Isoquinoline Chichibabin reaction

Chichibabin reaction, 5, 409-410 UV spectra, 5, 356 Naphthimidazoles, 2-amino-tautomerism, 5, 368 Naphth[2,3-h]imidazoles oxidation, 5, 405 Naphth[l,2-d]imidazolium salts nucleophilic substitution, 5, 412 Naphth[l, 2-h]isoquinolines... 

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). 

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). 

The first step of the Chichibabin reaction involves attack on the aromatic ring by the nucleophilic amide ion. Novikov et al. (76CHE210) have shown that, for a series of heterocycles whose values lie within the most favorable region for the Chichibabin reaction, the ease of amination in aprotic solvents coincides with the magnitude of except for a disparity between isoquinoline and 1-methylperimidine (Table I). The compounds are listed in decreasing ease of amination. 

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. 

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. ... 

PROBLEM 15.88 Isoquinoline (1) undergoes the Chichibabin amination reaction when treated with potassium amide in liquid ammonia to yield 1-aminoisoquinoline (2) (p. 676). 

---