Transition Metal Catalyzed Routes to N-Heterocycles

University Of Utah, Salt Lake City UT

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Abstract

DESCRIPTION (provided by applicant): N-Heterocycles serve as a core to a many of biologically active pharmacophores. O f t h e 181 small molecule drugs that were approved by the FDA in the last 10 years, 51% i n c o r p o r a t e a 6 - m e m b e r e d N - h e t e r o c y cl e s t r u c t u r e. Of these 92 compounds, 25% comprise a pyridine, 22% comprise a pyrimidine, and 20% comprise a piperidine. Clearly, new and efficient methods to prepare N-heterocycles would have an enormous impact on the synthesis of current and future pharmaceuticals. To address the challenges of N-heterocycle synthesis, we chose to build a research program centered around the development of a general Ni-based cycloaddition catalyst system because 1) cycloaddition of unsaturated compounds, a reaction that provides an ideal, atom- efficient entry to ring systems, 2) mechanistically, heteroatom incorporation and concurrent inhibition of side product formation seemed more tangible for the Ni system; and 2) stoichiometric oxidative coupling reactions suggested that Ni may have a higher reactivity (and therefore more generality) than the traditional Co and existing Rh and Ru systems. We have since expanded our focus to include the development of new Fe based cycloaddition catalysts, which we have found to have complimentary reactivities compared to current catalytic systems. This proposal outlines our continuing efforts and encompasses the preparation N-heterocyclic compounds, not previously synthesized through cycloaddition chemistry, from environmentally friendly and readily available starting materials. Specifically, we seek 1) to expand Ni-catalyzed cycloadditions of azacyclobutanones, 2) develop new Fe cycloaddition catalysts for the preparation of pyrimidines, and 3) develop toolbox of catalysts that regioselectively couple alkynes and cyanamides to afford pyridines.