Controlling regioselectivity of cyclization in heterocyclic alkynylamides

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University of New Brunswick


Competitive 5-exo/6-endo anionic intramolecular cyclization reactions in heterocyclic alkynylamides were explored via experimental and computational analysis. The 5-exo-dig cyclization pathway is usually disfavoured in heterocyclic systems, and 6-endo products are often both the kinetic and thermodynamic products. However, it was discovered that it is possible to shift selectivity toward the 5-exo-dig pyrrolone products and away from the less strained pyridinone products that are produced via the 6-endo-dig cyclization. Parameters such as identity of heteroatom, heteroatom positioning within the heterocycle, and functionality on the alkyne were investigated and in many cases were found to strongly influence product ratios. A series of computational studies was performed to provide further insight into the 5-exo and 6-endo-dig pathways in these heterocyclic systems. Theoretical predictions were found to reproduce experimental results, highlighting the predictive capabilities of the computations in determining preferred products. The established experimental and predictive computational protocols were then applied to more complex bisalkynylamides. The subsequent competing tandem cyclization pathways, 5-exo/6-exo-dig and 5-exo/7-endo-dig, were predicted and controlled using established experimental and theoretical concepts from earlier studies.