By Chichibabin reaction

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... 

Aminopyridine, and ambident reactivity, 63 bromination of. 79 by Chichibabin reaction, 12 diazotization of. 67 and HSAB, 63 nJtration of. 72... 

Amines are insufficiently nucleophilic to react with most azoles which do not contain a ring oxygen, and the stronger nucleophile NH2 is required. When treated with amide ions, thiazoles can be aminated in the 2-position by NaNHa at 150 °C. Only TV-substituted condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions. Imidazoles are aminated by alkaline NH2OH. 

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. 

Sometimes, for example for analytical purposes, it is convenient to make use of the smooth cleavage of 3-substituted isoxazoles by sodium amide on heating in inert solvents. It is to be noted that, although the reaction occurs in an inert solvent, cleavage of the heterocyclic nucleus is effected rather than a Chichibabin reaction (125->126). 

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)]. 

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. 

Starting with 2,4-diphenyl-1,3,5-triazine and KNH2-NH3, adduct 63 (Table XIII) is formed.116 The reaction mixture slowly leads to 2-amino-4,6-diphenyI-l,3,5-triazine by a mechanism that is shown by l5N labeling to consist of an addition-elimination process. Therefore, adduct 63 is likely to be a true reaction intermediate for the Chichibabin reaction. Although a related substrate, 2-methyIthio-4,6-diphenyl-1,3,5-triazine, gives the 2-amino derivative exclusively by the ANRORC mechanism, which is likely to involve the addition of NH2" to a phenyl-bearing position in the initial step, the formation of such adducts as 64 has not been reported.116... 

The structure of the reaction product of 2-aminopyridine and diethyl malonate, described by Chichibabin as 2,4-dioxo-3,4-dihydro-2//-pyrido-[l,2-<7]pyrimidine,96 was first questioned by Snyder and Robison253 on the basis of the high melting point and poor solubility of the compound. They suggested the tautomeric 2-hydroxy-4-oxo-4H-pyrido[l,2-a]pyrimidine structure. The problem was solved by Katritzky and Waring273 who compared the UV spectrum of the product with that of fixed tautomers and found that the product may best be described as anhydro- 2-hydroxy-4-oxo-4/f-pyrido[l,2- ]pyrimidinium)hydroxide (63). Because of the chemical behavior of these compounds, however, the contribution of other mesomeric forms to the structure has also been considered.122 Thus, PPP-SCF quantum chemical calculations suggest that 1,4-dipolar cycloadditions to the C-3 and C-9a atoms are to be expected.352 This type of reaction does in fact occur (see Section III,C,10). Katritzky and Waring273 estimated the ratio of the mesomeric betaine (63 R = H) and the 2-hydroxy-4-oxo tautomers to be about 20 1. 

Phenanthridine is known to undergo direct amination readily with hydride extrusion (the Chichibabin reaction) and further examples have been reported.22 More interesting is the preparation of 6-aminophenanthridine in high yield by the action of the sodium salt of N,N-dimethylhydrazine on phenanthridine in benzene. The adduct (224) (R = Me) loses dimethylamine on heating leaving the sodium salt of the 6-amino compound (225).318... 

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],... 

Substituted indolizines 18 are formed in Chichibabin reactions of l-[alkyl(aryl)carbonylmethyl]-2-alkylpyridinium halides 17 (Scheme 11) <1972AJC1003>. Various modifications of this method are used for the preparation of many other pyrrolo[l,2-< ]azines and pyrrolo[l,2- ]azoles. Indolizines can also be made by intramolecular Michael additions, e.g., by the cyclization of 2-acylpyridine 19 (Scheme 12). 

Nucleophilic replacement of hydrogen on an isoxazole (cf. the Chichibabin reaction) is unknown, and only a few examples of replacement of substituents such as halogen have been reported.1,151 The activated methoxy group in compound 45 is displaced by dimethylamine, and even by phenyl-magnesium bromide, in which case the product is 46.152... 

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