Chichibabin reactions

This article attempts to cover the literature since 1967. Chemical abstracts has been searched by indexes and by CAS on line computer search from Volume 66 through Issue 8 of Volume 107. References are given prior to 1967 only when they provide essential background information. 

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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. 

Chichibabin reaction, 5, 409-410 sulfonation, 5, 429 synthesis, 5, 160, 161, 457-498, 496 tautomerism, 5, 365 toxicity, 1, 139 UV spectra, 5, 356, 357 2H-Benzimidazoles 3,3-dioxides synthesis, 6, 407 2V,7ST-dioxides reactions, 5, 456 Benzimidazoles, aryl-oxidation, 5, 433 Benzimidazoles, nitro-mass spectra, 5, 359 reduction, 5, 441 Benzimidazole-2-sulfonic acids reactions... 

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... 

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. 

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 an unusual variant on the Chichibabin reaction, treatment of 3-hydroxypyridine with sodium amide at 200° affords 2,6-di-aminopyridine (21). Coupling of the product with benzenediazo-nium chloride gives phenazopyridine (22). This drug is used as an analgesic for the urinary tract in conjunction with antibacterial agents for treatment of urinary infections. 

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). 

Chevron Phillips slurry process, 20 198-199 Chibata, Ichiro, 11 11-12 Chichibabin reaction, 21 99 Chicken pox vaccine, 25 491-492 Chickens... 

However, 2-aminopyridine and 4-aminopyridine exist almost entirely as the amino tautomers - indeed, we have just seen 2-aminopyridine as a product of the Chichibabin reaction. Which tautomer is preferred for hydroxy and amino heterocycles is not always easily explained but, as a generalization, we find that the oxygen derivatives exist as carbonyl tautomers and amino heterocycles favour the amino tautomers. At this stage, we should just register the potential for tautomerism in aminopyridines we shall see important examples with other heterocycles (see Section 11.6.2). 

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... 

The Chichibabin reaction is not used synthetically as a major route to pyrimidines, quinazolines, or perimidines, and earlier examples have been discussed elsewhere <1994HG(52)1, 1996HC(55)1, 1996CHEC-II(6)93, B-2001MI1>. 

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