C–H Activation Strategies in Maleimide Functionalization

C–H activation has emerged as a transformative tool for the direct functionalisation of maleimide frameworks, enabling the rapid assembly of complex molecular architectures from simple precursors. Central to this field are transition-metal-catalysed protocols that cleave inert C–H bonds and install diverse substituents at predefined positions on the imide or on coupling partners. These methods offer high atom economy, broad substrate scope and the ability to access spirocyclic, heteroaryl and alkylated motifs without pre-functionalisation. Complementary approaches exploit Lewis-acid or Brønsted-acid promoters to activate the olefinic C–H bonds of maleimides or the aromatic C–H bonds of heterocycles, achieving regioselective alkylation, arylation and annulation. Such advances underpin the synthesis of bioactive scaffolds, drug conjugates and functional materials, and they connect mechanistic insights in organometallic chemistry with practical applications in medicinal chemistry and chemical biology.

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Technical terms

C–H activation: A catalytic process that cleaves a carbon–hydrogen bond and forges a new bond at that carbon without prior functional group installation.

Spiroannulation: A cyclisation reaction that constructs a spirocyclic framework by joining two rings at a single shared atom.

Maleimide: A five-membered cyclic imide featuring a conjugated olefin and two carbonyl groups, widely used in bioconjugation and materials chemistry.

Friedel–Crafts arylation: An electrophilic aromatic substitution that introduces an aryl group onto an aromatic or heteroaromatic substrate under Lewis-acid catalysis.

Lewis acid: A chemical species that accepts an electron pair to activate substrates towards nucleophilic attack or C–H functionalisation.

References

1. Rh(III)-catalyzed [5+1] spirocyclization to produce novel benzimidazole-incorporated spirosuccinimides. Green Synthesis and Catalysis (2023).
2. New Experimental Conditions for Diels–Alder and Friedel-Crafts Alquilation Reactions with Thiophene: A New Selenocyanate with Potent Activity against Cancer. Molecules (2022).