Amination of quinolines

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... 

In the amination of quinoline in liquid ammonia, the initially formed -complex 251 is fully isomerized on heating to the more stable -complex 252. Adding potassium permanganate to either -complex, allows 2-amino- or 4-aminoquino-lines to be obtained in good yields. 

Tondys, H., Van der Plas, H. C., Wozniak, M. a-Adduct formation in liquid ammonia. Part 41. On the Chichibabin amination of quinoline and some nitroquinolines. J. Heterocyd. Chem. 1985, 22, 353-355. 

Early work on the amination of quinoline and substituted quinolines showed that the parent compound gave only a 32% yield of 2-aminoquinoline (78) in aromatic hydrocarbons (20MI1). Many derivatives, including quinoline carboxylic acids and amides, formed amino products more readily. However, amino- and hydroxyquinolines do not participate in the Chichibabin reaction (78RCR1042). 

A more important Bergstrqm s idea was to use an oxidant (a reducible substance, as he called it) to promote elimination of the hydride ion [45]. A number of compounds were tested for this purpose, namely LiNOs, NaNOs, Sr(N03)2, Ba(N03)2, KSCN, Ba(SCN)2, NaNa, and KIO3. The best results were achieved with KNO3. For instance, amination of quinoline in the presence of KNO3 afforded 2-aminoquinoline in 22-53% yield, while without this oxidant it fell down to 6%. 

Scheme 8 Kinetic and themodynamic control in oxidative amination of quinoline...

Scheme 52 cine-Amination of quinoline 1-oxide with aminopyridines... 

The standard Chichibabin amination of quinoline with sodium amide in DMA gives 2-aminoquinoline in a low 7% yield and 2-amino-3,4-dihydroquinoline in a 24% yield. Not until the introduction of the Chichibabin oxidative amination variant (e.g., in the presence of KMn04) were these yields improved. Regio-chemical outcome depends on reaction temperature (kinetic or thermodynamic control). 2-aminoquinoline (39) forms at -65 °C, i.e., the kinetic adduct, and is isolated in a 50-55% yield with no evidence of 4-amino adduct formation, whereas 4-aminoquinoline (40) forms in 60-65% yield at 15 °C, i.e., the thermodynamic adduct (oxidant added at -45 C), with 6-7% of 39. Substituted quinolines give various... 

Nucleophilic substitution by amides converts acid chlorides to acid amides and pyridines to 2-aminopyridines (Tschitchibabin reaction). The amination of quinolines belongs to the few reactions where Ba(NH2)2 gives better results than the alkali amides [1, 2]. 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

Reductive amination of dihydropyran (which may be regarded as the dehydration product of the cyclic acetal of 5-hydroxy-pentanal) in the presence of isopropylamine and a trace of acid affords the aminoalcohol, 96. Treatment of this compound with thionyl chloride affords the haloamine, 97. Alkylation of the quinoline, 92, with this halide yields pentaquine (98). ... 

Beside metal salts, a variety of other modifiers, which include amines, chlorobenzene, hydroxides (S2,S2a), and sulfur compounds, have been used. Among amines used are quinoline (SJ0J7,S4), pyridine (29,33,50,60,64), piperidine, aniline, and diethylaniline. The reduction may be quite sensitive to these modifiers for instance, one drop of quinoline was sufficient to cause hydrogenation to come to an abrupt stop after absorption of I mol of hydrogen (2a). 

Silylation-aminations of a variety of other hydroxy-N-heterocycles, for example 4(lH)-pyridinone, 2(lH)-pyrimidone, uracil, 2(lH)-quinoline, and 9(10H)-acridone are described in the full paper, which was published in English [27]. 

Scheme 19 Synthesis of quinolines by iron(III)-catalyzed three-component coupling/hydroaryla-tion of aldehydes, alkynes, and amines...

With aliphatic amines, the decomposition catalysis is moderate with heterocyclic aromatic amines (pyridine, quinoline), 0.1 % of amine is sufficient to cause maleic anhydride to decompose. An accident has also been mentioned with NaOH. This decomposition also takes place in the presence of sodium, lithium, ammonium, potassium, calcium, barium, magnesium and beryllium cations. 

Table 1 Amines co-fed in the hydrogenation of quinoline, their quadrant classification (16) and pKa values (15) n.a. = not available.

Table 2 Catalytic activity for the hydrogenation of quinoline in the presence of aliphatic or aromatic amines (0.3 g of the 5 wt% Rh/Al203-1 catalyst T = 373 K PH2 = 2.0 MPa reaction time (where not indicated) = 6 h 41 mmoles of quinoline (82 in the test in absence of amine) and 41 mmoles of amine in 100.0...

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