Cesium carbonate → 2-[4-[5-(5,6-Dimethoxy-3-pyridyl)-1-oxo-isoindolin-2-yl]pyrazol-1-yl]acetonitrile

HRID 1259339Notes

Reaction equation

HRID 1259339 reaction equation
[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[N:25]([C:31]1[CH:32]=[N:33][N:34]([CH2:36][C:37]#[N:38])[CH:35]=1)[CH2:24]2.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O.O>CS(C)=O.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]>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([C:31]2[CH:32]=[N:33][N:34]([CH2:36][C:37]#[N:38])[CH:35]=2)[CH2:24]3)[CH:5]=[N:4][C:3]=1[O:2][CH3:1]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 22728543Water ethylacetateHCID 453617702,3-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine2×HCID 667427042-[4-(5-Bromo-1-oxo-isoindolin-2-yl)pyrazol-1-yl]acetonitrile

Product 1

HCID 533272662-[4-[5-(5,6-Dimethoxy-3-pyridyl)-1-oxo-isoindolin-2-yl]pyrazol-1-yl]acetonitrile

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
100 °C

Procedure

As shown in step 5-iii of Scheme 5, 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [Compound 2021, 376 mg, 1.42 mmol; prepared by reacting 5-bromo-2,3-dimethoxypyridine with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane], 2-[4-(5-bromo-1-oxo-isoindolin-2-yl)pyrazol-1-yl]acetonitrile (450 mg, 1.42 mmol), and cesium carbonate (925 mg, 2.84 mmol) were taken up in DMSO (7.5 mL) in a sealable tube. Nitrogen gas was bubbled through the solution for 5 minutes, dppfPdCl2 (141 mg, 0.17 mmol) added, and the vessel sealed. The reaction mixture was heated to 100° C. for 50 min. After cooling, the mixture was poured into EtOAc/H2O, the resulting dark solid material filtered off, and the organics passed through a plug of florisil. The filtrate was concentrated to a solid under reduced pressure, the residue was suspended in MeOH, and the solid collected by filtration to give 2-[4-[5-(5,6-dimethoxy-3-pyridyl)-1-oxo-isoindolin-2-yl]pyrazol-1-yl]acetonitrile as a solid (Compound 3, 323 mg, 57% yield): ESMS (M+H) 376.28; 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.84 (m, 2H), 7.64 (d, J=1.7 Hz, 1H), 5.55 (s, 2H), 4.93 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H).

Workup

  1. customNitrogen gas was bubbled through the solution for 5 minutes
  2. customthe vessel sealed
  3. temperatureAfter cooling
  4. filtrationthe resulting dark solid material filtered off
  5. concentrationThe filtrate was concentrated to a solid under reduced pressure
  6. filtrationthe solid collected by filtration

Sources & evidence

ORD record
ord-c95aa5ba5dc046a99b112dca55288784
Source dataset
uspto-grants-2013_06
Patent number
US08466288B2

Reaction notes

Loading…