tert-Butanol → 1,4,6-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

HRID 60404

Reaction equation

HRID 60404 reaction equation
[NH2:1][C:2]([CH3:7])=[CH:3][C:4](=O)[CH3:5].CO[C:10]1(OC)[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15].C(O[Na])(C)(C)C.CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:10]2=[N:1][C:2]([CH3:7])=[CH:3][C:4]([CH3:5])=[C:14]2[CH2:13][CH2:12]1

Participants

6

Reactant 4

HCID 6386tert-ButanolHCID 1368734-Amino-3-penten-2-oneHCID 110735522,2-Dimethoxy-1-methylpyrrolidineHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 141770291,4,6-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution containing 1.20 g (12.1 mmol) of 4-amino-3-penten-2-one in 8 mL of toluene was added 3.00 g (20.7 mmol) of 2,2-Dimethoxy-1-methylpyrrolidine. The reaction mixture was heated at reflux and stirred for 2 h, cooled to 90° C., and then treated with 2.38 g (24.8 mmol) of t-BuONa and 2 mL of t-BuOH. The reaction mixture was stirred at 90° C. for another 16 h. The cooled reaction mixture was quenched by the addition of 10 mL of sat aq. NH4Cl. The mixture was extracted with three 30-mL portions of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (42×2.5 cm). Step gradient elution with 1:4→1:1 ethyl acetate-hexanes as eluent gave 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a brown oil: yield 0.62 g (32%); silica gel TLC Rf 0.15 (1:4 ethyl acetate-hexanes); 1H NMR (CDCl3) 1.91 (s, 3H), 2.20 (s, 3H), 2.65 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 3.23 (t, 2H, J=8.4 Hz), 5.98 (s, 1H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux
  3. stirringThe reaction mixture was stirred at 90° C. for another 16 h
  4. customThe cooled reaction mixture
  5. customwas quenched by the addition of 10 mL of sat aq. NH4Cl
  6. extractionThe mixture was extracted with three 30-mL portions of EtOAc
  7. washThe combined organic layer was washed with brine
  8. dry with materialdried over anhydrous MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated under diminished pressure
  11. customThe residue was purified via flash chromatography on a silica gel column (42×2.5 cm)
  12. washStep gradient elution with 1:4→1:1 ethyl acetate-hexanes as eluent

Sources & evidence

ORD record
ord-6a1a862d12ca4ee68b06b2ac9d4c2abb
Source dataset
uspto-grants-2016_09
Patent number
US09440967B2

Linked notes

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