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Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann–Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable  ortho -substitutions and the inability to conjugate vitamin B 3  to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B 3 ) from tryptophan, we herein report the development of a strategy for the synthesis of  meta- aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted  meta -aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C–N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to  ortho- unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.

Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines