3-Fluoro-4-methylaniline → Methyl 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate

HRID 2298687Notes

Reaction equation

HRID 2298687 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C:65]1[CH:66]=[C:67]([CH:69]=[CH:70][C:71]=1[CH3:72])[NH2:68]>>[F:64][C:65]1[CH:66]=[C:67]([NH:68][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:69]=[CH:70][C:71]=1[CH3:72]

Participants

5

Reactant 4

HCID 99573-Fluoro-4-methylanilineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 86583861Methyl 4-bromo-5-methylthiothiophene-2-carboxylate

Product 1

HCID 86758186Methyl 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxylateYield 78%

Conditions

Temperature
100 °C

Procedure

To an oven-dried glass vial with stir bar was added a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 70 mg (0.56 mmol) of 3-fluoro-4-methylaniline. The vial was transferred to a glove bag, flushed with dry argon and anhydrous toluene (0.9 mL) was added. The vial was capped with a Teflon-lined screw cap and heated at 100° C. for 48 h. To the cooled suspension was added ethyl acetate (4 mL), the mixture filtered (Celite) washing with ethyl acetate (2×2 mL), and the solvents removed in vacuo. The resulting residue was purified by silica gel preparative thin layer chromatography (10% Et2O in hexane) to afford 103 mg (78%) of the title compound as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ2.22 (d, 3H, J=1.6 Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 (s, 1H), 6.68 (m, 1H), 6.71 (s, 1H), 7.08 (m, 1H), 7.72 (s, 1H).

Workup

  1. additionwas added
  2. customThe vial was transferred to a glove
  3. custombag, flushed with dry argon and anhydrous toluene (0.9 mL)
  4. additionwas added
  5. customThe vial was capped with a Teflon-
  6. customcap
  7. additionTo the cooled suspension was added ethyl acetate (4 mL)
  8. filtrationthe mixture filtered (Celite)
  9. washwashing with ethyl acetate (2×2 mL)
  10. customthe solvents removed in vacuo
  11. customThe resulting residue was purified by silica gel preparative thin layer chromatography (10% Et2O in hexane)

Sources & evidence

ORD record
ord-0060874cf25a4ecaa7a1d8733bf8f2d1
Source dataset
uspto-grants-2002_12
Patent number
US06492403B1

Reaction notes

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