In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Jon Tunge of the Department of Chemistry at The University of Kansas will develop new decarboxylative coupling reactions. The proposed decarboxylative allylation and benzylation methods utilize CO2 release as a driving force for the synthesis of chemotypes that are prevalent in materials and pharmacologically important small molecules. Compared to other coupling methods, decarboxylative coupling offers the following benefits: i) carboxylic acids are abundant, ii) loss of CO2 provides an inherent large energetic driving force for reactions, iii) it avoids expensive, toxic, and highly basic reagents commonly employed for transmetallation, and iv) the byproduct is gaseous and therefore easily removed. At the completion of this project, it is expected that new methods for the synthesis of benzyl ketones, phenethylamines, benzyl coumarins, diaryl ethanes and asymmetric syntheses of gamma, delta-unsaturated esters, benzyl ketones, and diaryl methanes will have been developed. Furthermore, the proposed research will provide the chemical community with fundamental insight into these unique processes which involve the oxidative addition of C-O bonds.

The broader impacts include advancing the fundamental knowledge of chemical reactions and providing synthetic chemists with environmentally friendly methods for the synthesis of enantioenriched compounds that are important intermediates in the synthesis of medicinally relevant natural products and small molecules. In addition to providing chemists with the tools to construct molecules in a highly selective manner, the proposed research will also provide a cornerstone for the training of undergraduate and graduate students who are society's future research scientists. Outreach via partnering with a small Midwestern school (Hastings College) to provide undergraduates research opportunities and free dissemination of "notes" on catalytic chemistry via the Tunge group website are just two of the ways that funding of this proposal will impact the broader community of upcoming scientists.

Project Report

relate to the development of more environmentally friendly methods to make small molecules that are common precursors to pharmaceuticals and functional materials. Synthetic methods were developed that accomplish C-C bond formation from inexpensive alcohols that are much less toxic that reagents that are typically used in C-C coupling chemistry. In addition, synthetic methods were developed that result in the use of ubiquitious, inexpensive carboxylic acids as precursors. While typical methods utilize high energy stoichiometric organometallics that also produce stoichiometric, often toxic waste, the methods developed as part of this proposal utilize the loss of carbon dioxide as a natural energy source to drive the formation of reactive species for coupling. Ultimately, only carbon dioxide is a byproduct. Carbon dioxide, by virtue of being non-toxic and non-flammable, is among the most benign byproducts that can be produced in such organic syntheses. Furthermore, methods were developed to utilize the carbon dioxide produced as a catalyst that activates simply non-toxic alcohols toward substitution. In these cases organic synthesis is accomplished using the readily available gas carbon dioxide and produces only water as a byproduct. The methods that were developed were all applied to the syntheis of organic structures that are commonly found in, or commonly used as precursors to, pharmaceutical small molecules. Thus, this research contributes to the development of the next generation of "green" synthesis for the elimination of waste associated with typical pharmaceutical production.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Tingyu Li
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University of Kansas
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