Skraup quinoline ring synthesi

Skeletal rearrangement s. Rearrangement, skeletal Skraup quinoline ring synthesis... 

Some of the classical quinoline syntheses utilize intramolecular ring-closing SnAr reactions. Among them, the Combes synthesis and the Skraup-Doebner-Miller synthesis are of general relevance. 

A very large group of syntheses in which the /3,y-bond is formed are those in which a side chain electrophile attacks the benzene ring. These include the Skraup and Doebner-von Miller syntheses (dealt with in Section 2.08.2.2.3(ii)), the Knorr, Conrad-Limpach and Combes syntheses of quinolines (dealt with here), the Pomerantz-Fritsch synthesis of isoquinolines, and many syntheses of phenanthridines and of acridines. 

Nitro compounds in alkaline medium are used for rather specific oxidations. 2-Nitropropane in the form of its sodium salt converts benzylic halides into aromatic aldehydes under fairly mild conditions [987. Nitrobenzene transforms isoeugenol [95S] and similar aromatic compounds with side chains that contain double bonds conjugated with the aromatic rings into aldehydes [988, 989], In the Skraup synthesis, nitrobenzene dehydrogenates the dihydroquinoline intermediate to quinoline. 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

This reaction is related to the Skraup Reaction, but is used for the synthesis of quinolines bearing substitutents in the pyridinoid ring. This reaction is also related to the Gould-Jacobs Quinoline Synthesis and Knorr Quinoline Synthesis. 

Quinolines, heterocyclic compounds that contain a pyridine ring fused to a benzene ring, are commonly synthesized by a method known as the Skraup synthesis, in which aniline reacts with glycerol under acidic conditions. Nitrobenzene is added to the reaction mixture to serve as an oxidizing agent. The first step in the synthesis is the dehydration of glycerol to propenal. 

In an early series of papers (50, 51) Kametani et al. attempted to prepare some quinoline-quinones having methoxyl and primary amino substituents in the A-ring. However, these workers were only able to make the demethyl compound (43) via the route outlined in Scheme 3. A key step here involved use of a classical Skraup synthesis for formation of the intermediate quinoline (42). 

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