Benzophenone imine → (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester

HRID 571809Notes

Reaction equation

HRID 571809 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:35]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 136809Benzophenone imineHCID 23676156Sodium t-butoxideHCID 68325716Tert-butyl 2-(4-bromo-3-fluorophenyl)morpholine-4-carboxylate

Product 1

HCID 86671396(RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.57 g) and benzophenone imine (1.15 ml) in toluene (40 ml) was added sodium tert-butoxide (691 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (280 mg) and tris(dibenzylideneacetone)dipalladium(0) (120 mg) were added and the reaction mixture was heated to 100° C. and stirred for 1 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (2.215 g, quant.) as a yellow viscous oil. MS (ISP): 461.3 ([M+H]+), 405.4 ([M+H—C4H8]+), 361.3 ([M+H—C4H8—CO2]+).

Workup

  1. customThe reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (280 mg) and tris(dibenzylideneacetone)dipalladium(0) (120 mg)
  2. additionwere added
  3. additionThe reaction mixture was poured into water
  4. extractionextracted twice with EtOAc
  5. dry with materialThe organic layers were dried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-53fda4e91ba64f23a70df273f471ac4f
Source dataset
uspto-grants-2015_05
Patent number
US09029370B2

Reaction notes

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