Tschitschibabin reaction

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

Finally, the elimination-addition mechanism has been proposed to explain the course of the weU-known Tschitschibabin reaction, but this extension of hetaryne chemistry has been rightly objected to by several authors. 

Pyridine (76) requires no more than its own in-built capacity for electron withdrawal and is itself attacked by powerful nucleophiles, e.g. by eNH2 (sodamide, NaNH2) in N,N-dimethylaniline as solvent—the Tschitschibabin reaction ... 

Some systems have been obtained by a modification of the above procedure in which propargyl bromide replaces the cr-halogenoketone. Table II summarizes the systems that have been prepared by the Tschitschibabin reaction, together with the preparative route used. However, certain difficulties are encountered with this method. The syntheses of imidazo[l,2-6]-s-triazoles and imidazo[l,2-d]tetrazoles have been reported,20813 but repetition of this work more recently209 has cast doubt on these results. 5-Aminotetrazole was found to react with arylacyl bromides to give products shown to be AT-substituted tetrazoles 203 and not imidazol 1,2-rf]tetrazoles (204) as previously suggested.20813... 

The failure of the Tschitschibabin reaction has also been observed with other NH-aminoazoles. Werbel and Zamora214 found that 2-amino-1-methylbenzimidazole reacted rapidly with phenacyl bromide to give an intermediate that cyclized easily to the imidazo[l,2-a]benzimidazole, but 2-aminobenzimidazole gave no product. In the same way, 2-amino-thiazole yielded a bicyclic system but 3-amino-s-triazole did not.225... 

Generally speaking, 2-aminothiazoles, -oxazoles, and N-substituted imidazoles react with or-halogenoketones more easily than NH compounds, though 2-amino-4,5-dimethyloxazole and 3-amino-l-methyl-4-phenylpyrazole are reported214 not to undergo the Tschitschibabin reaction. 

A Tschitschibabin reaction in Scheme 7 with Y = NH B Tschitschibabin reaction in Scheme 7 with Y = S a a-halogeno ketone used b propargyl bromide used. 

The Tschitschibabin reaction represents the most versatile way to substituted indolizines. It fails only in the case of indolizines bearing no substituents on the five-membered ring. Usually the intermediate quaternary salt (108) is isolated, but in some cases a one-pot reaction has been performed. The cyclization of (108) normally proceeds directly to the indolizine (110). A carbinol intermediate (109), however, has been isolated from the reaction of 2-picoline and 2-bromopropiophenone in the absence of a solvent (73JCS(P1)2595). 

The reaction of 2-acylpyridinium bromides (117) with hydrazine hydrate provides an excellent method for the preparation of 1,2-disubstituted indolizines (119). The yields are generally better than in the corresponding Tschitschibabin reaction. The reaction may proceed via the derivative (118), which loses nitrogen to give the indolizines (Scheme 17). 

The methods belonging to this section may provide indolizines unsubstituted in the five-membered ring, for which the Tschitschibabin reaction fails. Since they have been treated in great detail (76S209, 78AHC(23)103), only selected examples will be given here. 

Although 1-aminoindolizine could be diazotized and coupled with jS-naphthol, both the base and its hydrochloride salt were air- and light-sensitive. Various substituted 1-aminoindolizines have been prepared via a Tschitschibabin reaction from substituted 2-nitromethyl- or 2-acetamidomethylpyridines.31 The l-hydroxy-2-phenylindolizine prepared from 2-hydroxymethylpyridine and phenacyl bromide was isolated as its hydrochloride, but this too was unstable and was characterized as the 0-benzoyl derivative. 

This route has been particularly investigated to provide indolizines unsubstituted in the five-membered ring, for which the Tschitschibabin reaction fails. 

Most of the amines could be acetylated at nitrogen and, under refluxing conditions, at the 1-position. Other routes to acetamidoindoli-zines are from the corresponding acetyl compounds via the Schmidt reaction,79-180 from pyridines via Tschitschibabin reactions, and from acetolysis of an azomethine79 such as 124, which may be derived from the reaction of an indolizine and diphenylformamidine.186... 

Tschitschibabin reaction,290 thus counteracting the example based on 3-hydroxypyridine. The second reaction to be discussed is that of 2-picoline with sodamide at a relatively high temperature, when 3,6-diamino-2-picoline (126) is one of the products isolated.293 If this is so, this represents another example of the type of orientation recently observed in the phenylation of pyridine with phenylcalcium iodide which gave some 2,5-diphenylpyridine.264 Alternatively, a 3,4-pyridyne intermediate (125) might perhaps actually be involved here. The evolution of hydrogen is not mentioned in this case. The decarboxylation of pyridine carboxylic acids under strongly basic conditions is unexceptional. 

Molecular orbital calculations of the w-electron distribution in pyridine predict that more 4- than 2-aminopyridine should be formed in the Tschitschibabin reaction.4 The fact that no 4-aminopyridine can be detected when the two positions are allowed to compete for a deficiency of sodamide (see, e.g., Abramovitch et al 268) has led to the suggestion that the observed orientation in this reaction depends on the relative ease of elimination of a hydride ion from C-2 and C-4 and not upon the initial mode of addition (which, by implication, must take place predominantly at C-4 as predicted by the molecular orbital calculations).4 This hypothesis necessitates that the addition step be rapidly reversible and that the second stage, the elimination of hydride ion, be the rate-determining one (Scheme VII). Although it seems reasonable to assume that the hydride ion eliminations are the slow steps in this reaction, the fact that no deuterium isotope effect was observed in the reaction of 3-picoline-2d and of pyridine-2d with sodamide implies that the first stage must be virtually irreversible,268 as was found also in the case of the addition of phenyllithium to pyridine.229 The addition stage must, therefore, be the product-... 

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