Energy-Transfer-Enabled Dearomative Cycloaddition Reactions of Indoles/Pyrroles via Excited-State Aromatics

Exploring the enormous chemical space through an expedient building-up of molecular diversity is an important goal of organic chemistry. The development of synthetic methods toward molecules with unprecedented structural motifs lays the foundation for wide applications ranging from pharmaceutical chemistry to materials science. In this regard, the dearomatization of arenes has been recognized as a unique strategy since it provides novel retrosynthetic disconnections for various spiro or fused polycyclic molecules with increased saturation and stereoisomerism. However, inherent thermodynamic challenges are associated with dearomatization processes. The disruption of the aromaticity of arene substrates usually requires large energy inputs, which makes harsh conditions necessary for many ground-state dearomatization reactions. Therefore, further expansion of the scope of dearomatization reactions remains a major problem not fully solved in organic chemistry. The past decade has witnessed tremendous progress on photocatalytic reactions under visible light. Particularly, reactions via an energy transfer mechanism have unlocked new opportunities for dearomatization reactions. Mediated by appropriately chosen photosensitizers, aromatic substrates can be excited. This kind of precise energy input might make feasible some dearomatization reactions that are otherwise unfavorable under thermal conditions because of the significant energy increases of the substrates. Nevertheless, the lifetimes of key intermediates in energy-transfer-enabled reactions, such as excited-state aromatics and downstream biradical species, are quite short. How to regulate the reactivities of these transient intermediates to achieve exclusive selectivity toward a certain reaction pathway among many possibilities is a crucial issue to be addressed. Since 2019, our group has reported a series of visible-light-induced dearomative cycloaddition reactions for indole and pyrrole derivatives. It was found that the aromatic units in substrates can be excited under the irradiation of visible light in the presence of a suitable photosensitizer. These excited aromatics readily undergo various [m + n] cycloaddition reactions with appropriately tethered unsaturated functionalities including alkenes, alkynes, N-alkoxy oximes, (hetero)arenes, and vinylcyclopropanes. The reactions yield polycyclic indolines and pyrrolines with highly strained small-and/or medium-sized rings embedded, some of which possess unique bridge-or cagelike topologies. Systematic mechanistic studies confirmed the involvement of an energy transfer process. Density functional theory (DFT) calculations revealed the correlation between the substrate structure and the excitation efficiency, which accelerated the optimization of the reaction parameters. Meanwhile, DFT calculations demonstrated the competition between kinetically and thermodynamically controlled pathways for the open-shell singlet biradical intermediates, which allowed the complete switches from [2 + 2] cycloaddition to 1,5-hydrogen atom transfer in reactions with N-alkoxy oximes and to [4 + 2] cycloaddition in reactions with naphthalene. Furthermore, ab initio molecular dynamics (AIMD) simulations uncovered post-spin crossing dynamic effects, which determine the regioselectivity for the open-shell singlet biradical recombination step in the reactions of pyrrole-derived vinylcyclopropanes. An increasing number of scientists have joined in the research on visible-light-induced dearomative cycloaddition reactions and contributed to more elegant examples in this area. The visible-light-induced dearomatization reaction via energy transfer mechanism, although still in its infancy, has exhibited great potential in the synthesis of molecules that can hardly be accessed by other methods. We believe that future development will further push the boundary of organic chemistry and find applications in the synthesis of functional molecules and related disciplines.

Automated summary

Exploring the chemical space and developing synthetic methods for molecules with unprecedented structural motifs in organic chemistry are important goals. Dearomatization of arenes, as a unique strategy, provides retrosynthetic disconnections for various molecules with increased saturation and stereoisomerism. However, inherent thermodynamic challenges make further expansion of dearomatization reactions a major problem. Visible-light-induced dearomative cycloaddition reactions have shown potential in synthesizing molecules that are difficult to access by other methods. Regulating the reactivities of transient intermediates in these reactions remains a crucial issue.