Benzene, 1-bromo-4-(trifluoromethyl)- → HCID 71712048, compound

HRID 528540Notes

Reaction equation

HRID 528540 reaction equation
COC1C=CC(C[N:8]([C:28]2[S:32][N:31]=[CH:30][N:29]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18][O:17][C:16]=3[CH:27]=2)(=[O:11])=[O:10])=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:78]1[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=1.CC(C)([O-])C.[Na+]>O.CO.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:21]1([CH:19]2[CH2:18][O:17][C:16]3[CH:27]=[C:12]([S:9]([NH:8][C:28]4[S:32][N:31]=[CH:30][N:29]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=3[N:20]2[C:78]2[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

9

Reactant 4

HCID 67872Benzene, 1-bromo-4-(trifluoromethyl)-HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 89761802HCID 89761802, compound2×

Product 1

HCID 71712048HCID 71712048, compoundYield 53.4%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A vial was charged with N-(4-methoxybenzyl)-3-phenyl-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE R, 93.6 mg, 0.189 mmol), xantphos (21.89 mg, 0.038 mmol), Pd2(dba)3 (17.32 mg, 0.019 mmol), toluene (1891 μL), 1-bromo-4-(trifluoromethyl)benzene (31.8 μl, 0.227 mmol), and sodium tert-butoxide (36.4 mg, 0.378 mmol). The vial was sealed and placed in a 130° C. heating bath for 10 min. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL). The resulting mixture was stirred for 20 minutes, then concentrated. The product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give a yellow foam. The material was dissolved in MeOH/DCM and loaded onto a 1 g anion exchange column. The column was eluted with MeOH, then with 10% HCl/MeOH (prepared by dissolving 1 mL of conc. HCl in 9 mL of MeOH). The acidic fractions were concentrated, and the residue was concentrated from DCM to give 3-phenyl-N-(1,2,4-thiadiazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (52.2 mg, 0.101 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 7.71 (d, J=8.8 Hz, 2 H), 7.44 (d, J=8.4 Hz, 2 H), 7.37-7.23 (m, 6H), 7.16 (dd, J=3.3, 5.4 Hz, 2 H), 5.28-5.23 (m, 1 H), 4.60 (dd, J=2.4, 11.2 Hz, 1 H), 4.40 (dd, J=2.8, 11.3 Hz, 1 H). m/z (ESI) 519.0 (M+H)+.

Workup

  1. customThe vial was sealed
  2. customplaced in a 130° C.
  3. temperatureheating bath for 10 min
  4. extractionextracted with EtOAc (3×)
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in DCM (0.5 mL)
  9. concentrationconcentrated
  10. customThe product was purified by chromatography on silica gel (0 to 5% MeOH/DCM)
  11. customto give a yellow foam
  12. washThe column was eluted with MeOH
  13. concentrationThe acidic fractions were concentrated
  14. concentrationthe residue was concentrated from DCM

Sources & evidence

ORD record
ord-95734afd7fde4a0bb073240c23899afe
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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