Dimethylformamide → Methyl 5,6,7,8-Tetrahydroindolizine-2-carboxylate

HRID 1411501Notes

Reaction equation

HRID 1411501 reaction equation
[CH:1]1[C:2]([C:10]([OH:12])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.[CH3:13]N(C=O)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CO.C(Cl)Cl>[CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 580441405,6,7,8-Tetrahydroindolizine-2-carboxylic acid

Product 1

HCID 13115072Methyl 5,6,7,8-Tetrahydroindolizine-2-carboxylateYield 58%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A 500-mL round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 5,6,7,8-tetrahydroindolizine-2-carboxylic acid (30.4 g, 184 mmol), DMF (1.00 g, 13.6 mmol) and methylene chloride (300 mL). The solution was cooled to 0° C. using an ice bath. Oxalyl chloride (28.0 g, 221 mmol) was added dropwise, and the reaction mixture was warmed to room temperature over 30 min and stirred for 5 h. After this time, the resulting solution was concentrated to afford a brown solid. This solid was dissolved in anhydrous methanol (400 mL), and the solution was cooled to 0° C. Triethylamine (57 g, 552 mmol) was added to the reaction mixture, and it was stirred for a further 2 h at room temperature. After this time, the reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with methylene chloride (300 mL) and washed with water (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was titrated with hexane (200 mL) to afford 112a in 58% yield (19.1 g) as a white solid: mp 72-74° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.13 (s, 1H), 6.23 (s, 1H), 3.93 (t, 2H, J=6.0 Hz), 3.77 (s, 3H), 2.75 (t, 2H, J=6.0 Hz), 1.93 (m, 2H), 1.80 (m, 2H); (APCI+) m/z 180.1 (M+H)

Workup

  1. customA 500-mL round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet
  2. customwas purged with nitrogen
  3. temperaturethe reaction mixture was warmed to room temperature over 30 min
  4. concentrationAfter this time, the resulting solution was concentrated
  5. customto afford a brown solid
  6. temperaturethe solution was cooled to 0° C
  7. stirringwas stirred for a further 2 h at room temperature
  8. concentrationAfter this time, the reaction mixture was concentrated to dryness under reduced pressure
  9. additionThe residue was diluted with methylene chloride (300 mL)
  10. washwashed with water (200 mL) and saturated aqueous sodium bicarbonate (200 mL)
  11. dry with materialThe organic layer was dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-d005d71497cb48e7a4a9e984c9caa002
Source dataset
uspto-grants-2014_12
Patent number
US08921353B2

Reaction notes

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