Krohnke reaction

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. 

Another reagent that convert benzylic halides to aldehydes is pyridine followed by /7-nitrosodimethylaniline and then water, called the Krohnke reaction. Primary halides and tosylates have been oxidized to aldehydes by trimethylamine N-oxide, and by pyridine N-oxide with microwave irradiation. ... 

From 3- or 5-chloromethyl-l,2,4-oxadiazoles, the 3- or 5-carbaldehydes, respectively, have been prepared by the Krohnke reaction <79JHC1469>. These aldehydes exist predominantely as hydrates (164) and (165), which are stabilized by intramolecular hydrogen bonds. 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

Chloro-3-fonnylquinolines 161 (Scheme 31) were transformed in the presence of acetic acid to 3-formylquinolones which upon reaction with acetophenones provided the intermediate a,p unsaturated Knoevenagel adducts. Subsequent Krohnke reaction of these adducts with pyridinium salts 162 and ammonium acetate provided the final quinoline-pyridines 163 in excellent yields [68]. All the compounds were tested... 

The first preparation of 1,3,4-thiadiazole aldehydes was described by Ohta and Isowa, who used the Krohnke reaction on 2,5-dimethyl- and 2-methyl-5-phenyl-l,3,4-thiadiazole. They described 2,4-dinitrophenylhydrazones and thiosemicarbazones, oxidation to acid, and acyloin condensation. Bacchetti has shown that 2-phenyl-... 

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 new substituted tridentate ligands L5c-e are synthesized in six steps using a Krohnke reaction for the construction of the 4-substituted central pyridine ring.25 Novel polymeric benzimidazole ligands as an extended system of H2L7 and H2Lllb are also available.2, 27... 

Krohnke reactions. A halogen compound reacts with pyridine in ethanol to form a pyridinium salt (1), which is treated with p-nitroso-N,N-dimethylaniline and alkali to produce a nitrone (2), which on acid hydrolysis affords an aldehyde. 

In the Krohnke reaction a benzyl halide or a-haloketone is converted into the pyridinium salt, which reacts with p-nitrosodimethylaniline to give a nitrone this. 

By using l-[methoxycarbonylmethyl]-pyridinium bromide in the solid-phase Krohnke reaction, pyridones were obtained [33]. Six compounds were synthesized, with HPLC-purities between 68% and 76% (A.=214 nm), and yields of the crude products ranging from 71 % to 78% (Fig. 6.23). 

The net outcome of the Sommelet reaction is the oxidation of the benzyl methylene position into the corresponding carbonyl, and in that sense, the Krbhnke reaction may be considered a close variant. The KrOhnke reaction transforms benzyl halides to benzaldehydes using pyridine and an aromatic nitroso compound 16.16,17 As shown below, quaternary pyridinium salt (15) is formed from addition of pyridine to benzyl halide 1. Oxidation of 15 with p-nitrosodimethylaniline (16) affords nitrone 17, which is then hydrolyzed to benzaldehyde 3 and hydroxylamine 18. 

WBenzylpyridinium ions 235 condense with 4-nitroso-A, iV-dimethylaniline to form nitrones 236 which can be hydrolysed to yield aldehydes Krohnke reaction) ... 

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 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. 

Attack of pyridine on the bis-dibromocarbene adduct (474) results in formation of a pyridinium benzocyclobutene (475). Krohnke reaction of the latter with p-nitro-sodimethylaniline affords the benzocyclobutenone (476), which is opened by sodium hydroxide to the arylacetic acid (477 R = H, n = 1). Direct oxidation of (475) with alkaline permanganate gives a mixture of the phthalate (478) and benzoate (477 R = Br, = 0) the latter probably being formed via (476). °... 

In the Krohnke reaction, the pyridine system serves as vehicle for the conversion CH3 CH=0 of methyl groups in arenes or heteroarenes [140]. 

---