Quinolines, activation 2- amino-, formation

Egan, T. J., Hunter, R., Kaschula, C. H., Marques, H. M., Misplon, A., and Walden, J. (2000). Structure-function relationships in aminoquinolines Effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity. J. Med. Chem. 43, 283-291. 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

The addition of water (see Section II,B) and other nucleophiles across the 3,4-double bond of quinazoline is well established. More recently other nucleophiles, such as dimedone, have given isolable 3,4-adducts. ° Similarly, malononitrile and other compounds with active methylene groups added across the 3,4-double bond of quinazoline, but in this case the reaction proceeded further with ring opening and formation of 2-amino-3-cyano-quinoline. The dimedone adduct was also made to react further in the presence of alkali to form the acridone 38. ... 

An intramolecular amino-defluorination reaction at C-8 in the N-amidino-substituted quinolones 292, activated by acetic anhydride, affords tricyclic compounds 293 with the [5,6,l-7,y]-annelation of the triazine ring relative to the quinoline system through the N4-C5 bond formation (Scheme 179) <1997MC109, 2001JEC25, 2002RCB663, 2006HAC579>. 

In 1961, Priest el al. (6S) found that kidney and liver contiuned a soluble enzyme system which could promote the oxidation of 3-hydroxyanthranilic acid to quinolmic acid. Bokman and Schweigert (64) were able to demonstrate that an intermediate was involved in the oxidation. This intermediate can be characterized by an absorption maximum at 360 laix and has been referred to as compound 1, which spontaneously decomposes to quinolinic acid (66-67). Oxygen and ferrous ion are required for the formation of the intermediate (67), but not for its quantitative conversion to quinolinic acid. Compoimd I has been established by Wiss and Bettendorf (68) to be l-amino-4-formyl-l,3-butadiene-l,2-dicarboxylic acid. The enzyme 3-hydroxyanthranilic acid oxidase from beef liver has been purified slightly and evidence for the requirement of ferrous ion and sulfhydryl groups for activity has been obtained (68a). 

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