An exhaustive computational mechanistic study of the Gould-Jacobs type thermal cyclization using Coupled Clusters and DFT first principles methodologies

IVANA MALVACIO; E. LAURA MOYANO; D. MARIANO, A. VERA

Villa Carlos Paz, Cordoba

Congreso; 13a Conferencia Latinoamericana de Físico-Química Orgánica (CLAFQO-13); 2015

The quinolone structure is extensively used in a variety of pharmacologically active synthetic and natural compounds. Particularly, 4-quinolones derivatives are an important class of antibacterial, antidiabetic and anticancer agents, besides being used as structural moiety for drug candidates. The synthesis of several ethyl-quinolon-4-one-3-carboxylates was performed from diethyl 2-((phenylamino)methylene)malonate precursors evaluating two approaches: microwave induced thermolysis in solution and flash vacuum pyrolysis procedure. In both cases, quinolones were obtained in good yields and high purity; however, microwave irradiation resulted more advantageous for target compounds preparation. A detailed mechanistic study was carried out to understand the formation of quinolones from the aminomethylenemalonate derivatives at different levels of theory, mainly CAM-B3LYP and CCSD(T) with basis up to 6-311+G(d,p). Despite the cyclization steps were thought to follow a Gould-Jacobs scheme, known since 1939, important mechanistic insights were revealed from the highly correlated calculations. A comprehensive series of intermediates on each reasonably possible path were characterized and the thermochemically favored reaction paths were identified for three representative aminomethylenemalonate starting materials. Synthetic aspects such as the appearance of lateral products and the slight sensitivity to the substituents on the aminomethylenemalonate precursor were understood at molecular level. Finally, the availability of gas phase experimental data in conditions which allow to focus on unimolecular processes was also helpful to illustrate some of these observations from the thorough potential energy surface.