Bridge Heteroarylation of Bicyclo[1.1.1]pentane Derivatives

Abstract

Herein we report the decarboxylative Minisci heteroarylation of bicyclo[1.1.1]pentane (BCP) derivatives at the C2 (bridge) position. The developed process directly couples free BCP C2-carboxylic acids with non-prefunctionalised heteroarenes to provide rare examples of polysubstituted BCPs in synthetically useful yields. An extension of the methodology to the related 2-oxa-bicyclo[2.1.1]hexane motif was also achieved. Finally, the impact of the BCP core on the physicochemical properties of a representative example compared to its all-aromatic ortho- and meta-substituted analogues was evaluated.

Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes

“…Overall, we speculated that these milder conditions would favor bridge monofunctionalization over multifunctionalization and/or ringopened products which are traditionally favored in BCP C−H bridge functionalization protocols. 14 We first examined this bromination protocol with the commercially available 1,3-dicarboxylic acid BCP 1. Pleasingly, exposure of 1,3-dicarboxylic acid BCP and NCS to visible-light (450 nm) conditions, in the presence of brominating agent bromotrichloromethane, led to the formation of 2-brominated-1,3-dicarboxylic acid BCP 3 in moderate yields (Tables S1−S7).…”

“…12,13 However, despite the wide adoption of 1(,3)substituted BCPs in medicinal chemistry programs, the corresponding 2-substituted BCPs are virtually nonexistent in the patent literature. While there is substantial interest in synthesizing these bridge-substituted BCPs (i.e., BCPs substituted at the 2-position) as a means to access novel chemical space and replace ortho-or metasubstituted arene rings in bioactive molecules, 5,14,15 no methods exist that allows the direct preparation of complex 2-substituted BCP scaffolds. Although current approaches have enabled the introduction of some drug-like substituents at the bridge position, they suffer from long step counts and often lack modularity as they require preinstallation of the desired 2-substituents prior to BCP core construction.…”

A BN-Benzvalene

“…5 Among them, benzvalene has captured the attention of synthetic chemists due to its unique bonding and reactivity. 2 The development of a practical and facile synthesis of benzvalene by Katz 6 has led to the access to additional strained hydrocarbon scaffolds, including bicyclo[1.1.1]pentane 7,8 and bicyclo[2.1.1]hexane 9 derivatives that are of current interest as 3D bioisosteres of benzene in medicinal chemistry. 10 In comparison to the carbonaceous benzvalene, main group heteroatom-containing benzvalene derivatives have been less developed.…”

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes

“…1 The recognized merits of three-dimensionality in this regard have led to the development of methods to access saturated bioisosteric replacements of unsaturated molecular scaffolds. 2−4 Molecular frameworks containing a high fraction of sp 3 -hybridized atoms exhibit improved solubility, 5−10 metabolic stability, 2,6,8,11 and target specificity, 12−14 and are positively correlated with clinical success. 15 Despite the attractive features of sphere-like, 16,17 sp 3rich building blocks, this chemical space remains underexplored due to the paucity of methods for their synthesis (Figure 1A).…”