(3°)- or (4°)-3-Alkylquinolones via Heteroaromatic Claisen Rearrangement

Described is a synthesis of quinolones with 3°- or 4°-3-alkylquinolones via a nucleophilic aromatic substitution and heteroaromatic Claisen rearrangement sequence. This particular substitution pattern is nearly absent in the literature as the motif is challenging to prepare by the conventional condensation-based approach. We report the optimization of a nucleophilic aromatic substitution reaction between 2°-allyl alcohols and 4-sulfonylquinolines and a 3°- or 4°-generating Claisen rearrangement. Key studies include improving and understanding the energetics and stereoselectivity of [3,3], the scope and limitations for the two-step sequence, and a proof-of-concept synthesis of “quaternary endochin-like quinolones” (4°-ELQs), a unique direction for the development of novel antiinfective agents.