Potassium Carbonate → 4-Chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde

HRID 592659Notes

Reaction equation

HRID 592659 reaction equation
Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2[CH:17]=[C:18]3[N:23]([C:15]=2[CH2:14][CH2:13][NH:12]1)[CH2:22][CH2:21][CH2:20][CH2:19]3.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-].[K+].[K+]>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:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([N:12]2[CH2:13][CH2:14][C:15]3[N:23]4[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:17][C:16]=3[C:11]2=[O:24])[N:9]=[CH:8][CH:7]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 580442873,4,6,7,8,9-Hexahydropyrido[3,4-b]indolizin-1(2H)-oneHCID 866839142-Bromo-4-chloropyridine-3-carbaldehyde

Product 1

HCID 866842464-Chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehydeYield 50%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 2-bromo-4-chloronicotin-aldehyde 103a (1.4 g, 6.4 mmol), 3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one 112d (0.6 g, 3.2 mmol), Pd2(dba)3 (293 mg, 0.32 mmol), XantPhos (370 mg, 0.64 mmol), and potassium carbonate (627 mg, 6.4 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. overnight. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM/CH3OH (20:1, V/V) to afford 139a (528 mg, 50%) as a yellow solid. MS: [M+H]+ 330. 1H NMR (500 MHz, CDCl3) δ 10.09 (s, 1H), 8.37 (d, J=5.5, 1H), 7.16 (d, J=5.5, 1H), 6.25 (s, 1H), 4.29-4.32 (m, 2H), 3.83-3.86 (m, 2H), 2.96-2.99 (m, 2H), 2.75-2.78 (m, 2H), 2.00-2.07 (m, 2H), 1.82-1.85 (m, 2H)

Workup

  1. customA 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter three cycles of vacuum/argon flush
  4. temperatureAfter this time the reaction was cooled to room temperature
  5. filtrationIt was then filtered
  6. customthe filtrate was evaporated in vacuo
  7. customThe residue was purified by silica gel column chromatography
  8. washeluting with DCM/CH3OH (20:1, V/V)

Sources & evidence

ORD record
ord-51dc8cd836f04178959120f8733cbab2
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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