6-bromo-3-methyl-3,4-dihydroisochromen-1-one

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

実験手順: A solution of 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2.000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one. was cooled washed with aqueous ammonium chloride (25 mL) The organic layer was then dried over magnesium sulfate filtered the solvent was evaporated under reduced pressure MPLC purification (15-60% EtOAc/Hex)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and tri-t-butylphosphine-BF4 complex (0.072 g, 0.249 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12.44 ml) and 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.11 mmol) were added followed by bromo(1,3-dioxolan-2-ylmethyl)zinc (6.22 ml, 3.11 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): δ 8.04 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 5.11 (t, J=4.7 Hz, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.88 (m, 2H), 3.03 (d, J=4.9 Hz, 2H), 2.93 (m, 2H), 1.54 (d, J=6.4 Hz, 3H); LC-MS (IE, m/z): 249 [M+1]+. sealed The tube was evacuated were added after which it was cooled filtered concentrated purified via MPLC (20-50% E/H)

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

実験手順: A −78° C. solution of diisopropylamine (13.26 ml, 93 mmol)) in THF (155 ml) was treated with nBuLi (1.6M in Hexanes; 58.1 ml, 93 mmol) over a period of 15 minutes using a syringe pump. In a separate flask, a solution of 2-methyl-4-bromo benzoic acid (10 g, 46.5 mmol) and HMPA (8.33 ml, 46.5 mmol) in THF (155 ml) was cooled to −78° C. Methyl Lithium (29.1 ml, 46.5 mmol) was added slowly via syringe to the cooled solution in order to make the lithio carboxylate. The resulting solution was stirred for 10 minutes and then transferred via cannula to the LDA solution at −78° C. The resulting bright red solution was stirred at −78° C. for an additional 1 hour before being quenched with anhydrous acetaldehyde (7.88 ml, 140 mmol) (color changed from red to orange to clear yellow) and the reaction was then taken out of the dry ice acetone bath and allowed to stir for an additional 1 hour. The flask containing the reaction mixture was then resubmerged in the dry ice acetone bath before it was quenched with 4M HCl in Dioxane (50 mL) followed by 25 mL of MeOH. The reaction was stirred at room temp for an additional 1 hour. The crude reaction was partitioned b/w 200 mL EtOAc and 200 mL water. The organic layer was washed with waster, brine, dried with mag. sulfate, filtered and concentrated. Purification via MPLC (30-70% DCM/Hexanes) afforded 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one. The resulting bright red solution was stirred at −78° C. for an additional 1 hour to stir for an additional 1 hour The flask containing the reaction mixture was quenched with 4M HCl in Dioxane (50 mL) The reaction was stirred at room temp for an additional 1 hour The crude reaction was partitioned b/w 200 mL EtOAc and 200 mL water The organic layer was washed with waster, brine dried with mag sulfate, filtered concentrated Purification via MPLC (30-70% DCM/Hexanes)

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

実験手順: A solution of diisopropylamine (13 ml, 93 mmol)) in THF (155 ml) at −78° C. was treated with n-BuLi (1.6M in Hexanes; 58 ml, 93 mmol) over a period of 15 minutes using a syringe pump. In a separate flask, a solution of 2-methyl-4-bromo benzoic acid (10 g, 46 mmol) and HMPA (8.3 ml, 46 mmol) in THF (155 ml) was cooled to −78° C. Methyl Lithium (29 ml, 46 mmol) was added slowly via syringe to the cooled solution in order to make the lithio carboxylate. The resulting solution was stirred for 10 minutes and then transferred via cannula to the LDA solution at −78° C. The resulting bright red solution was stirred at −78° C. for an additional 1 hour before being quenched with anhydrous acetaldehyde (7.9 ml, 140 mmol) (color changed from red to orange to clear yellow) and the reaction was then taken out of the dry ice acetone bath and allowed to stir for an additional 1 hour. The flask containing the reaction mixture was then resubmerged in the dry ice acetone bath before it was quenched with 4M HCl in Dioxane (50 mL) followed by 25 mL of MeOH. The reaction was stirred at room temp for an additional 1 hour. The crude reaction was partitioned b/w 200 mL EtOAc and 200 mL water. The organic layer was washed with waster, brine, dried with mag. sulfate, filtered and concentrated. Purification via MPLC (30-70% DCM/Hexanes) afforded 9.4 g (84% yield) of 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one as an off white solid. 1H NMR (500 MHz; CDCl3): 7.98 (d, J=8.2 Hz, 1H), 7.56 (dd, J=1.5, 8.2 Hz, 1H), 7.45 (s, 1H), 4.71 (m, 1H), 2.94 (m, 2H), 1.55 (d, J=6.3 Hz, 3H). LC-MS (IE, m/z): 241 [M+1]+. The resulting bright red solution was stirred at −78° C. for an additional 1 hour to stir for an additional 1 hour The flask containing the reaction mixture was quenched with 4M HCl in Dioxane (50 mL) The reaction was stirred at room temp for an additional 1 hour The crude reaction was partitioned b/w 200 mL EtOAc and 200 mL water The organic layer was washed with waster, brine dried with mag sulfate, filtered concentrated Purification via MPLC (30-70% DCM/Hexanes)