Pyridine A-oxides and pyridinium Salts

A common and often efficient method for the preparation of saturated piperidines is the catalytic reduction of pyridines, pyridine Ar-oxides, or pyridinium salts <2001CHE797, 2003T2953>. Reduction of the naphthylpyridyl alcohol 188... 

The reaction of pyrylium salts with hydroxylamines and primary amines produces pyridine Moxides and pyridinium salts, respectively. These pyridine derivatives have interesting properties and are also useful intermediates for the preparation of a variety of new materials. For example, nucleophilic substitution on the pyridine ring is facilitated by the formation of an A -oxide or pyridinium salt. 

Both pyridinium salts and pyridine A-oxides are of increased interest as chiral catalysts in organic reactions. Connon and Yamada independently designed and examined pyridinium salts as chiral catalysts in the acylation of secondary alcohols <06OBC2785 06JOC6872>. These two catalysts can be used for kinetic resolution of various sec-alcohols and uf/-diols in good to moderate enantiomeric excess. 

Similar results are obtained from reaction of pyridine A-oxide derivatives with 146 and several transformations, including ring opening, have been described. Reaction of pyridinium salts and 146 gives the corresponding 4-substituted-1,4-dihydropyridine derivatives 212 (Scheme 7.65). 

Again, as expected, pyridine A-oxides are very susceptible to nucleophilic attack. Unlike the situation usually prevalent with the quaternary pyridinium salts, the elimination stage of the two-step nucleophilic substitution can occur with relative ease, the oxide grouping serving as a good sink for the leaving hydride ion electron-pair and being itself eliminated in the process. Considerably more work has been carried out on quinoline and isoquinoline A-oxides than on pyridine A-oxide derivatives. 

The reactions of pyridine A-oxides are of great interest, differing significantly from those of both neutral pyridines and pyridinium salts. 

The synthesis and utilization of pyridinium and pyridine N-oxides has also been a topic of interest in 2001. While pyridine A -oxides are normally synthesized via the pyridine <01T7501, 01T5009>, the direct construction of these systems was reported by cyclization of vinamidinium salts in a [3+2+1] annulation reaction <010L209>. Accordingly, vinamidinium salt 37 is treated with the enolate of methyl acetoacetate (36) then with hydroxylamine to afford substituted pyridine N-oxide 38 in good yield. 

Addition of an ammonia source to pyrylium salts readily affords pyridine derivatives and provides a good method for the preparation of the pyridine moiety if the corresponding pyrylium salt is accessible. The carbon oxygen double bond present in the pyrylium salt is an oxonium ion however, owing to aromatic stabilization they are easily formed by a variety of methods. The reactivity of pyrylium salts toward nucleophiles makes them useful reagents for the preparation of structurally diverse heterocyclic compounds. Thus pyrylium salts afford pyridines by reaction with ammonia, pyridine-A -oxides by reaction with hydroxylamine and pyridinium salts by reaction with primary amines. 

In an analogous reaction, 2-benzylpyridine was prepared from reaction of pyridine N-oxide and benzyltrimethylsilane in the presence of tetrabutylammonium fluoride. 9 Substituent effects on the base-catalysed rearrangement of N-(aryloxy)pyridinium salts have been studied. A 3-methyl group directs rearrangement to the 6-position whereas an electron-withdrawing group directs rearrangement mainly to the 2-position. With a suitable choice of substituent it is therefore possible to form tricyclic products as illustrated in Scheme 11. 

In 1981 we published the first paper [22] on the synthesis of s-triazolo[4,3-a]pyridinium salts, 4, by the anodic oxidation of hydrazones 3 in the presence of pyridine (Scheme 5). In our working mechanistic scheme we proposed nitrilimine as the possible intermediate and pointed out that this reaction opens the door to a wide range of heterocyclic systems via anodic oxidation of aldehyde hydrazones through 1,3-dipolar cycloaddition reactions of the nitrilimine involved. 

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