Palladium-Mediated Carbon-Carbon Bond formation: Methodology and Mechanism. Part I: Palladium-Catalyzed Α-Arylation of Aryl Nitromethanes, Phosphonoacetates, and Phosphine Oxides. Part II: Mechanistic Study of the Palladium-Mediated Chemoselective Activation of C(sp3)-H Bonds
Date of Award
Doctor of Philosophy (PhD)
Marisa C. Kozlowski
Part I: The catalytic α-arylation of aryl nitromethanes has been a longstanding challenge, due to the reported lack of reactivity of these compounds under cross-coupling conditions. Conditions for this transformation have been developed using mechanistically-driven high-throughput experimentation. The method efficiently provides access to a variety of isolable diaryl nitromethanes, which are useful synthetic intermediates, as well as diaryl ketones and diaryl methyl amines in sequential transformations. Additionally, a one-pot process has been developed for the differential di-arylation of nitromethane.
The catalytic α-arylation of phosphonoacetates has also been achieved using mechanistically-driven high-throughput experimentation. α-Arylated phosphonoacetates are biologically active structural motifs, and are synthetically useful in the Horner-Wadsworth-Emmons olefination. The conditions developed provide a significant improvement to the range of accessible phosphonoacetates, as previously reported methods were limited in scope and/or required harsh reaction conditions. The method is useful for both aryl bromide and aryl chloride starting materials at low catalyst loadings, and has been shown to be robust on large scale.
The challenging racemic quaternary α-arylation of phosphine oxides has been achieved as well, in 50% yield. Reaction conditions were thoroughly investigated using high-throughput experimentation. Improvements to the yield of the quaternary product were limited by decomposition of both the starting material and the product. More mild conditions with palladium catalysts were investigated, and a preliminary investigation of alternative catalysts was undertaken. The asymmetric quaternary α-arylation reaction was also studied.
Part II: A unique C(sp3)–H bond activation of toluene by Pd(OAc)2 was recently discovered. The mechanism of this reaction was studied. The initially proposed mechanism was ruled out, and another mechanism, more consistent with experimental evidence, is proposed. Evidence for a rate-limiting C–H activation event is presented, as is as evidence for radical character in both the oxazolone starting material and toluene coupling partner. Kinetics studies were undertaken, which revealed a completely zero-order reaction, perhaps implicating an intramolecular rate-determining step.
Vangelder, Kelsey Faith, "Palladium-Mediated Carbon-Carbon Bond formation: Methodology and Mechanism. Part I: Palladium-Catalyzed Α-Arylation of Aryl Nitromethanes, Phosphonoacetates, and Phosphine Oxides. Part II: Mechanistic Study of the Palladium-Mediated Chemoselective Activation of C(sp3)-H Bonds" (2016). Publicly Accessible Penn Dissertations. 2073.