Potassium Carbonate → 3-(4''-Amino-5''-methyl-3'H-dispiro[cyclopropane-1,2'-indene-1',2''-imidazol]-6'-yl)-5-chlorobenzonitrile

HRID 1770980Notes

Reaction equation

HRID 1770980 reaction equation
Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][C:7]3([C:10]42[N:14]=[C:13]([NH2:15])[C:12]([CH3:16])=[N:11]4)[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>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].C1COCC1>[NH2:15][C:13]1[C:12]([CH3:16])=[N:11][C:10]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:26]4[CH:25]=[C:22]([CH:21]=[C:20]([Cl:19])[CH:27]=4)[C:23]#[N:24])[CH:18]=3)[CH2:6][C:7]32[CH2:9][CH2:8]3)[N:14]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 532171293-Chloro-5-cyanophenylboronic acid, pinacol ester2×HCID 573871706'-Bromo-5''-methyl-3'H-dispiro[cyclopropane-1,2'-indene-1',2''-imidazol]-4''-amine

Product 1

HCID 573871713-(4''-Amino-5''-methyl-3'H-dispiro[cyclopropane-1,2'-indene-1',2''-imidazol]-6'-yl)-5-chlorobenzonitrileYield 8.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
130 °C

Procedure

6′-Bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 77, 0.10 g, 0.33 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 35, 0.121 g, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.048 g, 0.07 mmol), 2 M aq. K2CO3 (0.493 mL, 0.99 mmol) and THF (1 mL) were added to microwave vial. The mixture was degassed by bubbling N2 (g) through it. The vial was sealed and heated in a microwave reactor at 130° C. for 30 min. [1,1′-Bis(diphenylphosphino)-ferrocene]palladium(II) chloride (0.048 g, 0.07 mmol) was added and the mixture was degassed by bubbling N2 (g) through it. The vial was sealed and heated in a microwave reactor at 130° C. for 30 min. The residue was dissolved in EtOAc and the mixture was extracted with 1.0 M HCl (2×10 mL). The organic layer was discarded while the aq phase was basified to pH 12 by addition of 1 M NaOH (aq). The basic water phase was extracted with DCM (2×20 mL). The organic phase was dried through a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% 0.1 M NH3 in McOH, in DCM, 25 g SiO2 column). The product was purified by a second flash chromatography (0-100% EtOAc in heptane, 25 g SiO2 column) followed by preparative chromatography. The fractions containing pure product were combined and concentrated. DCM was added and the organic phase was collected and dried through a phase separator and concentrated in vacuo, yielding the title compound (10 mg, 0.028 mmol, 8% yield): 1H NMR (500 MHz, CD3OD) δ ppm 0.14-0.23 (m, 1H), 0.50-0.58 (m, 1H), 0.62-0.70 (m, 1H), 0.80 (ddd, 1H), 2.30 (s, 3H), 2.96 (d, 1H), 3.49 (d, 1H), 7.02-7.08 (m, 1H), 7.47 (d, 1H), 7.59 (dd, 1H), 7.73 (s, 1H), 7.88 (s, 2H); MS (MM-ES+APCI)+ m/z 361 [M+H]+.

Workup

  1. customThe mixture was degassed
  2. customby bubbling N2 (g) through it
  3. customThe vial was sealed
  4. additionwas added
  5. customthe mixture was degassed
  6. customby bubbling N2 (g) through it
  7. customThe vial was sealed
  8. dissolutionThe residue was dissolved in EtOAc
  9. extractionthe mixture was extracted with 1.0 M HCl (2×10 mL)
  10. additionwas basified to pH 12 by addition of 1 M NaOH (aq)
  11. extractionThe basic water phase was extracted with DCM (2×20 mL)
  12. customThe organic phase was dried through a phase separator
  13. concentrationconcentrated in vacuo
  14. customThe crude product was purified by flash chromatography (0-10% 0.1 M NH3 in McOH, in DCM, 25 g SiO2 column)
  15. customThe product was purified by a second flash chromatography (0-100% EtOAc in heptane, 25 g SiO2 column)
  16. additionThe fractions containing pure product
  17. concentrationconcentrated
  18. additionDCM was added
  19. customthe organic phase was collected
  20. customdried through a phase separator
  21. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3117832c62584e898050f1db7f4a9dea
Source dataset
uspto-grants-2016_02
Patent number
US09248129B2

Reaction notes

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