Quaternary pyridinium salts, reduction

Somewhat less useful is the aluminum hydride reduction of quaternary pyridinium salts. Reduction of the salts may be more conveniently performed by the use of sodium borohydride (see Section II, B, 6). Moreover, the aluminum hydride reductions of some dialkyl-pyridinium salts are accompanied by reductive cleavage of the pyridine ring,77 For example, methiodides of 2,5-dimethylpyridine,77 2-methyl-5-ethylpyridine,77 and 2-ethyl-5-methylpyridine61 afford mixtures of the corresponding tetrahydro and hexahydro bases along with a secondary amine, viz., 5-methylaminomethyl-2,4-hexadiene, 5-methylaminomethyl-2,4-heptadiene, and 7-methylamino-6-methyl-2,4-heptadiene, respectively. 

Reduction of quaternary pyridine salts with sodium amalgam afford the 1,2-dihydro whereas sodium hydrosulphite gives the 1,4-dihydro derivative, respectively362. From a preparative point of view, partial hydrogenation of quaternary pyridinium salts in alkaline media to give substituted 1-methyl-A2-piperideines is very important363,364. 

Piperideines unsubstituted at the nitrogen atom may be prepared from the corresponding pyridine compounds by partial reduction with sodium and boiling alcohols (the Ladenburg reduction), by electrolytic reduction, or, preferably, by reduction with aluminum hydride. l-Alkyl-3-piperideines are prepared by reduction of quaternary pyridinium salts with formic acid (the Lukes reduction) or with complex hydrides. 

Electrolytic reductions of quaternary pyridinium salts, especially of methyl methosulfates, lead to mixtures of 1-methylpiperidines and... 

Reductions of quaternary pyridinium salts to 1-alkyl-3-piperideines may be performed preferably with the use of sodium or potassium borohydride in aqueous or alcoholic solutions. Lithium aluminum... 

In contrast to aluminum hydride reductions (see Section II, B, 4), no ring openings have been observed in reductions of quaternary pyridinium salts by means of sodium borohydride. Whenever possible, both isomeric tetrahydropyridines are formed, as it may be seen from the following examples (aluminum hydride, electrolytic, and formic acid reductions are included for comparison). 

Diphosphopyridine nucleotide and analogous quaternary pyridinium salts form complexes with bisulphite and with thiols 2-5, xhe orientation of these additions is usually uncertain and may vary with the reaction solvent used " 4, The dithionite addition products formed by quaternary pyridinium salts have attracted interest because of their connection with the dithionite reduction of diphosphopyridine nucleotide (p. 259). Thus, the formation of a 1,4-dihydropyridine (122) by reduction of (120) has been represented 6 as proceeding through a 1,2-addition product (121). Regardless of the correctness or otherwise of structure (121), the relevance of the intermediate for diphosphopyridine nucleotide reduction by dithionite has been questioned, and the yellow intermediate formed in this reaction has been formulated 8 as a charge-transfer complex between the pyridinium nucleus and 820 (see p. 261). 

Reduction of quaternary pyridinium salts by metal hydrides presents interesting features. Sometimes J 4 tetrahydropyridines result from boro-hydride reductioni Borohydride in presence of alkali has been... 

Reduction of quaternary pyridinium salts by formic acid containing potassium formate, which recalls the Leuckart reaction, is basically a nucleophilic attack by hydride ion ... 

To Sa] It has been confirmed that borohydride reduction of quaternary pyridinium salts can produce piperidines. 1,2,5,6-Tetrahydropyridines result from initial attack at C(2) and piperidines from attack at C(4). Thus, the relative amounts of piperidine and tetrahydropyridines produced are an indication of the relative rates of attack of hydride at C(4) and C(2). As the quaternizing alkyl group is increased in size, the relative amount of piperidine formed increases ssc,... 

