Conrad-Limpach synthesis

A few extensions of the Conrad-Limpach synthesis have been applied to the synthesis of 4,7-phenanthrolines. Unlike o-phenylenediamine, which gives a quinoxaline derivative, p-phenylenediamine reacts with excess of ethyl ethoxalylpropionate to give an intermediate bisanil, which cyclizes in hot diphenyl ether to afford 3,8-dicarboethoxy-l,10-dihydroxy-2,9-dimethyl-4,7-phenanthroline in high yield.237 With diethyl ethoxymethylenemalonate as condensing agent, 6-amino-8-methoxy-quinoline has been converted into 2-carboethoxy-l-hydroxy-6-methoxy-4,7-phenanthroline.238 A related condensation affording 1-... 

Similar to the Combe synthesis, primary aromatic amines condense with alkyl acetoacetates at lower temperatures to give / -anilinocrotonates, which can be used as precursors for cyclization to 4-hydroxyquinolines177 by action of hot sulphuric acid or hydrochloric acid in a Conrad-Limpach synthesis. 

A modification of the known Conrad-Limpach synthesis of quinolines, using anilino-methylenemalonates instead of / -anilinocrotonates, has long been known290,291. 

This sequence calls to mind an old, long-known reaction the thermal version of the Conrad-Limpach synthesis of quinoline-4-one derivatives by thermolysis of aryl-aminocrotonates110a arylaminomethylenemalonates1 lob c arylaminomethylene-cyanoacetates110d and related compounds111-114. ... 

The Conrad-Limpach synthesis has been extended also to corresponding derivatives of 3-aminopyridines. With position 2 blocked in the starting aminocrotonate (289), one obtains 1,7-naphthyridineones (290)lll but if this position is free, as in the aminomethylenemalonate derivative (291), only 1,5-naphthyridineones (292) are formed113 ... 

A modification of the known Conrad-Limpach synthesis of quinolines, using anilino-methylenemalonates instead of j -anilinocrotonates, has long been known ° N-Aryl and N-heteroaryl derivatives of aminomethylene malonates are also very useful and fruitful synthons for formation of 4-aminoquinolines used as antimalarials (equation 215), of the anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates and of antibacterial nalidixic acid derivatives (equation 216). Each of these is an important group of pharmaceuticals, developed in the last twenty years. Because of its medicinal interest this route is widely used for synthesis of quinolines and pyridinofused heterocycles. The chemistry has been comprehensively reviewed in a recent monograph . Hence, no further details are given here. 

EUP521368>. The pyrrolopyridazines (272) are obtained by a Conrad-Limpach synthesis (Equation (129)) <94JHC409>. 

Synthetic pharmaceuticals based on the quinoline ring are numerous. During World War II when supplies of the highly important antimalarial quinine became scarce, research was conducted in many laboratories to find a synthetic substitute. From this research came the dmg chloro-quine (9.103) and many related highly active compounds. Chloroquine is still in use today in the treatment of malarial infections. It is synthesized by a modification of the Conrad-Limpach synthesis as shown in Scheme 9.52. 

Alternatively, several new methods were unfolded which eventirally became conventional for synthesizing the structural core of quinoline. These are (a) Combes synthesis using anilines and p-diketones (b) Conrad-Limpach synthesis employing anilines and P-ketoesters (c) Doebner-Miller reaction involving anilines and a,P-unsatmated carbonyl compotmds (d) Friedlander synthesis using 2-amino-benzaldehyde and acetaldehyde (e) Povarov reaction which involves reaction of an aniline, a benzaldehyde and an activated alkene also known as Aza-Diels-Al-... 

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