Solvent-Controlled Monoselective Suzuki–Miyaura Cross-Coupling of Symmetrical 1,1-Dichloroalkenes: Scope and Origin of Selectivity

The Suzuki–Miyaura cross-coupling reaction is a vital transformation, as it enables the construction of carbon–carbon bonds with extraordinary generality and efficiency. However, challenges remain in controlling and predicting the cross-coupling selectivity of polyhalogenated species. Although some elegant reports have showcased selective examples of Suzuki–Miyaura cross-coupling with both symmetrical and unsymmetrical multihalogenated arenes, there is no reported success with 1,1-dihaloalkenes due to a lack of understanding of the factors controlling reactivity and selectivity. Initial evaluation of reaction conditions revealed that the halogen and alkylidene identity plays a critical role in the selectivity. The unexpected reactivity trends uncovered within this study were further investigated through both experimental and computational analyses, offering deeper insights into the properties of these motifs in palladium-mediated catalysis. Reoptimization of the reaction conditions delivered a significant improvement in the generality of this process, affording higher yields and selectivity ratios for a broad range of 1,1-dihaloalkenes. The key to the improved reactivity hinges on solvent selection with solvent polarity being directly tied to the observed selectivity ratios. To display the utility of this method, a series of derivatizations were enacted on the single cross-coupled alkylidene cyclobutane, providing access to several structurally distinct scaffolds. Furthermore, a concise, streamlined synthesis of the δ-opioid receptor agonist ARM-390 was achieved, demonstrating the potential of this strategy in drug discovery.