Quinoline Chichibabin reaction

For instance, both quinoline and isoquinoline undergo the Chichibabin reaction (with formal hydride elimination, see Chapter 5) to give 2-aminoquinoline 6.23 and 1-aminoisoquinoline 6.24 respectively. Halogen substituents ortho to the nitrogen atoms are easily displaced, as in the preparations of 6.25 and 6.26. 

The Chichibabin reaction is exemplified by the amination of 2-methylpyridine (308) by sodium amide in toluene via intermediate 309 to yield 6-amino-2-methylpyridine (310). This reaction has been applied to pyridines, quinolines, isoquinolines, and naphthyridine as well as to benzimidazole, and was reviewed in great detail (66AHC229 78RCRI042 88AHC1). 

Kametani, T., Nemoto, H. Syntheses of heterocyclic compounds. CCLIII. Mechanism of the formation of an abnormal product in the Chichibabin reaction of quinoline. Chem. Pharm. Bull. (Tokyo) 1968,16, 1696-1699. 

Pyridine is an aromatic 6n electron heterocycle, which is isoelectronic with benzene, but electron deficient. Nucleophiles thus add almost invariably to carbon C2 of the imine-like C=N double bond. Perhaps the best known nucleophilic addition is the Chichibabin reaction with sodium amide in liquid ammonia, giving 2-aminopyr-idine. Reactions of the quinoline moiety of cinchona alkaloids can be more complex. Although expected 2 -addition can be achieved easily with organolithium reagents to yield 13 (Scheme 12.6) [9], LiAlH4, for example, has been shown to attack C4 en route to quincorine and quincoridine (Schemes 12.4 and 12.5). C4 selectivity is due to chelation of aluminum by the C9 OH oxygen. 

Under classical Chichibabin conditions (heterogeneous), basicity of the heterocycle plays an important role in the outcome of the reaction. Compounds having a pK in the range 5-8 have successfully been aminated. They include pyridines, quinolines, isoquinolines, and benz- and naphthimidazoles. Outside of this pK range, the Chichibabin reaction proceeds with difficulty or not at all (72CHE1280 78RCR1042). 

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). 

The Chichibabin amination (see p 277) proceeds with alkali amides in liquid ammonia. In this reaction, quinoline provides a mixture of the 2- and 4-amino compound 14 and 15, whereas 2-phenylquinoline yields the 4-amino compound ... 

The question of the rate-determining step in the Chichibabin reaction is still open. Clearly, it is difficult to expect that such a complex process can be controlled by any single parameter. On the basis of the rate of hydrogen gas evolution, the following sequence of the reactivity of aza-heterocyclic compounds has been established 1-R-benzimidazoles > isoquinoline > 1-R-perimidines > benzo[/]quinoline > pyridine acridine. Evidently, this raw indicates that sodamide amination depends on number of factors, involving electron deficiency of the substrate C(a)-atom, ease of the adduct aromatization, substrate basicity, etc. Evidently, acridine s position in this raw reflects the difficulty of the y-amination. 

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. 

Nucleophilic reactions take place on the hetero ring of isoquinoline, preferably in the 1-position. For instance, the Chichibabin amination with NaNH2 in liquid ammonia yields 1-aminoisoquinoline 5. The Ziegler reaction with w-butyllithium furnishes the 1-substituted product 7 as with quinoline, benzene ring annulation stabilizes the primary addition product 6 (1,2-dihydroisoquinoline), which can be isolated and dehydrogenated to 7 by nitro compoxmds ... 

Similar to that of pyridine, the Chichibabin amination on quinoline and isoquinoline proceeds with alkali metal amides in liquid ammonia. In accordance to that, the reaction of quinoline with liquid ammonia initially forms a complex, which allows amide anion to add to the heterocyclic core of quinoline and isoquinoline bicycle, obtaining 2- or 4-aminoquinolines and 1-aminoisoquinolines, respectively, in good yields. ... 

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... 

Cacchi synthesis (indole) 140 Chichibahin reaction 352 Chichibabin synthesis (indolizine) 153 Claisen synthesis (isoxazole) 188 Combes synthesis (quinoline) 399 Cook-Heilbron synthesis (thiazole) 206 Corey synthesis (oxirane) 22 Cornforth rearrangement 171 imino-Corey reaction 36... 

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