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

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Exploring the enormous chemical space through an expedient buildingup 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 s...

Translating Planar Heterocycles into Three‐Dimensional Analogs by Photoinduced Hydrocarboxylation**

“…indole and benzofuran derivatives), and accordingly hydrofunctionalization of these molecules has remained dominated by intramolecular approaches and harsh conditions. [12][13][14][15][16] We questioned whether direct hydrocarboxylation of indoles and related heterocycles could be accomplished under sufficiently mild conditions to serve as a general platform for heteroarene hydrofunctionalization (Figure 1B). This target reaction would transform heteroarene substructures, which are widely represented in drug discovery libraries, [17][18][19] into versatile heterocyclic α-amino acids with distinct biological properties.…”

Translating planar heterocycles into 3D analogs via photoinduced hydrocarboxylation

“…Of note, substrates bearing coupling handles, such as aryl chlorides ( 6) and boron pinacol esters (8), could be transformed into the desired indoline carboxylic acid building blocks in high yield. Upon probing other heteroarene cores, we found that diverse azaindoles could be readily converted to the desired product (12)(13)(14)(15)(16). Hydrocarboxylation of more structurally distinct benzofuran (17), furopyridine (18,19), and isoquinolone (20) substructures similarly resulted in high yields of the dearomatized products in each case.…”

“…indole and benzofuran derivatives), and accordingly hydrofunctionalization of these molecules has remained dominated by intramolecular approaches and harsh conditions. [12][13][14][15][16] Unfortunately, implementation of a heteroarene hydrofunctionalization strategy in drug discovery imposes numerous additional design constraints beyond the energetic demands underpinning any dearomatization process. The reaction must be (1) mild and functional group tolerant, (2) reliable and operationally simple, and (3) chemoselective for specific sites in heterocyclic moieties in the presence of the other (hetero)arenes.…”

“…14,[28][29][30][31][32] Established indole dearomative functionalization strategies rely on intramolecular nucleophiles or difunctionalization via delivery of two specific groups across the p-system. [12][13][14][15][16] Formal hydrocarboxylation of indole is currently accomplished via lithiation- carboxylation-hydrogenation sequences, resulting in poor chemoselectivity that largely precludes implementation in complex settings. While recent work has introduced a collection of powerful metalhydride-based alkene hydrocarboxylation reactions, 33,34 these approaches have been challenging to adapt to indole dearomatization.…”

Photoinduced Vinylogous Dearomatization

“…Central to the success of this platform is the efficient transfer of photo energy to chemical energy and the capability to allow the highly reactive radical-based pathways, therefore enabling numerous thermodynamically and kinetically unfavorable transformations to occur. It is important to note that such synthetic dominance has led to the establishment of a considerable number of dearomatization reactions, contributed by the groups of Glorius, Gaik, Meggers, Bach, You, etc. , The impressive achievements motivated us to assess the feasibility of photochemistry for important vinylogous manifolds. We wondered if the reaction of the radicals generated by photoinduced hydrogen-atom transfer (HAT) of allylic substrates with aromatic compounds could pave the way to a viable approach (the upper half of Scheme B).…”