Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin.

Automated summary

In this study, bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were rapidly constructed by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered to a series of electronically unactivated heterocyclic precursors. The substitution reaction enables a ring expansion, facilitated by the conformationally constrained tether between the nitrile and the heterocycle. X-ray crystallography revealed ring-dependant strain within the hydantoin intermediate.