An intriguing use of a quaternary ammonium salt in a two-phase reaction is to be found with the regeneration of 1 -benzyl-1,4-dihydronicotinamide by sodium dithionite in a biomimetic reduction of thiones to thiols [12], The use of sodium dithionite in the presence of sodium carbonate for the 1,4-reduction of the pyri-dinium salts to 1,4-dihydropyridines is well established but, as both the dithionite and the pyridinium salts are soluble in water and the dihydropyridine and the thione are insoluble in the aqueous phase and totally soluble in the organic phase, it is difficult to identify the role of the quaternary ammonium salt in the reduction cycle. It is clear, however, that in the presence of benzyltriethylammonium chloride, the pyridine system is involved in as many as ten reduction cycles during the complete conversion of the thione into the thiol. In the absence of the catalyst, the thione is recovered quantitatively from the reaction mixture. As yet, the procedure does not appear to have any synthetic utility. 

The pyridinium salts have been shown to have electrophilic positions at the 2-, 4-, and 6-carbon atoms. Of these, the 2- and 6-positions should be the more positive because of the proximity to the quaternary nitrogen. From the ultraviolet absorption spectra of the reaction mixtures during the reduction and of the isolated products, it can be demonstrated that the predominant attack of the hydride ion from sodium borohydride occurs at these two positions.5,6 The 1,6-dihydro-pyridine (such as 5) formed from the reduction of a 1,3-disubstituted pyridinium ion appears to be stable toward further reduction, for a number of such compounds have been isolated from sodium borohydride reductions containing sufficient borohydride to complete the reduction to the tetrahydro-state.7"10 Since 1,4-dihydropyridines having a 3-substituent which is electron-withdrawing have also been... 

Cyanide ions attack the 4-position in pyridinium salts. For example, nicotinamide pyr-iV-methiodide (143, R = CHS) and di-phosphopyridine nucleotide give the 4-cyano- 1,4-dihydro derivatives (144) 328,329 3-Acetyl-iV-benzylpyridinium chloride similarly gives the 4-cyano-1,4-dihydro derivative and no attack at C-2 has been reported.330 Hydrosulfite reduction of nicotinamide quaternary salts... 

Partial reductions of quaternary salts to dihydro compounds can be achieved with borohydride but such processes are much less well studied than in pyridinium salt chemistry. 1,4-Dihydropyrazines have been produced with either silicon or amide substitution at the nitrogen atoms, and all the diazines can be reduced to tetrahydro-derivatives with carbamate protection on nitrogen, which aids in stabihsation and thus allows isolation. " ... 

Before truly reliable criteria for distinguishing between 1,2- and 1,4-dihydropyridines were available, the products of dithionite reduction of many quaternary salts, mainly nicotinamide derivatives, had been examined, notably by Karrer and his co-workers and wrongly formulated as 1,2-dihydropyridines. Whilst each example requires careful examination, it seems to be almost generally true that dithionite reduction of pyridinium salts gives l,4-dihydropyridinesi 1077, 1090-2, 1101 An exception is the... 

One-third of all pyridine electrochemical citations deal with the electrolysis of quaternary salts of pyridines two out of five cathodic reports are concerned with them. Moreover, the products of reduction and the salts themselves are commercially valuable. A whole class of biochemical transformations depends on the reactivity of pyridinium ions. Agricultural products are also derived from these salts, and the value of bipyridiniiim herbicides is directly linked to their redox chemistry. 

The reduction of pyridinium quaternary salts with LAH has been reported to yield dihydro- and tetrahydropyridines, depending upon the structure of the salt and the conditions of the reaction. Kuss and Karrer63 reported the formation of a 1,2-dihydropyridine from the reaction of 1,2,6-trimethyl-4-phenyl-3,5-diethoxycarbonylpyridinium methosulfate and lithium aluminum hydride in ether. Ferles64 indicated that 1,3-dimethylpyridinium iodide (46) gave exclusively l,3-dimethyl-l,2,5,6-tetrahydropyridine (47) on reaction with LAH in chloroform. 

In addition to compounds quoted by Lyle and Anderson," the following quaternary salts have recently been reduced with sodium borohydride ethiodides of pyridine and its homologs, methiodides of 3-ethylpyridine, 4-ethylpyridine, 2-methyl-5-ethylpyridine, and 3-methyl-4-ethylpyridine,102 and the methiodide of 2-benzyl-4-methylpyridine.103 Reductions (NaBH4) of l,2-dimethyl-5-ethyl-pyridinium iodide and l,3-dimethyl-4-ethylpyridinium iodide afford as principal products those 3-piperideines (94, 95) which carry the maximum number of substituents on the double bond, presumably due to hyperconjugation.102... 

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