Pyridinium salts, 2-acyl-, oxidation

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. 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles with activated pyridines [69, 70]. The first examples of this chemistry involved either 77-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal alkynes as activating agents in a one-step protocol. The reaction proceeds under mild conditions that include AI2O3 catalysis. Quinolines 1 and chloroformates afford the expected adducts 68. The latter structures can be easily oxidized with O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates obtained this way have been used in Wittig-Homer chemistry. The whole sequence offers ready access to alkyl substituted isoquinolines [71]. Analogously, sUyl substituents have been introduced into A-acylated pyridines by using silylcuprates [72]. 

Ai-methylpyridinium-2-carbaldoxime (2-PAM = a Figure 36.30b) constitutes the most potent reactivator of acetylcholinesterase poisoned by organophosphorus acylation. However, due to its quaternary nitrogen, 2-PAM penetrates the biological membranes poorly and does not appreciably cross the blood-brain barrier. For this compound Bodor et designed an ingenious dihydropyridine-pyridinium salt type of redox delivery system. The active drug is administered as its 5,6-dihydropyridine derivative (Pro-2-PAM = b), which exists as a stable immonium salt c. The lipoidal b (pA"a = 6.32) easily penetrates the blood-brain barrier where it is oxidized to the active a. 

In the base-induced conversion of pyridinium salts (199) to pyrazolo[l,5-a]pyridines, 4,4a-di-hydropyrido[l,2-t ][l,3,4]thiadiazine intermediates (200) could be identified by H NMR, but were not isolable. Their subsequent oxidation may afford 127t antiaromatic systems (201) which upon disrotatory cyclization to tricyclic thiiranes (202), followed by desulfurization or acyl migration, gave differently substituted pyrazolo[l,5-a]pyridines, (203) and (204), respectively (Scheme 14) <85BCJ1432,84H(22)2237>. A similar desulfurization reaction of this ring system has also been reported <73CPB2146>. 

In comparison to the standard two-step sequence, the Ortoleva-King method offers convenience as a one-pot procedure and, in most cases, better yield. In addition, it is very valuable when the halide intermediate is difficult to obtain. For example, converting a-tetralone 6 to its acyl halides such as 8 would be complicated by over-oxidation at the electron-rich phenyl ring. However, the preparation of its pyridinium salt 7 succeeds using the Ortoleva-King protocol due to its mild condition. ... 

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