Diisopropylethylamine → 9-(1-Isopropylpiperidin-4-ylsulfanyl)-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

HRID 1530389Notes

Reaction equation

HRID 1530389 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:22]=1.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:22]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 199366054-Piperidinethiol, 1-(1-methylethyl)-HCID 683126959-Bromo-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

Product 1

HCID 683130359-(1-Isopropylpiperidin-4-ylsulfanyl)-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azuleneYield 77.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 9-bromo-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (147 mg, 0.411 mmol), 1-isopropylpiperidine-4-thiol (98 mg, 0.617 mmol), Pd2(dba)3 (19 mg, 5 mol %), XantPhos (24 mg, 10 mol %) and DIPEA (288 l, 1.64 mmol) in dioxane (5 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was then diluted with DCM (100 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM followed by C18, gradient 10-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording the title compound as a colorless foam (138 mg, 77%). LCMS: RT1.79 min [M+H]+ 435.2

Workup

  1. customwas purged with nitrogen
  2. custommicrowave irradiation
  3. additionThe reaction mixture was then diluted with DCM (100 mL)
  4. custompurified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM followed by C18, gradient 10-50% MeOH in 0.5% TFA/H2O)
  5. additionThe product containing fractions
  6. concentrationconcentrated in vacuo
  7. washwas washed with MeOH
  8. washthe product eluted with 0.5M NH3/MeOH
  9. concentrationThe basic fractions were concentrated under reduced pressure

Sources & evidence

ORD record
ord-9c1293ec0449488f8e6cb9a83f647585
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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