Cesium carbonate → (R)-t-butyl 4-(3-(1-(2,4-dichlorophenyl)ethylamino)-4-fluorophenyl)piperazine-1-carboxylate

HRID 75133Notes

Reaction equation

HRID 75133 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C@H:37]([NH2:39])[CH3:38].CC(P(C(C)(C)C)C1C(C2C(N(C)C)=CC=CC=2)=CC=CC=1)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(N(CC)CC)C.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:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C@H:37]([NH:39][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:7][C:2]=1[F:1])[CH3:38]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 2496565(alphaR)-2,4-Dichloro-alpha-methylbenzenemethanamineHCID 27349362-Di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenylHCID 86689050HCID 86689050, compound

Product 1

HCID 86689049(R)-t-butyl 4-(3-(1-(2,4-dichlorophenyl)ethylamino)-4-fluorophenyl)piperazine-1-carboxylateYield 3,666.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8471TriethylamineSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of t-butyl 4-(4-fluoro-3-(trifluoromethylsulfonyloxy)phenyl)piperazine-1-carboxylate (0.50 g, 1.17 mmol) and (IR)-1-(2,4-dichlorophenyl)ethanamine (0.58 g, 3.05 mmol), tBuDavePhos (0.025 g, 0.070 mmol), and Cs2CO3 (0.80 g, 2.44 mmol) in triethylamine (3 mL) was purged with nitrogen for 3 min. Addition of Pd2(dba)3 (0.034 g, 0.037 mmol) was followed, and the mixture was purged with nitrogen for 1 min. The resulting mixture was heated at 100° C. under nitrogen for 4 h. After cooling to room temperature, the suspension was filtered through a plug of Celite, and washed with ethyl acetate (25 mL). The filtrate was concentrated in vacuo and the resulting residue purified by flash chromatography (SiO2, 10-50% ethyl acetate in hexanes) to afford (R)-t-butyl 4-(3-(1-(2,4-dichlorophenyl)ethylamino)-4-fluorophenyl)piperazine-1-carboxylate (0.36 g, 42.9 mmol, 62%).

Workup

  1. customwas purged with nitrogen for 3 min
  2. customthe mixture was purged with nitrogen for 1 min
  3. temperatureAfter cooling to room temperature
  4. filtrationthe suspension was filtered through a plug of Celite
  5. washwashed with ethyl acetate (25 mL)
  6. concentrationThe filtrate was concentrated in vacuo
  7. customthe resulting residue purified by flash chromatography (SiO2, 10-50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-3c8d9d63d14046f789c0cf16292fed82
Source dataset
uspto-grants-2014_09
Patent number
US08835419B2

Reaction notes

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