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

HRID 1432641Notes

Reaction equation

HRID 1432641 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]([Cl:23])[CH:3]=1.C1COCC1.Br[C:30]1[N:31]=[CH:32][S:33][CH:34]=1>CCOC(C)=O.[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:23][C:4]1[CH:3]=[C:2]([C:30]2[N:31]=[CH:32][S:33][CH:34]=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

7

Reactant 3

HCID 8028TetrahydrofuranHCID 27632184-BromothiazoleHCID 579329223-(5-Bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 579330083-(3-Chloro-5-thiazol-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineYield 16%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalyst2×HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a 0° C. solution of 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.45 mmol) and THF (2 mL) is added 0.05 g/mL of Reike® Zn (3.80 mL, 2.91 mmol). The solution is heated at a reflux for 1 hour, and the excess Zn allowed to settle for 1 hour at ambient temperature. The solution is transferred to a flask of 4-bromo-thiazole (Kelly, T. et al. Tetrahedron, Lett. 1995, 51, 9293) (0.29 g, 1.74 mmol). PdCl2(dppf) (0.027 g, 0.036 mmol) is added and the solution heated at 65° C. overnight, diluted with EtOAc (40 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) followed by ISCO column chromatography (100% Et2O) to furnish the title compound (0.098 g, 0.24 mmol, 16%). 1H NMR (CDCl3) δ 0.88 (d, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.28-3.38 (m, 1H), 6.70 (s, 1H), 7.45 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H). LC/MS (m/z): calcd. for C20H21ClN4S2 (M+H)+: 417.1; found: 417.3.

Workup

  1. temperatureThe solution is heated at
  2. temperaturea reflux for 1 hour
  3. washwashed with sat. NH4Cl (30 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-932c488503304d87be4757fb52285084
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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