Polarity Inversion and Photoredox Strategies in Heterocycles and Ketones Synthesis

A central goal in synthetic chemistry remains the development of reactivity platforms that can turn stable and readily available building blocks into complex molecules under mild conditions. Among the strategies that have gained significant traction in recent years are carbonyl umpolung and radical-based methods, which provide ways to move beyond the constraints of traditional two-electron reactivity. This thesis focuses on the use of 1,2-diaza-1,3-dienes (azoalkenes) as versatile, bench-stable, carbene-like intermediates that serve as practical C1 synthons. These intermediates offer a safer and more practical alternative to classical diazo compounds or sensitive organometallics. In the presence of Lewis acids, they are excellent building blocks in selective multicomponent reactions and cycloadditions–leading to heterocyclic frameworks not easily accessible through standard Diels–Alder-type chemistry. Photoredox catalysis is explored in parallel as a complementary strategy. Through light-driven access to open-shell intermediates, it enables the formation of new C–C and C–X bonds under redox-neutral conditions. When merged with polarity inversion logic, it provides a direct path to increased molecular complexity starting from simple feedstocks. Chapter 2 presents a Mannich-type multicomponent reaction where azoalkenes serve as electrophilic carbene surrogates. Promoted by ZnCl2, the reaction integrates primary amines and formaldehyde into a three- or four-component cascade that proceeds via a 3SM– or 4SM–5CR pathway, giving access to imidazolidines with either same or different substitution. The intrinsic polarity switch along the pathway plays a key role in guiding selectivity. Chapter 3 extends this chemistry through a ZnCl2-catalyzed cycloaddition between azoalkenes and 1,3,5-triazinanes, yielding imidazolidines with quaternary all-carbon centers. This transformation avoids the use of diazo compounds or traditional carbenoids, and a multicomponent variant was developed to allow broader scope and good control over chemo- and regioselectivity. Chapter 4 describes a photoredox-catalyzed deoxygenative coupling between alcohols and carboxylic acids to access sp3-rich ketones. Developed during my time at Princeton, this method avoids the use of organometallic reagents and relies on a photoredox/nickel dual catalytic platform was developed for the double deoxygenative coupling of alcohols and carboxylic acids to generate sp3-rich ketones. This approach bypasses the need for organometallic reagents by combining NHC activation, radical β-scission, and Ni-mediated acyl cross-coupling. The strategy proved broadly general and was compatible with late-stage functionalization of bioactive molecules such as ibuprofen, biotin, and gemfibrozil. Chapter 5 introduces a formal [3+2] cycloaddition between cyanoacetyl indoles and azoalkenes, affording indole–pyrrole hybrids under mild and green conditions. Some of these compounds exhibited low micromolar IC50 values against Leishmania infantum, along with reduced cytotoxicity compared to standard treatments, pointing to potential applications in medicinal chemistry. Finally, Chapter 6 focuses on the development of a formal [3+2] annulation between 5-aminopyrazoles and azoalkenes, providing efficient access to 1,6-dihydropyrrolo [2,3-c]pyrazole scaffolds. These fused N-rich heterocycles represent valuable architectures in medicinal chemistry, owing to their high degree of functionalization and potential biological relevance. Taken together, the work described in this thesis outlines a set of synthetic tools that leverage radical reactivity, umpolung logic, and multicomponent reactions to build complex molecules from simple precursors under conditions that are operationally simple and broadly applicable.