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

HRID 2281312Notes

Reaction equation

HRID 2281312 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[C:16]([CH3:22])[CH:15]=1.[BH4-].[Na+].[OH:25]S(O)(=O)=O.C1[CH2:34][O:33]CC1>CCOC(C)=O.CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:20][CH:21]=1)[C:18](=[O:25])[O:33][CH2:34][CH2:22]2

Participants

9

Reactant 6

HCID 1118Sulfuric AcidHCID 7912DiisopropylamineHCID 8028Tetrahydrofuran2×HCID 1442674-Bromo-2-methylbenzonitrileHCID 4311764Sodium borohydrideHCID 178418339Butyllithium

Product 1

HCID 441308436-bromo-3,4-dihydro-1H-2-benzopyran-1-one

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (4.36 mL, 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 minutes. The reaction 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 hour. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 minutes and then charged with DMF (ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 minutes. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.77 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. H2SO4 (98%, 10.9 mL, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 hours. 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, washed with brine, and solvent-switched to MTBE. Crystallization from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one.

Workup

  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 hour
  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 minutes
  9. stirringThe reaction mixture was stirred at −40° C. for 15 minutes
  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 hours
  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
  19. washwashed with brine, and solvent-switched to MTBE
  20. customCrystallization from 1:1 MTBE

Sources & evidence

ORD record
ord-9f326655921f4a86a19c9c2a714cc5e7
Source dataset
uspto-grants-2015_09
Patent number
US09139585B2

Reaction notes

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