4-(Boc-amino)pyridine

White to light brown solid

4-Aminopyridine (600 mg, 6.36 mmol), DMAP (600 μg, 5.00 μmol), Boc2O (1.57 mL, 7.00mmol) and Et3N (1 mL, 7.63 mmol) were suspended in anhydrous THF (3 mL) at rt, and stirredfor 20 min under argon atmosphere. After completion of the reaction, the reaction mixture was diluted with CH2Cl2 (5 mL) and washed with 0.1 N HCl (5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. Purification by column chromatography (30:1 CH2Cl2/MeOH) yielded S1w (1.30 g, >99percent) asa white solid.General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CHPreparation of isatin derivatives To a well stirred solution of Boc anhydride (2.56 g, 11.7 mmol) in THF (10 mL) was added 4- aminopyridine (1.0 g, 10.6 mmol) in portions over 3 minutes while maintaining the temperature between 20°C and 25°C. No more exotherm was observed after 5 minutes. The reaction was then stirred at room temperature for 3.5 hours. After in vacuo concentration the crude mixture was then titurated in hexane (20 mL), filtered and washed with more hexane (~5 mL). The resulting solid dried under reduced pressure to yield 1.93 g (9.9 mmol, 94percent) of pyridin-4-yl-carbamic acid tert-butyl ester as a white solid and was used without further purification. LCMS (BDS-Hypersil C18, 50 mm X 2.1 mm, 5 μ, 2.5 minutes) m/z 195 [MH]+ retension time 0.90 minutes, 100percent by UV at 215 nm.General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)).#10;To a stirred solution of pyridin-4-amine (A; 100 g, 1.06 mol) in CH2CI2 (1 L) under inert atmosphere were added triethylamine (161.47 g, 1.59 mol) and Boc-anhydride (255 g, 1.17 mol) at 0 °C. The reaction was warmed to RT and stirred for 3 h. After complete consumption of the starting material, the reaction mixture was diluted with water (400 mL) and the compound was extracted with CH2CI2 (2x500 mL). The combined organic extracts were washed with water (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through column chromatography eluting with 5percent MeOH/CHTo a solution of 4-aminopyridine (50.0 g, 531 mmol) in triethylamine/CH4-Aminopyridine (25 g, 265 mmol) was added slowly by a solid addition funnel to a stirred solution of di-t-butyl-di-carbonate (63.75 g, 292 mmol) in THF at room temperature. The solution was further stirred for 1 h at room temperature. The solvent was removed under reduced pressure and the residue was recrystalised by ether to yield 43.5 g (84 percent) of pyridine-4-yl-carbamic acid-tert-butyl ester (117) as white solid. MP: 260 °C ; 1H-NMR (DMSO-d6): d 1. 48 (s, 9H), 7.40 (dd, J = 1.2, 4.8 Hz, 1H), 8.33 (dd, J = 1. 2, 4. 8 Hz, 1H), 9.93 (s, 1H) ; EIMS m/z 195 (M+1).To a stirring solution of 4-aminopyridine (15 g, 159 mmol) and triethylamine (24 mL, 175 mmol) in DMF (300mL) was addeddi-t-butyl dicarbonate (38 g, 175 mmol). After stirring overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 mL); and the solution was washed with satd aq sodium bicarbonate, water and then brine. The organic phase was then dried withMgSO4, filtered and concentrated in vacuo to a volume of about 100 mL. The mixture was then sonicated and the precipitate was filtered and dried in vacuo to give 9.52 g (31percent) of the title compound. To the mother liquor was added about 50 g of silica gel and the mixture was concentrated in vacuo. The resulting dry pack was loaded onto a silica gel column prepared with a solution of 50percent ethyl acetate in hexanes and eluted with20percent ethyl acetate in dichloromethane, followed by a step gradient of50percent ethyl acetate in hexanes through ethyl acetate. The product containing fractions were combined and concentrated in vacuo to give another 16.16 g (52percent) of the title compound. 1NMR IS-MS, m/e 195.3(m+1)A solution of di-tert-butyl dicarbonate (3.274g, 15 mmol) in CH2C12 (8 mL) was added to a solution of 4-aminopyridine (1.412g, 15 mmol) in CH2C12 (15 mL), and was stirred at room temperature for 30 minutes. Acidified with 1M HC1. Washed with CH2C12. Neutralized aqueous layer with K2C03. PARTITIONED between CH2C12 and water. The organic layer was washed with brine, dried (MGSO4), filtered, and concentrated under vacuum to provide 2. 41G (83percent) of PYRIDIN-4-YL-CARBAMIC acid tert-butyl ester.Di-tert-butyl dicarbonate (79.30 g, 0.36 mol) in dichloromethane (250 ml) was added dropwise over 45 min to a stirred suspension of 4-aminopyridine (27.05 g, 0.29 mol) and triethylamine (88 ml, 0.63 mol) in dichloromethane (250 ml) at 0 °C. The solution was stirred at room temperature for 18 h and then washed with water (2 x 250 ml). The organic layer was then dried and concentrated in vacuo to leave a residue which was slurried in ethyl acetate, filtered and dried in vacuo to give pyridin-4-yl-carbamic acid tert-butyl ester (39.62 g, 71 percent) as an off-white solid. No.H (400 MHz, CDC13) 8.44 (2H, dd J 6.4, 1. 6 Hz), 7.31 (2H, dd J 6.4, 1.6 Hz), 6.84 (1H, br s), 1.53 (9H, s) ; Tr = 0.90 min, m/z (ES+) (M+H)+ 195.18.A. EXAMPLE 10

The Boc protecting group can be quickly removed with nitric acid in dichloromethane.