Synthetic methods for functionalised heterocycles using aryne chemistry

Overview

This research programme develops new synthetic organic chemistry methods centred on aryne intermediates to either functionalise existing heterocycles or construct them from simpler precursors. The work targets several heterocyclic frameworks of known biological interest, including substituted 5-arylmethyloxazoles, tetrahydroisoquinoline (THIQ) derivatives, benzodiazepines, dihydropyridines, and spirocyclic benzocyclobutenes.

The programme explores multiple aryne-based strategies: gold-catalysed aryne cyclisation to access substituted oxazoles, C–H functionalisation pathways to THIQ derivatives, aryne insertion into imidazolidines to build benzodiazepines, and aryne ene reactions with Hantzsch esters to produce dihydropyridines and spirocyclic benzocyclobutenes. Collectively, these methods aim to enable faster synthesis of known compounds, unlock previously inaccessible substitution patterns, and provide metal-free conditions where appropriate.

Technical specifications

Key chemistry platforms:

• Substituted 5-arylmethyloxazoles via gold-catalysed aryne cyclisation, enabling efficient access to arylated oxazole scaffolds
• THIQ derivatives through C–H functionalisation, streamlining synthesis of this biologically privileged scaffold
• Benzodiazepines via aryne insertion into imidazolidines, offering a novel disconnection for this important drug class
• Dihydropyridines and spirocyclic benzocyclobutenes through aryne ene reactions of Hantzsch esters, providing access to both medicinally relevant and structurally unusual motifs

Design objectives:

• Faster routes to existing heterocyclic targets compared to classical methods
• Access to substitution patterns that are difficult or impossible to achieve with current chemistry
• Alternative conditions, including metal-free protocols, for broader substrate compatibility and reduced reliance on precious metal catalysts
• Focus on heterocyclic frameworks with established biological relevance, supporting downstream pharmaceutical and agrochemical applications

Technology readiness level

The research is at an early stage of method development, focused on designing and validating new synthetic transformations. The proposal outlines the rationale and design of these approaches but does not yet present extensive validation procedures or future validation milestones. Further experimental work will be required to establish scope, substrate tolerance, and reproducibility before the methods can be considered for broader adoption or licensing.