2-Methyltetrahydrofuran → 7'-(5-Chloropyridin-3-yl)-5-methyl-3',4'-dihydro-2'H-spiro[imidazole-2,1'-naphthalen]-4-amine

HRID 1770973Notes

Reaction equation

HRID 1770973 reaction equation
CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.Br[C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][CH2:33][CH2:34][C:35]32[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]3)=[CH:30][CH:29]=1.CC1CCCO1.C([O-])([O-])=O.[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][CH2:34][C:35]43[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]4)=[CH:30][CH:29]=2)[CH:21]=[N:22][CH:23]=1

Participants

7

Reactant 5

HCID 73012-MethyltetrahydrofuranHCID 11430Potassium CarbonateHCID 201118775-Chloropyridine-3-boronic acidHCID 249491873-(Di-tert-butylphosphonium)propane sulfonateHCID 57386415HCID 57386415, compound

Product 1

HCID 573864167'-(5-Chloropyridin-3-yl)-5-methyl-3',4'-dihydro-2'H-spiro[imidazole-2,1'-naphthalen]-4-amineYield 33.4%

Reagents, catalysts & solvents 1

HCID 178479786HCID 178479786, compoundCatalyst

Conditions

Temperature
90 °C

Procedure

Sodium tetrachloropalladate(II) (3.52 mg, 0.01 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (6.43 mg, 0.02 mmol), 5-chloropyridin-3-ylboronic acid (51.6 mg, 0.31 mmol) and 7′-bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine (Example 51 Step 4, 70 mg, 0.24 mmol) were added to a vial. 2-Methyl-tetrahydrofuran (1 mL) and K2CO3 (2 M aq.) (0.359 mL, 0.72 mmol) were added and the mixture was degassed by bubbling N2 (g). The vial was sealed and heated in a microwave reactor at 90° C. for 30 min. EtOAc (5 mL) and water (5 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc twice and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (4 g SiO2, 0-10% McOH containing 0.1M NH3 in DCM). The fractions containing product were combined and concentrated, yielding the title compound (26 mg, 33% yield). 1H NMR (500 MHz, CD3OD) δ ppm 1.85-1.94 (m, 1H), 2.01 (ddd, 1H), 2.08-2.17 (m, 1H), 2.17-2.27 (m, 1H), 2.35 (s, 3H), 3.02 (t, 2H), 6.84 (d, 1H), 7.34 (d, 1H), 7.48 (dd, 1H), 7.97 (t, 1H), 8.48 (d, 1H), 8.57 (d, 1H); MS (ES+) m/z 325 [M+H]+.

Workup

  1. customthe mixture was degassed
  2. customby bubbling N2 (g)
  3. customThe vial was sealed
  4. additionEtOAc (5 mL) and water (5 mL) were added
  5. customthe phases were separated
  6. extractionThe aqueous phase was extracted with EtOAc twice
  7. dry with materialthe combined organic layers were dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by flash chromatography (4 g SiO2, 0-10% McOH containing 0.1M NH3 in DCM)
  11. additionThe fractions containing product
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-5e6801beeb34489e9562f9ed1d29d4f6
Source dataset
uspto-grants-2016_02
Patent number
US09248129B2

Reaction notes

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