3-Nitro-2-substituted-quinolines

The first condensation is conducted selectively on a variety of 3-ketoesters and a-formylesters. The first step works well on most simple anilines even when sterically congested and is mostly affected by basicity. Formation of intermediate 3 is problematic when strong electron-withdrawing groups (EWG) are attached to the aniline (e.g., nitro). The cyclization step is promoted thermally in inert solvents as well as using acidic solvents at elevated temperature. When there exists an opportunity to form isomers on cyclization (e.g., m-substituted anilines) a mixture of the 5- and 7-substituted quinolines usually results. 

Under acidic conditions, the formation of a nearly 1 1 mixture of 5- and 7-substituted quinoline-3-carboxylates, with a slight excess of the former, was observed from the 3-chloro- and 3-methyl derivatives. The cycliza-tions of 3-nitro, 3-trifluoromethyl, and methoxy derivatives were carried out only in polyphosphate to give mainly the 7-substituted isomers. 

The Ziegler reaction (see p 278) with organolithium compounds leads exclusively to 2-alkyl- or 2-arylquinolines. For instance, 20 is produced with -butyllithium. After hydrolysis, the primary adducts (e.g. 16) yield stable 1,2-dihydroquinolines (e.g. 17) which can be dehydrogenated by nitro compounds. It is obvious that control of the RLi addition occurs through coordination, because even 2-substituted quinolines (e.g. 18) yield mainly 2-addition products (e.g. 19). 

Syntheses of quinolines from the products of the nucleophilic substitution of hydrogen proved to be also valuable. For instance, orf/io-nitrobenzyl sulfones react with dialkyl maleates and fumarates to produce directly quinoline 2,3-dicarboxylate N-oxides [211]. The reaction proceeds via the Michael addition of the nitrobenzyl carbanion followed by elimination of benzenesulfinic acid and subsequent intramolecular addition of the allylic carbanion to the nitro group. This approach has recently been used for the synthesis of fluorine-substituted quinoline N-oxides (Scheme 89) [212]. 

FrielA,nderSynthesis. The methods cited thus far all suffer from the mixtures which usually result with meta-substituted anilines. The use of an ortho-disubstituted benzene for the subsequent constmction of the quinoline avoids the problem. In the FrieWider synthesis (52) a starting material like 2-aminoben2aldehyde reacts with an CX-methyleneketone ia the presence of base. The difficulty of preparing the required anilines is a limitation ia this approach, but 2-nitrocarbonyl compounds and the subsequent reduction of the nitro group present a usehil modification (53). 

The reaction of /V-henzylideneaniline (19) with alkynes leads to quinolines substituted in the heterocychc ting (56). Except for benzyhdenes bearing nitro substituents, the reaction occurs in good yield and under mild conditions. The method appears capable of elaboration. 

Quinoline, 4-methyl-5,6,7,8-tetrahydro-synthesis, 2, 471 Quinoline, 2-methylthio-3-nitro-3-substituted... 

Quinoline-3-carboxylic acid, l-methyl-6-nitro-4-oxo-antibacterial activity, 1, 180 Quinoline-3-carboxylic acid, 2-oxo-3-substituted... 

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