Benzene, 1-bromo-3-(trifluoromethyl)- → N-((R)-1-(Naphthalen-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)morpholine-3-carboxamide

HRID 1048855Notes

Reaction equation

HRID 1048855 reaction equation
[C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[CH2:21][O:20][CH2:19][CH2:18][NH:17]2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[CH2:21][O:20][CH2:19][CH2:18][N:17]2[C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1

Participants

8

Reactant 4

HCID 9817Benzene, 1-bromo-3-(trifluoromethyl)-HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 68293286N-((R)-1-(Naphthalen-1-yl)ethyl)morpholine-3-carboxamide

Product 1

HCID 68293184N-((R)-1-(Naphthalen-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)morpholine-3-carboxamideYield 33.3%

Reagents, catalysts & solvents 3

HCID 71406666Palladium--tri-tert-butylphosphane (1/1)CatalystHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
110 °C

Procedure

To a mixture solution of N-((R)-1-(naphthalen-1-yl)ethyl)morpholine-3-carboxamide (Intermediate-1) (400 mg, 1.4 mmol) in toluene (10 mL), bis(tri-tert-butylphosphine palladium(0) (19.3 mg, 0.021 mmol), xantphos (36.67 mg, 0.047 mmol), 1-bromo-3-(trifluoromethyl)benzene (244 μL, 1.69 mmol) and Cs2CO3 (688 mg, 2.11 mmol) were added. The reaction mass was heated to 110° C. and further maintained for 20 h under nitrogen atmosphere. After reaction completion the mixture was diluted with diethylether, filtered through celite, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluent to afford the title compound (200 mg), m/z 429.1.

Workup

  1. temperaturefurther maintained for 20 h under nitrogen atmosphere
  2. customAfter reaction completion the mixture
  3. filtrationfiltered through celite
  4. concentrationconcentrated under vacuum
  5. customThe residue was purified by column chromatography on silica gel using
  6. additiona mixture of ethyl acetate and hexane as eluent

Sources & evidence

ORD record
ord-55d8455482f24bab87b8ad851a7d425f
Source dataset
uspto-grants-2016_07
Patent number
US09382216B2

Reaction notes

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