Carbonyl derivatives with 2-aminopyridine

Aminopyridines also react with aldehydes, ketones, and other carbonyl derivatives to give products that can be converted to secondary or tertiary amines these reactions are discussed in Section 1.4.C. 

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). 

Improved procedures for the Chichibabin amination of pyridine derivatives have been reported (83JAP(K)58-208266, 83USP4386209, 83USP4405790). A general method has been developed for the conversion of 2-aminopyri-dines into 2-pyridones via 2-cthoxycarbonyl-l-(2-pyridyl)pyridinium ions 15. The pyridinium ions 15 are easily made from the 2-aminopyridines 14 and the corresponding pyrylium salt 13. On treatment with aqueous sodium hydroxide, pyridinium ions 15 are converted into the l-(substituted-2-pyridyl-carbonyl)-2-pyridones 16, which are readily hydrolyzed to the 2-pyridones 17 and the picolinic acid 18 (83JCS(P1)2623). 

The 3,4-dioxoperhydro derivative of (3) was obtained by cross carbonylation of 2-hydroxymethyl-pyridine <87CC125>. Reaction of Schiff bases, prepared from 2-aminopyridine and its 5,6-benzologue with aldehydes and dichlorocarbene, afforded 2-aryl-3-chloro-4-oxo-4/f derivatives of (12) and its 6,7-benzologue <9lKGS8io>. 

In 1999, Katritzky reported a novel [3+2+1] synthesis of 2,4,6-trisubstituted pyridine derivatives that used the Michael addition of a-benzotriazolyl ketones to a,P-unsaturated carbonyl compounds. This reaction resembles the Krohnke pyridine synthesis and is an extension of Katritzky s earlier studies with benzotriazolyl derivatives that provided access to pyridones, 2-thiopyridones, 5-alkyl-2,4-diphenylpyridines and 2-aminopyridines. This approach is attractive as both components are readily synthesized or commercially available. The availability of these starting materials allows for an efficient access to structurally diverse 2,4,6-triaryl pyridines when combined with ammonium acetate in acetic acid at reflux. In addition, it is possible to access fused 2,3,4,6-tetrasubstituted pyridines from the requisite fused bicyclic ketone starting material. The preparation of the pyridine ring via benzotriazole methodology has resulted in improved yields for many compounds and the opportunity to synthesize molecules with a substitution pattern that would be difficult to prepare by other methods. 

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