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45095-G1
A Novel Synthesis of Nitrogen Heterocycles by Ring-Opening Reactions of Pyridinium Salts

Christopher D. Vanderwal, University of California (Irvine)

The ring opening reaction of pyridinium salts dates back over a century to the pioneering work of Zincke and Kšnig. Treatment of appropriately activated pyridinium salts such as 2 (Figure 1) with secondary amines cleanly affords the products of ring opening. The product 5-amino-2,4-pentadienals (3), now known as Zincke aldehydes, appear ideally suited for manifold applications in synthesis; to date, however, this potential has remained largely unrealized.

In the research funded by our grant from the American Chemical Society's Petroleum Research Fund, we have found that tethering nitrogen-based nucleophiles to the 3-position of the pyridine enables a new heterocycle synthesis (see 4 to 5). After activation of the pyridine nucleus and cyclization of the tethered nucleophile onto C2 of the electrophilic pyridinium salt, which induces pyridine ring-opening, new non-pyridine heterocycles with integrated Zincke aldehyde motifs result. This new reaction was primarily applied to the synthesis of a variety of substituted indoles, that each bear the versatile propenal functional group appended to C3 of the indole. A variety of substituents are tolerated, and even azaindoles can be made in this way. Finally, as a model study for an eventual synthesis of the porothramycin/ anthramycin family of antitumor antibiotics, an N-benzoylated dihydropyrrole was synthesized, which corresponds to the central core of these compounds. In the last year of our support from ACS–PRF, we have published these initial results as a Communication in Angewandte Chemie. We have also recently made excellent progress in adapting our published synthesis of N-benzoylated dihydropyrroles to the synthesis of the porothramycins; we anticipate completion of this synthesis and publication by the end of 2008.

The use of the century old pyridinium ring opening reaction with tethered nucleophiles has led to a convergent two-step synthesis of a series of indole-3-propenals. Preliminary experiments with tethered amides have indicated that with the correct choice of experimental parameters, variation of nucleophile/tether combinations is also tolerated. Therefore, this reaction of pyridinium salts represents not simply a new indole synthesis, but rather the first step towards a potentially general protocol for heterocycle synthesis. We envision extension to oxygen- and sulfur-containing heterocycles, and carbocycles, as well as applications in natural product synthesis and medicinal chemistry.

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