Cubane (C₈H₈) is a cube-shaped, strained hydrocarbon. Its derivatives can, for example, be used in bioactive compounds, metal–organic frameworks, or high-energy materials. However, the synthesis of many cubane derivatives is challenging. Most often, 1- and/or 4-substituted cubanes have been synthesized because they can be made from commercially available 1,4-cubanedicarboxylic acid.

Akiko Yagi, Kenichiro Itami, Nagoya University, Japan, and colleagues have developed a process for the regioselective arylation of amidocubanes. The approach allows the regioselective, late-stage installation of different aryl groups and the preparation of mono-, di-, tri -, or tetraarylated cubanes.

The team started from a 1-(N,N-diisopropylamido)-4-cyanocubane, which was first reacted with lithium tetramethylpiperidide (LiTMP) and Zn^tBu₂, and then with an aryl iodide in the presence of palladium catalyst system. This results in the formation of monoaryl cubanes. The process is based on a directed ortho-C–H metalation next to the amido group, followed by a palladium-catalyzed cross-coupling to install the aryl in the ortho-position.

The reaction can be repeated two more times to install different aryl substituents in all three possible ortho-positions next to the amido group. A fourth aryl group can be introduced in place of the original cyano group at the 4-position by hydrolysis and subsequent decarboxyphenylation of the CN group.

• Programmable Synthesis of Multiply Arylated Cubanes through C-H Metalation and Arylation,
  Kenichiro Itami, Ryo Okude, Genki Mori, Akiko Yagi,
  Chem. Sci. 2020.
  https://doi.org/10.1039/d0sc01909g