Krohnke reaction in preparation

Double Krohnke reactions have been employed in the preparation of quaterpyridines and sexi-pyridines. Thus, the chalcone dimer (77a,b) reacts with the pyridinium salt (78) to provide (79a,b) (Scheme 13).84 An alternative approach involves a bischalcone species based on bpy that can be elaborated to (76c), as well as several 4, 4""-disubstituted derivatives.85 A dimeric analogue of (78), having a central bpy moiety, undergoes condensation with a Krohnke-type salt to provide the parent sexipyridine (76c).86... 

The first fully aromatic 2-azaquinolizinium salts were prepared by Krohnke et al. (64CB3566), who examined three approaches to the l-hydroxy-3-phenyI-2-azaquinoIizinium ion (262 Scheme 130). The first involved the reaction of picolinamide (261) with phenacyl bromide which produced (262) in unspecified yield. Most effective was refluxing 2-cyanopyridine (263) in moist acetonitrile with phenacyl bromide. Finally, it was shown that 2-ethoxycarbonyl-l-phenacylpyridinium ion (265) could serve as a starting material if ammonium acetate were present in the solvent. 

Several complementary reactions, such as the Hantzsch, the Krohnke, and the Chichibabin, lead to tpy in which the central pyridine ring is built up in a condensation process.2 These reactions lend themselves well to the formation of 4 -substituted derivatives. The basic ingredient is acetylpyridine, which provides the two distal rings of tpy, as well as C2, C3, C5, and C6 of the central ring. C4 originates from an aldehyde which is generally aromatic. In the example in Scheme 2, an intermediate 1,5-diketone condenses with a nitrogen source, often ammonium acetate, to provide the final tpy. Table 1 summarizes some tpy derivatives which have been prepared by similar condensation approaches. 

All these reactions can be effected conveniently under mild conditions and at low temperatures. Thus the procedure is especially advantageous for the preparation of, / -unsaturated aldehydes and substituted glyoxals. A review of the reaction has been published by Krohnke, where he gives also experimental details.545 The Krohnke process also enabled Ried and Bender546 to succed in the first synthesis of a heterocyclic dialdehyde (2,3-thionaphthenedicarbaldehyde). 

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. 

METHOX (22) was synthesized in three steps from the commercially available pinocarvone (47) using the Krohnke annulation (47 + 48 —> 50). Pinocarvone itself, commercially available only in one enantiomeric form, can be readily obtained from the much cheaper oi-pinene (46) via an ene-reaction with singlet oxygen. Since both enantiomers of oi-pinene are commercially available, this procedure can be utilized for the preparation of both enantiomers of METHOX (22) [28b], The Krohnke reagent 48 [52] is readily obtained in one pot via iodination of the corresponding acetophenone (49) in pyridine [28bj. 

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