Adventures in Catalysis: Development of Transition Metal-Catalyzed Reactions for C-X Bond Formations and High-Resolution Mass Spectrometry Tools for Probing Catalytic Reaction Mechanisms




Silva Villatoro, Roberto Napoleon

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The dissertation contained herein will chronical the development of new Pd- and Ni-catalyzed C-X bond forming reactions and the initial development of a new direct-injection high-resolution mass spectrometry (DI-HRMS) tool for detecting organometallic complexes in cross-coupling reactions at synthetically relevant concentrations.

Chapter 2 focuses on the development of a Pd-catalyzed, chemoselective O-selective benzylation of 2-quinolinones and 2-pyridones. These classes of N,O-heterocycles are deemed ambident nucleophiles, i.e. they have 2 nucleophilic sites on the same molecule. Though N-alkylation is well established, selective O-alkylation has been largely dependent on the use of stoichiometric Ag salts. In collaboration with the Chemical Process Development team at Bristol Myers Squibb (BMS), we have developed a novel Pd-catalyzed system capable of selectively alkylating the oxygen atom of 2-quinolinone using benzyl bromides as the electrophilic partner. Mechanistic experiments identified a surprising Xantphos mono-oxide Pd(II) η1-benzyl complex as the resting state of our catalyst and responsible for such high chemoselectivity. Expansion of this chemistry to 2-pyridone, a related heterocycle, has proven a much larger task than initially thought. Through optimization, new biphasic reaction conditions have been identified as a promising alternative to achieve a similar chemoselectivity as was observed with 2-quinolinones. Further mechanistic experiments have begun to probe the C-O bond forming step.

Chapter 3 stemmed from a curiosity from the work in Chapter 1. The Xantphos mono-oxide Pd(II) η1-benzyl complex was first identified through DI-HRMS. Without this piece of data, the discovery of this intermediate would have been greatly hindered. Given the capabilities of high-resolution mass spectrometers to detect compounds even at low concentrations, we set out to explore other canonical Pd-catalyzed cross-coupling reactions in a similar manner. So far we have explored both Sonogashira reactions and C-O coupling reactions. We have successfully detected multiple on-cycle complexes as well as some surprising off-cycle species. Current works are focused on exploring several protocols for Heck reactions and Buchwald-Hartwig aminations so explore the effects of different conditions on the detectable species.

Chapter 4 follows a second collaboration with the Chemical Process Development team at Bristol Myers Squibb. Though Ni-catalyzed C-N coupling has been studied for decades, their applicability to a broad range of substrate classes and large scale reactions has left much to be desired. Using the power of HTE at BMS, we set out to establish a Ni catalyst to unify the reactivity and substrate scopes of previous incarnations while making dramatic improvements to functional group tolerability and scalability. Herein, we have demonstrated a Ni-catalyzed system capable of the C-N coupling of aryl chlorides with anilines and aliphatic amines under markedly milder conditions to those previously reported. We have demonstrated the unique reactivity of our Ni-catalyzed system and are currently pursuing expanding the electrophile scope.



Ambident, Buchwald-Hartwig, Catalysis, Nickel, Palladium