Pyridine, 5-bromo-2-ethyl-

A suspension of 2, 5-dibromo-pyridine (lOg, 42.21 mmol) and Pd(PPh3)4 (2.43g, 2.11 mmol) in THF (100 mL) was added 1M Et2Zn (42.2 mL, 42.21 mmol) at 0 00 Thereaction mixture was stirred at 0 00 for 30 mm and then allowed to stir at RT for lh. Thereaction mixture was quenched with NaHCO3 solution and extracted with EtOAc. TheEtOAc layer was washed with water, brine, dried (Na2504), filtered and concentrated invacuo. The crude compound was purified by silica gel column chromatography eluting with 4percent EtOAc/pet-ether to obtain 5-bromo-2-ethyl-pyridine as a pale yellow liquid (3g, 38percent).R: 0.6 (10percent EtOAc/pet-ether).1H NMR (400MHz, CDCI3): O 8.57 (d, J= 2.4 Hz, 1H), 7.72-7.69 (m, 1H), 7.06 (d, J= 8.0 Hz, 1H), 2.81-2.75 (m, 2H), 1.29 (t, J= 8.0 Hz, 3H).Step 1: 5-Bromo-2-ethylpyridine 280 mL of 5N sodium hydroxide (1.4 mol, 2.09 eq) was added to a solution of 158 g of 2, 5-dibromopyridine (0.67 mol, 1 eq) in 1.4 L of THF. To the resulting solution, 700 mL of 1N triethylboron in THF (0.70 mol, 1.04 eq), 195 mg of bis(acetonitrile)palladium(II) chloride (0.75 mmol, 0.0011 eq) and 414 mg 1, 1'-bis(diphenylphosphino)ferrocene (0.75 mmol, 0.0011 eq) were added. The reaction was slowly heated to a very slight reflux for 3 hours. It was then cooled down to 0 and treated sequentially with 140 mL of 5N sodium hydroxide (0.70 mol, 1.04 eq) and 53 mL of 30% hydrogen peroxide (0.70 mol, 1.05 eq) at such a rate that the temperature never exceeded 10 C. The mixture was extracted with ether, and the ether extracts washed with sodium hydroxide, water, brine and dried over MgSO4. The ether solution was then concentrated and the brown residue was distilled under vacuum (40 C., 1 Torr) to give 112 g of the title compound as a clear oil slightly contaminated with the starting material and 2, 5-diethylpyridine. Yield ~90%. The 1 H NMR is comparable to that reported by J. W. Tilley and S. Zawoiski; J. Org. Chem., 1988, 53, 386-390. The material is suitable for use in the next step without further purification.PREPARATION 65 2-Ethyl-5-bromopyridine STR202 A solution of ethylmagnesium bromide in ether (100 ml, 3M, 0.3 mol) was added dropwise to a cold (5 C.) solution of anhydrous zinc chloride (40.9 g, 0.3 mol) in THF (500 ml) under nitrogen. After stirring for one hour at 0 C., tetrakis(triphenylphosphine)-palladium (0) (1.0 g, 0.87 mmol) was added followed by a solution of 2, 5-dibromopyridine (50 g, 0.21 mol) in THF (200 ml). The resulting yellow suspension was stirred at room temperature overnight, quenched by the addition of water (200 ml) and then evaporated in vacuo. The residue was treated with a suspension of ethylenediaminetetraacetic acid (200 g) in water (1000 ml) and dichloromethane (500 ml). The organic layer was separated and the aqueous layer again extracted with dichloromethane (500 ml). The combined extracts were dried (MgSO4), solvent evaporated in vacuo, and the residue distilled (123-124 C., 60 mmHg) to give the required product as a colourless oil (28.8 g, 76%). 1 H-NMR(300 MHz, CDCl)=1.30 (t, 3H); 2.80 (q, 2H); 7.10 (d, 1H); 7.7 (dd, 1H); 8.6 (d, 1H)ppm.PREPARATION 1 2-Ethyl-5-bromopyridine A solution of ethylmagnesium bromide in dry ether (3M; 100 ml, 0.30 mol) was added dropwise to a stirred, ice-cooled solution of anhydrous zinc chloride (40.9 g, 0.30 mol) in dry tetrahydrofuran (500 ml) under nitrogen and the resulting solution stirred for a further 1 hour before the sequential addition of tetrakis (triphenylphosphine)palladium(0) (1.0 g, 0.87 mmol) and a solution of 2, 5-dibromopyridine (50 g, 0.21 mol) in dry tetrahydrofuran (200 ml). The resulting yellow suspension was stirred at room temperature for 18 hours, quenched by the addition of water (200 ml) and evaporated under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and a suspension of ethylenediaminetetraacetic acid (200 g) in water (1 l). The organic phase was separated, combined with a dichloromethane extract (500 ml) of the aqueous phase, dried (MgSO4) and evaporated under reduced pressure. Distillation under reduced pressure of the residue gave the title compound (28.8 g) as a colourless oil, b.p. 123-124 C./8 kPa (60 mm Hg). delta(CDCl3): 1.30(3H, t), 2.80(2H, q), 7.10(1H, d), 7.70(1H, dd), 8.60(1H, d).(i) 5-Bromo-2-ethylpyridine A solution of ethylmagnesium chloride (2M in diethyl ether, 21.1 ml, 42.2 mmol) was added to dry THF (75 ml) and then treated with zinc chloride solution (1.0M in diethyl ether, 42.2 ml, 42.2 mmol). The suspension was stirred for 30 minutes at room temperature and was then cooled in ice. Tetrakis-(triphenylphosphine)palladium(0) (0.5 g) was added to the suspension followed by a solution of 2, 5-dibromopyridine (5.0 g, 21.1 mmol) in THF (25 ml). The mixture was stirred at 5 C. for 5 hours and then shaken with a suspension of ethylenediamine-tetraacetic acid, disodium salt dihydrate (7.9 g, 21 mmol) in water (100 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The residue was distilled under reduced pressure (60 mm) at an oven temperature of 180 C. using a Kugelrohr (trade mark) apparatus to give the title compound, (2.25 g). 1 H-NMR (300 MHz, CDCl3): delta=1.27(t, 3H), 2.79(q, 2H), 7.05(d, 1H), 7.70(dd, 1H), 8.58(d, 1H) ppm.