Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation

Like Comment
Read the Paper

Our paper published in Nature Communication can be found here:

Anti -selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation | Nature Communications

Five years ago, the Engle lab first opened its doors at Scripps Research and began an exciting adventure in the field of directed difunctionalization of unactivated alkenes. Meanwhile, Huiqi Ni (me), then 19 years old, began my university life at USTC in Hefei, China. I had already developed a strong interest in organic reactions that could forge cyclic structures since high school, and several years later, in 2019, I accepted the offer from Scripps Research and joined the Engle lab to begin my Ph.D. research. I was still motivated by these fascinating reactions that I had first learned about in high school, and I recognized that I could explore this passion in the Engle lab.

Figure 1. [3+2] alkene annulation projects

My first research project was revisiting a [3+2] annulation reaction between alkenyl amides and 2-naphthol (as of yet unpublished) that was first discovered by a former graduate student Zhen Liu and undergraduate student Tian Zeng in our lab. One limitation of this reaction in its current state of development is that it requires an excess amounts of bystanding oxidant, and the only oxidants that are effective are aryl iodides; this makes the reaction less useful due to inevitable side reactions, not to mention concerns about atom economy. Nevertheless, I was inspired  by this reaction, and I came up with a question: could 2-iodophenol be used as an all-in-one coupling partner and oxidant? To our surprise and delight, the first reaction I tried was a big success, and around 70% yield of the desired product was obtained.

Figure 2. Chemicals obtained from Pfizer.

We quickly finished the optimization of the reaction conditions by a careful screening of concentrations, and we also started collaborating with Pfizer to explore the substrate scope and with the Liu group at the University of Pittsburgh to study the reaction mechanism. During meetings with our collaborators, we generated many ideas regarding potential coupling partners. If the anilines with electron-withdrawing groups work well, could electron-deficient pyridine-type substrates be compatible? What about carbon-based coupling partners and amino-acid-derived alkene substrates? These questions propelled our initial understanding of the reaction much deeper, and fortunately many of these ideas actually panned out, which in turn improved the quality of our manuscript.

Figure 3. First version of crystal structure 3bn’. There is disordered solvent in the pore of the crystal.

We were lucky enough to collect almost all of the data that we needed before our respective institutions temporarily shut down in-person operations in March of 2020 due to the COVID-19 pandemic. During the two month hiatus that ensued, we were able to carefully write the manuscript and identify final experiments that needed to be performed. When we eventually submitted the manuscript and received reviewer comments back, we suffered a setback: one of the referees doubted our structural assignment of 3bn’. Even though we were confident about the connectivity based on the NMR data and had obtained a X-ray crystal structure, the diffraction data indicated significant disorder. For several weeks, we crystalized the product again and again until finally we obtained a nice crystal and a publishable report.

Fortunately, our work was met with enthusiasm from the editor and reviewers at Nature Communications, who offered helpful suggestions to further improve the manuscript. All told, from the first day I discovered this reaction until the day this manuscript was officially accepted, the project took 446 days to complete. Considering that this involved designing the reaction, optimizing the conditions, examining the substrate scope, scaling up the reaction, performing mechanistic experiments and calculations, and finally writing the paper, 446 days is not a very long time (especially while balancing first-year coursework and a pandemic!). Indeed, it was only possible due to the sustained efforts of such a wonderful team from two academic institutions and one company working together towards a common goal with a shared love of chemistry.

Huiqi Ni

student, Scripps Research