Project Summary The goal of this proposal is to design new Ti-catalyzed oxidation reactions to modularly assemble pyrazole derivatives and difunctionalize alkynes. The rationale for developing Ti catalysis is that Ti is earth-abundant and generally nontoxic, which obviates the need for efficient catalyst removal and recovery in fine chemical synthesis. Early transition metals can access different structures and elementary reaction steps than late transition metals, resulting in bond forming strategies that are complementary or orthogonal to existing technology. First, the proposed research concerns developing new dual catalytic strategies for the [2+2+1] synthesis of pyrazoles. Using preliminary data gained in our laboratory on stoichiometric oxidation-induced N-N reductive elimination reactions, we will explore single-electron catalytic and photocatalytic strategies for oxidant turnover. Development of a catalytic strategy for electronegative bond couplings like N-N coupling will ultimately lead to mild and general dual catalyst systems for the rapid, modular construction of high-value bioactive pyrazoles, and also open avenues for advancing other challenging bond coupling reactions in catalysis. Further, we will design selective alkyne carboamination reactions, building off of preliminary results into this reaction class. Alkyne carboamination reactions can lead to iminocyclopropanes and unsaturated imines, each of which are valuable heterocycle building blocks. Our strategy for selective reaction design will be to use ISPCA, a new statistical analysis method we have developed that aids in determination of key control factors in a reaction. Concurrent refinement of ISPCA along with carboamination catalysis will yield both synthetically practical reactions, as well as a tool and roadmap for other catalysis researchers to follow in designing selective reactions. Finally, we will use our mechanistic insight of Ti redox catalysis to design new multicomponent alkyne oxidation reactions. A key focus of this work will be to develop strategies that incorporate more heteroatoms into the products, using our preliminary discoveries in dual catalysis and N-N reductive elimination. These reactions will result in catalytic methods to rapidly produce functional-group rich carbon scaffolds. Relevance to public health. Nitrogen heterocycles constitute the single most prevalent class of functional groups in FDA-approved small-molecule drugs: 59% of all unique small molecule drugs contain at least one N- heterocycle. Pyrazoles are an important class within this group, and have broad bioactivity. Although many reactions to form pyrazoles exist, their synthesis often relies on using potentially toxic and explosive hydrazines, and have well-established regioselectivity limitations. A general synthesis of pyrazoles that overcomes these limitations is an unmet challenge. By designing methods to pyrazoles, and more generally to the catalytic formation of weak bonds like N-N bonds, synthetic chemists will have rapid and convergent access to diverse and novel molecular architectures. These building blocks will aid in the development of new small molecule drug- like architectures for the biomedical community.

Project Narrative Pyrazoles are an important class of bioactive molecules that are found in many FDA-approved drugs such as celecoxib (Celebrex®), a non-steroidal anti-inflammatory used to treat arthritis, and apixaban (Eliquis®), an anti-coagulant used to treat blood clots and prevent strokes. Although pyrazoles are commonly used in medicinal chemistry, their synthesis often relies on using potentially toxic hydrazine reagents in reactions with poor regiocontrol. A general synthesis of pyrazoles that avoids the use of these reagents is an unmet challenge. The objective of this proposal is to design a general synthesis of pyrazoles from alkynes and nitriles, forming the key N-N bond in the pyrazole using titanium catalysts. This strategy, and the related method for making N-N bonds and other heteroatom-carbon bonds, will allow synthetic chemists to access diverse molecular building blocks that will ultimately aid in widespread distribution of new drug-like architectures to the biomedical community.