Zincke salt

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. ... 

Zincke salts have played an important role in the synthesis of NAD /NADH coenzyme analogs since a 1937 report on the Zincke synthesis of dihydropyridine 7 for use in a redox titration study.The widely utilized nicotinamide-derived Zincke salt 8, first synthesized by Lettre was also used by Shifrin in 1965 for the preparation and study of NAD /NADH analogs. In 1972, Secrist reported using 8 for synthesis of simplified NAD analogs such as 10 for use in spectroscopic studies (Scheme 8.4.4). Subsequent utilization of 8 is discussed later in this article. 

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... 

With Af-acyl or Af-sulfonyl hydrazines as nucleophiles, Zincke salts serve as sources of iminopyridinium ylides and ylide precursors.Reaction of the nicotinamide-derived Zincke salt 8 with ethyl hydrazino urethane 42 provided salt 43, while the tosyl hydrazine gave ylide 44 (Scheme 8.4.14). ° Benzoyl hydrazines have also been used in reactions with Zincke salts under similar conditions.Af-amino-1,2,3,6-tetrahydropyridine derivatives such as 47 (Scheme 8.4.15), which showed antiinflammatory activity, are also accessible via this route, with borohydride reduction of the initially formed ylide 46. ... 

With a chiral phenylglycinol nucleophile (Scheme 8.4.17), use of the chloride Zincke salt 6 (cf. Scheme 8.4.16) gave decomposition of the salt back to isoquinoline and 2,4-dinitrochlorobenzene. The desired reaction was enabled by exchanging chloride for the weakly nucleophilic dodecyl sulfate anion. The resulting salt 49 also had improved... 

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

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. ... 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

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). 

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

R-(-)-Phenylglycinol (5 g, 36.5 mmol) was added to a solution of Zincke salt 115 (10.3 g, 33.3 mmol) in n-butanol (100 mL) at 20 °C. The resulting deep red solution was refluxed during 20 h. Removal of the solvent under reduced pressure left a residue that was treated with HpO (70 mL). The precipitate (2,4-dinitroaniline hydrochloride) was eliminated by filtration, and the operation was repeated twice. The combined aqueous phase was basified with concentrated ammonia (5 mL) and washed twice with EtOAc (200 mL) in order to remove the remaining 2,4-dinitroaniline and the excess of R- )-phenylglycinol. Evaporation of water gave salt 122 (7.53 g, 86%) as a pale orange gum. 

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. 

N-Arylation. Only highly activated aryl halides react with pyridines. Thus, 2,4-dinitrochlorobenzene with pyridine forms l-(2,4-dinitrophenyl)pyridinium chloride (Zinckes salt) active heteroaryl halides such as 2-chloropyr-imidine react similarly. To N-phenylate pyridine, diphenyliodonium ions are needed Pf UBFzj + pyridine 1-phenylpyridinium BF4 +PhI. This reaction may involve initial electron transfer. 

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. 

The above example in which a pyridinium ring serves as a latent primary amino substituent is an extension of the classical "Zincke salt" procedure for transfer of the five carbon atoms of the pyridinium ring to an attacking nucleophile. A further example is the conversion of pyridine into 1-substituted 3-formyl-2(lH)-pyrldlnethiones by reaction of glutacondialde-hyde (the hydrolytic Jeavage product of the Zincke salt formed from pyridine) with Isothiocyanates. 

The Zincke salt (A -(2,4-dmitrophenyl) salt) of isoquinoline is easily transformed into chiral isoquinolinium salts on reaction with chiral amines - an ANRORC sequence in which the ninogen of the chiral amine ends up as the nitrogen of the isoquinolinium product - nucleophilic addition of Grignard reagents to these salts shows good stereoselectivity. ... 

Ar-(2,4-Dinitrophenyl)pyridinium chlorides ( Zincke salts 10,25-2 15) are starting materials for another preparation of N-aminopyridinium salts. Zincke salts react with hydrazines, aryl hydrazines, acyl hydrazines, and semicarbazides to form 5-(2,4-dinitroanilino)-2,4-pentadienal hydra-zones and semicarbazones, respectively, by ring-opening.17,25,27-32 The recyclization of these compounds (16) with molar quantities of acids yields the quaternary salts 17 and 2,4-dinitroaniline. 

The Zincke salt of isoquinoline is easily transformed into chiral isoquinolinium salts on reaction with chiral amines.Nucleophilic addition of Grignard reagents to these salts shows good stereoselectivity. " ... 

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