Sodium Carbonate → 2-Chloro-4-[7-(2-chloro-pyridin-4-yl)-benzo[b]thiophen-2-yl]-pyrimidine

HRID 1640919Notes

Reaction equation

HRID 1640919 reaction equation
[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=3)[C:2]1=2.C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:38][C:39]1[N:44]=[C:43](Cl)[CH:42]=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:38][C:39]1[N:44]=[C:43]([C:5]2[S:1][C:2]3[C:9]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=4)=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[CH:42]=[CH:41][N:40]=1

Participants

10

Reactant 5

HCID 10340Sodium CarbonateHCID 21531Triisopropyl borateHCID 775312,4-DichloropyrimidineHCID 2724682Lithium diisopropylamideHCID 866402544-Benzo[b]thiophen-7-yl-2-chloro-pyridine

Product 1

HCID 866402552-Chloro-4-[7-(2-chloro-pyridin-4-yl)-benzo[b]thiophen-2-yl]-pyrimidineYield 68.3%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 21906603Chloroform isopropyl alcoholSolvent

Procedure

In a 500 mL round bottom flask, cool a solution of 4-benzo[b]thiophen-7-yl-2-chloro-pyridine (13 g, 53.1 mmol) and triisopropylborate (20 g, 106 mmol) in THF (150 mL) to −70° C. under nitrogen. To the cooled solution, add lithium diisopropylamide (2 M in THF, 53 mL, 106 mmol) gradually over a period of 30 min. Stir the mixture continually for an additional hour in the cooling bath. Gradually transfer the mixture into a refluxing solution of 2,4-dichloro-pyrimidine (12 g, 106 mmol), Pd(dppf)Cl2 (2.2 g, 53 mmol) and sodium carbonate (35 mL, 3 M, 106 mmol) in THF (150 mL) over a period of 30 min. Reflux for an additional 1 h. Cool the mixture to RT and dilute with 500 mL of chloroform/IPA (3/1) and 200 mL of water. Collect the resulting solid by filtration and reserve the chloroform/IPA/water mixture. Wash the solid with DCM and dry it under vacuum. Separate the layers of the chloroform/IPA/water mixture. Wash the organic phase with water and aqueous saturated sodium chloride, dry over sodium sulfate and concentrate in vacuo to give a brown residue. Purify the residue by FCC (10% methanol in DCM) to afford additional product. Combine the two portions to give the title compound (13 g, 68%). MS (ES) m/z 358 [M+1]+.

Workup

  1. temperatureReflux for an additional 1 h
  2. customCollect the resulting solid
  3. filtrationby filtration and reserve the chloroform/IPA/water mixture
  4. washWash the solid with DCM
  5. customdry it under vacuum
  6. customSeparate the layers of the chloroform/IPA/water mixture
  7. washWash the organic phase with water and aqueous saturated sodium chloride
  8. dry with materialdry over sodium sulfate
  9. concentrationconcentrate in vacuo
  10. customto give a brown residue
  11. customPurify the residue by FCC (10% methanol in DCM)
  12. customto afford additional product

Sources & evidence

ORD record
ord-e848145ecbba432f91b66959c69850e9
Source dataset
uspto-grants-2012_02
Patent number
US08114872B2

Reaction notes

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