Tris(1,1-dimethylethyl)phosphine → Methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinate

HRID 2046875Notes

Reaction equation

HRID 2046875 reaction equation
Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[CH2:13]([O:20][C:21]1[C:22]([F:31])=[C:23](B(O)O)[C:24]([F:27])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.O.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]>[CH2:13]([O:20][C:21]1[C:22]([F:31])=[C:23]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=2[F:12])[C:24]([F:27])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 522689Potassium FluorideHCID 162177043-(Benzyloxy)-2,6-difluorobenzeneboronic acidHCID 46311204Methyl 6-bromo-5-fluoropyridine-2-carboxylate

Product 1

HCID 59226393Methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) in THF and water (10:1, 0.1 M) was added 3-(benzyloxy)-2,6-difluorophenylboronic acid (2.5 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed with nitrogen, then Pd2(dba)3 (0.25 equiv.) and tri-tert-butylphosphine (0.5 equiv.) were added and the reaction was heated to 80° C. for one hour. LC/MS analysis indicated complete conversion of the starting material to product. The reaction was cooled to room temperature, then concentrated in vacuo and fused to silica gel. The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate) to provide methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinate as the desired product as a light yellow oil in 96% yield. LC/MS=374.0 (M+H), Rt=1.07 min.

Workup

  1. customThe reaction was degassed with nitrogen
  2. temperatureThe reaction was cooled to room temperature
  3. concentrationconcentrated in vacuo
  4. customThe crude product was purified by ISCO flash chromatography
  5. washeluting with ethyl acetate and hexanes (0% to 30% ethyl acetate)

Sources & evidence

ORD record
ord-95f4e110b15f451b8fac52b56ded4a88
Source dataset
uspto-grants-2013_11
Patent number
US08592455B2

Reaction notes

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