Hydrochloric Acid → 3-Pyridin-3-ylmethylene-5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

HRID 333167

Reaction equation

HRID 333167 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=O)[N:19]([CH2:23][O:24]CC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](C=O)[CH:39]=1.Cl>C1(C)C=CC=CC=1.CO>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:20]=[C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=3)[NH:19][C:23]2=[O:24])[CH:39]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 103713-PyridinecarboxaldehydeHCID 667788935-(3,4,5-Trimethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

Product 1

HCID 667792563-Pyridin-3-ylmethylene-5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-oneYield 72%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent

Procedure

To a solution of 5-(3,4,5-trimethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (157 mg, 0.365 mmol) in toluene (2 mL) was added triethylamine (56 μl, 0.365 mmol), molecular sieves 4 Å (100 mg), and 3-pyridinecarboxaldehyde (38 μl, 0.401 mmol). The resulting mixture was stirred overnight at room temperature, after which it was filtered and partitioned between DCM and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40-70% EtOAc:Hexanes to yield the SEM-protected precursor as a mixture of cis and trans isomers (101 mg, 53%). 41 mg (0.079 mmol) of this material was dissolved in MeOH (1.5 ml), 6 N HCl (3 ml) was added, and the mixture was stirred for 3 hours at 45° C. The reaction was quenched with 1 N NaOH (15 ml), neutralized by the addition of saturated NaHCO3 and extracted with DCM. Silica gel chromatography eluting with 0-5% MeOH:DCM yielded the title compound (22 mg, 72%) as a cis/trans-mixture. 1H NMR (CDCl3, 300 MHz): δ 9.15 (d, J=4.8 Hz, 1H), 9.11 (bs, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.98 (d, J=1.1, 1H), 8.69 (dd, J=0.9, 2.9 Hz, 1H), 8.66 (dd, J=0.9, 2.8 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.95 (m, 1H), 7.93 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.44 (m, 1H), 6.75 (s, 2H), 6.59 (s, 2H), 3.97 (s, 6H), 3.91 (s, 3H), 3.90 (s, 6H), 3.86 (s, 3H).

Workup

  1. filtrationafter which it was filtered
  2. custompartitioned between DCM and H2O
  3. customThe organic layer was separated
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by silica gel chromatography
  8. washeluting with 40-70% EtOAc
  9. customHexanes to yield the SEM-protected precursor
  10. additionas a mixture of cis and trans isomers (101 mg, 53%)
  11. stirringthe mixture was stirred for 3 hours at 45° C
  12. customThe reaction was quenched with 1 N NaOH (15 ml)
  13. additionneutralized by the addition of saturated NaHCO3
  14. extractionextracted with DCM
  15. washSilica gel chromatography eluting with 0-5% MeOH

Sources & evidence

ORD record
ord-e0e01d0c90c24d4ba09f3e64981dd741
Source dataset
uspto-grants-2014_11
Patent number
US08877772B2

Linked notes

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