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

HRID 1634951Notes

Reaction equation

HRID 1634951 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 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 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 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) δ7.89 (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 solvent
  6. customthe residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1)

Sources & evidence

ORD record
ord-2854d5e05c0a4a82886a1d6d5293e7b2
Source dataset
uspto-grants-2003_01
Patent number
US06509334B1

Reaction notes

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