Toluene → Tert-butyl (2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

HRID 1430841Notes

Reaction equation

HRID 1430841 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[O:53]1[CH2:56][CH:55]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:54]1.Br[C:64]1[C:65]([Cl:90])=[C:66]([N:73]([CH2:81][C:82]2[CH:87]=[CH:86][C:85]([O:88][CH3:89])=[CH:84][CH:83]=2)[C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH:67]=[C:68]([CH:70]([F:72])[F:71])[CH:69]=1.C1(C)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:90][C:65]1[C:64]([N:60]2[CH2:61][CH2:62][N:57]([CH:55]3[CH2:56][O:53][CH2:54]3)[CH2:58][CH2:59]2)=[CH:69][C:68]([CH:70]([F:72])[F:71])=[CH:67][C:66]=1[N:73]([CH2:81][C:82]1[CH:83]=[CH:84][C:85]([O:88][CH3:89])=[CH:86][CH:87]=1)[C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77]

Participants

7

Reactant 5

HCID 1140TolueneHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 574162871-(Oxetan-3-yl)piperazineHCID 86708468Tert-butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate

Product 1

HCID 86708530Tert-butyl (2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
106 °C

Procedure

Cesium carbonate (672 mg, 2.063 mmol), BINAP (64.2 mg, 0.103 mmol), 1-(oxetan-3-yl)piperazine (176 mg, 1.238 mmol) and Pd2(dba)3 (94 mg, 0.103 mmol) were weighed into a 25 mL round bottom flask at rt. A solution of tert-butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate in toluene (4294 μl, 1.031 mmol) was added and the reaction was degassed 3 times by evacuating the flask under vacuum and then purging with N2. The reaction mixture was heated to 106° C. for 16 h and then cooled to rt. The reaction mixture was diluted with EtOAc, sonicated, filtered through celite and concentrated. The product was purified by column chromatography (40 g SiO2, 30 to 100% EtOAc-hexane gradient elution) to afford 312 mg of tert-butyl (2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate.

Workup

  1. customthe reaction was degassed 3 times
  2. customby evacuating the flask under vacuum
  3. custompurging with N2
  4. temperaturecooled to rt
  5. additionThe reaction mixture was diluted with EtOAc
  6. customsonicated
  7. filtrationfiltered through celite
  8. concentrationconcentrated
  9. customThe product was purified by column chromatography (40 g SiO2, 30 to 100% EtOAc-hexane gradient elution)

Sources & evidence

ORD record
ord-e8b8f649ecf143e682001dffe21c7f75
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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