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

Makenzie J Millward,Jonathan Clayden,John W Ward,Emily Ellis

doi:10.1039/d0sc06188c

Abstract

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.

Highlights

Medium (8–12 membered) ring heterocycles are attractive target structures for medicinal chemistry: their limited conformational mobility limits unfavourable binding entropy while allowing three-dimensional organisation of functionality within the cyclic scaffold.[1,2] Medium rings lie at the core of a range of natural products having biological activities, such as antiviral, anticancer and anticoagulant agents.[1,2,3] very few marketed pharmaceutical agents contain medium rings.[4,5] This can be attributed principally to difficulties associated with their synthesis, namely the unfavourable transannular interactions and entropic factors that disfavour the corresponding cyclisation reactions.[6]
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
Ring expansion is a valuable strategy for the formation of medium rings, avoiding the difficulties associated with unfavourable cyclisations

Summary

Introduction

Medium (8–12 membered) ring heterocycles are attractive target structures for medicinal chemistry: their limited conformational mobility limits unfavourable binding entropy while allowing three-dimensional organisation of functionality within the cyclic scaffold.[1,2] Medium rings lie at the core of a range of natural products having biological activities, such as antiviral, anticancer and anticoagulant agents.[1,2,3] very few marketed pharmaceutical agents contain medium rings.[4,5] This can be attributed principally to difficulties associated with their synthesis, namely the unfavourable transannular interactions and entropic factors that disfavour the corresponding cyclisation reactions.[6]. Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C–N bonds† The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle.

Results

Conclusion