To optimize the performance of bioactive molecules, medicinal chemists must fine-tune drug properties such as water solubility, metabolic stability, and permeability through the cell membrane. Towards this goal, bicyclo[1.1.1]pentanes (BCPs) have recently attracted significant attention as bioisosteres of benzene rings, an abundant feature in drug molecules. Despite three decades of literature on the synthesis of BCPs, efficient methods to incorporate them into target drug molecules are limited. In our effort to prepare BCP analogues of ubiquitous diaryl methylamines (Ar2CH-NH2), we have discovered new reactivity of [1.1.1]propellane, the highly strained parent structure from which many BCPs are derived. 2-Azaallyl anions, which are derived from N-benzyl ketimines, add reversibly with [1.1.1]propellane. Though this equilibrium lies far to the side of the 2-azaallyl anion, protonation of the BCP anion drives reactivity forward to enable C—C bond formation at room temperature with no external additives. This principle of anionic “propellerization” can be extended to the reaction of other pronucleophiles with [1.1.1]propellane as well as to the synthesis of 1,3-difunctionalized BCPs.

New bicyclo[1.1.1]pentanes via anionic reactivity of [1.1.1]propellane

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.