2,5-Dihydrofuran → 6-(Cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester

HRID 632144

Reaction equation

HRID 632144 reaction equation
[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4].[O:17]1[CH2:21][CH:20]=[CH:19][CH2:18]1.C([O-])(=O)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:40][O:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH2:51][O:52][CH2:53][CH:54]=2)=[C:46]([O:55][CH2:56][CH:57]2[CH2:59][CH2:58]2)[N:45]=1)=[O:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:40][O:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH2:51][O:52][CH2:53][CH:54]=2)=[C:46]([O:55][CH2:56][CH:57]2[CH2:59][CH2:58]2)[N:45]=1)=[O:43].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[O:17][CH2:21][CH2:20][CH:19]=2)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4]

Participants

10

Reactant 5

HCID 155702,5-DihydrofuranHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 517045Sodium AcetateHCID 71087286Methyl 5-bromo-6-(cyclopropylmethoxy)picolinateHCID 710874196-(Cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester

Product 2

HCID 710874196-(Cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl esterHCID 710879866-(Cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl esterYield 79%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (0.5 g, 1.7 mmol), 2,5-dihydrofuran (CAN 1708-29-8, 1.2 g, 17 mmol), palladium(II) acetate (CAN 3375-31-3, 0.02 g, 0.09 mmol), sodium acetate (0.17 g, 2 mmol) and tri-tert-butylphosphine (CAN 13716-12-6, 0.037 g, 0.2 mmol) in DMF (10 mL) was stirred at 120° C. for 2.5 h under a nitrogen atmosphere. Water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, eluting with 5% ethyl acetate in petroleum ether) to yield 6-(cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 6-(cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2) (mixture b1:b2=3:2, 0.38 g, 1.4 mmol, 79%) as yellow oil; MS (EI): m/e=376.1 [M+H]+.

Workup

  1. extractionthe resulting mixture was extracted with ethyl acetate (3×30 mL)
  2. washThe combined organic extracts were washed with water and brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customevaporated
  5. customThe residue was purified by column chromatography (silica gel, 10 g, eluting with 5% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-8ad01b23e74547839002cc2aea169b00
Source dataset
uspto-grants-2016_04
Patent number
US09321727B2

Linked notes

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