Pyridine Chichibabin reaction

First described in 1905, the Chichibabin reaction was carried out by passing vapors of aliphatic aldehyde 31 and ammonia over alumina at 300-400°C to produce the corresponding pyridine derivative 32. As a consequence, this method generates 2,3,5-trisubstiluted pyridines. 

No direct nucleophilic substitution of the hydrogen atoms in the isoxazole nucleus a or y to the nitrogen is as yet known. Thus, the Chichibabin reaction fails in the isoxazole series because of the cleavage of the heterocyclic nucleus under these conditions. It is the lability of the isoxazole ring toward nucleophilic reagents that makes the chemical behavior of isoxazole fundamentally different from that of pyridine. 

Pyridine and other heterocyclic nitrogen compounds can be aminated with alkali metal amides in a process called the Chichibabin reaction The attack is always in the 2 position unless both such positions are filled, in which case the 4 position is attacked. Substituted alkali metal amides (e.g., RNH and R2N ) have also been used. The mechanism is probably similar to that of 13-15. The existence of intermediate ions such as 15... 

The Chichibabin reaction for the synthesis of indolizines has been revisited and some variations have been proposed. The modified benzotriazole 168 reacted with substituted pyridines 167 in refluxing dimethylformamide (DMF). The indolizine 169 bears a triazole moiety that proved useful for the construction of benzo-annulated indolizines <2000JOC8059>. Also, cyclic iminium ylides like 170 can be used in the Chichibabin reaction. Their solvolysis produced the corresponding indolizinones 171 (Scheme 40). 

Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 308-309. (Review). 

In general, the 1,3-diazoles do not react by nucleophilic substitution, although imidazole can participate in the Chichibabin reaction with substitution at C-2 the position of substitution is eqmvalent to that noted with pyridine (see Section 11.4.1). Nucleophilic species that are strong bases, like... 

Aminopyridines possess preparative interest and are conventionally prepared by substitution at ready-made pyridine rings. Pyridine may be converted into 2-aminopyridine using the so-called Chichibabin reaction in which pyridine is reacted with sodium amide in dimethylaniline [Eq.(26)]. 

Pyridine and other heterocyclic nitrogen compounds an be aminated with the alkali-metal amides by chichibabin reaction. The attack is always in the 2 position unless both such positions... 

Only very powerful nucleophilic reagents such as HO-, NHJ, RLi, LAH, etc., react effectively at the ring carbon atoms of simple pyridines (c/. equation 22), and even then forcing conditions may be required. Oxidation of pyridine to 2-pyridone with potassium hydroxide, for example, requires a temperature of ca. 300 °C. Nevertheless, some of these reactions can be of very considerable synthetic importance, especially the classical Chichibabin reaction for the preparation of 2-amino, alkylamino and hydrazino heterocycles (equation 28). The sequence of substitution is C-2, then C-6 and finally C-4. The Chichibabin reaction also requires rather vigorous conditions and often proceeds in only moderate yield the simplicity of the approach, however, is such that it often represents the method of choice for the preparation of the requisite substituted heterocycle. 

The results of some of the many aminations of pyridine and its derivatives that have been carried out appear in Table 14. Yields are quoted where possible but these should not be used for quantitative comparisons as reaction and work up conditions vary widely. 2-Alkylpyridines aminate at the vacant a-position, except when the substituent is very large. 2-f-Butylpyridine does not undergo the Chichibabin reaction, probably because the bulky 2-f-butyl group prevents adsorption on to the sodamide surface. In contrast, 2-phenylpyridine undergoes amination in very good yield. Aminations of 2- and 4-methyl-pyridines do not involve attack on the anhydrobases in aprotic solvents, but some ionization does take place in liquid ammonia. 4-Benzylpyridine forms a carbanion (148) which is only aminated with difficulty by a second mole of sodamide (equation 103). 

Bipyridyls are by-products in the Chichibabin reaction. The dimerization of methyl-pyridinium salts has been patented, as it provides a route to the important herbicide paraquat (69USP3478042). Pyridine may undergo reduction in the presence of other nftetals as mentioned in Sections 2.05.4.7.5 and 2.05.4.7.6. 

Figure 8-19. In the Chichibabin reaction a pyridine reacts with sodium amide in a solvent such as yV,yV-dimethylaminobenzene. The initial product is a dihydropyridine, which is oxidised to give a 2-aminopyridine. The attack of the amide nucleophile occurs predominantly at the 2-position of the pyridine.

Under conditions of high temperatures the intermediate anion can re-aromatise by loss of a hydride ion, even though it is a very poor leaving group. This is illustrated by the Chichibabin reaction of pyridine and sodamide to produce 2-aminopyridine 5.26. The immediate product of the reaction is 5.27, the sodium salt of 5.26, as the eliminated hydride ion is very basic. Protonation of this sodium salt during the aqueous workup then regenerates 5.26. A simplistic rationale is shown below. 

Because of the presence of nitrogen in the aromatic ring, electrons in pyridine are distributed in such a way that their density is higher in positions 3 and 5 (the P-positions). In these positions, electrophilic substitutions such as halogenation, nitration, and sulfonation take place. On the contrary, positions 2, 4, and 6 (a- and y-positions, respectively) have lower electron density and are therefore centers for nucleophilic displacements such as hydrolysis or Chichibabin reaction. In the case of 3,5-dichlorotrifluoropyridine, hydroxide anion of potassium hydroxide attacks the a- and y-positions because, in addition to the effect of the pyridine nitrogen, fluorine atoms in these position facilitate nucleophilic reaction by decreasing the electron density at the carbon atoms to which they are bonded. In a rate-determining step, hydroxyl becomes attached to the carbon atoms linked to fluorine and converts the aromatic compound into a nonaromatic Meisenheimer complex (see Surprise 67). To restore the aromaticity, fluoride ion is ejected in a fast step, and hydroxy pyridines I and J are obtained as the products [58],... 

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). 

The reactivity of pyridine toward nucleophilic substitution is so great that even the powerfully basic hydride ion, H", can be displaced. Two important examples of this reaction are amination by sodium amide (Chichibabin reaction), and alkylation or arylation by organolithium compounds. 

Aminopyridine is prepared conventionally by the substitution of the pyridine ring via the so-called Chichibabin reaction using sodium amide in dimethylaniline [36]. 2-Aminopyridine is used in the manufacture of several chemotherapeutics and of dyes for acrylic fibers, and as an additive for lubricants [37]. Alkyl thiocyanates react [38] to give 2-alkylthiopyridines (eq. (12)) which are otherwise accessible only by multistep synthetic pathways [39]. The catalytic reaction (eq. (12)) seems to offer on easy entry into the pyrithione systems. 

In the laboratory of J.S. Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1/-/-imidazo[4,5- i]pyridine (PHIP), a mutagenic compound isolated from cooked beef, and its 3-methyl isomer have been accomplished. The synthesis of PHIP began with the commercially available 3-phenylpyridine, which was aminated at the 6-position with sodium amide in toluene by the Chichibabin reaction in 58% yield. 

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