Making a Ring

This article illustrated here describes a new method developed by researchers at Emory University for synthesizing valuable heterocyclic compounds called dihydroquinolines. These compounds have potential applications in medicinal chemistry.
The key innovation is the use of a commercially available one-carbon "linchpin" reagent (1) that can be easily attached to simple aniline starting materials. This installs an alkyl boron group, which can then undergo a rhodium-catalyzed reaction sequence:
The rhodium catalyst binds to the alkyl boron group, positioning it near a specific C-H bond on the aniline ring.
The rhodium activates and cleaves this C-H bond, forming a 5-membered rhodacycle intermediate.
An alkyne coupling partner is then inserted into the rhodacycle, forming a larger 7-membered ring.
Finally, the desired dihydroquinoline product is released by reductive elimination from the rhodium catalyst.
The researchers demonstrated this method works well with a diverse range of substituted anilines and alkynes, often with excellent regioselectivity favoring the less sterically hindered product isomer.[6a-6h, 7a-7d, 8-26] They also showed the dihydroquinoline products can be readily transformed into other valuable heterocyclic motifs. Mechanistic studies suggest the key C-H activation step is irreversible and not the rate-limiting step.
In summary, this work introduces a novel "one carbon linchpin" strategy for carbon-directed C-H annulation reactions, providing a modular synthesis of medicinally relevant dihydroquinolines from simple starting materials.