Dimethylformamide dimethyl acetal → 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

HRID 2385592Notes

Reaction equation

HRID 2385592 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=O)=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:19]OC(OC)N(C)C.Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:31]([CH:28]([CH3:30])[CH3:29])[N:32]=[CH:19][N:17]=4)=[N:8][C:7]=3[C:6]=2[CH:18]=1

Participants

9

Reactant 4

HCID 78373Dimethylformamide dimethyl acetalHCID 855731-Isopropylhydrazine hydrochlorideHCID 516892Sodium BicarbonateHCID 582039029-Bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide

Product 1

HCID 532349749-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneYield 35.2%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (2.12 g, 6.52 mmol) in toluene (35 mL) was added 1,1-dimethoxy-N,N-dimethylmethaneamine (7.3 mL, 54.8 mmol). The reaction mixture was allowed to stir and heat to 95° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was treated with a suspension of isopropylhydrazine hydrochloride (0.865 g, 7.82 mmol) in acetic acid (18.5 mL) and water (2.35 mL). The mixture was heated in a sealed vial at 95° C. overnight. The reaction mixture was slowly poured onto a mixture of ice, sodium bicarbonate, and ethyl acetate. The mixture was extracted with ethyl acetate carefully after bubbling subsided. The layers were separated and the organic extract was washed sequentially with water and brine. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in a minimal amount of ethyl acetate and purified via ISCO chromatography (hexane to 20% hexane in EtOAc over 45 minutes). Collected fractions and concentrated to give 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.897 g, 35%). LC/MS (ESI+): m/z 393 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=2.5, 1H), 7.93 (s, 1H), 7.34 (dd, J=8.6, 2.5, 1H), 6.96 (d, J=8.6, 1H), 5.84 (dt, J=13.5, 6.8, 1H), 4.40 (t, J=5.0, 2H), 3.42 (t, J=5.0, 2H), 1.66 (d, J=6.6, 6H)

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. temperatureThe mixture was heated in a sealed vial at 95° C. overnight
  4. extractionThe mixture was extracted with ethyl acetate carefully
  5. customafter bubbling
  6. customThe layers were separated
  7. extractionthe organic extract
  8. washwas washed sequentially with water and brine
  9. dry with materialThe combined organic extracts were dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. dissolutionThe crude residue was dissolved in a minimal amount of ethyl acetate
  13. custompurified via ISCO chromatography (hexane to 20% hexane in EtOAc over 45 minutes)
  14. concentrationCollected fractions and concentrated

Sources & evidence

ORD record
ord-cc6c99131fca42caa828dec0df69c7c7
Source dataset
uspto-grants-2012_09
Patent number
US08263633B2

Reaction notes

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