# Bicyclo[1.1.1]pentane Ketones via Friedel–Crafts Acylation

## 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.

## Key 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. Reaction optimization, substrate scope, and reactivity
of the products are discussed. A total of 35 mono- and diketones are
reported, accompanied by 7 examples of postsynthetic modifications.
The synthesis of a BCP analogue of fenofibrate is reported. Noncovalent
interactions of the compounds in the solid state are discussed, including
a Hirshfeld analysis.