Regiodivergent Palladium-Catalyzed Decarboxylative Coupling of Stabilized Benzylic Nucleophiles

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Project Summary Transition metal-catalyzed carbon-carbon bond formation plays a critical role in bioactive small molecule synthesis, both in academic and pharmaceutical industry settings. A particularly attractive tool is the palladium-catalyzed decarboxylative allylic alkylation (DAA) reaction, which facilitates carbon-carbon bond formation via the extrusion of a single byproduct, carbon dioxide. Despite its extensive applications in the preparation of medicinally relevant molecules, existing strategies to engage carbon-centered nucleophiles in DAA chemistry is limited to stabilized enolate-based and related nucleophiles whose conjugate acid pKa is less than 25. On the other hand, the reaction of less stabilized nucleophiles (conjugate acid pKa of > 25) is less well documented, in part due the energetic barriers associated with promoting their decarboxylation. Additionally, the majority of Pd-catalyzed decarboxylative couplings proceed through a mechanism in which the intermediate nucleophile and allylpalladium species react to predominantly deliver allylation products. In contrast, reports that detail the formation of the regioisomeric cyclopropanation product remain relatively scarce. To address these limitations, we have devised a new approach that relies on the use of aromatic anions as a means to stabilize and engage otherwise recalcitrant nucleophiles in decarboxylative coupling chemistry. Specifically, we recently demonstrated that allyl ester-substituted phthalides undergo efficient allylation in the presence of a Pd/Xantphos catalyst, delivering a variety of functionalized phthalides in excellent yield. Interestingly, when Xantphos is replaced with the bisamino ligand tetramethylethylenediamine (TMEDA), a cyclopropanated phthalide is isolated in high regioselectivity. The goal of Aim 1 is to significantly expand on these preliminary findings by applying our optimal Pd/Xantphos DAA catalyst to access a variety of biologically relevant motifs, including functionalized isoindolinone and fluorene derivatives. Alternatively, Aim 2 seeks to exploit the reactivity Pd/TMEDA-based catalyst to develop a general decarboxylative cyclopropanation of phthalide-based nucleophiles. Finally, the goal of Aim 3 is to elucidate the mechanistic basis of the regioselectivity for allylation versus cyclopropanation chemistry via structural, kinetic, and computational studies. The successful implementation of this proposal constitutes a significant expansion of the breadth of Pd-catalyzed decarboxylative coupling, establishing access to a wider family of bioactive structural motifs while engaging undergraduates in impactful yet practical research endeavors.