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

HRID 1432651Notes

Reaction equation

HRID 1432651 reaction equation
Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[C:3]=1[CH3:24].C1COCC1.[Li]CCCC.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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]>[CH3:23][C:4]1[C:3]([CH3:24])=[C:2]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[S:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 764302-BromothiazoleHCID 579330573-(5-Bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 579329083-(3,4-Dimethyl-5-thiazol-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 6%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a −78° C. solution of 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 THF (1 mL) is added 1.6 M n-BuLi (0.16 mL). The solution is stirred for 45 minutes and 0.5 M ZnCl2 in THF (0.52 mL, 0.26 mmol) is added. The solution is warmed to ambient temperature and stirred for 30 minutes. 2-Bromo-thiazole (0.044 mL, 0.49 mmol), and PdCl2(dppf) (0.009 g, 0.012 mmol) are added and the solution heated at 65° C. overnight, diluted with EtOAc (25 mL), washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient), furnish the title compound (6.1 mg, 0.015 mmol, 6%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.07 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.29-3.39 (m, 1H), 6.68 (s, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.86 (d, J=3.1 Hz, 1H). LC/MS (m/z): calcd. for C22H26N4S2 (M+H)+: 411.6; found: 411.2.

Workup

  1. stirringstirred for 30 minutes
  2. temperaturethe solution heated at 65° C. overnight
  3. washwashed with sat. NH4Cl (20 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-3672df6a819f456e9a985826ba2a264a
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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