Synthesis Strategies for Cyclic Anhydrides and Imines

Synthesis of cyclic anhydrides and imines underpins the construction of numerous nitrogen‐containing heterocycles, most notably lactams and related scaffolds of pharmaceutical relevance. Traditional approaches involve condensation of carboxylic acid precursors followed by dehydration to afford the anhydride, which then undergoes nucleophilic attack by an imine or Schiff base. Control of reaction conditions—temperature, solvent polarity and catalyst choice—enables fine tuning of chemoselectivity, leading to ring‐closure or multicomponent annulations. Recent developments have broadened the palette of accessible cyclic anhydrides through aryl‐substitution and heteroatom incorporation, facilitating successive condensations and domino processes. Mechanistic elucidation, including kinetic and stereoelectronic studies, has clarified pathways to distinct diastereomers and even enantiomerically enriched products without recourse to chiral auxiliaries. One‐pot sequences that integrate Staudinger or aza‐Wittig steps with anhydride–imine coupling have emerged, delivering polyheterocyclic frameworks in a single operation. Solvent‐promoted protocols, particularly those exploiting fluoroalcohols, have further allowed catalyst‐free access to densely substituted lactams with high atom economy. These strategies collectively advance efficient assembly of complex architectures for applications ranging from medicinal chemistry to materials science.

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Synthesis Strategies for Cyclic Anhydrides and Imines publication trend

The graph below shows the total number of articles in synthesis strategies for cyclic anhydrides and imines across all publications each year (not limited to Nature Index journals).

Technical terms

Cyclic anhydride: A five- or six-membered ring derived from two carboxylic acid units by intramolecular dehydration, serving as an electrophile in ring-forming reactions.

Imine (Schiff base): A C=N functional group formed by condensation of an amine and an aldehyde or ketone, acting as a nucleophilic partner in annulation.

Lactam: A cyclic amide generated by intramolecular cyclisation of an amine onto a carboxylic derivative, central to many bioactive compounds.

Multicomponent reaction: A single-pot transformation in which three or more reactants combine to form a product, maximising complexity in one operation.

Diastereoselectivity: Preference for the formation of one diastereomer over another in a chemical reaction, critical for controlling three-dimensional architecture.

References

1. The Castagnoli–Cushman Reaction. Molecules (2023).
2. The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli–Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center. Molecules (2022).
3. One-Pot Sequence of Staudinger/aza-Wittig/Castagnoli–Cushman Reactions Provides Facile Access to Novel Natural-like Polycyclic Ring Systems. Molecules (2022).
4. Trifluoroethanol Promoted Castagnoli–Cushman Cycloadditions of Imines with Homophthalic Anhydride. Molecules (2022).