The Role of the Catalyst on the Reactivity and Mechanism in the Diels–Alder Cycloaddition Step of the Povarov Reaction for the Synthesis of a Biological Active Quinoline Derivative: Experimental and Theoretical Investigations

Abstract

An experimental and theoretical study of the reactivity and mechanism of the non-catalyzed and catalyzed Povarov reaction for the preparation of a 4-ethoxy-2,3,4,4a-tetrahydro-2-phenylquinoline as a biological active quinoline derivative has been performed. The optimization of experimental conditions indicate that the use of a catalyst, namely Lewis acid with an electron-releasing group, creates the best experimental conditions for this kind of reaction. The chemical structure was characterized by the usual spectroscopic methods. The prepared quinoline derivative has been also tested in vitro for antibacterial activity, which displays moderate inhibitory activity against both Escherichia coli and Staphylococcus aureus. The antioxidant activity was investigated in vitro by evaluating their reaction with 1,1-diphenyl-2-picrylhydrazyl DPPH radical, which reveals high reactivity. The computational study was performed on the Diels–Alder step of the Povarov reaction using a B3LYP/6-31G(d,p) level of theory. The conceptual DFT reactivity indices explain well the reactivity and the meta regioselectivity experimentally observed. Both catalysts enhance the reactivity of the imine, favoring the formation of the meta regioisomers with a low activation energy, and they change the mechanism to highly synchronous for the Lewis acid and to stepwise for the Brønsted acid. The reaction of imine with allyl alcohol does not give any product, which requires high activation energy.

Essential Oils and Eutectic Solvents in the Povarov Reaction for the Synthesis of Tetrahydroquinolines: A Lesson of Cycloadditions, Stereochemistry, and Green Chemistry

“…Regarding the mechanism, although there is debate in literature, it is believed that the reaction starts with the formation of N-arylimines (azadiene) in the more stable E stereoisomer which are activated by the catalyst and might follow a formal [4 + 2] concerted cycloaddition through a trans - endo -favored transition state followed by a 1,3-hydrogen shift or a stepwise polar mechanism proceeding via zwitterionic intermediates (Figure ). − …”

A Mechanism Study and an Investigation of the Reason for the Stereoselectivity in the [4+2] Cycloaddition Reaction between Cyclopentadiene and Gem-substituted Ethylene Electrophiles

“…Today, in addition to conjugated 1,3-dienes, conjugated nitroalkenes [5][6][7] are tried quite often as hetero-analogues of dienes. The use of ethene heteroanalogues as components of the cycloaddition reaction includes molecular segments containing nitrogen [8,9], oxygen [10,11], sulphur [12,13], selenium [14].…”

Synthesis of tetrahydroquinolines and quinoline derivatives through the Lewis acid catalysed Povarov reaction: A comparative study between multi step and multi-component methods

“…In continuation of our research program in the field of enantioselective synthesis of the heterocyclic compounds by cycloaddition reactions [14,15], herein, we have interested for the synthesis of some tetrahydroquinolines and or the corresponding quinolines using the Povarov reaction ([4+2] cycloaddition reaction).…”