4-AMINO-5-IODO-2-METHYLPYRIDINE

5-iodo-2-methylpyridin-4-amine (i55): To a solution of 2-methylpyridin-4-amine (5 g, 46 mmol) in water (25 ml_), NaA solution OF 2-METHYL-4-NITROPYRIDINE-N-OXIDE (3.80 g, 24.6 mmol) in 100 ML of acetic acid was slowly heated with iron powder (6.89 g, 124 mmol) in a large flask (caution: the reaction becomes very exothermic upon turning brown). The resulting slurry was heated for 2 hours at 80 C. Excess acetic acid was removed IN VACUO, THE residue was taken up in 20percent aqueous sodium hydroxide solution, and 100 mL of chloroform (CHC13) was added and the mixture filtered through CELITES FILTER aid. The aqueous phase was extracted with two 200 mL portions of chloroform. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (2.2 g, 83percent yield) was used without further purification. A solution OF KI (1. 96 g, 11. 9 mmol) and 12 (1.87 g, 7.36 mmol) in 10 ML of water was added to a REFLUXING solution of the 2-methylpyridin-4-ylamine (1.00 g, 9.25 mmol) and sodium carbonate (683 mg, 6.44 mmol) in 5 ML of water. The mixture was heated at reflux for 2 hours, cooled to room temperature, and treated with 20 mL of ethyl acetate (EtOAc). Phases were separated and the aqueous layer was extracted with three 20 ML portions of ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium thiosulfate (NA2S203) solution, dried over magnesium sulfate, and concentrated ILL vacuo. Flash chromatography (30percent ethyl acetate in hexanes to 100percent ethyl acetate, gradient) of the resulting residue yielded 4-amino-3-iodo-6-methylpyridine (first eluting: 226 mg, 11percent yield) and 4- AMINO-3-IODO-2-METHYLPYRIDINE (second eluting : 116 mg; 5percent yield).5-iodo-2-methylpyridin-4-amine (i55): To a solution of 2-methylpyridin-4-amine (5 g, 46 mmol) in water (25 ml_), NaA solution OF 2-METHYL-4-NITROPYRIDINE-N-OXIDE (3.80 g, 24.6 mmol) in 100 ML of acetic acid was slowly heated with iron powder (6.89 g, 124 mmol) in a large flask (caution: the reaction becomes very exothermic upon turning brown). The resulting slurry was heated for 2 hours at 80 C. Excess acetic acid was removed IN VACUO, THE residue was taken up in 20percent aqueous sodium hydroxide solution, and 100 mL of chloroform (CHC13) was added and the mixture filtered through CELITES FILTER aid. The aqueous phase was extracted with two 200 mL portions of chloroform. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (2.2 g, 83percent yield) was used without further purification. A solution OF KI (1. 96 g, 11. 9 mmol) and 12 (1.87 g, 7.36 mmol) in 10 ML of water was added to a REFLUXING solution of the 2-methylpyridin-4-ylamine (1.00 g, 9.25 mmol) and sodium carbonate (683 mg, 6.44 mmol) in 5 ML of water. The mixture was heated at reflux for 2 hours, cooled to room temperature, and treated with 20 mL of ethyl acetate (EtOAc). Phases were separated and the aqueous layer was extracted with three 20 ML portions of ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium thiosulfate (NA2S203) solution, dried over magnesium sulfate, and concentrated ILL vacuo. Flash chromatography (30percent ethyl acetate in hexanes to 100percent ethyl acetate, gradient) of the resulting residue yielded 4-amino-3-iodo-6-methylpyridine (first eluting: 226 mg, 11percent yield) and 4- AMINO-3-IODO-2-METHYLPYRIDINE (second eluting : 116 mg; 5percent yield).5-iodo-2-methylpyridin-4-amine (i55): To a solution of 2-methylpyridin-4-amine (5 g, 46 mmol) in water (25 ml_), Na2C03 (3.4 g, 32 mmol) was added and the reaction mixture was refluxed. Kl (9.8 g, 59 mmol) and l2 (9.3 g, 36 mmol in 50 mL water) were added and refluxed for 7h. The reaction mixture was quenched with sodium thiosulphate solution and the compound was extracted with DCM. The organic layer was separated dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by silica gel (100:200 mesh) column chromatography using 25% ethyl acetate in hexane as eluent to afford desired product 5-iodo-2-methylpyridin-4-amine (i55) (0.85 g, Yield 8%). 1H NMR (400 MHz, DMSO-d6): delta 2.20 (s, 3H), 6.00 (s, 2H), 6.49 (s, 1 H), 8.22 (s, 1 H). MS (ESI) m/e (M+1 )+: 235General procedure: Step 1: A vial equipped with a magnetic stir bar was charged with the ortho-haloaminopyridine and BrettPhos G1 precatalyst (6 mol %). The vial was sealed with a teflon screw cap, and evacuated and backfilled with argon three times. The amine (1 to 1.5 mol eq) was added via syringe, followed by LiHMDS solution (1M in THF, 2.5 mol eq). Amines that were solid at room temperature were added with the catalyst. The reaction mixture was stirred at 40 C for 4-18 h, until LC/MS indicated complete conversion of the starting material. The mixture was cooled to room temperature, diluted with dichloromethane, and poured into water. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were dried over Na2SO4. The solvent was removed under reduced pressure.A solution OF 2-METHYL-4-NITROPYRIDINE-N-OXIDE (3.80 g, 24.6 mmol) in 100 ML of acetic acid was slowly heated with iron powder (6.89 g, 124 mmol) in a large flask (caution: the reaction becomes very exothermic upon turning brown). The resulting slurry was heated for 2 hours at 80 C. Excess acetic acid was removed IN VACUO, THE residue was taken up in 20% aqueous sodium hydroxide solution, and 100 mL of chloroform (CHC13) was added and the mixture filtered through CELITES FILTER aid. The aqueous phase was extracted with two 200 mL portions of chloroform. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (2.2 g, 83% yield) was used without further purification. A solution OF KI (1. 96 g, 11. 9 mmol) and 12 (1.87 g, 7.36 mmol) in 10 ML of water was added to a REFLUXING solution of the 2-methylpyridin-4-ylamine (1.00 g, 9.25 mmol) and sodium carbonate (683 mg, 6.44 mmol) in 5 ML of water. The mixture was heated at reflux for 2 hours, cooled to room temperature, and treated with 20 mL of ethyl acetate (EtOAc). Phases were separated and the aqueous layer was extracted with three 20 ML portions of ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium thiosulfate (NA2S203) solution, dried over magnesium sulfate, and concentrated ILL vacuo. Flash chromatography (30% ethyl acetate in hexanes to 100% ethyl acetate, gradient) of the resulting residue yielded

Molecular Weight:234.04
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:233.96540
Monoisotopic Mass:233.96540
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:97.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes