6- Aminoquinolines, reaction with potassium

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). ... 

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. 

Alkylpyridines are aminated preferentially at the 2-position, but reaction is slower than in the parent system. Quinoline is difficult to aminate and only a low yield of 2-aminoquinoline (32%) is obtained from reaction with sodamide in toluene. When dimethylaniline is employed as solvent, 2-amino-3,4-dihydroquinoline (24%) becomes the major product, and the yield of 2-aminoquinoline drops to 7%. The best yields of 2-aminoquinoline (53-69%) have been obtained by using barium or potassium amide in liquid ammonia. Use of the potassium salt also produces a 10% yield of the 4-amino isomer. The... 

Heating of 4-chloroquinolines with potassium fluoride (tetrabutylphosphonium fluoride) in DMSO affords only low yields of the corresponding 4-fluoro compounds [39, 40], however use of microwave irradiation (300 W) results in the formation of 2-fluoroquinolines from 2-chloroquinolines in 60-62 % yields [41], Replacement of the diaza group with the fluoride ion, the method which is widely used in heterocyclic chemistry, has also found its application to obtain fluo-roquinolines, as illustrated, for instance, by the syntheses of 3-fluoroquinoline from 3-aminoquinoline [42] and 3,5-difluoroquinoline from 3-fluoro-5-aminoquinoline, respectively [43], 3,7-Difluoro-6-methoxyquinoline 69, one of the key intermediates for the synthesis of antibacterial agents, has been obtained by the reaction of 3-amino-7-fluoro-6-methoxyquinoline with sodium nitrite in the presence of hydrogen borotetrafluoride (Scheme 26) [44],... 

In a Chichibabin-type reaction (see Section 2.4.2), quinoline reacts with potassamide (KNH2) in liquid ammonia at -70 °C to give 2-amino-1,2-dihydroquinoline and this is oxidized by potassium permanganate [manganate(VII)] at the same temperature to yield 2-aminoquinoline (Scheme 3.6). If the temperature is allowed to increase to -45 °C the adduct rearranges into 4-amino-1,4-dihydroquinoline, and upon oxidation this product gives 4-aminoquinoline. 

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... 

Reactivity of 5,6,7,8-tetrafluoroquinoline 130 with the fully fluorinated benzene ring towards the amide anion has been studied [104]. The Chichibabin amination at C-2 has been shown to occur by action of sodium (potassium) amide in liquid ammonia in the presence of potassium permanganate, however only a low yield of the corresponding 2-aminoquinoline has been reached due to concurrent amino-defluorination reactions, taking place at positions 6 and 7 (Scheme 69). 

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