Tetrahydrofuran → HCID 57932934, compound

HRID 1432576Notes

Reaction equation

HRID 1432576 reaction equation
[CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C1COCC1.C([Li])CCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[CH:19]=1>C(Cl)Cl.[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]>[CH2:33]([CH:32]([C:31]1[C:26]2[N:27]([C:23]([C:21]3[S:22][C:18]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][N:5]=4)=[CH:19][C:20]=3[CH3:39])=[C:24]([CH3:38])[N:25]=2)[N:28]=[C:29]([CH3:37])[CH:30]=1)[CH2:35][CH3:36])[CH3:34]

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 224591H-1,2,4-Triazole, 1-methyl-HCID 579329433-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineHCID 178418339Butyllithium

Product 1

HCID 57932934HCID 57932934, compoundYield 60%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a −78° C. solution of 1-methyl-1,2,4-triazole (0.15 mL, 2.04 mmol) and THF (3 mL) is added a 1.34 M solution of n-Bu-Li in hexanes (1.60 mL, 2.14 mmol) over 20 minutes, then stirred at −78° C. for 1.5 hours. A 0.5 M solution of ZnCl2 in THF (4.28 mL, 2.14 mmol) is added and the solution warmed to ambient temperature. 3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.019 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and the solution heated at 65° C. overnight diluted with CH2Cl2 (30 mL). The organic layer is washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (20%-60% EtOAc/hexane gradient). The residue is dissolved in Et2O, treated with Darco®-60 for 15 minutes, dried with Na2SO4, and filtered to furnish the title compound (0.24 g, 0.61 mmol, 60%). 1H NMR (CDCl3), δ 0.88 (t, J=7.4 Hz, 6H), 1.75-1.93 (m, 4H), 2.20 (s, 3H), 2.50 (s, 3H), 2.51 (s, 3H), 3.28-3.37 (m, 1H), 4.14 (s, 3H), 6.69 (s, 1H), 7.45 (s, 1H), 7.87 (s, 1H). LC/MS (m/z): calcd. for C21H26N6S (M+H)+: 395.6; found: 395.2.

Workup

  1. temperaturethe solution warmed to ambient temperature
  2. temperaturethe solution heated at 65° C. overnight
  3. washThe organic layer is washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by ISCO (20%-60% EtOAc/hexane gradient)
  8. dissolutionThe residue is dissolved in Et2O
  9. additiontreated with Darco®-60 for 15 minutes
  10. dry with materialdried with Na2SO4
  11. filtrationfiltered

Sources & evidence

ORD record
ord-ada5207c826042f281dfba95a16143a5
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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