Aromatic Metamorphosis: Skeletal Editing of Aromatic Rings

Abstract

Aromatic rings are fundamental structural motifs found in natural products, synthetic intermediates, pharmaceuticals, agrochemicals, and functional materials. While transformations at the periphery of these rings are well-established, modifying their core frameworks has remained an underexplored frontier. Our group has pioneered the concept, termed “aromatic metamorphosis”, enabling skeletal transformations of aromatic rings by replacing an endocyclic atom with a different atom or inserting an atom into aromatic rings, which leads to novel synthetic strategies and diverse molecular architectures.

The concept of aromatic metamorphosis was first demonstrated in the stepwise conversion of dibenzothiophenes and dibenzofurans into triphenylenes. These transformations, facilitated by palladium and nickel catalysts, involve the strategic activation of robust C–S and C–O bonds as the key steps. Next, the approach was extended to the two-step conversions of dibenzothiophenes into carbazoles, dibenzophospholes, fluorenes, etc., which involve oxidation into the corresponding sulfones and subsequent sequential inter- and intramolecular nucleophilic aromatic substitution reactions. These new synthetic routes have provided efficient access to optoelectronic materials. Especially, the S_NAr-based aromatic metamorphosis facilitated the construction of a heterohelicene library with systematic variation in endocyclic atoms. This strategy has revolutionized the way molecular libraries are constructed and enables the rapid discovery of functional molecules.

In addition to the endocyclic substitutions, ring-expanding aromatic metamorphosis through atom insertion has also been explored. We developed nickel-catalyzed boron insertion into benzofurans, generating benzoxaborins, which are important scaffolds for medicinal chemistry. This novel catalytic transformation has been successfully scaled to industrial synthesis by companies, which demonstrates the practical utility of aromatic metamorphosis. Furthermore, manganese-catalyzed and lithium–metal-promoted methodologies have expanded the ranges of heteroatoms inserted and aromatic frameworks cleaved, providing methods to access heterocycles with a diversity in element compositions.

Reductive dilithiation of thiophenes efficiently yields 1,4-dilithiobutadienes, which react with a variety of electrophiles to produce a series of nonbiogenic heteroles, such as boroles, phospholes, and siloles. In principle, this method should allow the sulfur atom in readily available thiophenes to be replaced with any atom and is therefore considered an ideal example of aromatic metamorphosis in terms of rapid construction of diverse chemical spaces with a variety of elements.

Aromatic metamorphosis proposes many new synthons and retrosynthetic disconnections that defy the conventional wisdom of organic synthesis. By making full use of metamorphosing the aromatic skeleton, a library with skeletal diversity can be constructed directly with minimal effort and time investment. Its applications span from pharmaceuticals to materials science, paving the way for a new paradigm in molecular design as well as synthetic strategy.