Photoredox Cross-Coupling for Propellane-Curious Chemists

Key words

propellanes - photoredox reaction - nickel catalysis - bicyclopentanes

Significance

The escape from flatland can be a treacherous adventure. Our familiar cross-couplings are often useless when faced with the dreaded sp³-hybridized carbon. It is even more challenging when that sp³ carbon belongs to [1.1.1]propellane. Although bicyclo[1.1.1]pentanes (BCPs; the products of reactions with [1.1.1]pro­pellane) are touted as isosteres for para-phenylenes that might improve solubility and metabolic stability, it can be challenging to implement them generally in synthesis of heterocyclic compounds. Generation of a metalated or otherwise activated BCP is first necessary (J. Kanazawa, M. Uchiyama Synlett 2019, 30, 1). The mild conditions developed by ­Molander and co-workers quickly assemble molecules containing a BCP core from [1.1.1]propellane itself. Of note, this report includes a variety of pharmaceuticals (including 4 and 5) rescued from flatland by using this method. Although it is limited to tertiary trifluoroboronates, due to the inherent reactivity of the resulting propellane radical, this represents a practical advancement in BCP synthesis.

Comment

[1.1.1]Propellane, with its unique internal bond, is fascinating in its own right. This paper reports both an interesting utilization of that internal bond and a clear understanding of its reactivity. By walking the tightrope between reactivity and inertness, some useful reactive electrophiles, including a sulfonylfluoride 3 and a molecule containing both a ketone and a 2-fluoropyridine group 6, were left unscathed during the transformation, which is not possible with typical BCP coupling methods. Nucleophiles such as amines or alcohols, however, were suspiciously absent from the scope, and a pyrrole and primary amide substrate were reported to fail. [1.1.1]Propellane was only involved in the reaction if tertiary trifluoroboronates were used, which is a key scope limitation. Despite this, for specific syntheses, this protocol could be used to eliminate several synthetic steps from a BCP preparation, as the authors have clearly shown that this reaction is tolerant of diverse and synthetically useful coupling partners.

Publication History

Article published online:
20 September 2022