Tetrahydrofuran → 3-[3,4-Dimethyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

HRID 1432653Notes

Reaction equation

HRID 1432653 reaction equation
I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]1COCC1.[Li]C(C)(C)C.Br[C:19]1[S:23][C:22]([C:24]2[N:28]3[N:29]=[C:30]([CH3:38])[CH:31]=[C:32]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:27]3=[N:26][C:25]=2[CH3:39])=[C:21]([CH3:40])[C:20]=1[CH3:41]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:40][C:21]1[C:20]([CH3:41])=[C:19]([C:5]2[CH:6]=[CH:7][CH:2]=[C:3]([CH3:8])[N:4]=2)[S:23][C:22]=1[C:24]1[N:28]2[N:29]=[C:30]([CH3:38])[CH:31]=[C:32]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:27]2=[N:26][C:25]=1[CH3:39]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 707143-IodopyridineHCID 579330573-(5-Bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418306HCID 178418306, compound

Product 1

HCID 579329493-[3,4-Dimethyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 6%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a −78° C. solution of 3-iodo-pyridine (0.15 g, 0.74 mmol) and 0.5 M ZnCl2 in THF (1.5 mL, 0.75 mmol) is added t-BuLi (0.88 mL, 1.49 mmol). The slurry is warmed to ambient temperature and stirred for 30 minutes. 3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.25 mmol) and Pd(PPh3)4 (0.014 g, 0.012 mmol) are added and the solution stirred at ambient temperature for 2 days, diluted with EtOAc (35 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish the title compound (6.1 mg, 0.015 mmol, 6%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.07 (s, 3H), 2.29 (s, 3H), 2.49 (s, 3H), 2.53 (s, 3H), 3.30-3.39 (m, 1H), 6.68 (s, 1H), 7.36 (dd, J=8.0, 4.5 Hz, 1H), 7.79-7.83 (m 1H), 8.57 (d, J=4.5 Hz, 1H), 8.79 (d, J=0.9 Hz, 1H). LC/MS (m/z): calcd. for C24H28N4S (M+H)+: 405.6; found: 405.2.

Workup

  1. stirringthe solution stirred at ambient temperature for 2 days
  2. washwashed with sat. NH4Cl (30 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-35a1f235c8a44d7e90daf337317140d5
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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