Potassium Acetate → 4-Methoxy-5''-methyl-6'-[4-methyl-5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

HRID 1965142Notes

Reaction equation

HRID 1965142 reaction equation
CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C:27]#[C:28][CH3:29])[C:25]=1[CH3:26].C([O-])(=O)C.[K+].CC1C(B2OC(C)(C)C(C)(C)O2)=CN=CC=1C#CC.CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.Br[C:71]1[CH:92]=[C:91]2[C:74]([CH2:75][C:76]3([C:84]42[N:88]=[C:87]([NH2:89])[C:86]([CH3:90])=[N:85]4)[CH2:81][CH2:80][CH:79]([O:82][CH3:83])[CH2:78][CH2:77]3)=[CH:73][CH:72]=1>O1CCOCC1.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].C(Cl)Cl.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.C(#N)C>[CH3:83][O:82][CH:79]1[CH2:80][CH2:81][C:76]2([C:84]3([N:88]=[C:87]([NH2:89])[C:86]([CH3:90])=[N:85]3)[C:91]3[C:74](=[CH:73][CH:72]=[C:71]([C:20]4[CH:21]=[N:22][CH:23]=[C:24]([C:27]#[C:28][CH3:29])[C:25]=4[CH3:26])[CH:92]=3)[CH2:75]2)[CH2:77][CH2:78]1

Participants

11

Reactant 6

HCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 249491873-(Di-tert-butylphosphonium)propane sulfonateHCID 573851176'-Bromo-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amineHCID 679795183-Bromo-4-methyl-5-(prop-1-YN-1-YL)pyridine2×HCID 679795494-Methyl-3-(prop-1-ynyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Product 1

HCID 573869164-Methoxy-5''-methyl-6'-[4-methyl-5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amineYield 15%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 178479786HCID 178479786, compoundCatalystHCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent2×

Procedure

A suspension of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (160 mg, 0.63 mmol), 3-bromo-4-methyl-5-(prop-1-ynyl)pyridine (Intermediate 45, 66 mg, 0.31 mmol) and potassium acetate (93 mg, 0.94 mmol) in dioxane (3 mL) was degassed with a stream of argon for a couple of min. PdCl2(dppf) CH2Cl2 (13 mg, 0.02 mmol) was added and the mixture was heated at reflux under N2 for 4 h. The mixture was allowed to cool, filtered and concentrated in vacuo. The obtained residue (80 mg, 4-methyl-3-(prop-1-ynyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine) was mixed with sodium tetrachloropalladate(II) (4 mg, 0.01 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (6 mg, 0.02 mmol), and (1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 19, 90 mg, 0.24 mmol) in dioxane (3 mL). The mixture was degassed with a stream of argon for a couple of min. and then heated at reflux. The reaction mixture was allowed to cool and the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was dried (Na2SO4) and evaporated to give a crude product which was purified by flash chromatography (4 g SiO2, heptane-(EtOAc/MeOH/NH3 90:10:1) gradient. The obtained material was purified by preparative chromatography. Fractions containing the product were pooled and the organic solvent was removed in vacuo. The residue was partitioned between 1 M NaOH and EtOAc. The organic phase was dried (Na2SO4) and evaporated to give an oily residue which was solidified by co-evaporation with acetonitrile to give the title compound (15 mg, 15% yield) after drying in vacuo at 40° C.: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, 1 H), 1.11-1.34 (m, 2 H), 1.34-1.57 (m, 3 H), 1.83 (d, 2 H), 2.13 (m, 9 H), 2.87-3.13 (m, 3 H), 3.20 (s, 3 H), 6.50 (d, 3 H), 7.18 (d, 1 H), 7.39 (d, 1 H), 8.16 (br. s., 1 H), 8.46 (br. s., 1 H); MS (APCI+) m/z 427 [M+H]+.

Workup

  1. customwas degassed with a stream of argon for a couple of min
  2. temperaturethe mixture was heated
  3. temperatureat reflux under N2 for 4 h
  4. temperatureto cool
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe mixture was degassed with a stream of argon for a couple of min
  8. temperatureand then heated
  9. temperatureat reflux
  10. temperatureto cool
  11. customthe solvent was removed in vacuo
  12. customThe residue was partitioned between water and EtOAc
  13. dry with materialThe organic phase was dried (Na2SO4)
  14. customevaporated
  15. customto give a crude product which
  16. customwas purified by flash chromatography (4 g SiO2, heptane-(EtOAc/MeOH/NH3 90:10:1) gradient
  17. customThe obtained material was purified by preparative chromatography
  18. additionFractions containing the product
  19. customthe organic solvent was removed in vacuo
  20. customThe residue was partitioned between 1 M NaOH and EtOAc
  21. dry with materialThe organic phase was dried (Na2SO4)
  22. customevaporated
  23. customto give an oily residue which

Sources & evidence

ORD record
ord-4fbd738aca3e4bdabf34b49ebc4ac4fa
Source dataset
uspto-grants-2013_04
Patent number
US08415483B2

Reaction notes

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