Sodium Carbonate → 5-(2-amino-4-methoxycarbonylphenyl)-1-isobutyl-1H-imidazole-4-carbonitrile

HRID 574014Notes

Reaction equation

HRID 574014 reaction equation
C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:21]1[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[N:23][C:22]=1[C:30]#[N:31].Cl.[NH2:33][C:34]1[CH:39]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:33][C:34]1[CH:39]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1[C:21]1[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[N:23][C:22]=1[C:30]#[N:31]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 164270832-Amino-4-(methoxycarbonyl)benzeneboronic acid hydrochlorideHCID 445414195-iodo-1-isobutyl-1H-imidazole-4-carbonitrile

Product 1

HCID 867279625-(2-amino-4-methoxycarbonylphenyl)-1-isobutyl-1H-imidazole-4-carbonitrileYield 89%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 equiv) and PPh3 (26.2 mg, 0.1 mmol, 0.1 equiv) in DME (4 mL) were sequentially added 5-iodo-1-isobutyl-1H-imidazole-4-carbonitrile S5 (275 mg, 1 mmol, 1 equiv), 2-amino-4-methoxycarbonylphenyl-boronic acid hydrochloride salt (347 mg, 1.5 mmol, 1.5 equiv) and 1.5 M aqueous Na2CO3 (2.0 mL, 3.0 mmol, 3.0 equiv) at 25° C. The reaction was heated at 100° C. for 3 h. TLC and MS analysis indicated complete conversion of S5. The reaction was then cooled down to 25° C. and partitioned between EtOAc (50 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with saturated aqueous NaCl (20 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (265 mg, 89%) as a light yellow foam: 1H NMR (CDCl3, 600 Hz) δ 0.71 (d, J=9.6 Hz, 3H), 0.75 (d, J=9.6 Hz, 3H), 1.75 (hept, J=9.6 Hz, 1H), 3.64-3.67 (m, 2H), 3.90 (s, 3H), 7.15 (d, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz), 7.45 (s, 1H), 7.57 (s, 1H); 13C NMR (CDCl3, 150 Hz) δ 19.6, 19.7, 29.5, 52.3, 53.6, 117.0, 128.4, 128.5, 131.7, 131.9, 131.9, 132.0, 132.1, 133.2, 139.8, 166.5; LRMS (ESI+): calcd C16H19N4O2 [M+H]+299.2. found 299.1.

Workup

  1. customat 25° C
  2. temperatureThe reaction was then cooled down to 25° C.
  3. custompartitioned between EtOAc (50 mL) and H2O (10 mL)
  4. extractionThe aqueous layer was extracted with EtOAc (3×15 mL)
  5. washthe combined organic layers were washed with saturated aqueous NaCl (20 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customPurification by flash column chromatography on silica gel (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient)

Sources & evidence

ORD record
ord-e1eb5b2924c047938a1ff30d64a794ff
Source dataset
uspto-grants-2015_05
Patent number
US09034336B2

Reaction notes

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