Pyridines Katritzky synthesis

Katritzky Pyridine Synthesis David A. Conlon 6.2.1 Description... 

The Katritzky pyridine synthesis is similar to the Krohnke pyridine synthesis, because both involve the Michael addition of a-substituted ketones 2 to a,P-unsaturated carbonyl compounds 1 in the presence of ammonium acetate, followed by the loss of the a-substituent to generate the pyridine 3. The a-substituent on the ketone in the Krohnke pyridine synthesis is typically a pyridinium salt. The a-substituent on the ketone in the Katritzky pyridine synthesis is the benzotriazolyl moiety. 

The first step in the Katritzky pyridine synthesis is believed to be the Michael addition of a a-benzotriazolyl ketone 2 to the a,p-unsaturated carbonyl compound 1 to generate a 1,5-diketone derivative 4. The 1,5-diketone is not typically isolated although its formation has been confirmed via preparation under typical Michael reaction conditions in the absence of ammonium acetate. 1,5-Diketone derivatives are known intermediates in the synthesis of pyridines and undergo condensation with ammonia or its equivalent followed by cyclization to form dihydropyridine 5. Elimination of benzotriazole completes the aromatization process and generates the pyridine ring. 

Katritzky, A. R., Ostercamp, D. L., Yousaf, T. I. Mechanism of heterocyclic ring closures. 3. Mechanism of the Hantzsch pyridine synthesis a study by nitrogen-15 and carbon-13 NMR spectroscopy. Tetrahedron 1986, 42, 5729-5738. 

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. 

Katritzky, A.R., Keay, J.G., and Sammes, M.P., Regiospecific synthesis of dialkyl pyridin-4-yl, quinolin-4-yl, and isoquinolin-l-yl-phosphonates, /. Chem. 

In an interesting study with potential for the synthesis of 3-substituted pyridines, Katritzky has shown that LDA metalation of the benzothiazol-2-yl thioether 479 gives the highly coordinated lithio species 480, as demonstrated by quench with several electrophiles to give products 481 (Scheme 144) [87H(26)427]. 

Jones, G. Pyridines and their Benzo Derivatives (v) Synthesis, in Comprehensive Heterocyclic Chemistry (eds. Katritzky, A. R.,Rees, C. W.), 2, 395-510 (Pergamon Press, Oxford, 1984). 

The susceptibility of pyrylium salts to attack at C-2 by nucleophiles and the subsequent ring opening and ring closure is of value in the synthesis of a range of heterocyclic compounds. During the course of the transformation of the primary amino group into another functionality, pyrylium salts are converted into pyridinium salts and thence into pyridine derivatives (A.R. Katritzky, Tetrahedron, 1980, 36, 679). 

The synthesis of 1-azatyrosine relied on the formation of an N-oxide to achieve acceptable results in an asymmetric hydrogenation (40->41). All attempts to conduct the same hydrogenation reaction with pyridine 39 met with failure. Presumably, the N-oxide prevents non-productive metal-substrate complex during the reaction <01OL3157>. Pyridine N-oxides have also been utilized by Katritzky as an effective way to activate the 2-posilion to nucleophilic attack <01H1703>. 

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