Krohnke pyridine synthesis

Pyridines from a-pyridinium methyl ketone salts and a,P-unsaturated ketones. 

Galatsis, P. Krohnke Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 311—313. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 143, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 152, Springer International Publishing Switzerland 2014 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The research team of E.-S. Lee synthesized and evaiuated severai 2,4,6-trisubstituted pyridine derivatives as potential topoisomerase I inhibitors. One of these compounds, 4-furan-2-yl-2-(2-furan-2-yl-vinyl)-6-thiophen-2-yl-pyridine, was prepared by the Krohnke pyridine synthesis and showed strong topoisomerase I inhibitory activity. 

tetrahydroquinoline-based A/,S-type ligands were prepared by the Krohnke pyridine synthesis and their 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

While this reaction to pyridine 56 occurs in a single pot, it is proposed to proceed via the 1,5-diketo derivative 55 obtained by a Michael addition of the pyridinium species 53 to enone 54. Although one does not typically isolate this intermediate, it has been obtained in reactions of the isoquinolinium series.  

A route to pyridines which involves an isolated 1,5-dicarbonyl compound, has been reported. Aldol reaction of enone 57 with methylketone 58 generated 1,5-diketone 59. When this was submitted to the reaction conditions for a Krohnke reaction, thiopyridine 60 was isolated. 

Newkome employed this methodology in his synthesis of halogenated terpyridines. The requisite pyridinium ion 62 was prepared from the corresponding 

Kelly applied this chemistry to the synthesis of cyclosexipyridine 66. This is an example of an intramolecular variation to this method. Masked enal 65 was prepared and treated with the standard reagents. The acidic medium liberated the aldehyde from its acetal protection. This in situ formation of the reactive species, similar to the above example, then undergoes cyclization to the expected pyridine derivative 66. 

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Krohnke pyridine synthesis Condensation of an unsaturated ketone with an a-halo ketone to give highly substituted pyridines. 254... 

Grosche et al. [33] established the classic Krohnke pyridine synthesis on the solid phase (Fig. 6.22 (A, B a, c)). The polymer-bound enones used in this reaction were obtained from polymer-bound acetophenones as well as polymer-bound aldehydes, thus providing enones with different substitution patterns (Fig. 6.19 (B and C)). 

Intramolecular KrOhnke pyridine synthesis as well as Krohnke pyridine synthesis imder microwave irradiation have also been reported. In addition, indium trichloride can be used as a catalyst in the Krdhnke pyridine synthesis. " ... 

This reaction is related to the Hantzsch Dihydropyridine Synthesis and Krohnke Pyridine Synthesis. 

This reaction is related to the Guareschi-Thorpe Pyridine Synthesis, Chichibabin Pyridine Synthesis, KrOhnke Pyridine Synthesis, and Petrenko-Kritschenko Piperidone Synthesis. 

This reaction was first reported by Krohnke et al. in 1961. It is the synthesis of 2,4,6-trisubstituted pyridine derivatives involving the formation of pyridinium ylide from pyridine and a-bromoketone, which undergoes the 1,4-Michael addition to an a, -unsaturaled compound to form 1,5-dicarbonyl compounds and cyclizes with ammonium acetate. Therefore, it is generally known as the Krohnke pyridine synthesis or Krohnke reaction. In this reaction, the intermediate 1,5-dicarbonyl compounds do not need to be isolated from reaction mixture. Because three different substituents can be introduced into pyridine ring, this reaction becomes the ideal model for combinatorial synthesis, and a library pool containing pyridine from 9 to over 200 has been generated by this reaction. 

Illustrated below is the mechanism of the Krohnke pyridine synthesis in which an ammonium ion attacks the carbonyl group close to R3. It should be pointed out that the... 

Other references related to the Krohnke pyridine synthesis are cited in the literature. ... 

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. 

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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