Cross-electrophile Coupling to Form S-C Bonds

In this project, Professor Patrick J. Walsh of the University of Pennsylvania is studying new methods to make bonds between carbon and sulfur (C–S). Significantly, the products of the processes under investigation are typically useful in their own right (e.g., biologically active) and they may also serve as building blocks from which other, more elaborate molecules can be prepared. As such, the research will facilitate the manufacture of materials of importance to society and including fine chemicals, pharmaceutical agents, and agrochemicals. Development of the catalysts and processes of interest will be aided by extensive mechanistic studies (to understand how the catalysts operate) and the use of modern high throughput experimental (HTE) methods, wherein exploratory reactions can be conducted 24 or 96 at a time using automated analysis. Reactions can be further optimized using machine learning to map how complex mixtures of solvents can be used to maximize reaction outputs such as yields and selectivities. Through these studies, the broader impacts of the funded project extend to the education and training of the graduate students conducting the research and societal benefits accrued as Professor Walsh and his coworkers engage in outreach activities with junior students from teaching universities and other venues. Of note, this award will enable Professor Walsh to continue to participate in international outreach to promote science and STEM education within and beyond the US. Enantioenriched sulfoxides are vital building blocks in organic synthesis and medicinal chemistry. This proposal introduces sustainable approaches to develop C–S bond forming reactions via transition metal catalyzed cross-electrophile coupling (XEC) processes. The overriding premise of this application is that enantioenriched sulfur-based building blocks can be generated from common sulfur electrophiles and aryl or alkyl halides using earth-abundant nickel catalysts in a straightforward fashion. By focusing on XEC reactions with earth-abundant nickel, the first sustainable method for the synthesis of enantioenriched sulfoxides will be investigated. Because Ni-catalysts for XEC reactions typically involve radical intermediates, high chemoselectivity can be achieved in the coupling step. The main objectives addressed herein are: 1) To develop enantioselective Ni-catalyzed XEC to generate diaryl and alkyl aryl sulfoxides, 2) Application of XEC to azasulfur compounds, 3) Investigation of reaction mechanisms for XEC in C–S bond-forming reactions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.