Methane → 3-(2''-Aminotrispiro[cyclobutane-1,2'-chromene-4',4''-[1,3]oxazole-3',3'''-oxetan]-6'-yl)pyridine-2-carbonitrile

HRID 594906Notes

Reaction equation

HRID 594906 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:61]1[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=1.C([O-])([O-])=O.[Na+].[Na+].C>O1CCOCC1.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:22][C:19]1[O:20][CH2:21][C:17]2([C:13]3([CH2:14][O:15][CH2:16]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:61]2[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=2)=[CH:7][CH:6]=3)[N:18]=1

Participants

11

Reactant 6

HCID 297MethaneHCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 8176943-Bromopyridine-2-carbonitrileHCID 2733548Bis(pinacolato)diboraneHCID 86724300Di-tert-butyl (6'-bromotrispiro[cyclobutane-1,2'-chromene-4',4''-[1,3]oxazole-3',3'''-oxetan]-2''-yl)imidodicarbonate

Product 1

HCID 900256583-(2''-Aminotrispiro[cyclobutane-1,2'-chromene-4',4''-[1,3]oxazole-3',3'''-oxetan]-6'-yl)pyridine-2-carbonitrileYield 68.4%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (300 mg, 0.531 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (150 mg, 0.584 mmol), potassium acetate (91.1 mg, 0.928 mmol) and bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) in dioxane (2.4 mL) was stirred for 7 hours at 100° C. To the mixture was added 3-bromo-2-cyanopyridine (243 mg, 1.33 mmol), Na2CO3 (225 mg, 2.12 mmol) and water (0.60 mL), and the mixture was stirred for 2 hours at 100° C. The mixture was treated with charcoal, and filtered off. The filtrate was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated to give a pale brown oil. The oil was dissolved in toluene (3.0 mL) and to the mixture was added silica gel (neutral; 900 mg). The mixture was refluxed for 1 hour. The solvent was evaporated off. Silica gel column chromatography (CHCl3-EtOH, a linear gradient of EtOH from 0 to 10%) afforded a solid. The solid was triturated in Et2O, collected by filtration, washed with Et2O and dried at reduced pressure at 70° C. to give 3-(2″-aminotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-6′-yl)pyridine-2-carbonitrile (141 mg).

Workup

  1. stirringthe mixture was stirred for 2 hours at 100° C
  2. filtrationfiltered off
  3. customThe filtrate was partitioned between EtOAc and water
  4. washThe organic layer was washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customthe filtrate was evaporated
  8. customto give a pale brown oil
  9. additionwas added silica gel (neutral; 900 mg)
  10. temperatureThe mixture was refluxed for 1 hour
  11. customThe solvent was evaporated off
  12. customSilica gel column chromatography (CHCl3-EtOH, a linear gradient of EtOH from 0 to 10%) afforded a solid
  13. customThe solid was triturated in Et2O
  14. filtrationcollected by filtration
  15. washwashed with Et2O
  16. customdried at reduced pressure at 70° C.

Sources & evidence

ORD record
ord-aafecc7884504b97a3e05206c23a1368
Source dataset
uspto-grants-2016_01
Patent number
US09242973B2

Reaction notes

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