Iodine → HCID 90200445, compound

HRID 718841Notes

Reaction equation

HRID 718841 reaction equation
[Br:1][C:2]1[C:3]2[O:21][CH2:20][CH2:19][C:18](=[CH:22][C:23]#[N:24])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.[O:25]1CCOC[CH2:26]1.II.[CH3:33][OH:34]>[N+]([O-])([O-])=O.[Ag+]>[C:7](#[N:8])[CH3:6].[Br:1][C:2]1[C:3]2[O:21][CH2:20][CH2:19][C:18]([O:34][CH3:33])([O:25][CH3:26])[CH:22]([C:23]#[N:24])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2

Participants

6

Reactant 4

HCID 807IodineHCID 887Methanol3×HCID 312751,4-DioxaneHCID 86722448HCID 86722448, compound

Product 1

HCID 90200445HCID 90200445, compoundYield 74%

Reagents, catalysts & solvents 1

HCID 24470Silver NitrateCatalyst2×

Procedure

Silver(I) nitrate (7.67 g, 45.1 mmol) was added to a solution of 2-(9-bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5 (1H)-ylidene)acetonitrile (100, R1=4-Fluorophenyl) (6.67 g, 17.4 mmol) and 1,4-dioxane (60.0 mL). MeOH (150 mL) was added. The mixture was warmed to reflux. A solution of iodine (5.74 g, 22.6 mmol) and MeOH (22.6 mL) was added over about 20 min. After about 16 h, the mixture was allowed to cool to rt. The volatiles were removed under reduced pressure. The residue was slurried in DCM (200 mL) then filtered rinsing with 10% EtOAc/DCM (6×50 mL). The volatiles were removed under reduced pressure. The residue was purified on silica gel (220 g) using a gradient of 0-50% EtOAc in DCM. The fractions containing the product and intermediate were combined and concentrated under reduced pressure. The material was dissolved in 1,4-dioxane (30 mL). Silver(I) nitrate (2.95 g, 17.4 mmol) was added. MeOH (75 mL) was added and the mixture was warmed to reflux for about 14 h. The mixture was allowed to cool to rt then the volatiles were removed under reduced pressure. The residue was slurried in DCM (100 mL) then filtered rinsing with 10% EtOAc/DCM (4×25 mL). The organics were concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) then washed with water (2×100 mL). The aqueous layers were extracted with DCM (25 mL) then dried over Na2SO4, filtered and concentrated under reduced pressure to afford 10-bromo-1-(4-fluorophenyl)-6,6-dimethoxy-5,6,7,8-tetrahydro-1H-oxepino[3,2-f]indazole-5-carbonitrile acetonitrile (101, R1=4-Fluorophenyl) (5.75 g, 74% yield) as an orange solid. LC/MS, method 3, Rt=2.45 min, MS m/z 446 and 448 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.06 (s, 1H), 7.64-7.55 (m, 2H), 7.42-7.31 (m, 2H), 5.04 (d, J=1.8 Hz, 1H), 4.51-4.38 (m, 1H), 3.70-3.58 (m, 1H), 3.29 (s, 3H), 3.10 (s, 3H), 2.53-2.40 (m, 1H), 2.30-2.21 (m, 1H).

Workup

  1. temperatureThe mixture was warmed to reflux
  2. customThe volatiles were removed under reduced pressure
  3. filtrationthen filtered
  4. washrinsing with 10% EtOAc/DCM (6×50 mL)
  5. customThe volatiles were removed under reduced pressure
  6. customThe residue was purified on silica gel (220 g)
  7. additionThe fractions containing the product and intermediate
  8. concentrationconcentrated under reduced pressure
  9. dissolutionThe material was dissolved in 1,4-dioxane (30 mL)
  10. temperaturethe mixture was warmed
  11. temperatureto reflux for about 14 h
  12. temperatureto cool to rt
  13. customthe volatiles were removed under reduced pressure
  14. filtrationthen filtered
  15. washrinsing with 10% EtOAc/DCM (4×25 mL)
  16. concentrationThe organics were concentrated under reduced pressure
  17. dissolutionThe residue was dissolved in DCM (100 mL)
  18. washthen washed with water (2×100 mL)
  19. extractionThe aqueous layers were extracted with DCM (25 mL)
  20. dry with materialthen dried over Na2SO4
  21. filtrationfiltered
  22. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-707f95d11a84407681097611da095765
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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