Ethyl Acetate → 1-(4-Amino-3'-chloro-biphenyl-3-yl)-ethanone

HRID 1793373Notes

Reaction equation

HRID 1793373 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:19]=2)C(N(OC)C)=O)[CH:5]=[CH:6][CH:7]=1.C[Li].[Cl-].[NH4+:23].C([O:27][CH2:28][CH3:29])(=O)C>C1COCC1.CCOCC>[NH2:23][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:12]=1[C:28](=[O:27])[CH3:29]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 220218875-(3-chlorophenyl)-N-methoxy-N-methylbenzamideHCID 178418348HCID 178418348, compound

Product 1

HCID 159081311-(4-Amino-3'-chloro-biphenyl-3-yl)-ethanoneYield 47%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodium carbonate (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and heated at 85° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed (brine) and dried (MgSO4). After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone as a yellow solid (2 g, 47%): mp 89–90° C.; 1H-NMR (CDCl3) δ 7.89 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.25–7.40 (m, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268([M+Na]+, 60%); Anal. Calc. For C14H12ClNO: C, 68.44, H, 4.92, N, 5.70. Found: C, 68.40, H, 4.89, N, 5.61.

Workup

  1. customorganic layer was separated
  2. extractionaqueous layer was extracted with ethyl acetate (3×20 mL)
  3. washThe combined organic layers were washed (brine)
  4. dry with materialdried (MgSO4)
  5. customAfter removal of the solvent
  6. customthe residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1)

Sources & evidence

ORD record
ord-eb2f155c4449479dbc7f4fd79ec84839
Source dataset
uspto-grants-2006_07
Patent number
US07081457B2

Reaction notes

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