Water → 4-(1-methylpiperidin-4-yloxy)-2-p-tolyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

HRID 1773861Notes

Reaction equation

HRID 1773861 reaction equation
I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.O.[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)=[CH:3]3)[CH2:14][CH2:15]1

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 79799Tolylboronic acidHCID 726957782-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

Product 1

HCID 867039484-(1-methylpiperidin-4-yloxy)-2-p-tolyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 152416121,1`-Bis(diphenylphosphino)ferroceneCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2) (50 mg, 0.12 mmole) in 1,4-dioxane (0.5 mL) are added water (0.1 mL), 4-methylbenzeneboronic acid (25 mg, 0.18 mmole), Pd(OAc)2 (1.4 mg, 6 μmmole), 1,1-bis(diphenylphosphino)ferrocene (3.3 mg, 6 μmmole) and K2CO3 (50 mg, 0.36 mmole). The vial is evacuated and filled with argon. The reaction mixture is stirred at 100° C. for 3.5 hours. Water is added to the reaction mixture, and the pH is adjusted to 9-10 by adding saturated Na2CO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:5:0.1) to (95:5:0.5). The residue is purified by preparative TLC eluting with (CH2Cl2:MeOH:NH4OH) (9:9:0.1) to give 4-(1-methylpiperidin-4-yloxy)-2-p-tolyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.

Workup

  1. customThe vial is evacuated
  2. additionfilled with argon
  3. additionWater is added to the reaction mixture
  4. additionby adding saturated Na2CO3 solution
  5. extractionThe aqueous phase is extracted three times with AcOEt
  6. dry with materialThe organic phase is dried over magnesium sulphate
  7. filtrationfiltered
  8. customthe solvent is removed under reduced pressure
  9. customThe residue is pre-purified by silica gel chromatography
  10. customThe residue is purified by preparative TLC
  11. washeluting with (CH2Cl2:MeOH:NH4OH) (9:9:0.1)

Sources & evidence

ORD record
ord-425e076ded39491e89b87be12cafc526
Source dataset
uspto-grants-2016_02
Patent number
US09255101B2

Reaction notes

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