乙基 (E)-3-(2-氨基-5-溴苯基)丙-2-烯酸乙酯

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9 equiv, GLR) and degassed with nitrogen for 20 mins. XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR), and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv, Hindustan Platinum) was added to the reaction mixture. The mixture was purged with nitrogen and heated to 80° C. for 30 mins. The reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, Alfa Aesar) was added and the reaction was heated at 80° C. for an additional 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through celite and the celite bed was washed with ethyl acetate (2×1.0 L). The filtrate was concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%), as yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. Product's Rf: 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1). NMR (400 MHz, DMSO) δ 7.79 (d, J=16.1 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J=7.2 Hz, 3H). degassed with nitrogen for 20 mins The mixture was purged with nitrogen The reaction was cooled to RT the reaction was heated at 80° C. for an additional 4 h The reaction was cooled to room temperature The mixture was filtered through celite the celite bed was washed with ethyl acetate (2×1.0 L) The filtrate was concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equiv) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 equiv, Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 equiv). The reaction mixture was degassed with nitrogen for 20 min followed by the addition of palladium acetate (28.8 g, 128.27 mmol, 0.05 equiv, Hindustan Platinum). The reaction mixture was heated at 70° C. for 3 h. The reaction was filtered through celite and the celite bed was washed with ethyl acetate (2×500 mL). The filtrate was concentrated under reduced pressure to obtain the crude residue which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate in hexanes) to obtain (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%), as yellow solid. TLC solvent system: 20% ethyl acetate in hexanes. Product's Rf: 0.4. MS (ESI, positive ion) m/z; 270.2 (M+1). 1H NMR (400 MHz, DMSO) δ 7.75 (d, J=16.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.16 (dd, J=9.1, 2.4 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.43 (d, J=8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). The reaction mixture was degassed with nitrogen for 20 min The reaction was filtered through celite the celite bed was washed with ethyl acetate (2×500 mL) The filtrate was concentrated under reduced pressure to obtain the crude residue which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate in hexanes)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (0.820 g, 2.086 mmol), xantphos (0.092 g, 0.159 mmol), tris(dibenzylideneacetone)dipalladium (0.073 g, 0.080 mmol), 1,4-Dioxane (3.18 ml), and DIPEA (1.108 ml, 6.37 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to RT and benzyl mercaptan (0.395 ml, 3.34 mmol) was added and the reaction was continued heating at 80° C. for an additional 30 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.80 g of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate. m/z (ESI) 314.1 (M+H)+. A screw cap vial The vial was purged with Argon sealed The reaction was cooled to RT the reaction was continued heating at 80° C. for an additional 30 minutes The reaction was cooled to RT extracted with DCM (3×) The combined organics were washed with water and brine dried over magnesium sulfate filtered concentrated The resulting material was concentrated dissolved in minimal DCM purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a microwave vial was added, 4-bromo-2-iodoaniline (1.70 g, 5.71 mmol), PdOAc2 (0.064 g, 0.285 mmol), sodium bicarbonate (1.198 g, 14.27 mmol), ethyl acrylate (0.651 ml, 5.99 mmol) and DMF (1.902 ml). The reaction was heated in microwave for 1 hour at 80° C. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.860 g of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate. m/z (ESI) 270.1 (M+H)+. To a microwave vial was added The reaction was cooled to room temperature extracted with DCM (3×) The combined organics were washed with water and brine dried over magnesium sulfate filtered concentrated The resulting material was concentrated dissolved in minimal DCM purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane)