Methyl iodide → 5-Methyl-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid

Temperature

-75 °C

To a round bottom flask equipped with magnetic stirring, an addition funnel and a nitrogen inlet, was added benzo(1,4)dioxan-6-carboxylic acid (18.00 g, 99.91 mmol) and 1,2-dimethoxyethane (667 mL). This mixture was cooled to −75° C. in a dry ice-acetone bath. To this was added 1.3 M sec-butyl lithium in cyclohexane (230.6 mL, 299.7 mmol) over 1 hour, maintaining reaction temperature below −60° C. The reaction was removed from the cooling bath, allowed to warm to −20° C., and subsequently stirred at −20° C. for 45 min. The reaction was cooled to −50° C., and iodomethane (15.6 mL, 249.8 mmol) was added. The reaction was again removed from the cooling bath, allowed to warm to −20° C., and stirred at this temperature for 45 min. All cooling was removed and the reaction stirred at room temperature for 16 hours. The reaction was quenched by addition of a few mls of 1N HCl (aq) and the solvent removed by evaporation. The residue was made substantially acidic by the addition of aqueous 1N HCl. The resultant precipitate was filtered and washed with water to give a light brown solid, 5-methyl-benzo(1,4)dioxan-6-carboxylic acid, (0.60 g, 33.9 mmol) in 34% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.62 (d, 1H), 6.8 (d, 1H), 4.30 (br s, 4H), 2.52 (s, 3H).

1. customTo a round bottom flask equipped with magnetic stirring, an addition funnel and a nitrogen inlet
2. temperaturemaintaining
3. customreaction temperature below −60° C
4. customThe reaction was removed from the cooling bath
5. temperatureto warm to −20° C.
6. temperatureThe reaction was cooled to −50° C.
7. customThe reaction was again removed from the cooling bath
8. temperatureto warm to −20° C.
9. stirringstirred at this temperature for 45 min
10. customAll cooling was removed
11. stirringthe reaction stirred at room temperature for 16 hours
12. customThe reaction was quenched by addition of a few mls of 1N HCl (aq)
13. customthe solvent removed by evaporation
14. additionThe residue was made substantially acidic by the addition of aqueous 1N HCl
15. filtrationThe resultant precipitate was filtered
16. washwashed with water

ORD record

ord-30785ba2f51846cd98ffb9fc2bba7355

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09272986B2