Development of decarboxylative coupling processes

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Heteroaromatics play a large role in the discovery of new molecules with important biological properties for the pharmaceutical industry. Thus, the development of novel synthetic methods remains a key challenge. The main limitation of common reactions, such as the Suzuki and Stille cross-couplings, is the employment of stoichiometric amounts of organometallic species that must be prepared in separate chemical transformations and generate chemical by-product waste. The primary goal of our research program is to explore carboxylic acids as surrogates for the organometallic species in carbon-carbon bond forming reactions. Nature has evolved effective decarboxylative coupling processes for the preparation of carbon-carbon bonds, such as in the synthesis of fatty acids. However, until recently, these have been under utilized by organic chemists as synthetic tools. My previous work revealed that 2-carboxylic acid-heteroaromatics are useful cross-coupling partners that undergo efficient coupling with aryl halides. This approach provides an entry into a new field of research, where carboxylic acids now function as organometallic surrogates in cross-coupling reactions. This reactivity is important due to the inherent novelty, as well as industrially since these coupling partners are widely available commercially and indefinitely stable. Gaining insight into the operative mechanism of the decarboxylative coupling is essential to capitalize further on this technology. Longer-term goals will involve highlighting the practical uses of the coupling through the synthesis of versatile heteroaromatic products as well as the rapid screening of heteroaromatic substructures against biological targets. Further extensions will explore other metal surrogates such as sulfinic acids, which will undergo de-sulfinylation more readily than the corresponding carboxylic acid due to the weaker carbon-sulfur bond. Our research program, decarboxylative metal catalyzed couplings, is in its infancy, but this burgeoning and recently highlighted field will mark a paradigm shift in the choice of coupling partners in the synthesis of pharmaceutically important heteroaromatics.