Executive Summary : | Six-membered N-heterocycle pyridine and piperidine constitute important structural features for drugs and bioactive molecules, ligands for Lewis acids and transition metals, as well as in functional materials. For example, these are the most frequent heterocyclic structural motifs in the top 100 drugs, and FDA approved pharmaceuticals.1 Therefore their synthesis is one of the most explored fields in chemical synthesis. Although pyridine, quinoline, isoquinoline, and their saturated N-heterocyclic counterparts are abundant in nature and cheap; functionalized heterocycles required multi-step synthesis. Unfortunately, feedstock unsubstituted N-heterocycles are difficult to convert to the required functionalized ones; and their most common synthesis involves cyclization of highly functionalized acyclic precursors.2 These indirect methods required extra synthetic steps, additional cost and waste generation. Direct and regioselective functionalization of feedstock N-heterocycles would be an attractive option to attain sustainable processes.
Many of these drugs and drug-like molecules, as well as large numbers of N-heterocyclic ligands, are chiral in and around the heterocycles. Hence, their asymmetric synthesis holds great potential. Asymmetric reduction of N-heteroaromatics evolves as an attractive path for stereo-centers in the ring,3 but the limitation is again the preparation of the starting N-heteroaromatics. Generating stereocenters around the ring is less successful with only a handful of transition metal catalyzed methods available.4
The nitrogen on N-heteroaromatic compounds are sufficiently nucleophilic and can form stable quaternary nitrogen salts having N-C, N-O, and N-N bonds. The salt formation also makes the heteroaromatic ring stronger electrophile and susceptible to nucleophilic attack. We recently developed nucleophilic catalysis which adds to the N-heteroaromatic salts; transforming it to an electron-rich intermediate for photoredox aerobic oxidation via catalyst bound radical intermediate.5 The nucleophilic catalyst addition to N-heteroaromatic salt leads to a non-aromatic intermediate; and herein, we propose to explore those intermediates starting from different N-X salts for their regio- and stereoisomeric rearrangements to substituted N-heteroaromatic compounds. The findings of this proposal will bring about a set of mild and direct functionalization of feedstock N-heteroaromatics to value-added substituted N-heterocycles. Establishing those reaction pathways would help us understand the basic requirements and design criteria for asymmetric radical-ion as well as ionic reactions in general. With recent advancements in radical transformations, a general understanding of their possible asymmetric path would be a powerful solution for an unmet but desirable challenge. |