Cesium carbonate → Methyl 4-[3'-fluoro-4'-(formylamino)-1,1'-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate

HRID 30869

Reaction equation

HRID 30869 reaction equation
[F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[O:11].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:51])[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([O:47][CH3:48])=[O:46])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=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>[F:1][C:2]1[CH:7]=[C:6]([C:36]2[CH:37]=[CH:38][C:39]([C:42](=[O:51])[CH2:43][C:44]([CH3:49])([CH3:50])[C:45]([O:47][CH3:48])=[O:46])=[CH:40][CH:41]=2)[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[O:11]

Participants

10

Reactant 5

HCID 10796Cesium carbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 21985797Methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoateHCID 23549341N-(2-fluoro-4-iodophenyl)formamide

Product 1

HCID 21985807Methyl 4-[3'-fluoro-4'-(formylamino)-1,1'-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoateYield 46%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A suspension of 2-fluoro-4-iodophenylformamide (1.94 g, 7.35 mmol, prepared as described above), bis(pinacolato)diboron (1.86 g, 7.35 mmol), potassium acetate (2.16 g, 22.1 mmol), and palladium acetate (49.4 mg, 0.22 mmol) in N,N-dimethylformamide (50 mL) was degassed by bubbling a flow of argon through the mixture for 30 minutes. The mixture was then heated at 80° C. for 3 h. After the mixture was cooled to rt, methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (2.2 g, 7.4 mmol), tetrakis(triphenylphosphine)palladium(0) (254.8 mg, 0.22 mmol), and cesium carbonate (3.59 g, 11.0 mmol) were added, and the reaction mixture was heated at 80° C. for 16 h. The mixture was then cooled to rt and water was added. The mixture was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate. The mixture was concentrated under reduced pressure and the crude was purified by flash chromatography (Biotage Flash 40M, 1:1 ethyl acetate/hexane) to afford methyl 4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate (1.2 g, 46%). LC-MS ret. time 2.80 min, m/z 358.1 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.19 (s, 6H), 3.36 (s, 2H), 3.51 (s, 3H), 7.56 (d, 1H), 7.69 (dd, 1H), 7.82 (d, 2H), 7.99 (d, 3H), 8.21 (t), 10.25 (s, 1H).

Workup

  1. customwas degassed
  2. customby bubbling a flow of argon through the mixture for 30 minutes
  3. temperatureAfter the mixture was cooled to rt
  4. temperaturethe reaction mixture was heated at 80° C. for 16 h
  5. temperatureThe mixture was then cooled to rt
  6. extractionThe mixture was extracted with ethyl acetate
  7. dry with materialthe combined extracts were dried over sodium sulfate
  8. concentrationThe mixture was concentrated under reduced pressure
  9. customthe crude was purified by flash chromatography (Biotage Flash 40M, 1:1 ethyl acetate/hexane)

Sources & evidence

ORD record
ord-4c84fc06c9f0407e879a8ec9d9c31385
Source dataset
uspto-grants-2008_09
Patent number
US07423156B2

Linked notes

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