Nitrogen → 5-(Benzylthio)-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzaldehyde

HRID 1504454Notes

Reaction equation

HRID 1504454 reaction equation
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:44]1[CH:45]=[CH:46][C:47]([NH:52][C:53]2[C:58]([O:59][CH3:60])=[CH:57][C:56]([C:61]3[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([CH3:68])[CH:62]=3)=[C:55]([F:69])[CH:54]=2)=[C:48]([CH:51]=1)[CH:49]=[O:50].N#N.[C:72]1([CH2:78][SH:79])[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=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].O1CCOCC1>[CH2:78]([S:79][C:44]1[CH:45]=[CH:46][C:47]([NH:52][C:53]2[C:58]([O:59][CH3:60])=[CH:57][C:56]([C:61]3[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([CH3:68])[CH:62]=3)=[C:55]([F:69])[CH:54]=2)=[C:48]([CH:51]=1)[CH:49]=[O:50])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1

Participants

7

Reactant 4

HCID 947NitrogenHCID 7509Benzyl mercaptanHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 1177370735-Bromo-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzaldehyde

Product 1

HCID 1177373105-(Benzylthio)-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzaldehyde

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
90 °C

Procedure

A small microwave vial was charged with Pd2(dba)3 (0.064 g, 0.070 mmol), xantphos (0.081 g, 0.140 mmol). The vial was sealed with a septum cap and 0.3 mL dioxane was added. The vial was heated at 90° C. in an oil bath for 3 min. The solution was then cooled to rt. A separate vial was charged with 5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzaldehyde (1.26 g, 2.81 mmol) and sealed with a septum cap. The vial was flushed with N2 and 1,4-dioxane (9.36 ml), phenylmethanethiol (0.399 ml, 3.37 mmol) and dipea (1.471 ml, 8.42 mmol) were added. The pre-activated catalyst solution prepared in the microwave vial was transferred to the vial containing the reactants via syringe and the resulting mixture was heated at 90° C. for 3 h. The reaction mixture was partitioned between 1 N HCl/brine (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×20 mL). The combined organic layers were dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal DCM and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep® Gold pre-packed silica gel column (80 g) using 100% Heptane to 60:40 Heptane: EtOAc gradient to afford 5-(benzylthio)-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzaldehyde as a bright yellow foam. (ESI) 490.2 (M−H)−.

Workup

  1. customThe vial was sealed with a septum
  2. customcap
  3. temperatureThe solution was then cooled to rt
  4. customsealed with a septum
  5. customcap
  6. additionwere added
  7. customThe pre-activated catalyst solution prepared in the microwave vial
  8. additioncontaining the reactants via syringe
  9. temperaturethe resulting mixture was heated at 90° C. for 3 h
  10. customThe reaction mixture was partitioned between 1 N HCl/brine (20 mL) and EtOAc (30 mL)
  11. customThe layers were separated
  12. extractionthe aqueous layer was extracted with EtOAc (1×20 mL)
  13. dry with materialThe combined organic layers were dried (Na2SO4)
  14. concentrationconcentrated for purification by MPLC (Biotage Isolera)
  15. customabsorbed onto a 25 g loading cartridge

Sources & evidence

ORD record
ord-a5c4daf9a9da45a49fccd49732138c0d
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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