Krohnke reaction pyridine synthesis

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

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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). 

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)). 

The required pyridinium salts can be obtained by the King-Ortoleva reaction (see p 273), as is shown by the synthesis of benzothiazole-2-carbaldehyde 237. In the Krohnke reaction, the heterocycle pyridine ensures the targeted conversion CH3 -> CH=0 of methyl groups in arenes or heteroarenes [78]. 

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. 

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. 

The classic Krohnke aldehyde synthesis results from the displacement of pyridinium salts aromatic nitroso compounds to give nitrones which are hydrolyzed to aldehydes.Phenacyl bromide reacts with pyridine and then nitrosobenzene to give phenylglyoxal in 76% yield after acid hy lysis. The pyridinium salts in these reactions must be activated in some way toward displacement to effect efficient conversions. 

Patel and co-workers [61] have reported the microwave-assisted synthesis of a series of 3-(2,6-diphenyl-4-pyridyl)hydroquinolin-2-ones 10 by a one-pot cyclocondensation reaction under Krohnke s reaction conditions using 2-chloro-3-for-myl quinoline, an acetophenone and Al-phenacylpyridinum chloride in a mixture of ammonium acetate and acetic acid. Different kinds of substituents on the quinoline and acetophenone are well tolerated and most compounds 10 are obtained in high yield. This method allows the easy introduction of various substituents in the 2-, 4- and 6-positions of the pyridine 10 (Scheme 10). 

Much of the work on pyridinium ylids has been carried out by Krohnke and his papers should be consulted for background information on this subject 9M1). A general discussion of pyridinium ylids is also presented by Johnson 77>. Alkylation and acylation reactions are quite common with this ylid and it has been shown that C-alkylation followed by reductive cleavage of the pyridine residue is a useful method for the synthesis of alkylated ketones and esters 66>. Another interesting elimination occurs if the ylid is treated with nitrosobenzene 89). 

The same research group accomplished a benign synthesis of Krohnke pyridines via sequential solventless aldol condensation and Michael addition (Scheme 2.2-3) [21b] these are prominent building blocks in supramolecular chemistry characterized by their jt-stacldng ability, H-bonding, and coordination. The reaction has been... 

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