Tetrahydrofuran → 3-(3-Chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 1432621Notes

Reaction equation

HRID 1432621 reaction equation
Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].C1COCC1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25](I)=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]>[Zn].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:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:25]1[N:20]2[N:21]=[C:22]([CH3:24])[CH:23]=[C:18]([CH:15]([CH2:13][CH3:14])[CH2:16][CH3:17])[C:19]2=[N:27][C:26]=1[CH3:28]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 27245612-Bromo-3-chlorothiopheneHCID 577526818-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579329363-(3-Chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 104.2%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalyst2×HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst

Procedure

To a flask of 2-bromo-3-chloro-thiophene (Lemaire et. el., Synth. Commun., 1994, 24, 95) (2.53 g, 12.82 mmol) is added 0.05 g/mL Reike® zinc in THF (25 mL, 19.24 mmol). The solution is heated at a reflux for 2 hours. The excess zinc is allowed to settle and the solution transferred to a flask containing 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (example KW1-A03735-193) (2.01 g, 6.41 mmol) and PdCl2(dppf) (0.23 g, 0.32 mmol). The solution is heated at a reflux overnight, quenched with sat. NH4Cl (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (2%-15% EtOAc/hexane gradient) furnish the title compound (1.32 g, 6.68 mmol, 62%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.48 (s, 3H), 2.49 (s, 3H), 3.37-3.36 (m, 1H), 6.67 (s, 1H), 7.07 (d, J=5.4 Hz, 1H), 7.48 (d, J=5.4 Hz, 1H). LC/MS (m/z): calcd. for C17H20ClN3S (M+H)+: 334.1; found: 334.1.

Workup

  1. temperatureThe solution is heated at
  2. temperaturea reflux for 2 hours
  3. customthe solution transferred to a flask
  4. temperatureThe solution is heated at a reflux overnight
  5. customquenched with sat. NH4Cl (25 mL)
  6. extractionextracted with EtOAc (2×25 mL)
  7. dry with materialThe combined organic layers are dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue is purified by ISCO column chromatography (2%-15% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-6e9f41aed46a48538c69c458f30c0c37
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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