Pyridines Chichibabin amination reaction

Chichibabin amination reaction Direct amination of pyridine via SNAr reaction. 80... 

Alexei Eugenivich Chichibabin (Kusemino, nr. Poltava, Russia, 17 March 1871 (O.S.)-Paris, 15 August 1945), assistant in the University of Moscow (1900) and professor (1909) in the Technical High-School there, published much work in organic chemistry, notably on tervalent carbon. The Chichibabin amination reaction (1914) involves the formation of 2-aminopyridine by heating pyridine with sodamide in toluene, and hydrolysis of the product with water. The Chichibabin pyridine synthesis involves the condensation of aldehydes, ketones, etc., with ammonia or amines to form substituted pyridines. ... 

The Chichibabin amination reaction, first reported by Chichibabin and Zeide in 1914, is simply a reaction for the introduction of an amino group to azines. This is one of the first examples of nucleophilic hydrogen substitution (SnH) reactions and is considered one of the most influential reactions in heterocyclic chemistry transformations of pyridines and azines in the 20th century. " ... 

Nucleophilic substitution occurs at C-2, and to a lesser extent C-4, as might be predicted from similar reactions with pyridine. Chichibabin amination occurs rather more readily than with pyridine, giving 2-aminoquinoline. A typical hydride abstraction process occurs when qninoline is heated with sodinm... 

A classic reaction of this type is Chichibabin amination. leading mainly to 2-aminopyridine (Scheme 2.12a). This takes place when a pyridine is heated at 140 °C with sodamide (NH2 is a very strong nucleophile). Although hydrogen gas is certainly evolved during the reaction, the initial proton donor is not known. However, once some 2-aminopyridine is formed this product could function as the donor (Scheme 2.12b), and the process may then become a form of chain reaction. 

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). 

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. ... 

Amination of pyridine on heating with sodium amide in refluxing xylene observed by Chichibabin and Zeide nearly 100 years ago [132] was probably the first successful example of amino-dehydrogenation in the series of Jt-deficient aromatic systems. However, rather drastic reaction conditions and a requirement for an appropriate oxidant for the classic Chichibabin amination did not stimulate chemists in earlier days to enter this field of substitutions [23, 133, 134], Later on, van der Plas with coworkers [11, 19-21, 29, 35, 39, 40, 88], Vorbruggen [26], Pozharskii, Gulevskaya, and Maes [34, 45, 46, 48, 67, 68, 71, 72], McGill and Rappa [23], Pagoria, Mitchell, and Shmidt [59, 61, 63], Lopyrev [65, 66], Katritzky [58], and many other researches [11, 21, 45, 55, 58-74] contributed to the field of Sn amination reactions. 

Breuker K, Van der Plas HC. Occurrence of an S m(ANRORC) mechanism in the chichibabin amination of 4-phenylpyrimidine. J Org Chem. 1979 44 4677-4680. Francis RF, Davis W, Wisener JT. Reaction intermediates in the alkylation of pyridine... 

Note There is a great difference in the availability of 2-amino and 3-aminopyridine. The former is produced on an industrial scale via the amination of pyridine by sodium amide, known as the Chichibabin reaction (Scheme 8.7) [18, 19]. 

Scheme 8.7 Mechanism of the Chichibabin reaction, the amination 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... 

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... 

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