Liu, Richard YOnnuch, Polpum2026-10-1920262026-10-192026Onnuch, Polpum. 2026. Unconventional Pd-Catalyzed Cross-Coupling Reactions. Doctoral Dissertation, Harvard University Graduate School of Arts and Sciences.32861935https://dash.harvard.edu/handle/1/42760586Palladium-catalyzed cross-coupling reactions are among the most powerful tools in modern organic synthesis. Conventionally, however, each pair of coupling partners produces a single class of product. Accessing a closely related analogue—such as one containing an additional atom or a different substitution pattern—typically requires the preparation of an entirely different starting material. In the pharmaceutical industry, the rapid synthesis of structurally related candidates is essential during lead-optimization campaigns. These candidates may differ in their core scaffolds, such as biaryls, diarylamines, amides, sulfonamides, or ketones, or in the positions of their substituents, such as ortho, meta, or para. The “unconventional” cross-coupling reactions described in this thesis repurpose classical coupling partners to access alternative products, reducing the need to prepare a separate set of starting materials for each analogue. In Chapter 1, this is achieved through the insertion of a third component into a classical cross-coupling reaction. Chapter 2 instead harnesses an aryne pathway, typically regarded as an undesirable side process, to enable bond formation at a position distinct from that defined by the original leaving group. Chapter 3 extends this broader strategy of repurposing overlooked chemical processes to catalyst design by using a ligand self-modification pathway to tether a photocatalyst to a palladium ligand. This arrangement enables efficient photochemical activation, alters the kinetics of elementary organometallic steps, and provides access to reactivity and selectivity that are difficult to achieve under conventional thermal conditions. In Chapter 1, this is achieved through the insertion of a third component into a classical cross-coupling reaction, whereas Chapter 2 enables bond formation at a position distinct from that defined by the original leaving group. The unconventionality explored in this thesis is not limited to the overall transformations themselves. It also encompasses the use of chemical processes that are often overlooked or regarded as undesirable and their redirection toward useful reactivity. Chapter 3 extends this concept to catalyst design by using a ligand self-modification pathway to tether a photocatalyst to a palladium ligand. This arrangement enables efficient photochemical activation, alters the kinetics of elementary organometallic steps, and provides access to reactivity and selectivity that are difficult to achieve under conventional thermal conditions. Chapter 1: Aminative Suzuki–Miyaura Coupling The Suzuki–Miyaura and Buchwald–Hartwig coupling reactions are widely used to form carbon-carbon (C–C) and carbon-nitrogen (C–N) bonds, respectively. We report the incorporation of a formal nitrene insertion process into the Suzuki–Miyaura reaction, altering the products from C–C–linked biaryls to C–N–C–linked diaryl amines and thereby joining the Suzuki–Miyaura and Buchwald–Hartwig coupling pathways to the same starting-material classes. A combination of a bulky ancillary phosphine ligand on palladium and a commercially available amination reagent enables efficient reactivity across aryl halides and pseudohalides, boronic acids and esters, and many functional groups and heterocycles. Mechanistic insights reveal flexibility on the order of bond-forming events, suggesting potential for expansion of the aminative cross-coupling concept to encompass diverse nucleophiles and electrophiles as well as four-component variants. Chapter 2: Migratory Aryl Coupling A fundamental property of cross-coupling reactions is regiospecificity, meaning that the site of bond formation is determined by the leaving group’s location on the electrophile. Typically, achieving a different substitution pattern requires the synthesis of a new, corresponding starting-material isomer. As an alternative, we proposed the development of cross-coupling variants that would afford access to multiple structural isomers from the same coupling partners. Here, we first demonstrate that a bulky palladium catalyst can facilitate the efficient, reversible transposition of aryl halides by temporarily forming metal aryne species. Despite the nearly thermoneutral equilibrium governing this process, combining it with the gradual addition of a suitable nucleophile results in dynamic kinetic resolution of the isomeric intermediates and high yields of unconventional product isomers. The method accommodates a range of oxygen- and nitrogen-centered nucleophiles and tolerates numerous common functional groups. A Curtin–Hammett kinetic scheme is supported by computational and experimental data, providing a general mechanistic framework for extending this migratory cross-coupling concept. Chapter 3: Ligand Self-Modification Enables Photoredox Control of Palladium Cross-Coupling Photoredox cocatalysis can alter the redox and electronic states of first-row metal complexes to achieve remarkable reactions, but it has rarely been leveraged to control elementary steps in Pd-based cross-coupling. The Pd complexes involved in cross-coupling are comparatively resistant to one-electron and energy-transfer pathway. We exploit the dearomative rearrangement of a t-BuXPhos–Pd complex to install a pendant perylene diimide (PDI) photoredox unit directly on the ligand. Under green light, the resulting PhotoPhos–Pd catalyst enables N1-selective arylation of benzotriazoles and room-temperature nucleophilic fluorination of electron-rich aryl bromides, including five-membered heteroaryl bromides. Relative to an untethered Pd/PDI pair, the dyadic catalyst reacts much faster and avoids substrate/product inhibition. Stoichiometric photolysis, spectroscopy, kinetics, and density-functional calculations are consistent with intramolecular charge separation from LPdII(Ar)Nu, rapid reductive elimination from a formally Pd(III) state, and formation of a Pd(I) species that can be returned to the catalytic cycle. These results illustrate how covalent installation of a photoredox unit can beneficially modify the kinetic landscape of an established palladium cross-coupling catalyst.application/pdfenChemistryThesis or Dissertation2026-10-190009-0004-2107-345X