Toward Safe, Sustainable Chemical Synthesis: Iron-Catalyzed C-C and C-N Cross-Coupling

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 DESCRIPTION (provided by applicant): The advent of pharmaceutical drugs that prevent, diagnose and treat disease has facilitated a revolution in human health. The discovery and manufacture of these substances rely on chemical transformations. It is crucial to render these processes as safe, sustainable and cost-effective as possible and to develop novel synthetic methods to enable discovery of new medications. Of currently available methods, palladium-catalyzed C-C and C-N cross coupling reactions constitute two of the most widely practiced strategies in the pharmaceutical industry. While offering efficient transformations using easily handled, available starting materials, prominent drawbacks stem from a reliance on palladium catalysts. Palladium is considered toxic, making the removal of residual metal after a cross-coupling step a significant issue in the pharmaceutical industry. Moreover, taking its natural scarcity and growing consumption into account, dependence on palladium is detrimental to the sustainability of these processes. In contrast, iron is the fourth most abundant element on Earth and is classified as a metal with no significant toxicity, making it an ideal choice for the pharmaceutical industry. Indeed, Fe-catalyzed cross coupling is a primary initiative of the ACS Green Chemistry Institute Pharmaceutical Roundtable and is the long-term goal of this research. Furthermore, this work presents the opportunity to discover new reactivity with iron not available to less abundant catalysts. We have established a collaboration with the Catalysis Discovery Group of Bristol-Myers Squibb to develop Fe-catalyzed C-C and C-N cross coupling methodology. To be useful for pharmaceutical synthesis, these processes must incorporate stable carbon and nitrogen nucleophiles, reactivity that is currently unknown for iron catalysis. To overcome the considerable challenges associated with this transition, we will implement two parallel strategies - high throughput experimentation (HTE) and stoichiometric investigation. Rapid execution of considerable amounts of reactions enabled by HTE techniques will allow us to acquire extensive data regarding catalytic reactions in reasonable amounts of time. This information will be combined with fundamental knowledge gained in stoichiometric reactions of discrete, isolable iron complexes. A primary objective of the proposed research is the development of iron catalysts that engage in palladium-like behavior (two electron chemistry), efforts that will be facilitated by the preparation and observation of catalytically relevant iron complexes. The research described herein presents an innovative approach to solving the challenges of practical Fe-catalyzed cross coupling by capitalizing on the unique advantages offered by two distinct strategies, therefore maximizing the probability for success. Targeting the incorporation of stable coupling partners distinguishes this research from current Fe-catalyzed cross coupling efforts and, more importantly, will contribute safe, sustainable processes for large-scale chemical synthesis.