Significant Broadening of the Substrate Scope for the Hydrated Imidazoline Ring Expansion (HIRE) via the Use of Lithium Hexamethyldisilazide

Abstract

Substrates that are insufficiently activated towards the hydrated imidazoline ring expansion (HIRE) process have been previously found to deliver exclusively the products of aminoalkyl side-chain ring expansion. Attempted reversal of the process by thermal activation towards HIRE failed. We have found that for such problematic substrates the HIRE-type ring expansion can be effectively achieved by applying lithium hexamethyldisilazide (LHMDS) in toluene. LHMDS is thought to promote intramolecular transamidation, which leads to ring-expanded 10- and 11-membered heterocyclic products in modest to good yields. The process significantly broadens the substrate scope amenable to the HIRE strategy.

Ring Expansion Reactions through Intramolecular Transamidation

“…The authors further proposed a transamidation protocol suitable for ox‐ and thi‐azepinones without electron acceptor substituents in the aryl fragment and for diazepines 91 (Scheme 31). [29] This protocol relied on the interaction of 91 with 2 eq. lithium bis(trimethylsilyl)amide (LiHMDS) in toluene solution at RT.…”

“… Synthesis of medium‐sized cycles 92 by HIRE reaction using LiHMDS, developed by Krasavin's scientific group [29] …”