Acetaldehyde → 6-bromo-3-methyl-3,4-dihydro-1H-2-benzopyran-1-one

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]+.

1. stirringThe resulting bright red solution was stirred at −78° C. for an additional 1 hour
2. stirringto stir for an additional 1 hour
3. additionThe flask containing the reaction mixture
4. customwas quenched with 4M HCl in Dioxane (50 mL)
5. stirringThe reaction was stirred at room temp for an additional 1 hour
6. customThe crude reaction
7. customwas partitioned b/w 200 mL EtOAc and 200 mL water
8. washThe organic layer was washed with waster, brine
9. customdried with mag
10. filtrationsulfate, filtered
11. concentrationconcentrated
12. customPurification via MPLC (30-70% DCM/Hexanes)

ORD record

ord-239fedc3d8af43ad955ee7e1a5a94480

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09073882B2