Lithium Hexamethyldisilazide → 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

HRID 528582Notes

Reaction equation

HRID 528582 reaction equation
[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([O:26]C3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=O)[CH:21]=[CH:22][C:14]1=2)#[N:2].Cl.[S:39]1[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:44][C:42]3[N:41]=[CH:40][S:39][CH:43]=3)(=[O:25])=[O:26])[CH:21]=[CH:22][C:14]1=2)#[N:2]

Participants

5

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 68841472Thiazol-4-amine hydrochloride2×HCID 89762001perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate

Product 1

HCID 897619364-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamideYield 34%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 10-mL round-bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB) (48.92 mg, 0.089 mmol), thiazol-4-amine hydrochloride (Accel Pharmatech, East Brunswick, N.J., 15.78 mg, 0.116 mmol), and THF (889 μl) to give a suspension. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (293 μl, 0.293 mmol) was added dropwise over 30 s to give a bright orange mixture. The mixture was stirred for 5 min, then the flask was lowered into an ice-water bath. After 2 h, additional portions of thiazol-4-amine hydrochloride (15.78 mg, 0.116 mmol) and lithium bis(trimethylsilyl)amide (1M in THF) (293 μl, 0.293 mmol) were added in sequence. Following an additional 1 h of stirring, the mixture was quenched with glacial acetic acid (1 drop), diluted with MeOH, and concentrated in vacuo. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (14.11 mg, 0.030 mmol, 34.0% yield) as a tan solid: 1H NMR (400 MHz, DMSO-d6) 6=10.96 (s, 1 H), 8.88 (d, J=2.2 Hz, 1 H), 8.41 (d, J=1.7 Hz, 1 H), 8.09 (dd, J=1.9, 8.8 Hz, 1 H), 7.72 (d, J=8.7 Hz, 1 H), 7.30 (d, J=2.2 Hz, 1 H), 7.20 (dd, J=2.2, 8.6 Hz, 1 H), 6.99 (d, J=2.2 Hz, 1 H), 6.79 (d, J=8.6 Hz, 1 H), 4.38-4.28 (m, 2 H), 3.90-3.81 (m, 2 H); m/z (ESI) 467.2 (M+H)+.

Workup

  1. customto give a suspension
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
  3. customto give a bright orange mixture
  4. customthe flask was lowered into an ice-water bath
  5. waitAfter 2 h
  6. waitFollowing an additional 1 h
  7. stirringof stirring
  8. customthe mixture was quenched with glacial acetic acid (1 drop)
  9. additiondiluted with MeOH
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM)

Sources & evidence

ORD record
ord-6a9562a08aa44d8e93e561622f0af145
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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