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Published on: February 16, 2020
Bicyclo[1.1.1]pentane Ketones via Friedel-Crafts Acylation
Karolina Urbańska1, Freya Ritterling1, Brendan Twamley2
1School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
None:
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.
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