Dichloromethane → 4-[1-(3-Hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one

HRID 1948100Notes

Reaction equation

HRID 1948100 reaction equation
[CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:7][C:8]=2B2OC(C)(C)C(C)(C)O2)[C:3]1=[O:23].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][OH:33])[CH:29]=1.ClCCl.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].O.O1CCOCC1>[OH:33][CH2:32][CH2:31][CH2:30][N:28]1[CH:29]=[C:25]([C:8]2[CH:7]=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]3[C:9]=2[CH2:10][N:2]([CH3:1])[C:3]3=[O:23])[CH:26]=[N:27]1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 166406443-(4-bromo-1H-pyrazol-1-yl)propan-1-olHCID 672539682-Methyl-7-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one2×

Product 1

HCID 672550944-[1-(3-Hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A suspension of 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 289C, 1.825 g, 5.736 mmol), 3-(4-bromo-1H-pyrazol-1-yl)propan-1-ol (1.449 g, 7.066 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (509.5 mg, 0.6239 mmol), and potassium carbonate (2.397 g, 17.34 mmol) in a 4:1 ratio of dioxane (20 mL) to H2O (5 mL) was evacuated and charged with nitrogen several times. The sample was irradiated under microwave conditions [Biotage, 100° C.] for 45 min. The reaction mixture was transferred to a separatory funnel, brine was added, and the reaction was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 25 gram] and purified using the Teledyne/ISCO system [RediSepRf 40 gram silica GOLD], slowly eluting with 0-15% MeOH:CH2Cl2. Fractions containing product were pooled together and concentrated in vacuo, yielding the title material as a yellow solid, 920.0 mg (50%, 2.850 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.99 (d, J=8.34 Hz, 1H), 7.88 (d, J=8.34 Hz, 1H), 4.72 (s, 2H), 4.63 (t, J=5.05 Hz, 1H), 4.25 (t, J=7.07 Hz, 2H), 3.43 (q, J=6.06 Hz, 2H), 3.11 (s, 3H), 1.98 (quin, J=6.63 Hz, 2H). MS (ES+): m/z 317.11 (100) [MH+]. HPLC: tR=0.91 min (TOF, polar—3 min).

Workup

  1. customwas evacuated
  2. additioncharged with nitrogen several times
  3. customThe sample was irradiated under microwave conditions [Biotage, 100° C.] for 45 min
  4. customThe reaction mixture was transferred to a separatory funnel
  5. additionbrine was added
  6. extractionthe reaction was extracted with CH2Cl2
  7. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. custompurified
  11. washslowly eluting with 0-15% MeOH
  12. additionFractions containing product
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-09db150e3126494e8f57b4a0bc574167
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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