4-Pentynoic acid, 3,3-dimethyl-, ethyl ester → Ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate

HRID 1847914Notes

Reaction equation

HRID 1847914 reaction equation
Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([CH3:23])([C:21]#[CH:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCN(CC)CC.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:14]([CH3:23])([CH3:13])[C:21]#[C:22][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4])[CH3:20]

Participants

8

Reactant 2

HCID 100577294-Pentynoic acid, 3,3-dimethyl-, ethyl esterHCID 574885132-Bromo-5-fluoro-4-nitroaniline

Product 1

HCID 59129516Ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoateYield 58.9%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 2-bromo-5-fluoro-4-nitroaniline (45.7 g, 0.19 mol) and ethyl 3,3-dimethylpent-4-ynoate (88.3 g, 0.57 mol) in Et3N (700 mL) was added Pd(PPh3)2Cl2 (13.8 g, 0.02 mol) and CuI (3.6 g, 0.02 mol) under N2. The reaction mixture was stirred at 70° C. for 8 hours. The reaction mixture was diluted with 500 mL of ethyl acetate and 1500 mL of water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (500 mL×3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give ethyl-5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 57%). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 6.36 (d, J=13.2 Hz, 1H), 5.60 (brs, 2H), 4.16 (q, J=7.2 Hz, 2H), 2.51 (s, 2H), 1.40 (s, 6H), 1.28 (t, J=7.2 Hz, 3H).

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous phase was extracted with ethyl acetate (500 mL×3)
  3. washthe combined organic layers were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customthe residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1)

Sources & evidence

ORD record
ord-a501f4e017f14f9ebc0ed466df2d0448
Source dataset
uspto-grants-2015_02
Patent number
US08952049B2

Reaction notes

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