Bicyclo[1.1.1]pentane Ketones via Friedel–Crafts Acylation
Karolina Urbańska, Freya Ritterling, Brendan Twamley, Oliver Cseh, Vitalina Levchenko, Vasyl Ripenko, Pavel K. Mykhailiuk, Mathias O. Senge
TL;DR
This paper introduces a new method to synthesize bicyclo[1.1.1]pentane ketones, which are useful in drug development as bioisosteres.
Contribution
The paper presents the first method for Friedel–Crafts acylation to access diaromatic BCP 1,3-diketones.
Findings
A protocol for Friedel–Crafts acylation of (hetero)aromatic hydrocarbons with BCP acyl chlorides was developed.
35 mono- and diketones were synthesized, including 7 examples of postsynthetic modifications.
A BCP analogue of fenofibrate was successfully synthesized.
Abstract
Bicyclo[1.1.1]pentane (BCP) is a rigid aliphatic hydrocarbon with a three-dimensional (3D), propeller-like shape and a molecular size that makes it a targeted bioisosteric replacement for phenylene and acetylene groups in medicinal chemistry. For the pharmaceutical application of BCP, simple, efficient, and cost-effective synthetic tools are required to enable the exploration of BCP’s potential as a bioisostere across a broad chemical space. With numerous sophisticated protocols for C(sp3) functionalization of rigid aliphatic hydrocarbons reported in the literature, the synthesis of BCP mono- and diketones remains a challenging task, limited by both substrate scope and expensive photocatalysts. Here, we present a protocol for Friedel–Crafts acylation of (hetero)aromatic hydrocarbons with BCP acyl chlorides; in particular, the first method to access diaromatic BCP 1,3-diketones.…
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Taxonomy
TopicsRadical Photochemical Reactions · Cyclopropane Reaction Mechanisms · Synthesis and Characterization of Pyrroles