Gas Phase Synthesis of Ethyl Quinolin-4-one-3-Carboxylates: Experimental and Mechanistic Aspects

LIC. IVANA MALVACIO, DRA. PAOLA L. LUCERO, DRA. E. LAURA MOYANO, DR. D. MARIANO VERA

Congreso; 12 a Conferencia Latinoamericana de Físico-Química Orgánica; 2013

The quinolone structure is extensively used in a variety of pharmacologically active synthetic and natural compounds. All of these applications justify the effort to develop new efficient strategies to synthesize this structural moiety. However, existing synthetic methods for 3-substituted-quinolin-4-ones usually require multistep process, high reflux temperatures (> 250 oC) in organic solvent and laborious isolation of the intermediates. In order to avoid the use of high boiling solvent we have applied the flash vacuum pyrolysis (FVP) methodology to obtain ethyl 6-substituted-quinolin-4-one-3 carboxylates (3) from diethyl 2-((phenylamino)methylene)malonates (1) in a gas phase process. The mechanism for the formation of quinolones 3 was studied using the GAUSSIAN 09 series of programs, at the B3LYP/6-31+G* level of theory. Gas phase pyrolysis of malonates 1 were carried out between 250-400 oC using a typical FVP equipment working at low pressures (10-2 Torr) and contact times (10-2 s) under N2 flow. After the experiments were completed, the pyrolysate was removed with acetone and the quinolones were directly filtered. These products were then recrystallized from dimethylformamide to obtain it in extremely pure form. Yields of the desired products were lower than the values obtained in conventional synthesis, however; in this case the methodology is fast and clean avoiding the use of reaction solvents as diphenyl ether or o-dichlorobenzene. Thus, we found an environmentally benign procedure to prepare ethyl 6-substituted-quinolin-4-one-3 carboxylates. Theoretical calculations are consistent with experimental results involving a ketene intermediate 2 which afford a fast electrocyclization to form the quinolone product 3.