The Evolution of Decarboxylative Allylation: Overcoming pK_a Limitations

Abstract

Since early focus on development of the allylation of non-stabilized enolates, decarboxylative allylation has undergone tremendous evolution. This account describes the progression of decarboxylative allylation within the Tunge group with a focus on efforts to identify and overcome pK a requirements that initially limited the carboxylates that would undergo decarboxylative allylation.

Palladium-Catalyzed Dearomatization of Benzothiophenes: Isolation and Functionalization of a Discrete Dearomatized Intermediate

“…One such underexploited strategy involves a Pd-catalyzed dearomatization-rearomatization sequence that has been employed in allylation reactions of benzyl electrophiles. 7 9 11 Interestingly, these uncommon Pd-catalyzed C–H functionalization reactions of benzyl-substituted arenes have enabled functionalization at remote sites relative to the benzyl substituent, highlighting unique opportunities for reaction development (Scheme 1 ). These remote C–H functionalization reactions of benzyl and heterobenzyl electrophiles proceed through dearomatized π-benzyl–Pd intermediates, which then undergo a Pd-templated pericyclic step to dearomatize the benzyl moiety (Scheme 1a ).…”

“…[3][4][5][6] Historically, the most effective strategies for addressing issues of chemoselectivity have relied on properties inherent to the substrate, either through steric and electronic bias, or through noncovalent interactions that direct a reagent to specific C-H bonds. 1,2,[7][8][9] Extensive modern efforts have also explored control of selectivity through sophisticated reaction design, typically by [3][4][5][6][7][8]10 (a) employing small molecule catalysts with ligands capable of controlling substrate trajectories; (b) designing catalyst systems that coordinate to the substrate and deliver reagents to specific C-H bonds; and (c) employing and evolving enzymes to selectively functionalize an expanded scope of substrates. Beyond these strategies, the ability to exploit distinct and uncommon mechanisms can further expand the synthetic toolkit and enable access to novel heterocyclic compounds.…”

Palladium-Catalyzed Unimolecular Fragment Coupling of N-Allylamides Bearing a Tethered Nucleophile with the Translocation of an Amide Group

“…Deletion is the reverse process of insertion, in which a new chemical bond is forged by the ejection of an atom or a group from the substrate with the remaining fragments being recombined. Decarbonylation 6a and decarboxylation 6b c reactions are typical examples of deletion reactions. Substitution is a type of transformation that is a combination of deletion and insertion.…”

Decarboxylative Allylic Alkylation of Phthalides: Stabilized Benzylic Nucleophiles for sp3–sp3 Coupling

“…Enolate derivatives and related “soft” nucleophiles, whose conjugate acid has a p K a of <25, have proven to be successful Pd-catalyzed DAA substrates and have served as a robust platform for complex molecule synthesis . On the contrary, adaptation of this chemistry to “hard” nucleophiles (those with conjugate acid p K a values of >25) remains a significant challenge . Indeed, the more reactive nature of such nucleophiles often requires the use of harsher conditions to promote decarboxylation and can preclude the incorporation of electrophilic functional groups into the substrate.…”