Aniline → HCID 86706298, compound

HRID 2205885Notes

Reaction equation

HRID 2205885 reaction equation
Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:78][O:79][C:80]1[CH:86]=[C:85]([O:87][CH:88]2[CH2:93][CH2:92][N:91]([CH3:94])[CH2:90][CH2:89]2)[CH:84]=[CH:83][C:81]=1[NH2:82].NC1C=CC=CC=1>O1CCOCC1.C(O)C>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]3[CH:3]=[C:2]([NH:82][C:81]4[CH:83]=[CH:84][C:85]([O:87][CH:88]5[CH2:89][CH2:90][N:91]([CH3:94])[CH2:92][CH2:93]5)=[CH:86][C:80]=4[O:79][CH3:78])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]

Participants

8

Reactant 5

HCID 6115AnilineHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 552341692-Methoxy-4-[(1-methylpiperidin-4-yl)oxy]anilineHCID 86706270HCID 86706270, compound

Product 1

HCID 86706298HCID 86706298, compound

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
80 °C

Procedure

To tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 10 (50 mg, 0.108 mmole) was added cesium carbonate (70 mg, 0.216 mmole, 2 eq) and Xantphos (6.2 mg, 0.0108 mmole, 10 mole %), then a solution of 2-methoxy-4-(1-methylpiperidin-4-yloxy)aniline (30.6 mg, 0.13 mmole, 1.2 eq) in dioxane (0.7 ml). Dioxane (0.5 mL) was added and the flask flushed twice with nitrogen. Pd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added and the flask was flushed again with nitrogen (×3) and heated at 80° C. for 4 hours. The reaction was cooled and diluted with ethyl acetate (11 mL). The solution was washed with water (4 mL). The organic layer was washed with brine, dried and evaporated. The residue was applied to two 1 mm 20×20 cm silica prep tlc plates, which were eluted with 10:1 ethyl acetate:2M ammonia in methanol. The product band was recovered with ethanol containing a little 2M ammonia in methanol. This gave a gum, 60 mg, containing (by NMR) ethanol (35%) and residual aniline. This gum was applied to one 1.5 mm alumina prep tlc plate (Merck) which was eluted with 30:1 dichloromethane:2-propanol. The product band was recovered with 30% 2-propanol in dichloromethane to give a gum, 36 mg. The residue was triturated with ether to give (after removal of the ether) the title compound as a solid (22 mg, 33%). 1H-NMR (CDCl3, 500 MHz): δ 1.50 (s, 9H), 1.69 (s, 9H), 1.84-1.93 (m, 2H), 2.02-2.09 (m, 2H), 2.29-2.39 (s, 3H over m, 2H), 2.71-2.80 (m, 2H), 3.87 (s, 3H), 4.26-4.32 (m, 1H), 6.53 (dd, J=2.52, 8.83 Hz, 1H), 6.56 (d, J=0.63 Hz, 1H), 6.58 (d, J=2.52 Hz, 1H), 6.67 (s, 1H), 7.45 (s, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.81 (d, J=0.63 Hz, 1H), 8.20 (d, J=0.63 Hz, 1H), 8.44 (d, J=0.95 Hz, 1H).

Workup

  1. customthe flask flushed twice with nitrogen
  2. additionPd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added
  3. customthe flask was flushed again with nitrogen (×3)
  4. temperatureThe reaction was cooled
  5. additiondiluted with ethyl acetate (11 mL)
  6. washThe solution was washed with water (4 mL)
  7. washThe organic layer was washed with brine
  8. customdried
  9. customevaporated
  10. washwere eluted with 10:1 ethyl acetate
  11. customThe product band was recovered with ethanol containing a little 2M ammonia in methanol
  12. customThis gave a gum, 60 mg
  13. washwas eluted with 30:1 dichloromethane
  14. customThe product band was recovered with 30% 2-propanol in dichloromethane
  15. customto give a gum, 36 mg
  16. customThe residue was triturated with ether
  17. customto give (
  18. customafter removal of the ether) the title compound as a solid (22 mg, 33%)

Sources & evidence

ORD record
ord-f94d652339b643599ceebaa5e98c55ce
Source dataset
uspto-grants-2016_06
Patent number
US09371319B2

Reaction notes

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