5-Bromo-2-methoxypyridine → HCID 54494848, compound

HRID 1264221Notes

Reaction equation

HRID 1264221 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.C([Li])CCC.[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[C:20]([Cl:32])[CH:19]=1>C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][C:21]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:20]([Cl:32])[CH:19]=1

Participants

9

Reactant 3

HCID 27348955-Bromo-2-methoxypyridineHCID 21841505Methyl 3-chloro-4-[[(trifluoromethyl)sulfonyl]oxy]benzoateHCID 178418339Butyllithium

Product 1

HCID 54494848HCID 54494848, compoundYield 30.8%

Reagents, catalysts & solvents 5

HCID 1542701,5-Diphenylpenta-1,4-dien-3-one;palladiumCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 3007855ZincchlorideCatalystHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

To a cooled solution (−78° C.) of 2-methoxy-5-bromopyridine (1.13 g, 6 mmol, reference example 41a) in THF (12 mL) is added over 10 min (2.5M)n-butyllithium (2.4 mL, 6 mmol) and the resulting solution stirred for 15 min. To this solution is added dropwise (0.5M)zinc chloride (12 mL, 6 mmol) and the temperature of this arylzinc bromide allowed to warm to 0° C. with stirring. To a cooled solution (0° C.), in a separate flask, of palladium bis(dibenzylideneacetone) (288 mg, 0.5 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (276 mg, 0.5 mmol) in THF (2 mL) is added a solution of 3-chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1.59 g, 5 mmol) (reference example 39) in THF (2 mL) followed by the arylzinc bromide solution. The resulting solution is heated to 65° C. and stirred for 2.5 hours then cooled to 20° C., diluted with ether, washed with sat NH4Cl soln and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 25% ether in hexanes) to give 428 mg of title compound as a yellow crystalline solid. 1H NMR(CDCl3) δ 3.95 (s, 3H), 4.00 (s, 3H), 6.84 (d, J=9 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.72 (dd, J=9, 2 Hz, 1H), 7.98 (dd, J=8, 2 Hz, 1H), 8.15 (s, 1H), 8.25 (d, J=2 Hz, 1H). MS (EI) m/z 277 (M+).

Workup

  1. stirringwith stirring
  2. temperatureThe resulting solution is heated to 65° C.
  3. stirringstirred for 2.5 hours
  4. temperaturethen cooled to 20° C.
  5. washwashed
  6. dry with materialbrine, dried over MgSO4
  7. concentrationconcentrated
  8. customThe residue is purified by flash chromatography (eluting with 25% ether in hexanes)

Sources & evidence

ORD record
ord-b96c3c2abe244477a4b7c42caa112f19
Source dataset
uspto-grants-2003_04
Patent number
US06541505B1

Reaction notes

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