tert-butyl N-(2-methoxyphenyl)carbamate → tert-Butyl (2-methoxy-6-(5-(trifluoromethyl)picolinoyl)phenyl)carbamate

HRID 921264Notes

Reaction equation

HRID 921264 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[Li]C(C)(C)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30](OC)=[O:31])=[N:28][CH:29]=1>CCOCC>[C:12]([O:11][C:10](=[O:16])[NH:9][C:4]1[C:5]([C:30](=[O:31])[C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:22])[F:35])=[CH:29][N:28]=2)=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:13])([CH3:15])[CH3:14]

Participants

5

Reactant 3

HCID 4935494tert-butyl N-(2-methoxyphenyl)carbamateHCID 189969195-Trifluoromethyl-pyridine-2-carboxylic acid methyl esterHCID 178418306HCID 178418306, compound

Product 1

HCID 86713383tert-Butyl (2-methoxy-6-(5-(trifluoromethyl)picolinoyl)phenyl)carbamateYield 69.5%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (443.3 mg, 1.986 mmol) in ether (5 mL) under N2 was added t-BuLi (2.6 mL, 4.42 mmol). The reaction mixture was stirred for 2 h, and then cooled to −78° C. To the reaction mixture was added a solution of methyl 5-(trifluoromethyl)picolinate (501.3 mg, 2.44 mmol) in ether (10 mL) dropwise via cannula over 5 min. After 2 h, the reaction mixture was warmed to room temperature, stirred for an additional hour, and then the reaction was quenched by the addition of water with vigorous stirring. The reaction mixture was diluted with EtOAc, the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield a yellow solid. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.83-8.88 (1H, m), 8.24 (1H, d, J=8.4 Hz), 8.07 (1H, dd, J=8.4, 1.8 Hz), 7.25 (1H, d, J=1.5 Hz), 7.18-7.24 (1H, m), 7.09 (1H, dd, J=8.0, 1.7 Hz), 6.95 (1H, s), 3.93 (3H, s), 1.25 (9H, s).

Workup

  1. waitAfter 2 h
  2. temperaturethe reaction mixture was warmed to room temperature
  3. stirringstirred for an additional hour
  4. customthe reaction was quenched by the addition of water with vigorous stirring
  5. additionThe reaction mixture was diluted with EtOAc
  6. customthe organic phase was separated
  7. washwashed with sat NaCl
  8. dry with materialthen dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto yield a yellow solid
  12. customThe residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g)
  13. customto obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid

Sources & evidence

ORD record
ord-fd4fd1f1d9b6419d95f8d5dc15afe887
Source dataset
uspto-grants-2016_03
Patent number
US09273014B2

Reaction notes

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