Internal alkynes in rhodium-catalysed, semi-intramolecular [2+2+2] cycloadditions

Abstract

Transition-metal catalysed [2+2+2] cycloadditions are an atom-economic method to generate highly complex arenes in a single step and can be classified into one of three categories depending on the number of molecules involved. The synthetic utility of the bimolecular (or semi-intramolecular) reaction is hampered by poor reactivity when the monoalkyne component is internal. This limitation is often described in the literature as an electronic effect in nature with little in the way of mechanistic evidence offered. This is the so-called “internal alkyne problem”.

The research reported herein details the full analysis of the limitations of this reaction, developing a rhodium-based manifold that can be generally applied to a variety of monoalkynes. It was found, in apparent disagreement with the literature, that the electronic nature of the monoalkyne was not a good predictor for the success of a reaction. Instead, the steric environment of the alkyne correlated much more strongly with the reaction outcome, with sterically encumbered alkynes performing significantly poorer than their unhindered counterparts. The apparent electronic effect was examined and as found to be an artifact of coordination, wherein the electron-withdrawing groups often contained an atom capable of acting as a secondary coordinating group, enhancing binding to the metal centre thus increasing reactivity.

Finally, the scope of the reaction was explored with a wide variety of functional groups being tolerated yielding highly complex benzene cores. This methodology was further extended to the use of borylated alkynes, which allowed for the synthesis of complex molecules with a valuable functional handle. Lastly, these borylated arenes were applied to the synthesis of benzoxaboroles, a moiety with an ever-growing presence in the pharmaceutical sector.