Dimethylformamide → Methyl 1-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylate

HRID 592807Notes

Reaction equation

HRID 592807 reaction equation
ClC(Cl)C.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[CH:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(#N)C>[CH:8]([C:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:9]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 63651,1-DichloroethaneHCID 24813Phosphorus oxychlorideHCID 13115072Methyl 5,6,7,8-Tetrahydroindolizine-2-carboxylate

Product 1

HCID 86684350Methyl 1-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylateYield 35%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

A 100-mL round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous dichloroethane (10 mL) and anhydrous DMF (0.7 mL, 9.0 mmol). The reaction mixture was cooled to 0° C. and phosphorus oxychloride (0.7 mL, 7.3 mmol) was added over a period of 2 min, while maintaining the reaction temperature between 0° C. and 10° C. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. A solution of methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate 112a (1.0 g, 5.6 mmol) in acetonitrile (10 mL) was added and the mixture was stirred at room temperature for additional 3 hours. After this time, the solvent was concentrated under reduced pressure and the oily residue was taken up with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with water (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 192a as a white solid (406 mg, 33%). MS: (M+H)+ 208.3. 1H NMR (500 MHz, DMSO) δ 10.29 (s, 1H), 7.43 (s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.76 (s, 3H), 2.95 (t, J=6.5 Hz, 2H), 1.90-1.85 (m, 2H), 1.78-1.74 (m, 2H).

Workup

  1. customA 100-mL round-bottomed flask equipped with a magnetic stirrer
  2. customwas purged with nitrogen
  3. temperaturewhile maintaining the reaction temperature between 0° C. and 10° C
  4. customThe cooling bath was removed
  5. stirringthe mixture was stirred at room temperature for additional 3 hours
  6. concentrationAfter this time, the solvent was concentrated under reduced pressure
  7. extractionThe aqueous layer was extracted with ethyl acetate (3×70 mL)
  8. washThe combined organic layer was washed with water (20 mL)
  9. dry with materialdried over Na2SO4
  10. customevaporated under reduced pressure
  11. customThe residue was purified by silica-gel column chromatography
  12. washeluting with 1:1 ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-c81838fa19bc470caa3718bae28c2b20
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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