Potassium Phosphate, Tribasic → 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxybenzonitrile

HRID 1616218Notes

Reaction equation

HRID 1616218 reaction equation
[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9](B(O)O)=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:29]1[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:29]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:30]=3[C:31]#[N:32])=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 5927972-Chloro-4-hydroxybenzonitrile2×HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl2×HCID 86691828[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]boronic acid

Product 1

HCID 866918272-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxybenzonitrile

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of [1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]boronic acid (16-1, 500 mg, 1.90 mmol) in anhydrous THF (15 ml) was added a solution of Potassium phosphate tribasic (807 mg, 3.80 mmol, 2.0 equiv) dissolved in water (2 ml). This mixture was treated with 2-chloro-4-hydroxybenzonitrile (409 mg, 2.66 mmol, 1.40 equiv), deoxygenated, then charged with Pd(OAc)2 (21 mg, 0.10 mmol, 0.05 equiv) and S-Phos (78 mg, 0.19 mmol, 0.10 equiv). The resulting dark mixture was irradiated in a microwave at 125° C. for 15 min. The reaction was 75% complete by LC/MS, so more 2-chloro-4-hydroxybenzonitrile (405 mg, 2.66 mmol, 1.40 equiv), Pd(OAc)2 (21 mg, 0.10 mmol, 0.05 equiv) and S-Phos (78 mg, 0.19 mmol, 0.10 equiv) were introduced, and the reaction mixture was irradiated at 140° C. for 25 min. The completed reaction was partitioned between EtOAc (3×75 ml) and saturated aqueous NaHCO3 (80 ml) and the combined organic layers were dried over MgSO4 and concentrated. The crude oil was purified via flash column chromatography (SiO2: 100% Hex to 50/50 Hex/EtOAc) which afforded the title compound, 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxybenzonitrile (16-2), as a yellow solid-oil. LRMS m/z: Calc'd for C19H20N4O2 (M+H) 337.3. found 337.0.

Workup

  1. customdeoxygenated
  2. customThe resulting dark mixture was irradiated in a microwave at 125° C. for 15 min
  3. additionwere introduced
  4. customthe reaction mixture was irradiated at 140° C. for 25 min
  5. customThe completed reaction
  6. customwas partitioned between EtOAc (3×75 ml) and saturated aqueous NaHCO3 (80 ml)
  7. dry with materialthe combined organic layers were dried over MgSO4
  8. concentrationconcentrated
  9. customThe crude oil was purified via flash column chromatography (SiO2: 100% Hex to 50/50 Hex/EtOAc) which

Sources & evidence

ORD record
ord-d26cb371737d425699ba1e21f1df8499
Source dataset
uspto-grants-2014_07
Patent number
US08765784B2

Reaction notes

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