Desulfonylative Arylation: An Academia/Industry Collaborative Success Story

Our most recent work as part of a longstanding industry/academia collaboration between the Baran group at TSRI and Pfizer was published today in Science (on a Sunday!). As far as details of the publication and SI are concerned, we will leave that to you to explore on your own, so this blog post will discuss the origin of the project.

You could say that this project actually began back in 2014 when our lab was initially approached by Pfizer to solve the synthesis of [1.1.1]-bicyclopentylamine on process scale.  This simple idea led to a much greater topic of what we called strain-release amination. A section of this work focused on the use of strained sulfone reagents to access cyclobutanes, and a follow up report showed that we can similarly access enantiopure functionalized cyclopentanes through “housane” strain-release reagents. Although the sulfone functional group was useful for subsequent anionic functionalizations (alkylation, fluorination, etc.), one limitation of this work was that the sulfone had to be removed using strong reducing conditions.

In particular, scientists at Pfizer wanted a way to conduct a desulfonylative cross-coupling. Due to our prior experience in the development of decarboxylative cross-coupling reactions, they approached us and asked if we could help them development a transformation of this type. A key precedent for our work was an elegant comprehensive study from the Denmark Group at UIUC where it was shown that alkyl phenyl sulfones could be desulfonylatively arylated under Fe catalysis with aryl Grignard reagents.

After discussing this potential project with Pfizer, we realized that we could potentially solve a research problem that we were interested in working on; namely, new ways to synthesize (fluoro)alkylated arenes through cross-coupling chemistry. While we wanted to do this in a decarboxylative sense from mono- or difluoro carboxylic acids, these substrates proved recalcitrant, presumably due to the instability of the redox-active ester intermediate.  Fluorinated sulfones, however, are well-established in the literature and have a high degree of stability.

To make a long story short, we found that under Ni-catalysis with arylzinc reagents, we could indeed conduct our desulfonylative arylation reaction. A key to the success of this reaction was the incorporation of the phenyltetrazole group onto the sulfone; in our hands under these and related reaction conditions, this was the only group on the sulfone that permitted the desired reactivity. With the help of two talented visiting students, Monika and Cheng, we were able to quickly realize the scope of the reaction and applied the developed reaction to a variety of examples we found in the patent literature; in many cases, our desulfonylative cross-coupling simplified access to drug-like compounds.

We think the key take away from this work is shown in the scheme below; that is, from a single sulfone intermediate, three analogues (alkyl, monofluoroalkyl, and difluoroalkyl) can be accessed divergently from a common intermediate without the need for toxic and difficult-to-handle deoxyfluorination reagents.

During the course of this work, we identified a few reagents that we thought could be useful to medicinal chemists, shown in the scheme below. In partnership with Asymchem, we prepared these on large scale and have made them available via Twitter for free to chemists interested in trying out our reactions.  Let us know if you’re interested, and we would be happy to ship some to you!

As many of you may know, ChemRXiv, a preprint server for chemistry, was recently established, and the idea of preprints was intriguing to us because it would allow for our work to be viewed and used even prior to publication. We decided to take the plunge and become the Baran Group’s experimental test case in preprints. We really enjoyed the streamlined process by which the work shows up online; within a day, our manuscript was viewable to anyone interested free of charge.

While the manuscript was in review, we were curious about the ranking of alkyl PT sulfones relative to other electrophiles in terms of reactivity. We were pleasantly surprised to find that under the optimized conditions for desulfonylative coupling, the primary RAEs (TCNHPI and NHPI) react preferentially whereas the PT sulfone reacts faster than the primary halides (Cl/Br). There, the qualitative trend would be:
Cl/Br<SO2PT<NHPI/TCNHPI.

We want to thank our collaborators at Pfizer for another successful entry into collaborative work as well as Asymchem for conducting large scale reactions.  Let us know if you have any questions or comments regarding the work! Thanks for reading!

Rohan, Jacob,  and Tian