Triethylamine → 7,8-difluoro-3-methyl-2H-1,4-benzoxazine

HRID 1638822Notes

Reaction equation

HRID 1638822 reaction equation
ClOC(C)(C)C.[F:7][C:8]1[CH:18]=[CH:17][C:11]2[NH:12][C@H:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19].C(N(CC)CC)C>C(OCC)(=O)C>[F:7][C:8]1[CH:18]=[CH:17][C:11]2[N:12]=[C:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 521297Tert-Butyl hypochloriteHCID 13192918HCID 13192918, compound

Product 1

HCID 109431177,8-difluoro-3-methyl-2H-1,4-benzoxazineYield 60.8%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

In a nitrogen stream, a solution of 2.11 ml of t-butyl hypochlorite and 2 ml of ethyl acetate were added dropwise to a mixture of 1.54 g of (R)-(+)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine (optical purity: 71.7% e.e., (R)), 5.21 ml of triethylamine and 9 ml of ethyl acetate while keeping the internal temperature at -52° C. over a period of about 4 minutes, and the resulting mixture was further stirred at -60° to -50° C. for 30 minutes. The reaction mixture was washed twice with 10 ml portions of 5% aqueous solution of citric acid and further with 10 ml of dilute aqueous ammonia (concentrated aqueous ammonia:water=1:4 (v/v)) and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the oily residue was purified over silica gel (50 g) column chromatography using chloroform (the bottom layer after shaking with concentrated aqueous ammonia) as the eluent. The solvent was removed from the eluate under reduced pressure to yield 693 mg of 7,8-difluoro-3-methyl-2H-[1,4]benzoxazine as pale yellow crystals (yield: 60.8%).

Workup

  1. customat -52° C.
  2. customof about 4 minutes
  3. washThe reaction mixture was washed twice with 10 ml portions of 5% aqueous solution of citric acid and further with 10 ml of dilute aqueous ammonia (concentrated aqueous ammonia:water=1:4 (v/v))
  4. dry with materialthe ethyl acetate layer was dried over anhydrous magnesium sulfate
  5. customThe ethyl acetate was removed under reduced pressure
  6. customthe oily residue was purified over silica gel (50 g) column chromatography
  7. stirringafter shaking with concentrated aqueous ammonia) as the eluent
  8. customThe solvent was removed from the eluate under reduced pressure

Sources & evidence

ORD record
ord-bc1fd5fee2c843c69685a28e87661fac
Source dataset
uspto-grants-1989_11
Patent number
US04880926

Reaction notes

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