The incorporation of three-dimensional small-ring scaffolds into bioactive molecules can improve their pharmacokinetic profile, including increased metabolic stability and solubility. Therefore, the rigid 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have shown promise as linear bioisosteres for para-substituted benzene rings in drug development. Construction of BCPs commonly requires the cumbersome use of a volatile and labile [1.1.1]propellane solution as reagent, and more stable reagents do not show the versatile reactivity of propellane itself. The lack of practical reagents for BCP introduction currently impedes the potential of this promising scaffold for pharmaceutical development. Here we report stable thianthrenium-based BCP reagents for practical oxygen-, nitrogen-, and carbon alkylation reactions that expand the bicyclopentylation scope of any other reagent, including [1.1.1]propellane; aryl BCP ethers are characterized as a new structural motif in chemistry. The redox and stereoelectronic properties of the thianthrene scaffold are relevant for both the synthesis via strain release as well as the subsequent reactivity of the new reagents. The weak carbon-sulfur bond can undergo selective mesolytic cleavage upon single-electron reduction to produce BCP radicals that engage in transition-metal-mediated bond formations, including alkylation of phenols, N-heterocycles, amines, amides, sulfonamides, anilines, arenes, and heteroarenes, even at a late-stage with a wide variety of functional groups present. Because the versatile BCP thianthrenium reagents can be prepared centrally and are stable to storage and transport in ambient conditions, they display potential for applications in pharmaceutical research for exploration of high-value structures that otherwise may not have been accessed. We anticipate that the disclosure of bicyclo[1.1.1]pentane sulfonium salts as bioisosteres of aryl sulfonium salts will open the opportunity to target other building blocks for the installation of the thianthrene-based group.

Eva Alvarez

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