Potassium Phosphate, Tribasic → 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester

HRID 1643612Notes

Reaction equation

HRID 1643612 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[CH3:15][O:16][C:17]([C:19]1[CH:29]=[C:28]([OH:30])[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=2[CH:20]=1)=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:30][C:28]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:29]=2)=[CH:7][N:6]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 24997839tert-Butyl 5-bromopyridine-2-carboxylateHCID 25067323Methyl 4-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-carboxylate

Product 1

HCID 595603535-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl esterYield 2.9%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of t-butyl 5-bromopicolinate (581 mg, 2.25 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K3PO4 (956 mg, 4.50 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (96 mg, 0.225 mmol), and Pd(OAc)2 (51 mg, 0.225 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 3 h, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 15-30% EtOAc in hexanes to give 26 mg of 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester and 400 mg mixture of the title compound with ˜40% of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=2.53 Hz, 1 H) 8.05 (d, J=8.84 Hz, 1 H) 7.23-7.36 (m, 2 H) 7.19 (d, J=1.26 Hz, 1 H) 3.87 (s, 3 H) 2.89 (s, 2 H) 1.64 (s, 9 H) 1.48 (s, 6 H); LCMS for C22H25NO6 m/z 344.00 (M-tBu+H+).

Workup

  1. temperaturecooled to room temperature
  2. filtrationfiltered through celite
  3. washwashed with EtOAc
  4. concentrationconcentrated
  5. custompurified by Biotage column chromatography with 15-30% EtOAc in hexanes

Sources & evidence

ORD record
ord-08a81f4095784494ab273d45d1ecc1d9
Source dataset
uspto-grants-2012_02
Patent number
US08119624B2

Reaction notes

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