2-Chloro-4-iodopyridine

Off-white Cryst

A solution of 2-chloro-3-iodopyridine (12 g, 50 mmol) in 20 ML of THF was slowly added to a cold (-78°C) lithium diisopropylamide solution (prepared by the addition of n- butyllithium 1.6 M (31.25 ML, 50 mmol) in hexanes to a solution of diisopropylamine (7 mL, 50 mmol) in THF (100 mL). After 3h, water (20 mL) was added to the mixture, which was extracted with ether (2 x 100 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum (20°C) to afford a brown solid, which was purified by filtration over silica (ethyl acetate/heptane 8/2). Yield: 95percent (11.4 g), pale yellow NEEDLES. IH NMR (CDC13) : 8 8.07 (d, J = 5.3 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.59 (dd, J = 5. 0/1. 1 Hz, 1H). 13C NMR (CDC13) : 8 151.7, 149.6, 133. 0, 131. 5, 106. 6. MS (EI) m/z 240 (M+1).To a THF solution (40 ml) of Diisopropyl amine (4.46 ml, 1.5 eqv) was added BuLi (1.88 M, 1.5 eqv) at -15° C. and the resulting reaction mixture was allowed to stir at same temperature for 20 minutes. It was then cooled to -78° C. and 2-chloro-3-iodopyridine (5 g, 20.92 mmol) in THF (10 ml) was added dropwise at the same temperature and allowed to stir for 1 hr at -78° C. Reaction was quenched with water (10 ml), stirred at ambient temperature for 15 minutes and extracted with ethyl acetate. Organic layer was washed successively with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was immediately used in the next step without any further purification. Yield: 80percent (Crude)Preparation of amine unit A4 1. A solution of diisopropylamine (12.7 g) in THF (160 ml) was cooled to -15° C., and n-BuLi (83 ml) was added dropwise over a period of 20 min at -10° C. After stirring for 20 min at -5° C., the reaction mixture was cooled to -78° C., and 2-chloro-3-iodo-pyridine (20 g) dissolved in THF (40 ml) was added dropwise over a period of 20 min. The reaction mixture was stirred for 1 h at -78° C. After addition of water (40 ml), stirring was carried out for 15 min. The organic phase was separated off and dried over NaTo a ice-cooled solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, 1eq) in water [(150ML)] was added concentrated 98percent HCl whilst maintaining the reaction at [0°C A] solution of sodium nitrite (5.65g, [82MMOL, ] 1.3eq) in water [(50ML)] was added slowly [AT-10°C.] The mixture was stirred at-10°C [FOR 40 MIN] and a solution of potassium iodide (12.55g, 75. [6MMOL, ] 1.2eq) in water [(50ML)] was added. The resulting mixture was stirred at [0°C] overnight. After treatment with [NAOH] 35percent, and extraction with ethyl acetate, the organic phases were combined and dried over [NA2SO4.] The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then [CH2CL2/CH30H] 99/1) to give the title compound as an orange solid (9.5g, 63percent) ;'H NMR (300 MHz, CDCl3) [6] : 7.99 (d, [1H), ] 7.68 (s, 1H), 7.52 (d, 1H) ; (GC-MS) m/z: 239.To a solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, [1EQ)] in water [(150ML)] cooled to [0°C] was added concentrated 98percent HCI. A solution of sodium nitrite (5.65g, [82MMOL, ] 1.3eq) in water (50mL) was added slowly at-10°C and the mixture was stirred at this temperature for 40 min. A solution of potassium iodide [(12.] 55g, 75. [6MMOL, ] 1.2eq) in water (50mL) was added and the resulting mixture was stirred at [0°C] overnight. After treatment with NaOH (35percent) and extraction with ethyl acetate, the organic phases were combined and dried over [NA2SO4.] The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then [CH2CI2/CH30H] 99: 1) to give the title compound as an orange solid (9.5g, 63percent) [; 1H] NMR (300 MHz, [CD13)] [8] ppm: 7.99 (1H, d), 7.68 (1H, s), 7.52 (1H, d); (GC-MS) m/z: 239.General procedure: To a mixture of copper source (1.2 eq., CuBr2 for 4b, CuCl2 for 4c, CuI for 4d)in acetonitrile (0.4M) was slowly added tBuONO (1.5 eq.). The mixture was stirred for15 min and then cooled to 0°C. A solution of 2-chloro-4-aminopyridine 3 (1.0 eq.) inacetonitrile (0.5M) was slowly added. The mixture was stirred for 1h at 0°C and thenallowed to warm to r.t. for 16h. After concentration in vacuo, aq. 15percent ammonia solution (1.3 mL/mmol) was added, and the aqueous layer was extracted withdichloromethane (10 mL/mmol; 3x). The combined organic layers were washed withbrine, dried (Na2SO4), filtered and carefully concentrated under reduced pressure(CAUTION: volatile products) to give the crude 4b-d, which was used in the next stepwithout purification.

Molecular Weight:239.44
XLogP3:2.5
Hydrogen Bond Acceptor Count:1
Exact Mass:238.89987
Monoisotopic Mass:238.89987
Topological Polar Surface Area:12.9
Heavy Atom Count:8
Complexity:78.8
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes