Reaction #308005

Reaction equation

4-(2-Carboxy-ethyl)-3-methyl-benzoic acid methyl ester

triethylamine

citric acid

Oxalyl chloride

(trimethyl-silyl)diazomethane

→

title compound

Yield 71.0%

4-(3-Carboxy-propyl)-3-methyl-benzoic Acid Methyl Ester

Yield 71.0%

Solvents

acetonitrile

water

dichloromethane

Ethyl acetate

Conditions

Workup

1. 1
   OtherSolvents were removed in vacuo
2. 2
   Otherazeotroped with toluene
3. 3
   workup.DISSOLUTIONThe residue was redissolved in acetonitrile (20 ml)
4. 4
   Temperaturecooled to 0° C
5. 5
   workup.STIRRINGthe reaction mixture was stirred for 5 h at 0° C.
6. 6
   Other20 h
7. 7
   Otherat room temperature
8. 8
   Otherthe layers were partitioned
9. 9
   WashThe organic layer was washed with saturated NaHCO3
10. 10
    Dryingbrine, dried
11. 11
    Concentrationconcentrated in vacuo
12. 12
    OtherThe residue was purified by flash chromatography on silica gel (eluant; 50% ethyl acetate:50% cyclohexane)
13. 13
    OtherThe product obtained
14. 14
    Otherwas sonicated in an ultrasound bath
15. 15
    workup.WAITAfter 30 min at room temperature
16. 16
    Othersolvents were removed in vacuo
17. 17
    workup.ADDITIONEthyl acetate and 10% aqueous citric acid solution were added
18. 18
    Otherthe layers were partitioned
19. 19
    WashThe organic layer was washed with brine
20. 20
    Otherdried
21. 21
    Concentrationconcentrated in vacuo
22. 22
    OtherThe residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane)

Procedure

4-(2-Carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (500 mg, 2.25 mmol) was dissolved in dry dichloromethane (10 ml) and a few drops of DMF. Oxalyl chloride (0.393 ml, 4.5 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in acetonitrile (20 ml) and cooled to 0° C. A solution of 2M (trimethyl-silyl)diazomethane in hexanes (2.25 ml, 4.5 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 0° C. then 20 h at room temperature. Ethyl acetate then 10% citric acid solution were added and the layers were partitioned. The organic layer was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% ethyl acetate:50% cyclohexane). The product obtained was dissolved in a mixture of acetonitrile and water. A solution of silver benzo-ate (103 mg, 0.45 mmol) in triethylamine (1.25 ml, 9 mmol) was added gradually while the mixture was sonicated in an ultrasound bath. After 30 min at room temperature, solvents were removed in vacuo. Ethyl acetate and 10% aqueous citric acid solution were added and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (378 mg, 71%).

Source