Activation of Pyridinium Salts for Electrophilic Acylation: a Method for Conversion of Pyridines into 3-acylpyridines

Electrophilic aromatic substitution reactions of pyridines are extraordinarily challenging. Instead of C-substitution at the pyridine ring, the electrophile typically forms an adduct with the pyridine nitrogen, which even further deactivates the already electron deficient pyridine ring toward electrophilic substitution. For example, the direct nitration of pyridine may require a reaction temperature of 330°C to provide only a 15% yield of 3-nitropyridine [1]. To the best of our knowledge, no direct, intermolecular C-acylations of pyridines have been reported [2]. This seriously limits the choice of methods for the preparation of the ubiquitous 3-substituted pyridines [3, 4]. In a limited number of cases, the lack of reactivity of pyridines toward electrophiles has been addressed by converting the recalcitrant pyridine into a temporarily activated 1,4-dihydropyridine [5-9]. In contrast to the electron poor parent pyridine, the electron rich 1,4-dihydropyridine features strongly enhanced reactivity toward electrophiles at the 3-position. Several steps are typically required including formation of the dihydropyridine, the subsequent reaction with an electrophile, and rearomatization to the desired 3-substituted pyridine. A similar concept has been ingeniously employed in a one pot nitration of pyridines in the presence of sulfite as the nucleophile that temporarily activates the pyridine, and then acts as a leaving group in an aromatization step [10, 11]. In principle, mechanistically analogous nucleophilic activation-aromatization sequences may also be possible with other combinations of nucleophiles and electrophiles, but other applications of this principle have not been reported. During our studies on indoloquinone synthesis involving the activation of oxazolium salts with cyanide ion [12], we fortuitously encountered the conversion from pyridinium salts to Reissert-type 4-cyano-1,4dihydropyridines having the general structure 1. We decided to explore their reactivity with electrophiles in anticipation that this might provide an indirect means for the introduction of a substituent into the 3-position of the pyridine ring. The results of this work are presented here.