Synthesis of Quinolines: A Green Perspective

Abstract

The quinoline scaffold is present in a vast number of natural compounds and pharmacologically active substances, comprising a significant segment of the pharmaceutical market. The classical methods for the synthesis of this heterocyclic skeleton require the use of expensive starting materials and high temperature conditions. Chemists play a fundamental role in the construction of a sustainable future through the pursuit of greener chemical processes. As so, the development of new synthetic methods using more efficient energy sources and less hazardous solvents as well as renewable and eco-friendly catalysts to attain the quinoline scaffold can provide significant environmental and economic advantages. This review unveils green methods used in the synthesis of quinolones. Important green metrics are calculated for each proposed method and the statistical analysis allowed us to propose the best approaches for further investigation. The applied research is eventually unveiling the full potential of Friedländer and/or multicomponent reactions, to improve atom economy. The quinoline structural motif is readily available through a number of classical synthetic routes and from commercially available reagents. The Friedländer synthetic method (A) from ortho-aminoacetophenones (10) and the Skraup (B), Combes (D) and Doebner-Miller (F) syntheses from anilines (11), as well as its adaptations, are good examples. Moreover, the Conrad-Limpach (C), Gould-Jacobs (E) and Camps (G) routes for the synthesis of quinolones are widely used methods (Scheme 1). Still, all classical methods have similar disadvantages, requiring highly acidic and/or oxidizing media, high temperatures and long reaction times.Moreover, most of these synthetic routes present selectivity problems with meta-substituted substrates and its versatility is limited by the reactivity of the methylenic carbon involved in the aldol reaction. 19 Although efficient and versatile, classical routes towards the synthesis of quinolines present serious environmental concerns as most synthetic routes use great excess of a reagents and produce a significant amount of toxic waste.

Inhibitors of the Detoxifying Enzyme of the Phytoalexin Brassinin Based on Quinoline and Isoquinoline Scaffolds

“…Quinolines can be synthesized using a number of classical methods including the Friedländer, Skraup, Combes, and Doebner–von Miller syntheses from anilines and carbonyl compounds, as well as metal-catalyzed dehydrogenative cyclization and other “greener” methods [ 14 , 15 , 16 , 17 ]. In the current work, quinolines 5a – 5f , 6a – 6f and 7a – 7g were synthesized using the Friedländer method by condensation of the corresponding 2-aminobenzaldehydes, prepared from substituted 2-nitrobenzaldehydes [ 18 ], with aldehydes or ketones.…”

Recent synthetic efforts in the preparation of 2-(3,4)-alkenyl (aryl) quinoline molecules towards anti-kinetoplastid agents

“…On the other hand, following pharmaceutical green chemistry principles, which seek to eliminate unnecessary environmental impact, but deliver efficiently life-saving medicines, each synthesis including quinoline synthesis, must strive for the right choice of starting material, ideal number and order of chemical steps, the suitable use of solvents and reagents, and effective strategies for isolation and purication. 34,35 Moreover, sometimes there are not available green methods for the preparation of active antitrypanosomal quinoline molecules, but in general, the developments in the quinoline chemistry towards new antiparasitic quinoline agents must harmonize the classical syntheses offering higher efficacy, promptness and a greater orientation to molecular diversication.…”

Deep Eutectic Solvents as Unconventional Media for Multicomponent Reactions

“…Quinoline derivatives, an important class of nitrogenbased heterocycles with remarkable biological activities, have attracted attention of the synthetic organic chemists over the past years. 93,94 Recently, Shahabi and Tavakol 95 showed that the reaction of anilines with aromatic and enolizable aldehydes, catalyzed by ChCl/SnCl 2 (1:2), can efficiently furnish trisubstituted quinolines (13) in good to excellent yields and mild conditions (Scheme 12).…”