Cesium carbonate → tert-butyl 8-carbamoyl-6-chloro-7-(4-methoxy-phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

HRID 1630015Notes

Reaction equation

HRID 1630015 reaction equation
Br[C:2]1[C:3]([C:19](=[O:21])[NH2:20])=[C:4]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]2[C:17]=1[Cl:18].C1C2N(C=CC=2)C=CN=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.C(OCC)(=O)C.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]>[C:19]([C:3]1[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[C:17]([Cl:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:4]=12)(=[O:21])[NH2:20]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 201262(4-Methoxyphenyl)boronic acidHCID 11018843Pyrrolo(1,2-a)pyrazineHCID 66585083tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Product 1

HCID 66585024tert-butyl 8-carbamoyl-6-chloro-7-(4-methoxy-phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylateYield 77.9%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture under nitrogen of 4.00 g (10.6 mmol) of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate under N2 with the bromo derivative of pyrrolo[1,2-a]pyrazine, 1.77 g (11.6 mmol) of 4-methoxyphenylboronic acid and 10.3 g (31.7 mmol) of caesium carbonate in a mixture of 80 ml of tetrahydrofuran and 4 ml of water is added 0.863 g (1.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (CAS 72287-26-4). The mixture is heated at 100° C. for 20 hours and, after cooling, the medium is then diluted with ethyl acetate and filtered through Celite. The filtrate is washed with water, the organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a column of 40 g of silica gel, eluting with 5 to 100% ethyl acetate in dichloromethane, to give 3.35 g of tert-butyl 8-carbamoyl-6-chloro-7-(4-methoxy-phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate after crystallization from ethyl acetate and drying.

Workup

  1. temperatureafter cooling
  2. filtrationfiltered through Celite
  3. washThe filtrate is washed with water
  4. dry with materialthe organic phase is dried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customthe residue is chromatographed on a column of 40 g of silica gel
  7. washeluting with 5 to 100% ethyl acetate in dichloromethane

Sources & evidence

ORD record
ord-dbe6ea4f285f4e78b35454d98b38dfe0
Source dataset
uspto-grants-2014_07
Patent number
US08791119B2

Reaction notes

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