Traditional and modern approaches to the synthesis of quinoline systems by the Skraup and Doebner-Miller methods. (Review)

Abstract

Recent data on classical and modified methods for the synthesis of quinoline systems by the Skraup andDoebner-Miller reactions, not included in reviews on heterocycles, are discussed.The need for compounds containing a quinoline fragment in various regions of human activity has increased in recent times. The great attention paid by researchers to the study of quinoline derivatives is explained by the fact that these compounds exhibit a broad range of antimicrobial activity [1-4] and, particularly, antitubercular activity [5] and antimalarial activity [6,7] and are also present in antiallergic and antiasthmatic agents [8]. Classical methods are widely used for their synthesis, and two of these are discussed in the present review.The most important way of constructing the quinoline system involves the cyclization of a substituent in the side chain of a benzene ring. This applies to the synthesis of quinolines by the Skraup and Doebner-Miller reactions. In the classical form, however, these syntheses take place under fairly harsh conditions, and this reduces their preparative value. In recent years, however, the efforts of synthetic chemists have been directed toward modification of these methods. Both traditional and modified approaches to the synthesis are discussed in this review.The first report on the synthesis of quinoline, realized by passing the vapor of ethylaniline and other alkylanilines over heated lead oxide, was published by Koenigs in 1879; in another method (1880) quinoline was obtained by heating the product from the addition of acrolein to aniline. Soon after this Skraup (1880) [9] and Doebner and Miller (1881) put forward their methods [10]; both these syntheses are close to Koenigs' acrolein method and have found widespread application. THE SKRAUP AND DOEBNER-MILLER REACTIONS (THE TRADITIONAL APPROACH)The construction of the quinoline system by the Skraup and Doebner-Miller methods is based on the reaction of an aromatic amine containing at least one free ortho position with a reagent providing a source of the three-carbon fragment.In the classical Skraup method the aromatic amine is heated with glycerol (1), sulfuric acid (which catalyzes the dehydration of glycerol to acrolein (2)), and an oxidizing agent 7, transforming the initially formed 1,2-dihydroquinoline (6) into the fully aromatized heterocycle 8. In the simplest case, with aniline (3) as amine and nitrobenzene (7) as oxidizing agent, the reaction is represented by the following scheme [11]. __________________________________________________________________________________________

Synthesis of Tetrazoloquinoline‐Based Mono‐ and Bisphosphonate Esters as Potent Anti‐Inflammatory Agents

“…The presence of quinolines in an abundant number of natural products and pharmaceutically active compounds continues to fuel the desire to develop new and/or improved methods for their synthesis . Many representatives have found clinical uses for the treatment of tumor diseases .…”

A Green, Solvent-Free One-Pot Synthesis of Disubstituted Quinolines via A3-Coupling Using 1 Mol% FeCl3

“…[36] The first stage of the Döebner-Miller reaction is a crotonic condensation of two molecules of either an aldehyde or ketone, which results in the formation of an α,β-unsaturated compound (Scheme 4). [31] Scheme 4: Döebner-Miller quinoline synthesis.…”

“…The Döebner-Miller reaction has several drawbacks such as harsh reaction conditions (concentrated hydrochloric acid and sulfuric acid) [31] and isolation of products from complex reaction mixtures which result in poor yields, [37] to name but a few. In 2000, Matsugi and coworkers used a two-phase system, an organic phase and an aqueous acid phase, to synthesize substituted quinolines 14.…”

1-(4-Chlorophenyl)-3-(2-methoxyanilino)propan-1-one

“…For the synthesis of quinoline derivatives, see: Peifer et al (2007). For background to the antimicrobial activity of quinolines, see: Yamashkin & Oreshkina (2006). For further synthetic details, see: Dienys et al (1977); Volkov et al (2007).…”