2-Methyltetrahydrofuran → 6'-(5-Chloropyridin-3-yl)-5''-methyl-3'H-dispiro[cyclobutane-1,2'-indene-1',2''-imidazol]-4''-amine

HRID 1770976Notes

Reaction equation

HRID 1770976 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:45]=[C:44]2[C:31]([CH2:32][C:33]3([C:37]42[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]4)[CH2:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=1.CC1CCCO1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:45]=[C:44]3[C:31]([CH2:32][C:33]4([C:37]53[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]5)[CH2:36][CH2:35][CH2:34]4)=[CH:30][CH:29]=2)[CH:21]=[N:22][CH:23]=1

Participants

8

Reactant 5

HCID 73012-MethyltetrahydrofuranHCID 11430Potassium CarbonateHCID 201118775-Chloropyridine-3-boronic acidHCID 249491873-(Di-tert-butylphosphonium)propane sulfonateHCID 573866666'-Bromo-5''-methyl-3'H-dispiro[cyclobutane-1,2'-indene-1',2''-imidazol]-4''-amine

Product 1

HCID 573866676'-(5-Chloropyridin-3-yl)-5''-methyl-3'H-dispiro[cyclobutane-1,2'-indene-1',2''-imidazol]-4''-amineYield 77%

Reagents, catalysts & solvents 2

HCID 178479786HCID 178479786, compoundCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

Sodium tetrachloropalladate (II) (2.77 mg, 9.43 μmol), 3-(di-tert-butylphosphonium)propane sulfonate (5.06 mg, 0.02 mmol), 5-chloropyridin-3-ylboronic acid (40.6 mg, 0.25 mmol) and 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 60 mg, 0.19 mmol), was added to a vial. 2-Methyl-tetrahydrofuran (1 mL) and 2 M aq. K2CO3 (0.283 mL, 0.57 mmol) was 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 aq phase was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography using a gradient of 0-10% MeOH, containing 1.2% 7M NH3 in MeOH, in DCM, afforded 51 mg of the title compound (77% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.62 (m, 4H) 1.83 (d, 1H) 2.16 (s, 1H) 2.21 (s, 3H) 3.23 (d, 2H) 6.60 (s, 2H) 6.94 (d, 1H) 7.43 (d, 1H) 7.58 (dd, 1H) 8.10 (t, 1H) 8.57 (d, 1H) 8.71 (d, 1H); MS (ES+) m/z 351 [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 aq phase was extracted with EtOAc
  7. dry with materialthe combined organic layers were dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by flash chromatography
  11. additioncontaining 1.2% 7M NH3 in MeOH

Sources & evidence

ORD record
ord-8b8e5b2241fa4c1f8f60c49fad392def
Source dataset
uspto-grants-2016_02
Patent number
US09248129B2

Reaction notes

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