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Coumarins are naturally occurring molecules that are found in plants that have numerous uses in the medical field because of its biological activity. The wide varieties of its uses include antibiotics, anticoagulants, and sometimes even used in the perfume industry.
SYNTHESIS
Synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2 catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in trifluoroacetic acid at room temperature (15-20 degrees C) under atmospheric conditions.
STEP 1
phenyl acetylene is the starting materialEthyl Phenylpropiolate:Phenylacetylene (500 mg, 4.896 mmol, 1 equivalent) was added to a round bottom flask and flushed with nitrogen. A septum and balloon of nitrogen was then attached and 3-4mL of THF was added by syringe. The flask was cool to -78oC in a dry ice and acetone bath. Next, n-butyllithium (2.36 mL, 1.2 equivalent) was added to the solution and allowed to warm to 0oC for 1 hour. The solution was cooled to -78oC again for 15 minutes, and then ethyl chloroformate (0.702 mL, 7.344 mmol, 1.5 equivalent) was added dropwise by syringe and allowed to warm again to 0oC. The reaction mixture was then quenched by adding 10mL of saturated aqueous NaHCO3 and allowed to stir for 15 minutes. The resulting substance Ethyl Phenylpropiolate was a yellowish-orange liquid. 1H NMR (200 MHz, CDCl3) δ 7.60-7.26 (m, 5H), 4.38 (m, 2H), -O CH2 CH31.44 (m, 3H); -O CH2 CH3IR (neat, NaCl)3551.4, 3399.9, 3958.2, 2934.4, 2872.2, 2236.4, 2211.6, 1744.0, 1709.5 cm-1The conversion of phenylacetylene to ethyl phenylpropiolate was made apparent by the comparison of IR spectras. The phenylacetylene reference IR spectra found on the Spectral Database of Organic Compounds shows a strong peak at about 3300 that the IR of the intermediate lacks. Also the intermediate’s IR contains strong peaks at 3000 and 2230 which are both absent from the starting material’s IR spectrum. Both of these changes indicate a successful conversion of phenylacetylene to the intermediate ethyl phenylpropiolate. STEP 2This specific reaction will result in a ring closure and addition of the ethyl phenylpropiolate aided by the palladium acetate catalyst. The palladium catalyst allows for the addition of an ester to a phenol resulting in a ring closure and product coumarin derivative.6,7-methylenedioxy-4-phenylcoumarin:Sesamol (0.075g, 0.5167mmol, 0.9 equivalent) and ethyl phenylpropiolate (102mg, 0.57405 mmol,1 equivalent) and Palladium acetate (Pd(OAc)2)(0.00394g, 3mol%) were added to a 1 dram vial and cooled to 0oC in an ice water bath. Trifluoroacetic acid (0.5mL) was added to the vial, then the vial was capped and the reaction allowed to proceed overnight. The resulting solid was a brown, sticky, crystalline (0.387 mmol, 67 %yield). 1H NMR (300 MHz, CDCl3) δ 7.55-7.38 (m, 5H), 6.90 (s, 1H), 6.83 (s, 1H), 6.24 (s, 1H), 6.05 (s, 2H);CH2 SANDWICHED BETWEEN 2 OXYGEN ATOMSIR (DCM, NaCl)3553.8, 3401.9, 2958.2, 2872.2, 2236.3, 2211.4, 1744.4, 1717.4 cm-1References
Kotani, M., Yamamoto, K., Oyamada, J., Fujiwara, Y., Kitamura, T.,Synthesis, 2004, 9, 1466-1470.
The insertion of the ethyl phenylpropiolate to the sesamol-palladium intermediate is initially achieved in a cis confirmation. There is then an internal rearrangement of the palladium and CO2Et ligands to the trans confirmation which then allows for an electrophilic aromatic substitution to close the ring.
Ethyl phenylacetylenecarboxylate~Phenylpropiolic acid ethyl ester
4-Bromo-1,2-(methylenedioxy)benzene
.PNG)
