2-Methyltetrahydrofuran → 5'-(5-Chloropyridin-3-yl)-4-methoxy-5''-methyldispiro[cyclohexane-1,2'-[1]benzofuran-3',2''-imidazol]-4''-amine

HRID 1965116Notes

Reaction equation

HRID 1965116 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:29]=[CH:30][C:31]2[O:42][C:41]3([CH2:47][CH2:46][CH:45]([O:48][CH3:49])[CH2:44][CH2:43]3)[C:34]3([N:38]=[C:37]([NH2:39])[C:36]([CH3:40])=[N:35]3)[C:32]=2[CH:33]=1.CC1CCCO1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.CCOC(C)=O.O>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:29]=[CH:30][C:31]3[O:42][C:41]4([CH2:43][CH2:44][CH:45]([O:48][CH3:49])[CH2:46][CH2:47]4)[C:34]4([N:38]=[C:37]([NH2:39])[C:36]([CH3:40])=[N:35]4)[C:32]=3[CH:33]=2)[CH:21]=[N:22][CH:23]=1

Participants

10

Reactant 5

HCID 73012-MethyltetrahydrofuranHCID 11430Potassium CarbonateHCID 201118775-Chloropyridine-3-boronic acidHCID 249491873-(Di-tert-butylphosphonium)propane sulfonateHCID 679795525'-Bromo-4-methoxy-5''-methyldispiro[cyclohexane-1,2'-[1]-benzofuran-3',2''-imidazol]-4''-amine2×

Product 1

HCID 679796325'-(5-Chloropyridin-3-yl)-4-methoxy-5''-methyldispiro[cyclohexane-1,2'-[1]benzofuran-3',2''-imidazol]-4''-amineYield 56%

Reagents, catalysts & solvents 4

HCID 178479786HCID 178479786, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

Sodium tetrachloropalladate (II) (2.294 mg, 7.80 μmol), 3-(di-tert-butylphosphonium)propane sulfonate (4.19 mg, 0.02 mmol), 5-chloropyridin-3-ylboronic acid (25.8 mg, 0.16 mmol) and 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine (Example 29, 59 mg, 0.16 mmol), was added to a vial. 2-Methyl-tetrahydrofuran (1 mL) and 2 M aq. K2CO3 (0.234 mL, 0.47 mmol) was added and the mixture was degassed by bubbling nitrogen gas through the solution. The vial was sealed and heated in a microwave reactor at 90° C. for 30 min and the crude mixture was combined with a second reaction from 20 mg (0.05 mmol) of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine. Water (5 mL) and EtOAc (5 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (5 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated. Purification by flash chromatography using a 0-10% gradient of MeOH, containing 1.2% 7M NH3 in MeOH, in DCM afforded 36 mg of the title compound (56% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22 (m, 1 H), 1.46 (m, 3 H), 1.81 (m, 2 H), 1.97 (m, 2 H), 2.21 (s, 3 H), 3.10 (m, 1 H), 3.22 (s, 3 H), 6.71 (br. s., 2 H), 7.01 (m, 2 H), 7.61 (dd, 1 H), 8.08 (t, 1 H), 8.51 (d, 1 H), 8.72 (d, 1 H); MS (APCI+) m/z 411 [M+H]+.

Workup

  1. customthe mixture was degassed
  2. customby bubbling nitrogen gas through the solution
  3. customThe vial was sealed
  4. customthe phases were separated
  5. extractionThe aqueous phase was extracted with EtOAc (5 mL)
  6. dry with materialthe combined organic layers were dried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customPurification by flash chromatography
  10. additioncontaining 1.2% 7M NH3 in MeOH

Sources & evidence

ORD record
ord-1d944b97131942859cae2b74e92a5502
Source dataset
uspto-grants-2013_04
Patent number
US08415483B2

Reaction notes

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