Triethylamine → [4-(3-Fluoro-phenylethynyl)-2-nitro-phenoxy]-acetic acid ethyl ester

HRID 570153Notes

Reaction equation

HRID 570153 reaction equation
[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)#[CH:19].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:2]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 5202181-Ethynyl-3-fluorobenzeneHCID 24903547Ethyl 2-(4-bromo-2-nitrophenoxy)acetate

Product 1

HCID 66578589[4-(3-Fluoro-phenylethynyl)-2-nitro-phenoxy]-acetic acid ethyl esterYield 52%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (4-bromo-2-nitro-phenoxy)-acetic acid ethyl ester (2.95 g, 9.70 mmol, 1 equiv) and 1-ethynyl-3-fluorobenzene (1.34 mL, 11.6 mmol, 1.2 equiv) in dimethylformamide (15 mL) in a microwave reactor vessel was added triethylamine (4.05 mL, 29.1 mmol, 3 equiv), copper iodide (55 mg, 0.29 mmol, 0.03 equiv) and trans-dichlorobis(tri-o-tolylphosphine) palladium(II) (152 mg, 0.19 mmol, 0.02 equiv). The reaction was placed under an argon atmosphere then heated to 80° C. in a microwave reactor for 30 min. The reaction mixture was then partitioned between ethyl acetate:heptane (1:1) and 1.0 N aqueous hydrochloric acid (100 mL each). The organic layer was separated and washed successively with saturated aqueous sodium bicarbonate, 1:1 saturated aqueous sodium bicarbonate:saturated aqueous ammonium chloride, saturated brine solution (100 mL each) then dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 120 g silica gel column as a solution in dichloromethane (5 mL) then eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 85 mL/min) to give 1.72 g (5.01 mmol, 52%) of the title compound as a brown oil.

Workup

  1. customThe reaction mixture was then partitioned between ethyl acetate:heptane (1:1) and 1.0 N aqueous hydrochloric acid (100 mL each)
  2. customThe organic layer was separated
  3. washwashed successively with saturated aqueous sodium bicarbonate, 1:1 saturated aqueous sodium bicarbonate
  4. dry with materialsaturated aqueous ammonium chloride, saturated brine solution (100 mL each) then dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe product was purified
  8. washthen eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 85 mL/min)

Sources & evidence

ORD record
ord-9ea4b9af7b2f4a28ad27c315027ad250
Source dataset
uspto-grants-2015_05
Patent number
US09023843B2

Reaction notes

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