Acetic Acid → 4-(Benzo[b]thiophen-2-yl)-5-bromo-2-chloropyrimidine

HRID 1986168Notes

Reaction equation

HRID 1986168 reaction equation
C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Br:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.C(O)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(Cl)(Cl)Cl.ClCCl.C(OCC)C>[S:6]1[C:10]([C:17]2[C:16]([Br:15])=[CH:21][N:20]=[C:19]([Cl:22])[N:18]=2)=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2

Participants

10

Reactant 5

HCID 176Acetic AcidHCID 67752,3-Dichloro-5,6-dicyano-1,4-benzoquinoneHCID 7221Benzo(B)Thiophene2×HCID 6066655-Bromo-2-chloropyrimidineHCID 178418339Butyllithium

Product 1

HCID 574288214-(Benzo[b]thiophen-2-yl)-5-bromo-2-chloropyrimidineYield 98.2%

Reagents, catalysts & solvents 4

HCID 3283Diethyl EtherSolventHCID 6212ChloroformSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

n-Butyl lithium (20.7 mL, 1.6 M in hexane) is added dropwise to a stirred solution of benzo[b]thiophene (4.12 g, 30.1 mmol) in anhydrous THF (50 mL) at −78° C. under nitrogen. The resultant solution is allowed to stir at −78° C. for 15 minutes. The lithiated benzo[b]thiophene is then added via canula over 20 minutes to a stirred solution of 5-bromo-2-chloro-pyrimidine (5.95 g, 30.1 mmol) in anhydrous THF (100 mL) at −30° C. Upon the completion of the addition, the solution is allowed to stir at −30° C. for an additional 30 minutes then at 0° C. for another 30 minutes. The reaction is quenched with acetic acid (1.99 g, 33.1 mmol), then after 5 minutes, it is treated with a solution of DDQ (7.17 g, 31.6 mmol) in anhydrous THF (150 mL) in portions at 10° C. The mixture is stirred for 20 minutes at 10° C. before it is concentrated to give a dark solid. The solid is then suspended in chloroform (500 mL) and the suspension is sonicated and filtered through a pad of silica. Additional 700 mL chloroform is used to wash the solid. The combined filtrates are concentrated to give a solid. The solid is re-suspended in dichloromethane (20 mL)/diethyl ether (20 mL) and the suspension is sonicated and filtered to give the title compound as a yellowish solid (9.62 g, 98% yield).

Workup

  1. additionUpon the completion of the addition
  2. stirringto stir at −30° C. for an additional 30 minutes
  3. waitat 0° C. for another 30 minutes
  4. waitafter 5 minutes
  5. stirringThe mixture is stirred for 20 minutes at 10° C. before it
  6. concentrationis concentrated
  7. customto give a dark solid
  8. customthe suspension is sonicated
  9. filtrationfiltered through a pad of silica
  10. washto wash the solid
  11. concentrationThe combined filtrates are concentrated
  12. customto give a solid
  13. customthe suspension is sonicated
  14. filtrationfiltered

Sources & evidence

ORD record
ord-55321ec47868406f8a6704e59b764c3f
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

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