Sulfuric Acid → 6-bromo-3,4-dihydro-1H-2-benzopyran-1-one

Temperature

0 °C

A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 min and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL). H2SO4 (98%, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one.

1. customA 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle
2. additionwas added dropwise via syringe
3. customthe internal temperature below 0° C
4. customThe resulting reaction mixture
5. additionwas added dropwise via syringe over 1 h
6. temperatureAn internal temperature of ca. −40° C. was maintained during the addition
7. customThe resulting reaction mixture
8. stirringwas stirred at −40° C. for 30 min
9. stirringThe reaction mixture was stirred at −40° C. for 15 min
10. customThe reaction mixture was quenched with MeOH (5 vol., 20 mL)
11. temperatureto warm to room temperature
12. customAfter complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling)
13. extractionThe reaction mixture was extracted with EtOAc
14. customthe resulting reaction mixture
15. stirringwas stirred
16. temperatureat reflux for 24 h
17. temperatureAfter complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature
18. washThe resulting organic layer was washed with water, brine, and solvent-switched to MTBE
19. customPrecipitation from 1:1 MTBE

ORD record

ord-1bcedad8d47445b790dbfa85485f163c

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206199B2