Zincke reaction, pyridinium salts

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... 

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... 

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 "... 

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). 

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. 

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. 

Fascinating transformations starting with an electrocyclization followed by a sig-matropic rearrangement were recently described by Vanderwal. Donor-acceptor dienes known as Zincke aldehydes, available by simple aminolysis of pyridinium salts [45, 46], rearrange cleanly at temperatures of 200-220 °C to (Z)-dienes under transformation of the aldehyde portion to an amide. The reaction is commonly performed in 1,2-dichlorobenzene under microwave irradiation (Scheme 6.28). The authors consider as the first step a thermally instigated ( )- to (Z)-isomerization... 

Katritzky converted pyrylium salts 44 (formed from the reaction of enone 42 and ethyl pyruvate 43) to the corresponding pyridiniums (45) via ANRORC reaction with a primary amines. This strategy serves as an alternative to the Zincke-Konig method for the formation of substituted pyridinium salts. 

A variation of the ANRORC reaction uses an intramolecular nucleophile to open the activated heterocycle. Vanderwal accomplished a short, formal synthesis of porothramycin A and B (not depicted) via opening of the pyridinium salt with the amide nitrogen found within 59. Product 60 contains the key functionalized pyrroline of the natural product, and the expelled Zincke aldehyde was further functionalized. 

Examples of the Zincke reaction are ring-opening reactions of the pyridinium salt 54 (A = 2,4-dinitrophenyl) with aqueous alkali (leading to aminodienal 57 and to gluta-condialdehyde 58 by hydrolysis) and with aniline (leading to bisanil 59 after subsequent amine exchange) ... 

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. 

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. 

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. 

Dinitrochlorobenzene reacts readily with pyridine, giving l-(2,4-dinitrophenyl) pyridinium chloride. Since Zincke s original observation of this reaction, several activated halogenobenzenes have been used, and activated nitro groups have also been replaced in quaternary salt formation. Examples are given in Table 5.16. 

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