Synthetic Strategies for Hydantoin Derivatives

Hydantoin derivatives represent a versatile class of five-membered heterocycles bearing two nitrogen atoms and two carbonyl functions. Their structural simplicity and rich reactivity profile have rendered them indispensable scaffolds in medicinal chemistry, agrochemicals and as synthetic precursors to non-proteinogenic amino acids. Traditional routes often rely on multicomponent condensations of carbonyl compounds, cyanide and amines, exemplified by the Bucherer–Bergs reaction, which combines operational simplicity with broad substrate scope. Advances in metal-catalysed and organocatalytic methodologies have expanded access to highly functionalised and chiral hydantoins under mild conditions. Oxidative carbonylation of α-amino amides and cycloaddition strategies, including Diels–Alder processes with activated methylidene intermediates, have unlocked spirocyclic and fused bicyclic frameworks with precise regiochemical control. Recent developments harness transition-metal catalysts and Lewis acids to enable selective ring closures, while enantioselective quaternary ammonium salt catalysis offers asymmetric C–C bond formation. Collectively, these innovations have improved yields, reduced step counts and introduced stereochemical control, underscoring the global significance of hydantoin chemistry in drug discovery and sustainable synthesis.

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Synthetic Strategies for Hydantoin Derivatives publication trend

The graph below shows the total number of articles in synthetic strategies for hydantoin derivatives across all publications each year (not limited to Nature Index journals).

Technical terms

Hydantoin: A heterocycle containing two nitrogen atoms at positions 1 and 3 and two carbonyl groups at positions 2 and 4 of a five-membered ring.

Bucherer–Bergs reaction: A three-component synthesis involving a carbonyl compound, cyanide and ammonia or amine to form hydantoins.

Diels–Alder reaction: A [4+2] cycloaddition between a conjugated diene and a dienophile to yield six-membered rings, often applied to methylidene-hydantoin derivatives.

Spirocyclic compound: A molecule in which two rings are joined through a single shared atom, creating a rigid three-dimensional framework.

Oxidative carbonylation: A metal-catalysed process in which CO and an oxidant are used to convert amides or amines into carbonyl-containing products under mild conditions.

Enantioselectivity: Preferential formation of one enantiomer over another in a chiral synthesis, often promoted by chiral catalysts or auxiliaries.

References

1. [4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones. International Journal of Molecular Sciences (2023).
2. The Bucherer–Bergs Multicomponent Synthesis of Hydantoins—Excellence in Simplicity. Molecules (2021).
3. Pd-Catalysed oxidative carbonylation of α-amino amides to hydantoins under mild conditions. Chemical Communications (2021).
4. Chiral Quaternary Ammonium Salt‐Catalyzed Enantioselective Addition Reactions of Hydantoins. Helvetica Chimica Acta (2024).