Zincke reaction

The Zincke reaction is an overall amine exchange process that converts N- 2,A-dinitrophenyl)pyridinium salts (e.g, 1), known as Zincke salts, to iV-aryl or iV-alkyl pyridiniums 2 upon treatment with the appropriate aniline or alkyl amine. The Zincke salts are produced by reaction of pyridine or its derivatives with 2,4-dinitrochlorobenzene. This venerable reaction, first reported in 1904 and independently explored by Konig, proceeds via nucleophilic addition, ring opening, amine exchange, and electrocyclic reclosure, a sequence that also requires a series of proton transfers. By 

Later in the 20th century, Vompe and Stepanov delineated efficient procedures for the preparation of the so-called Zincke salts (e.g., 1) from pyridines and 2,4-dinitrochlorobenzene, involving, for example, reflux in acetone. Vompe and Lukes also noted that electron-donating substituents on the pyridinium ring of the Zincke salt retarded reaction with amines at the 2-position of the pyridinium ring, sometimes leading instead to attack at the C-1 position of the 2,4-dinitrobenzene ring, with displacement of the pyridine. 

During the 1950s and 1960s Hafner used Konig salts, derived from the reaction of A -methyl aniline with Zincke salt 1, for azulene synthesis. The Zincke reaction also achieved prominence in cyanine dye synthesis and as an analytical method for nicotinamide determination.  

In terms of the final loss of aniline after ring closure, the fact that reactions using EtsN and BU3N, (ammonium ion as proton source) occurred at the same rate as the reactions with methoxide base (MeOH as proton source) suggested a lack of general acid catalysis. Also, it was found that varying the amount of available acid did not change the rate of cyclization appreciably.  

In addition to their reactions with amines, Zincke salts also combine with other nitrogen nucleophiles, providing various A -substituted pyridine derivatives. Pyridine A -oxides result from the reaction with hydroxylamine, as exemplified for the conversion of Zincke salt 38 to the A -oxide 39 Reactions of Zincke salts with hydrazine, meanwhile, lead 

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In 1904, Zincke reported that treatment of Al-(2,4-dinitrophenyl)pyridinium chloride (1) with aniline provided a deep red salt that subsequently transformed into A-phenyl pyridinium chloride 5 (Scheme 8.4.2). Because the starting salt 1 was readily available from the nucleophilic aromatic substitution reaction of pyridine with 2,4-dinitrochlorobenzene, the Zincke reaction provided access to a pyridinium salt (5) that would otherwise require the unlikely substitution reaction between pyridine and... 

From these various studies, the overall picture that emerged for the Zincke reaction mechanism is outlined in Scheme 8.4.10. When water is excluded, initial... 

Zincke-type salts derived from other aromatic nitrogen heterocycles also undergo Zincke reactions. The isoquinolinium salt 6 (Scheme 8.4.16) permitted incorporation of a phenyl ethylamine chiral auxiliary, providing salt 48. In this context and others (vide infra), Marazano and co-workers found that refluxing -butanol was a superior solvent system for the Zincke process. Additionally, the stereochemical integrity of the or-chiral amino fragment was reliably maintained. 

The Zincke reaction has also been adapted for the solid phase. Dupas et al. prepared NADH-model precursors 58, immobilized on silica, by reaction of bound amino functions 57 with Zincke salt 8 (Scheme 8.4.19) for subsequent reduction to the 1,4-dihydropyridines with sodium dithionite. Earlier, Ise and co-workers utilized the Zincke reaction to prepare catalytic polyelectrolytes, starting from poly(4-vinylpyridine). Formation of Zincke salts at pyridine positions within the polymer was achieved by reaction with 2,4-dinitrochlorobenzene, and these sites were then functionalized with various amines. The resulting polymers showed catalytic activity in ester hydrolysis. ... 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

The utility of the Zincke reaction has been extended to the preparation of various NAD and NADH analogs. Holy and co-workers synthesized a series of NAD analogs containing nucleotide bases as a means to study through-space interaction between the pyridinium and base portions. Nicotinamide-derived Zincke salt 8 was used to link with various adenine derivatives via tethers that contained hydroxyl (105 —> 106, Scheme 8.4.35), phosphonate (107—>108, Scheme 8.4.36), and carboxylate "... 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

An intriguing application of Zincke processes occurred in Marazano s synthesis of dimeric, tetrameric, and even octameric pyridinium macrocycles, including cyclostellettamine B, a sponge-derived natural product. The same strategy produced a synthesis of haliclamine A (121, Scheme 8.4.41), a cytotoxic sponge metabolite. Intermediate 119, itself produced via a Zincke route, underwent an intramolecular Zincke reaction, providing macrocycle 120, which was reduced to the natural product. 

The Zincke reaction is an overall amine exchange process that converts N- 2,A-dinitrophenyl)pyridinium salts, known as Zincke salts, to A -aryl or A -alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine. 

Kaiser et al. have reported a general entry for the selective synthesis of dimeric macrocycles like cyclostellettamines and for polymeric natural products [41]. It uses the Zincke reaction by which it is possible to control the number of units in a 3-alkylpyridinium polymer. As summarized in Fig. (33), the reaction of the free amine 89 with the Zincke salt 88 gives the dimer 90 (route b) which, after terminal amine deprotection and DNB functionalization at the A-pyridine centre, gives the cyclic dimer, as in the synthesis of cyclostellettamine B. Otherwise, compound 90 furnishes both the protected dimer 91 and the free linear dimer, which, refluxed together in butanol, give the linear tetramer (route c). By the same iterative sequence, the linear octamer was obtained from the tetramer, and from the latter the hexadecamer. 

Pyridinium ions 45 with iV-acceptor substituents also add O- and N-nucleophiles via C-2 to give 46. This is followed by ring opening, probably in an electrocyclic process, at N/C-2 resulting in the formation of 1-azatrienes 47 Zincke reaction, cf. the corresponding transformations of the pyrylium ion, see p 225) ... 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

Reactions with A/-acyl or AAsulfonyl hydrazines gave rise to iminopyridinium ylides and ylide precursors such as 43 and 44. " Benzwl hydrazines are also used in the Zincke reaction under simitar conditions. ... 

Solid-phase Zincke reaction was applied for the search of activators of the cystic fibrosis transmembrane conductance regulator protein. On the other hand, the tripeptide TRH (pGlu-His-Pro-NH2) was shown to be a hypothalamic releasing factor for the regulation of pituitary function. A solid-phase Zincke reaction was used to prepare analogues of TRH having the central histidine replaced with a 1,4-dihydropyridine unit (such as 48). Compound 48 was expected to cross the hydrophobic blood-brain barrier (BBB) but to be trapped within the central nervous system upon oxidation to the hydrophilic pyridinium form. 

A redox system (50/51) to affect brain delivery of y-aminobutyric acid (GABA) derivatives and analogues was also developed. Zincke reaction of 41 with acetal 49 followed by dithionite reduction afforded the 1,4-dihydropyridine prodrug 50, which was hydrolyzed and oxidized in vivo to the active GABA analogue 51. The neutral and lipophilic 1,4-dihydropyridine 50 can penetrate the blood-brain barrier (BBB), whereas the oxidized pyridinium salt 51 is retained in the brain for an extended period and then eliminated. 

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