ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate → ethyl 6-chloro-7-[(4-methylpyridin-2-yl)methyl]-2-(trifluoromethyl)-2H-chromene-3-carboxylate

HRID 855047Notes

Reaction equation

HRID 855047 reaction equation
Br[Mg][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2

Participants

6

Reactant 2

HCID 69517129ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylateHCID 178428553HCID 178428553, compound

Product 1

HCID 69519058ethyl 6-chloro-7-[(4-methylpyridin-2-yl)methyl]-2-(trifluoromethyl)-2H-chromene-3-carboxylateYield 5%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

The bromo (4-methylpyridin-2-yl)magnesium (10.4 mL, 2.6 mmole) was diluted by 5 mL THF and the solution was cooled to −78° C. ZnCl2 (340 mg, 2.5 mmole) was added to above solution and the mixture was slowly warmed to r.t and heated to 50 OC for 3 hrs. The mixture was cooled to −78° C. again and ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (1.0 g, 2.5 mmol) was added to above mixture and followed by PdCl2(PPh3)2 (18 mg, 0.025 mmole). The mixture was warmed to 50° C. for 3 hrs. LCMS indicated that around 40% product was formed. The reaction was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The filtrate was concentrated to afford the crude product, which was purified by RPHPLC eluted with 10 to 95% ACN in water with 0.05% TFA to give 50 mg the desired product as a brown oil (yield 5%), which had suitable purity to use without further purification.

Workup

  1. temperaturethe mixture was slowly warmed
  2. temperatureheated to 50 OC for 3 hrs
  3. temperatureThe mixture was cooled to −78° C. again
  4. temperatureThe mixture was warmed to 50° C. for 3 hrs
  5. customwas formed
  6. customThe reaction was quenched with 1 N HCl
  7. extractionextracted with EtOAc
  8. washThe organic layer was washed with brine
  9. dry with materialdried over MgSO4
  10. concentrationThe filtrate was concentrated
  11. customto afford the crude product, which
  12. customwas purified by RPHPLC
  13. washeluted with 10 to 95% ACN in water with 0.05% TFA

Sources & evidence

ORD record
ord-d85e46f85c114810bcc14160075dd473
Source dataset
uspto-grants-2007_08
Patent number
US07259266B2

Reaction notes

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