Cesium carbonate → 4-Chloro-2-(1-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-b]indolizin-2(3H)-yl)nicotinaldehyde

HRID 592959Notes

Reaction equation

HRID 592959 reaction equation
[C:1]1(=[O:13])[C:5]2[CH:6]=[C:7]3[N:12]([C:4]=2[CH2:3][NH:2]1)[CH2:11][CH2:10][CH2:9][CH2:8]3.Br[C:15]1[N:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=[O:18].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.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:23][C:19]1[C:16]([CH:17]=[O:18])=[C:15]([N:2]2[CH2:3][C:4]3[N:12]4[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]4)=[CH:6][C:5]=3[C:1]2=[O:13])[N:22]=[CH:21][CH:20]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866839142-Bromo-4-chloropyridine-3-carbaldehydeHCID 866844512,3,5,6,7,8-Hexahydro-1H-pyrrolo[3,4-b]indolizin-1-one

Product 1

HCID 866844524-Chloro-2-(1-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-b]indolizin-2(3H)-yl)nicotinaldehydeYield 42%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 238d (400 mg, 2.27 mmol), 2-bromo-4-chloronicotinaldehyde (1.50 g, 6.90 mmol, 3.0 eq.), Pd2(dba)3 (208 mg, 0.227 mmol, 0.1 eq.), xantphos (131 mg, 0.227 mmol, 0.1 eq.), Cs2CO3 (1.50 g, 4.54 mmol, 2.0 eq.), and dioxane (30 mL). After bubbling nitrogen through the resulting mixture for 30 minutes, the reaction mixture was stirred at 90° C. for 16 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residual was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 238e (300 mg, 42%) as a light yellow solid. MS-ESI: [M+H]+ 316.1.

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling nitrogen through the resulting mixture for 30 minutes
  3. temperaturethe mixture was cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe residual was purified by silica-gel column chromatography
  7. washeluting with 1:3 ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-49b9ae8bfb4a4852b4716c44fcb10918
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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