4-Aminoquinoline ring

Aminoquinolines have been synthesized in a manner analogous to the Niementowski reaction, wherein the carboxylic acid in 1 was replaced with a nitrile (49). This transformation has been carried out under either acidic or basic conditions. Under the former conditions, a variety of Lewis acids have been employed to effect this transformation, including zinc chloride, aluminum trichloride, boron trifluoride diethyl etherate, and titanium tetrachloride. In a representative example, 49 was combined with 50 and heated at reflux in the presence of boron trifluoride diethyl etherate to furnish 51, which contains an embedded 4-aminoquinoline ring system. ... 

Zinc chloride ammonium carbonate Cyclic amines from carboxylic acid amides 4-Aminoquinoline ring closure... 

Oxidation of 5-arylazo-6-aminoquinoline 146 with copper sulfate in pyridine gave the corresponding 2-aryltriazolo[4,5-/]quinolines 147. Condensation of halo-genated nitrobenzenes with triazolo[4,5-/]quinoline 145 yielded the appropriate 2H- and 3//-aryl derivatives. The nitration of 3-phenyl-3//-triazolo[4,5-/]quino-line 147 occurred at position 4 of the phenyl ring (Scheme 46) (73T221). 

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

One example, however, which involves closure of the central pyrimidine ring is the thermally induced intramolecular condensation of the pyrrolidone-substituted aminoquinoline derivative 246 (Equation 73) <1999JHC755>. 

It is of interest to mention that 2-bromoquinoIine, when treated with potassium amide in liquid ammonia, reacts very differently from 3-bromoisoquinoline hardly any 2-aminoquinoline is obtained, but as main product 2-methylquinazoline has been isolated (65RTC1569 67RTC187). This ring transformation involves breaking of the bond between C-3 and C-4 in the covalent o-amino adduct at C-4 (Scheme II.IO). Since this ring transformation cannot be considered degenerate, it is beyond the scope of this book to discuss this reaction in more detail. 

Note, however, that hydroxyls on the benzene ring would be typical phenols. Again, aminoquinolines follow the pyridine precedent and the tautomeric imino forms are not observed. 

Both 2-aminoquinoline and 4-aminoquinoline pro-tonate first on the ring nitrogen, with 4-aminoquinoline being the more basic, the conjugate acid benefiting from increased charge distribution through... 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

The condensation and cyclization of EMME with 4-aminopyridine and 4-aminoquinoline affords, in each case, the 1,6-naphthyridine ring system.59 Albert11 used this reaction to prepare the hydroxy ester (34), which he converted into the parent 1,6-naphthyridine by the following sequence of reactions. 

In the oxidative amination of quinoline, using potassium amide in liquid ammonia and permanganate as oxidant, it was found that the site of ami-nation is strongly depending on temperature. When the amination is carried out at — 65 °C 2-aminoquinoline is isolated (52%) 4-aminoquinoline is formed (with some 2-aminoquinoline) when the amination is performed at room temperature. By NMR spectroscopy it was unequivocally observed that at — 65 °C addition of the amide ion occurs at position 2 of the quinoline ring, yielding the a-adduct 2-amino-1,2-dihydroquinolinide, which under the conditions of the reaction remained stable. When warming up the solution this C-2 adduct irreversibly converts into the... 

Quinolone ring closure to fused heterocycles is possible as shown in equation 33 for the formation of pyrazoloquinolones, which are potential pharmaceuticals51. A modification of this kind of ring closure is the replacement of the carboxyl group by a nitrile leading to aminoquinoline derivatives51 (equation 33). 

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