Diisopropylethylamine → 3-(Oxazol-2-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

HRID 1505950Notes

Reaction equation

HRID 1505950 reaction equation
Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Cl-].[Li+].CCN(C(C)C)C(C)C.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][N:37]=1)CCC.[F-].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:34]1[CH:35]=[CH:36][N:37]=[C:33]1[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 433294Lithium ChlorideHCID 522689Potassium FluorideHCID 154861832-(Tri-n-butylstannyl)oxazoleHCID 58266751HCID 58266751, compound

Product 1

HCID 582663233-(Oxazol-2-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 45.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
165 °C

Procedure

A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (101 mg, 0.369 mmol) and lithium chloride (46.9 mg, 1.11 mmol) in DMF (0.63 mL) was treated with DIPEA (161 μL, 0.922 mmol) and 2-(tri-n-butylstannyl)oxazole (232 μL, 1.11 mmol), and then degassed by the bubbling of nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (21.3 mg, 18.4 μmol, 5.0 mol %) was added and the mixture heated at 165° C. for 15 hours. The mixture was allowed to cool and treated with saturated aqueous potassium fluoride solution at ambient temperature. The resulting solids were removed by filtration and washed with 20% methanol in DCM and water. The filtrate was filtered through a pad of celite, washing with 20% methanol in DCM. The layers were separated, the aqueous phase extracted into 20% methanol in DCM, and the combined organic phases concentrated in vacuo. The residue was dissolved in AcOH with sonication and heating, filtered hot, and allowed to cool. The resulting suspension was treated with water and then filtered to collect the tan-gray solid, which was redissolved in DMF and purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a tan solid (43.5 mg, 45%). 1H NMR (400 MHz, DMSO-D6): 9.29 (d, J=2.2 Hz, 1H), 9.26 (d, J=2.2 Hz, 1H), 9.03 (m, 1H), 8.97 (m, 1H), 8.28 (m, 1H), 7.43 (m, 1H). LCMS (Method D): RT=8.29 min, M+H+=262.

Workup

  1. customdegassed by the
  2. custombubbling of nitrogen for 5 minutes
  3. temperatureto cool
  4. customThe resulting solids were removed by filtration
  5. washwashed with 20% methanol in DCM and water
  6. filtrationThe filtrate was filtered through a pad of celite
  7. washwashing with 20% methanol in DCM
  8. customThe layers were separated
  9. extractionthe aqueous phase extracted into 20% methanol in DCM
  10. concentrationthe combined organic phases concentrated in vacuo
  11. dissolutionThe residue was dissolved in AcOH with sonication
  12. temperatureheating
  13. filtrationfiltered hot
  14. temperatureto cool
  15. additionThe resulting suspension was treated with water
  16. filtrationfiltered
  17. customto collect the tan-gray solid, which
  18. dissolutionwas redissolved in DMF
  19. custompurified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide]

Sources & evidence

ORD record
ord-77ec6c53202e4df283142dc574d33f0b
Source dataset
uspto-grants-2015_12
Patent number
US09216980B2

Reaction notes

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