Propionitrile → HCID 86656746, compound

HRID 452194Notes

Reaction equation

HRID 452194 reaction equation
[C:1](#[N:4])[CH2:2][CH3:3].P(Cl)(OCC)(OCC)=O.[Cl:14][C:15]1[N:20]=[C:19]2[CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25](=O)[C:18]2=[CH:17][CH:16]=1.C(OCC)(=O)C>C1COCC1.CN(C=O)C.O>[Cl:14][C:15]1[N:20]=[C:19]2[CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3/[C:25](=[C:2](\[CH3:3])/[C:1]#[N:4])/[C:18]2=[CH:17][CH:16]=1.[Cl:14][C:15]1[N:20]=[C:19]2[CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3/[C:25](=[C:2](/[CH3:3])\[C:1]#[N:4])/[C:18]2=[CH:17][CH:16]=1

Participants

9

Reactant 4

HCID 7854PropionitrileHCID 8857Ethyl AcetateHCID 13139Diethyl chlorophosphateHCID 86656744HCID 86656744, compound

Product 2

HCID 86656745HCID 86656745, compoundHCID 86656746HCID 86656746, compoundYield 159.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

[step 1] To a solution (100 mL) of 5,11-dihydrobenzooxepino[3,4-b]pyridine (Synthesis, 1997, 1, 113-116, 5.00 g, 23.7 mmol) in chloroform was added m-chloroperbenzoic acid (4.89 g, 28.4 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in chloroform (10 mL), phosphorus oxychloride (35 mL) was added and the mixture was stirred with heating at 90° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, the obtained black oil was dissolved in ethyl acetate, and the solution was added dropwise to aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture was extracted 3 times with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-one (3.50 g, 59%). [step 2] N-Lithium diisopropylamide (2.0 mol/L heptane/THF/ethylbenzene solution, 20 mL, 39.8 mmol) was diluted with THF (25 mL), propionitrile (1.4 mL, 19.9 mmol) was added dropwise over 15 min with stirring at 0° C. After stirring at room temperature for 1 hr, diethyl chlorophosphate (2.9 mL, 19.9 mmol) was added dropwise at 0° C. After stirring at room temperature for 2 hr, a solution (20 mL) of 2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-one (1.95 g, 7.96 mmol) in DMF was added, and the mixture was stirred at room temperature for 1.5 hr. To the mixture were added ethyl acetate and water, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give (E)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile and (Z)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (1.79 g, 80%). [step 3] Using (E)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile and (Z)-2-(2-chloro-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.890 g, 3.16 mmol) obtained in Reference Example B10, step 2, instead of (E)-2-(3-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylacetonitrile and (Z)-2-(3-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylacetonitrile, and in the same manner as in Reference Example B9, step 2, propyl(E)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carboxylate (0.374 g, 35%) and propyl(Z)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carboxylate (0.203 g, 20%) were obtained. [step 4] Using propyl(E)-5-(1-cyanoethylidene)-5,11-dihydrobenzooxepino[3,4-b]pyridine-2-carboxylate (0.370 g, 1.11 mmol) obtained in Reference Example B10, step 3 instead of propyl(E)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate and propyl(Z)-11-cyanocyclopropylmethylene-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate, and in the same manner as in Reference Example B9, step 3, (E)-2-(2-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.191 g, 62%) was obtained.

Workup

  1. additionwas added dropwise over 15 min
  2. stirringAfter stirring at room temperature for 1 hr
  3. stirringAfter stirring at room temperature for 2 hr
  4. stirringthe mixture was stirred at room temperature for 1.5 hr
  5. extractionthe mixture was extracted 3 times with ethyl acetate
  6. washThe organic layer was washed with brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1)

Sources & evidence

ORD record
ord-bbbb207a5ccc46f68f24e08c4925badc
Source dataset
uspto-grants-2013_07
Patent number
US08486980B2

Reaction notes

Loading…