4-Fluoroiodobenzene → Ethyl 5-(4-fluorobenzyl)-3-[(4-fluorophenyl)amino]pyridine-2-carboxylate

HRID 2364211Notes

Reaction equation

HRID 2364211 reaction equation
[NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].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.[F:69][C:70]1[CH:75]=[CH:74][C:73](I)=[CH:72][CH:71]=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].C(OCC)(=O)C.O1CCOCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][C:73]3[CH:74]=[CH:75][C:70]([F:69])=[CH:71][CH:72]=3)[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1

Participants

8

Reactant 4

HCID 96054-FluoroiodobenzeneHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 42637772Ethyl 3-amino-5-(4-fluorobenzyl)picolinate

Product 1

HCID 69482193Ethyl 5-(4-fluorobenzyl)-3-[(4-fluorophenyl)amino]pyridine-2-carboxylateYield 72%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a dry 100 mL flask under a nitrogen atmosphere was added ethyl 3-amino-5-(4-fluorobenzyl)pyridine-2-carboxylate (200 mg, 0.73 mmol) described in example 1, Cs2CO3 (333 mg, 1.02 mmol), Pd2dba3 (20.1 mg, 0.022 mmol), and Xantphos (38.2 mg, 0.066 mmol). Dioxane (15 mL) and 1-fluoro-4-iodobenzene (0.25 mL, 2.19 mmol) were added and the resulting solution was refluxed for 3 hrs or until judged complete by TLC (7:3 hexanes:ethyl acetate). The mixture was allowed to cool to ambient temperature, filtered through Celite eluting with dichloromethane and concentrated under reduced pressure. Purification by silica gel chromatography (0-45% ethyl acetate/hexanes gradient elution) afforded ethyl 5-(4-fluorobenzyl)-3-[(4-fluorophenyl)amino]pyridine-2-carboxylate (193 mg, 72% yield) as a yellow solid. 1H NMR (CDCl3) δ 9.35 (s, 1 H), 7.95 (s, 1 H), 7.14 (, s, 1 H), 7.10-6.99 (m, 6 H), 6.96-6.93 (m, 2 H), 4.46 (q, J=7.2 Hz, 2 H), 3.83 (s, 2 H), 1.44 (t, J=7.2 Hz, 3 H); MS m/z 369 (M+1).

Workup

  1. temperaturethe resulting solution was refluxed for 3 hrs
  2. filtrationfiltered through Celite
  3. washeluting with dichloromethane
  4. concentrationconcentrated under reduced pressure
  5. customPurification
  6. washby silica gel chromatography (0-45% ethyl acetate/hexanes gradient elution)

Sources & evidence

ORD record
ord-e3f270e27f9c4c8591d535ca814cf2ee
Source dataset
uspto-grants-2014_04
Patent number
US08691991B2

Reaction notes

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