Selenium Dioxide → 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde

HRID 562437Notes

Reaction equation

HRID 562437 reaction equation
[O:1]1[CH2:6][CH2:5]OCC1.[Se](=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:26](C)=[C:25](C)[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1.[Se]>CO.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:5]([CH:6]=[O:1])=[C:25]([CH3:26])[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1

Participants

7

Reactant 4

HCID 24007Selenium Dioxide3×HCID 312751,4-DioxaneHCID 6326970SeleniumHCID 668326292-(4-Fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

Product 1

HCID 866182842-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehydeYield 61%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
55 °C

Procedure

To a 1 L round-bottom flask equipped with a magnetic stir-bar was added dioxane (500 mL) and water (16.5 mL). The solution was heated to 55° C., and selenium dioxide (8.6 g, 77 mmole) was added. The mixture was stirred at 55° C. for one hour, over which time all the selenium dioxide had dissolved. To the solution was then added 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one. The flask was fitted with a reflux condenser and the resulting slurry heated to a bath temperature of 115° C. After 18 hours, additional selenium dioxide (4.0 g, 36 mmole) was added and stirring continued for 6 hours. The reaction mixture was dark red, with gray metallic selenium lining the sides of the flask. The reaction mixture was cooled to room temperature then filtered through a pad of celite and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo to produce a gummy red solid. Methanol (50 mL) was added, and the mixture stirred over an ice bath, during which time a flocculent yellow precipitate formed. The solid was isolated by filtration, and washed sparingly with cold methanol to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (3.90 g, 61%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.26 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): 365 (M+1)+.

Workup

  1. customTo a 1 L round-bottom flask equipped with a magnetic stir-bar
  2. dissolutionhad dissolved
  3. customThe flask was fitted with a reflux condenser
  4. temperaturethe resulting slurry heated to a bath temperature of 115° C
  5. waitcontinued for 6 hours
  6. temperatureThe reaction mixture was cooled to room temperature
  7. filtrationthen filtered through a pad of celite
  8. washwashed with 10% MeOH/DCM
  9. concentrationThe filtrate was concentrated in vacuo
  10. customto produce a gummy red solid
  11. stirringthe mixture stirred over an ice bath, during which time a flocculent yellow precipitate
  12. customformed
  13. customThe solid was isolated by filtration
  14. washwashed sparingly with cold methanol

Sources & evidence

ORD record
ord-bd6dbe7d7da742fdace5c8b82c98a9a4
Source dataset
uspto-grants-2011_11
Patent number
US08067395B2

Reaction notes

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