Cesium carbonate → HCID 66788609, compound

HRID 576094Notes

Reaction equation

HRID 576094 reaction equation
[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:29]1[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.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]>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([C:29]3[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:7][CH:8]=2)[CH2:3]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 2272543-Chloro-6-methylpyridazineHCID 66788460HCID 66788460, compound

Product 1

HCID 66788609HCID 66788609, compoundYield 21.4%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of the crude product from Step D (490 mg, 1.35 mmol), 3-chloro-6-methyl-pyridazine (217 mg, 1.69 mmol), and cesium carbonate (1.32 g, 4.05 mmol) in DMF (15 mL) and water (3 mL) was degassed with argon. To this mixture was added PdCl2(dppf) (66 mg, 0.08 mmol). The resulting mixture was degassed with argon and then heated to reflux for 5 hours. After completion by thin-layer chromatography analysis the cooled material was filtered through a bed of diatomaceous earth and washed with water (3×). The organic layers were separated, dried over sodium sulfate, filtered, and concentrated in vacuo. After purification by semi-preparative HPLC (95:5 acetonitrile/water gradient over 40 minutes), the material was free-based with sodium bicarbonate to afford 2-methyl-7-(6-methylpyridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline (95 mg, 21%) as a light-yellow solid; 1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.71-7.68, (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.13-7.09 (m, 4H), 7.01 (d, J=8.1 Hz, 1H), 4.30 (t, J=7.6 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H), 3.70 (d, J=14.9 Hz, 1H), 3.08-3.05 (m, 1H), 2.74 (s, 3H), 2.59 (t, J=9.4 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H).

Workup

  1. customwas degassed with argon
  2. customThe resulting mixture was degassed with argon
  3. temperatureheated
  4. temperatureto reflux for 5 hours
  5. filtrationAfter completion by thin-layer chromatography analysis the cooled material was filtered through a bed of diatomaceous earth
  6. washwashed with water (3×)
  7. customThe organic layers were separated
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customAfter purification by semi-preparative HPLC (95:5 acetonitrile/water gradient over 40 minutes)

Sources & evidence

ORD record
ord-c01ebf59211542e7b8b22c41350e1260
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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