Trifluoroacetic acid → 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[3,4-d]isoxazole

HRID 1506407Notes

Reaction equation

HRID 1506407 reaction equation
[OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][N:5]=1.[CH:20]([C:22]1[CH:31]=[C:30]2[C:25]([C:26](N3CCOCC3)=[CH:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)=[CH2:21].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>ClC(Cl)C.ClCCl>[C:13]1([C:7]2[O:6][N:5]=[C:4]([C:3]3[C:27]4[CH2:28][O:29][C:30]5[CH:31]=[C:22]([CH:20]=[CH2:21])[CH:23]=[CH:24][C:25]=5[C:26]=4[O:1][N:2]=3)[C:8]=2[C:9]([F:12])([F:11])[F:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 671681804-(7-vinyl-2H-chromen-4-yl)morpholineHCID 136374584(3Z)-N-hydroxy-5-phenyl-4-(trifluoromethyl)-1,2-oxazole-3-carboximidoyl chloride2×

Product 1

HCID 671686283-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[3,4-d]isoxazoleYield 12.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 63651,1-DichloroethaneSolvent

Procedure

To a mixture of (Z)—N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride (Intermediate 13, 0.221 g, 0.646 mmol) and 4-(7-vinyl-2H-chromen-4-yl)morpholine (Preparation 53A, 0.535 M in dichloromethane, 1.21 mL, 0.646 mmol) at 0° C. was added triethylamine (0.108 mL, 0.776 mmol) dropwise over 3 min. The ice-bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (15 mL), dried over anhydrous sodium sulfate, and concentrated to give a foamy solid. The product mixture was dissolved in dichloroethane (3 mL), TFA (0.075 mL, 0.970 mmol) was added, and the resulting solution was heated at 80° C. for ˜60 min. The reaction mixture was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (15 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12%-20%) afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[3,4-d]isoxazole (0.033 g, 0.078 mmol, 12% yield) as a white solid. The product had an HPLC ret. time=3.93 min. (condition A); LC/MS M+1=411.0.

Workup

  1. customThe ice-bath was removed
  2. additionThe reaction mixture was diluted with dichloromethane (30 mL)
  3. washwashed with water (15 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated
  6. customto give a foamy solid
  7. temperaturethe resulting solution was heated at 80° C. for ˜60 min
  8. washwashed with a saturated aqueous solution of sodium bicarbonate (15 mL)
  9. dry with materialdried over anhydrous sodium sulfate
  10. concentrationConcentration under reduced pressure
  11. customfollowed by purification by flash silica gel chromatography
  12. additiona mixture of ethyl acetate in hexane (5%-12%-20%)

Sources & evidence

ORD record
ord-30f1bd42ce3b4f22875f51ab32c0a961
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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