Photoinduced [4 + 2] Cycloaddition Unlocks New Pathways to Tetrahydroisoquinoline Scaffolds

A new study published in Chem by Wang Wang, Bodi Zhao, Xiaotian Qi, and led by Professor Kevin Brown of Indiana University developed a transformative method for synthesizing tetrahydroisoquinolines (THIQs), compounds that are foundational to many biologically active molecules and drug candidates. THIQs have long captivated synthetic chemists, not just for their medicinal value but also for the intellectual challenge they pose in terms of construction. Historically, strategies for making these structures have leaned heavily on classic reactions such as the Pictet–Spengler or Bischler–Napieralski cyclizations. These approaches depend on electrophilic aromatic substitution and, by design, require electron-rich aromatic systems. While effective in many scenarios, they inherently limit the diversity of accessible THIQ structures, particularly when electron-deficient motifs or quaternary centers are desired. This limitation has become a significant bottleneck for medicinal chemistry, where chemical space exploration is crucial. As the demand for new therapeutic leads grows, so does the need for synthetic methods that can reach beyond conventional substitution patterns. Unfortunately, the existing toolbox offers few efficient ways to generate THIQs with electron-withdrawing substituents or unconventional substitution topologies. Moreover, while hydrogenation of isoquinolines provides another route, it is largely confined to generating tertiary centers, offering little flexibility in terms of broader functional group incorporation. Faced with these challenges, the research team set out to explore an entirely different path. Leveraging their expertise in photochemistry and guided by a deep understanding of imine reactivity, they introduced a novel photochemical [4 + 2] cycloaddition between sulfonylimines and alkenes. This light-driven transformation operates via energy transfer and leads to high-yielding, highly selective THIQ products — even from starting materials bearing electron-deficient substituents. Unlike traditional strategies that rely on aromatic reactivity, this method accesses THIQs through an orthogonal disconnection strategy, enabling the formation of new bonds and stereocenters that are otherwise difficult to achieve. The implications are substantial. By using visible light and judiciously chosen catalysts, the authors unlocked a reaction that is not only operationally simple and mild but also convergent and modular. Their approach enables rapid synthesis of structurally diverse THIQs, many of which are directly translatable into drug-like molecules. Additionally, mechanistic studies, including computational modeling, uncovered the origins of the reaction’s chemoselectivity, highlighting subtle variations in HOMO energies as the key differentiator.

To bring their vision to life, the researchers began by exploring how sulfonylimines respond under light exposure in the presence of alkenes. Drawing inspiration from earlier work on the aza-Paternò–Büchi reaction and their own success with [2 + 2] cycloadditions, they shifted their focus toward a different goal: harnessing energy transfer to drive a [4 + 2] cycloaddition. Their curiosity centered around how subtle structural variations in sulfonylimines could influence product outcomes. They initially tested several sulfonylimine structures, noting that one specific variant led to a surprising outcome—it favored the formation of a tetrahydroisoquinoline instead of the expected azetidine product. This discovery opened the door to a new transformation they hadn’t anticipated at the outset. The team refined the structure of their sulfonylimines, introducing groups like ethoxy substituents that seemed to steer the reaction toward their desired product. They found that using a ketimine bearing an ethyl ester led to the tetrahydroisoquinoline product in remarkable 91% yield. Although the initial product mixture contained a 1:1 ratio of diastereomers, a simple treatment with triethylamine tilted the balance toward the anti-isomer with impressive selectivity (>20:1 dr). These early results not only validated the team’s hypothesis but also underscored the reaction’s promise in delivering high yields and diastereocontrol with minimal manipulation. The authors cast a wider net to test the reaction’s generality. Across dozens of experiments, the researchers found that a broad array of alkenes—including those with electron-donating and electron-withdrawing groups—reacted smoothly. Substrates with esters, chlorides, and heteroaromatic groups like pyridines and thiophenes all performed well. Even cyclic alkenes and sterically hindered styrenes produced THIQs with good yields and stereoselectivity. Interestingly, for certain substituted alkenes, the researchers noticed that the stereochemistry of the starting material didn’t matter much—photoisomerization of the alkene occurred so rapidly that it smoothed out these differences before the key bond-forming step took place. Notably, limitations were also observed: some electron-deficient alkenes and highly substituted alkenes led to messy reactions or failed to give isolable products, revealing the boundaries of this method’s applicability. The team wanted to understand how this reaction was unfolding at the molecular level. They used luminescence quenching experiments to show that the sulfonylimines were indeed accepting energy from the excited-state iridium photocatalyst. Further evidence came from direct UV irradiation of the imine in the absence of catalyst, which still produced the THIQ product—albeit in lower yield—confirming that energy transfer rather than electron transfer was key. They also tracked hydrogen and deuterium movement in labeled compounds, revealing a partial atom transfer consistent with a radical-based pathway. To tie it all together, they turned to computational chemistry. Their calculations showed that small changes in the HOMO (highest occupied molecular orbital) distributions of intermediate radicals were responsible for the observed product selectivity. For some sulfonylimines, the radical favored coupling to give a [2 + 2] product, while others—like the successful ethyl ester version—channeled reactivity into the [4 + 2] pathway. These insights not only matched the experimental results but also provided a roadmap for predicting outcomes with new substrates.

In the final stretch of their investigation, the team explored how their THIQ products could be modified further. They demonstrated several downstream reactions, including alkylations and deprotections, that converted these intermediates into structures resembling real-world drug scaffolds. One of their products was even made on a gram scale, underscoring the method’s practicality. Through this comprehensive mix of benchwork and theory, they painted a clear picture: this was not just a clever reaction—it was a powerful new tool for building molecular complexity in ways the field had not seen before.

In conclusion, Professor Kevin Brown and his team developed a new way to construct tetrahydroisoquinolines which are core building blocks in countless pharmaceuticals and natural products. Traditionally, the chemical community has been bound by synthetic methods that rely on electron-rich aromatic systems and well-established, decades-old pathways. While reliable, those approaches often fall short when targeting molecules with unconventional substitution patterns, especially ones bearing electron-withdrawing groups or quaternary centers. What makes this new method so valuable is that it sidesteps those limitations entirely. By utilizing a photochemically driven [4 + 2] cycloaddition, the researchers have shown that it’s possible to access previously elusive regions of chemical space. This reaction not only enables the formation of complex molecules from simple and readily available starting materials, but it also does so with remarkable selectivity and efficiency. That kind of precision is especially important in drug discovery, where the ability to introduce subtle structural changes can dramatically impact how a molecule behaves in a biological system. Medicinal chemists now have a new tool to explore molecular diversity, optimize drug candidates, and potentially improve therapeutic outcomes. Beyond the practical aspects, the study also provides a deeper understanding of photochemical reactivity and the influence of electronic structure on reaction pathways. The mechanistic insights gained from both experimental and computational work help clarify how slight changes in molecular orbitals can direct a reaction down entirely different pathways. These findings don’t just explain the current results—they equip chemists with a predictive framework to design new reactions in the future.

Importantly, the accessibility of the method is another major win. The reaction uses mild conditions, tolerates a wide range of functional groups, and doesn’t require elaborate reagents or complex setups. That practicality increases the chances of this method being adopted in both academic labs and pharmaceutical development pipelines. In a field where time, yield, and versatility all matter, this approach checks nearly every box. In essence, the work by Professor Kevin Brown and his team doesn’t just introduce a clever chemical reaction—it opens the door to reimagining how complex, bioactive molecules can be assembled. It redefines what’s possible in the synthesis of tetrahydroisoquinolines and sets the stage for future breakthroughs in organic and medicinal chemistry.