N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide

A 1 L four-necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a bubbler was charged55.91 g (0.26 mol) of 2-acetylamino-4-bromopyridine, 66.02 g (0.26 mol) of bis (pinacolato) diboron and 76.44 g(0.78mol), 450mL of dioxane was added and stirred. Under nitrogen atmosphere, 3.81g (0.0051mol) of ferrocenepalladium chloride was added, Temperature to 100 reaction 18 to 24 hours, TLC control to the end of the reaction, the temperature was precipitated solids, beating filtration, methanol was added 500mL dissolved, filtered and evaporated to dryness, add heptane beating, to give the product 62.08g, yield 91.1percent.Step 2: 1001161 To a mixture of N-(4-bromopyridin-2-yl)acetamide (17.2 g, 80 mmol), 4, 4, 4, 4, 5, 5, 5, 5- octamethyl-2, 2-bi-1, 3, 2-dioxaborolane (26.4 g, 104 mmol), Pd(dppf)C12 (11.7 g, 16 mmol) and KOAc (23.6 g, 240 mmol) under an atmosphere of nitrogen was added anhydrous DMF (1500 mL). The mixture was allowed to stir at 80 °C for 3.5 h. The solvent was removed and the residue was diluted with EtOAc (1000 mL). Activated carbon (100 g) was added. The slurry was heated at reflux for 5 mm and then filtered. The organic solution was concentrated and the residue was recrystallized from EtOAc to give N[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (6.1 g, 29percent) as a white solid. ‘H NMR (400 MHz, DMSO-d6): 1.29 (s, 12H), 2.09 (s, 3H), 7.24 (dd, J= 6.0, 1.2 Hz, 1H), 8.30-8.33 (m, 2H), 10.47 (br s, 1H).[00180] To a mixture of N-(4-bromopyridin-2-yl)acetamide (17.2 g, 80 mmol), 4, 4, 4, 4, 5, 5, 5, 5’- octamethyl-2, 2’-bi-1, 3, 2-dioxaborolane (26.4 g, 104 mmol), Pd(dppf)C12 (11.7 g, 16 mmol) and KOAc (23.6 g, 240 mmol) under an atmosphere of nitrogen was added anhydrous DMF (1500 mL). The mixture was allowed to stir at 80°C for 3.5 h. The solvent was removed and the residue was diluted with EtOAc (1000 mL). Activated carbon (100 g) was added. The slurry was heated at reflux for 5 mm and then filtered. The organic solution was concentrated and the residue was recrystallized from EtOAc to give N-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (6.1 g, 29percent) as a white solid. 1H NEVER (400 JVEFIz, DMSO-ds): 6 1.29 (s, 12H), 2.09 (s, 3H), 7.24 (dd, J= 6.0, 1.2 Hz, 1H), 8.30-8.33 (m, 2H), 10.47 (br s, 1H).Step 2: 2, 6-Dichloro-4-iodo-pyridine (1 g, 3.65 mmol), N-[4-(4, 4, 5, 5-tetramethyl-1 , 3, 2- dioxaborolan-2-yl)-2-pyridyl]acetamide (1 .2 g, 4.58 mmol), PdCI2(PPh3)2 (128 mg, 0.18 mmol) and K2CO3 (1 .51 g, 10.95 mmol) were taken up in 1 , 4- dioxane:H2O:EtOH (6:3:1 , 15 ml) and nitrogen was bubbled through the mixture for 5 min before being heated to 80 C for 2 h. When cooled to rt water (10 ml), brine (10 ml) and EtOAc (25 ml) were added, the mixture stirred vigorously for 5 min and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 20 ml) and the combined organics were washed with brine, dried over Na2SO4, filtered andconcentrated. Recrystallization from MeCN gave the product as a solid (760 mg, 74%). MS ES+ m/z 282 [M+H]+.2, 6-Dichloro-4-iodo-pyridine (0.5 g, 1 .83 mmol), N-[4-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-2-pyridyl]acetamide (0.53 g, 2.01 mmol), K2CO3(0.5 g, 3.65 mmol) and PdCI2(dppf) (0.07 g, 0.09 mmol) were dissolved in DME (3 ml) and water (1 ml) and the mixture was stirred at 80 C for 1 h. (2- Chlorophenyl)boronic acid (0.29 g, 1 .83 mmol), K2CO3(0.5 g, 3.65 mmol) and PdCl2(dppf) (0.07 g, 0.09 mmol) were added and the mixture was stirred for 4 h at 100 C. The organic layer was separated, filtered and concentrated. The crude material was taken up in toluene (4 ml), KOtBu (0.141 g, 1 .26 mmol) was added and the mixture stirred at 100 C for 30 min. When cooled to rt the mixture was concentrated, dissolved in MeOH/DMF, filtered and purified by preparative HPLC to give the product as a solid (6 mg, 4%).1H NMR (500 MHz, METHANOL-^) delta ppm 1 .92 (s, 1 H) 2.22 (s, 3 H) 6.75 (s, 1 H) 6.87 (s, 1 H) 7.43 (dd, 1 H) 7.46 - 7.52 (m, 1 H) 7.55 (td, 1 H) 7.57 - 7.67 (m, 2 H) 8.39 - 8.53 (m, 2 H). MS ES+ m/z 341 [M+H]+.A mixture of N-[4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-2- pyridyl]acetamide (3 g, 9.62 mmol), 2-tert-butoxy-6-chloro-4-iodo-pyridine {Bioorganic & Medicinal Chemistry Letters (2012), 22, (5), 1940-1943, 2.52 g, 9.62 mmol) and Na2CO3(3.05 g, 28.86 mmol) in 1 , 4-dioxane (20 ml) and water (4 ml) was degassed with nitrogen for 20 min. PdCl2(dppf) (351 mg, 0.48 mmol) was added and the resulting mixture was heated and stirred at 1 10 C overnight. When cooled to rt EtOAc was added, the mixture filtered through celite, concentrated and purified by preparative HPLC to give the product as a solid (1 .58 g, 22%). MS ES+ m/z 320 [M+H]+.

Molecular Weight:262.11
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:262.1488726
Monoisotopic Mass:262.1488726
Topological Polar Surface Area:60.4
Heavy Atom Count:19
Complexity:344
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes