tetrabromide (1.97 g, 5.940 mmol) before the resulting mixture was stirred at RT for 3 h. The crude reaction mixture was then concentrated in vacuo and the resultant residue purified by column chromatography to give the title compound as a pale pink oil (0.47 g, 52 percent). [M + H]Intermediate 11 : 2-(bromomethyl)-6-methylpyridi; (6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated andresidue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NHIntermediate 11: 2-(bromomethyl)-6-methylpyridine To a 250 mL flask, 2, 6-lutidine (5 mL, 43 mmol), NBS (N-bromosuccinimide) (7.65 g, 43 mmol) and CCl4 (75 mL) were sequentially added and the mixture was heated under reflux in an oil bath.To the above reflux solution was added AIBN (azobisisobutyronitrile) (0.125g / time, once every 1h, plus 7 times), the reaction was filtered off to remove the white succinimide precipitation, The filtrate was stripped to remove the solvent to give a tan oil, which was isolated as a pink oil (5.4 g, 68percent) by column chromatography using CH2Cl2 as eluent.2, 6-Lutidine (i) (5.1 g, 47.5 mmol, 1 equiv.) was dissolved in 300 mL of carbon tetrachloride, and the solution was degassed with argon. To a 250 mL flask, 2, 6-lutidine (5 mL, 43 mmol), NBS (N-bromosuccinimide) (7.65 g, 43 mmol) and CCl4 (75 mL) were sequentially added and the mixture was heated under reflux in an oil bath.To the above reflux solution was added AIBN (azobisisobutyronitrile) (0.125g / time, once every 1h, plus 7 times), the reaction was filtered off to remove the white succinimide precipitation, The filtrate was stripped to remove the solvent to give a tan oil, which was isolated as a pink oil (5.4 g, 68%) by column chromatography using CH2Cl2 as eluent.2, 6-Lutidine (i) (5.1 g, 47.5 mmol, 1 equiv.) was dissolved in 300 mL of carbon tetrachloride, and the solution was degassed with argon. Azobisisobutyronitrile (AIBN, 0.8 g, 4.8 mmol, 0.1 equiv.) and N-bromosuccinimide (NBS, 9.3 g, 52.3 mmol, 1.1 equiv.) were added to the solution of i in small portions over a period of 3 h, while the reaction mixture was heated at 60 C (Scheme S1). The reaction mixture was irradiated with UV light throughout the reaction. After the addition was complete, the reaction mixture was refluxed for another 8 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo producing a brown residue, which was subject to SiO2 column chromatography using a gradient of ethyl acetate from 10 to 20% in hexanes. Pure fractions were combined, and solvent was removed in vacuo to afford a yellow oil. The product solidified in the freezer producing slightly pinkish white needles. Yield: 4.0 g, 46%. 1H NMR, 400 MHz (CDCl3, ppm): delta = 7.55 t (1H, Ar), 7.22 d (1H, Ar), 7.04 d (1 H, Ar), 4.49 s (2H, CH2), 2.53 s (3 H, CH3). 13C NMR, 75 MHz (CDCl3, ppm): delta = 158.38, 156.04, 137.16, 122.59, 120.39, 34.08, 24.36. ESI-MS (m/z): [M + H]+, calculated: 186.0, found: 186.0.A. To a stirred solution of (6-methylpyridin-2-yl)methanol (640 mg, 5.2 mmol) and carbon tetrabromide (2.77 g, 8.35 mmol) in dichloromethane (12 mL) at 00C was added PPh3 (0.4 g x 4, 6.1 mmol) at 2 min intervals. The reaction was continued for total of 30 min. and then the mixture was directly purified with Flashmaster using 10% EtOAc in hexanes to give 2-(bromomethyl)-6- methylpyridine as a crystalline solid (675 mg, 70%).Reference Example 33 2-Bromomethyl-6-methyl-pyridine; To a solution of (6-methyl-pyridin-2-yl)-methanol (0.6 g, 4.872 mmol) in DCM (18 mL) were added triphenylphosphine (1.68 g, 6.405 mmol) and carbon tetrabromide (1.97 g, 5.940 mmol) before the resulting mixture was stirred at RT for 3 h. The crude reaction mixture was then concentrated in vacuo and the resultant residue purified by column chromatography to give the title compound as a pale pink oil (0.47 g, 52 %). [M + H]+ 185.8 (79Br) 187.8 (81Br)Intermediate 11 : 2-(bromomethyl)-6-methylpyridi; (6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated andresidue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NH3 (32%, aqueous). Organic layer was dried with MgS04 (anh). Solvent was evaporated to obtain the title compound (152 mg, 0.817 mmol, 33.5% yield). 1 H NMR (300 MHz, DMSO-cfe) delta ppm: 7.68 (t, 1 H), 7.33 (d, 1 H), 7.17 (d, 1 H), 4.62 (s, 2H), 2.44 (s, 3H). [ES+MS] m/z 186 (M).Intermediate 11: To an ice cooled a solution of (6-methylpyridin-2-yl)methanol (400 mg, 3.25 mmol) in dichloromethane (16 mL) under an atmosphere of dry nitrogen was added triphenylphosphine (1278 mg, 4.87 mmol) and carbon tetrabromide (1616 mg, 4.87 mmol). The mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica, eluting with 2-4% methanol in dichloromethane to give 2- (bromomethyl)-6-methylpyridine as an oil (402 mg).To a solution of the compound (6-methylpyridine-2-yl)methanol (2 g) (commercially available) in carbon tetrachloride (40 ml), was added phosphorous bromide (2.2 g) dropwise and stirred the reaction mixture at 800C for 3 hours and then at room temperature for overnight. It was quenched with water and 10% sodium hydroxide solution. The solvent was evaporated under reduced pressure and the aqueous layer was extracted with dichloromethane. The organic layer was collected and washed with 10% sodium hydroxide solution, water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 10% ethyl acetate in hexane to furnish the title compound.Yield = 1.7 g.12 g of 6-methyl-2-pyridinemethanol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 100 mL of tetrahydrofuran were added into a 300 mL three-necked flask under a nitrogen atmosphere and stirred at room temperature. After adding 25 g of phosphorus tribromide (manufactured by Tokyo Chemical Industry Co., Ltd.) dropwise while cooling the mixture with ice, and then, the mixture was stirred at room temperature overnight. An aqueous solution of saturated ammonium chloride and ethyl acetate were added thereto to perform liquid separating and extraction, an organic phase obtained was concentrated, a product was purified by a silica gel column chromatography (Developing solvent: Hexane/Ethyl Acetate), and thus, Benzylamine (16.07 g, 150 mmol) and potassium carbonate (1.66 g, 12 mmol) were added to the reaction flask. After

Molecular Weight:186.05
XLogP3:1.8
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:184.98401
Monoisotopic Mass:184.98401
Topological Polar Surface Area:12.9
Heavy Atom Count:9
Complexity:85
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes