6-bromo-2-methyl-4H-1,4-benzoxazin-3-one

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 726 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is stirred in 1.5 ml of triethylamine with 0.267 g of acrylamide as well as 8 mg of palladium(II) acetate and 46 mg of tri-ortho-toluyl-phosphine for several hours at 100° C. The product is taken up in methanol and purified by column chromatography with an ethanol/ethyl acetate mixture. Yield 36%. purified by column chromatography with an ethanol/ethyl acetate mixture

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 315 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is mixed in 4 ml of DME with 0.2 g of 2-thiopheneboronic acid and 150 mg of tetrakis-triphenylphosphine-palladium (O) and 340 mg of sodium bicarbonate (dissolved in 4 ml of water). It is stirred for some time at 100° C. The product is diluted with ethyl acetate, extracted 3 times with water, and dried with magnesium sulfate. It is concentrated by evaporation. The crude product is purified by column chromatography with a hexane/ethyl acetate mixture and yields pure 33% product. extracted 3 times with water dried with magnesium sulfate It is concentrated by evaporation The crude product is purified by column chromatography with a hexane/ethyl acetate mixture

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 315 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is mixed in 4 ml of DME with 0.2 g of 2-thiopheneboronic acid and 150 mg of tetrakis-triphenylphosphine-palladium (O) and 340 mg of sodium bicarbonate (dissolved in 4 ml of water). It is stirred for some time at 100° C. The product is diluted with ethyl acetate, extracted 3 times with water, and dried with magnesium sulfate. It is concentrated by evaporation. The crude product is purified by column chromatography with a hexane/ethyl acetate mixture and yields pure 33% product. extracted 3 times with water dried with magnesium sulfate It is concentrated by evaporation The crude product is purified by column chromatography with a hexane/ethyl acetate mixture

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 4-(4-methylenepiperidin-1-yl)benzoate 390C (145.8 mg, 0.594 mmol) was taken up with 0.5M THF solution of 9-BBN (1.189 mL, 0.594 mmol) under nitrogen and stirred at 75° C. for 1 h. The reaction mixture was then added to a suspension of 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (144 mg, 0.594 mmol), PdCl2(dppf)-CH2Cl2 adduct (14.56 mg, 0.018 mmol) and potassium carbonate (164 mg, 1.189 mmol) in DMF (2.0 mL) and water (0.2 mL) and stirred at 60° C. The reaction was pulled, cooled to RT, and diluted with water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL); the organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (10%-20%-30% EA/Hex) provided the desired product as an off-white solid (62 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.32 (m, 6H) 1.35-1.46 (m, 2H) 1.56-1.76 (m, 3H) 2.43 (d, J=6.82 Hz, 2H) 2.77 (t, J=11.75 Hz, 2H) 3.82-3.96 (m, 2H) 4.22 (q, J=7.07 Hz, 2H) 4.56-4.66 (m, 1H) 6.63-6.77 (m, 2H) 6.86 (d, J=8.08 Hz, 1H) 6.94 (d, J=9.09 Hz, 2H) 7.69-7.82 (m, 2H) 10.59 (s, 1H). ESI-MS: m/z 409.4 (M+H)+. stirred at 60° C cooled to RT The aqueous layer was extracted with ethyl acetate (2×20 mL) the organic layer was separated washed with brine dried over MgSO4 filtered concentrated in vacuo

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 20 mL screw cap vial, under N2, 4-methylene-1-phenylpiperidine (0.0906 g, 0.523 mmol) was diluted with 0.5M THF solution of 9-BBN (1.046 mL, 0.523 mmol) and stirred at 75° C. for 1 hr. The reaction mixture was then added to a suspension of 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (0.127 g, 0.523 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0128 g, 0.016 mmol) and K2CO3 (0.145 g, 1.046 mmol) in DMF (1.0 mL) and water (0.1 mL) and stirred at 60° C. for 4 hr. The mixture was cooled to RT, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10%-50% EA/Hex) provided the desired product as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.32 (m, 2H) 1.40 (d, J=6.82 Hz, 3H) 1.47 (br. s., 1 H) 1.64 (d, J=13.14 Hz, 2H) 2.45 (d, J=6.82 Hz, 2H) 2.52-2.62 (m, 2H) 3.59-3.70 (m, 2H) 4.55-4.67 (m, 1H) 6.65-6.78 (m, 3H) 6.81-6.94 (m, 3H) 7.11-7.22 (m, 2H) 10.58 (s, 1 H). ESI-MS: m/z 337.3 (M+H)+. To a 20 mL screw cap vial, under N2 stirred at 60° C. for 4 hr The mixture was cooled to RT extracted with ethyl acetate (2×20 mL) The combined organic layers was washed with brine dried with MgSO4 filtered concentrated in vacuo Purification by flash column chromatography (10%-50% EA/Hex)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 20 mL screw cap vial was added 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (100 mg, 0.5 mmol), 3-carboxy phenylboronic acid (91 mg, 0.55 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), and aqueous Na2CO3 (2M, 0.62 mL, 1.25 mmol) in DMF (4 mL). The reaction was heated at 80° C. overnight then cooled and filtered. The filtrate was purified by preparative HPLC-MS (15-60% MeCN in water). The appropriate fractions were combined and concentrated in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=13.11 (br. s., 1H), 10.72 (s, 1H), 8.09 (t, J=1.6 Hz, 1H), 7.91 (dt, J=7.6, 1.4 Hz, 1H), 7.80-7.85 (m, 1H), 7.54-7.62 (m, 1H), 7.27 (dd, J=8.3, 2.3 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.69-4.77 (m, 1H), 1.45 ppm (d, J=6.8 Hz, 3H). ESI-MS: m/z 284.2 (M+H)+. To a 20 mL screw cap then cooled filtered The filtrate was purified by preparative HPLC-MS (15-60% MeCN in water) concentrated in vacuo to give a white solid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 726 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is stirred in 1.5 ml of triethylamine with 0.267 g of acrylamide as well as 8 mg of palladium(II) acetate and 46 mg of tri-ortho-toluyl-phosphine for several hours at 100° C. The product is taken up in methanol and purified by column chromatography with an ethanol/ethyl acetate mixture. Yield 36%. purified by column chromatography with an ethanol/ethyl acetate mixture

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 315 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is mixed in 4 ml of DME with 0.2 g of 2-thiopheneboronic acid and 150 mg of tetrakis-triphenylphosphine-palladium (O) and 340 mg of sodium bicarbonate (dissolved in 4 ml of water). It is stirred for some time at 100° C. The product is diluted with ethyl acetate, extracted 3 times with water, and dried with magnesium sulfate. It is concentrated by evaporation. The crude product is purified by column chromatography with a hexane/ethyl acetate mixture and yields pure 33% product. extracted 3 times with water dried with magnesium sulfate It is concentrated by evaporation The crude product is purified by column chromatography with a hexane/ethyl acetate mixture