Cesium carbonate → 2,6-dichloro-N-(2-isobutyramidopyridin-4-yl)benzamide

HRID 449866Notes

Reaction equation

HRID 449866 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]([CH3:24])[C:21](N)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([CH3:24])[CH3:19])[CH:7]=1)=[O:18]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 68424IsobutyramideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59618313N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide

Product 1

HCID 596179212,6-dichloro-N-(2-isobutyramidopyridin-4-yl)benzamideYield 49%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

To a 10 ml microwave tube was added N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (60 mg, 0.21 mmol), followed by 2-methylpropanamide (43 mg, 0.5 mmol), cesium carbonate (162 mg, 0.5 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 11 mg, 0.02 mmol). The tube was degassed and filled with N2 three times. The resulting mixture was then heated 100° C. overnight. The next day, the mixture was cooled to room temperature, filtered through celite. The filtrate was concentrated to dryness and the resulting thick oil was dissolved in EtOAc (10 mL), and washed with H2O (10 mL). The aqueous layer was further extracted with EtOAc (10 mL). Combined organics were dried over Na2SO4, concentrated and purified by reverse-phase HPLC (Gemini, 3×10 cm, gradient: 5-85% CH3CN/H2O with 0.1% NH4OH over 10 min) to afford the desired product (30 mg, 49% yield). 1HNMR: (DMSO-d6, 400 MHz): δ 11.2 (s, 1H), 10.4 (s, 1H), 8.4 (s, 1H), 8.2 (d, J=5.2 Hz, 1H), 7.60-7.46 (m, 4H), 2.74 (m, 1H), 1.1 (d, J=6.8 Hz, 6H). LCMS (ESI) (m/z): 352.0 [M+H+].

Workup

  1. customThe tube was degassed
  2. additionfilled with N2 three times
  3. temperatureThe next day, the mixture was cooled to room temperature
  4. filtrationfiltered through celite
  5. concentrationThe filtrate was concentrated to dryness
  6. dissolutionthe resulting thick oil was dissolved in EtOAc (10 mL)
  7. washwashed with H2O (10 mL)
  8. extractionThe aqueous layer was further extracted with EtOAc (10 mL)
  9. dry with materialCombined organics were dried over Na2SO4
  10. concentrationconcentrated
  11. custompurified by reverse-phase HPLC (Gemini, 3×10 cm, gradient: 5-85% CH3CN/H2O with 0.1% NH4OH over 10 min)

Sources & evidence

ORD record
ord-c97a6196d3f24a98a66c68d9c54d896e
Source dataset
uspto-grants-2013_07
Patent number
US08486950B2

Reaction notes

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