What Is Bucherer-Bergs Reaction?
German chemists Hans Theodor Bucherer and Walter Bergs developed the Bucherer-Bergs reaction which serves as a multicomponent process enabling hydantoins synthesis from ketones alongside cyanide salts and ammonium carbonate.
Specifically, the Bucherer-Bergs reaction involves the condensation of a ketone with potassium cyanide (KCN) or sodium cyanide (NaCN) and ammonium carbonate [(NH4)2CO3] under aqueous or alcoholic conditions. The process proceeds via the formation of a cyanohydrin (R2C(OH)CN), which subsequently cyclizes to yield a hydantoin derivative. Hydantoins can be ring-opened to produce N-carbamoyl amino acids, which are then formed into amino acids by treatment with acids or appropriate enzymes.
First reported independently by Bucherer and Bergs in the 1920s, this reaction has become a cornerstone in heterocyclic chemistry, particularly for preparing substituted hydantoins, which are pivotal intermediates in medicinal and agrochemical applications.
- Reagents: KCN or NaCN; (NH4)2CO3; Aqueous or alcoholic solvent.
- Reactants: Ketones.
- Products: Hydantoins.
- Reaction type: Cyclization reaction (heterocyclic).
- Related reaction: Ugi reaction.
Fig 1. Bucherer-Bergs reaction and its mechanism. [1]
Mechanism of Bucherer-Bergs Reaction
Cyanide ions add to carbonyl compounds to form hydroxynitrile, and the ammonia released by ammonium carbonate reacts with hydroxynitrile to form aminonitrile by SN2 reaction. Then the nitrogen atom of the amine group in aminonitrile performs nucleophilic addition onto carbon dioxide resulting in the formation of cyano-containing carbamic acid. After forming 5-imino-oxazolidin-2-one through intramolecular cyclization of the carbamic acid the oxazolidinone structure transforms into 5,5-disubstituted hydantoin via an isocyanate intermediate. In the originally proposed mechanism, it was incorrectly assumed that 5-iminooxazolidin-2-one was directly rearranged to hydantoin in one step. It was not until the 1980s that an isocyanate intermediate was discovered between the two substances.
Experimental Tips for Bucherer-Bergs Reaction
- Reagent Ratios: Use a 1:2:2 molar ratio of ketone: KCN : (NH4)2CO3 for balanced reactivity. Excess cyanide may lead to side products (e.g., over-alkylation).
- pH Control: Maintain pH ~8-9 using ammonium carbonate as a buffer. Strongly alkaline conditions degrade cyanide, while acidic conditions hinder cyanohydrin formation.
- Temperature and Solvent: Reflux in water or ethanol (80-100°C) ensures efficient reaction progress.
- Workup: Acidify with HCl post-reaction to precipitate the hydantoin. Purify via recrystallization (ethanol/water mixtures are ideal).
- Safety: Cyanide salts are highly toxic; use gloves, fume hoods, and proper waste disposal protocols.
Application Examples of Bucherer-Bergs Reaction
- Example 1: Keisuke Tomohara et al. reported a direct synthesis of hydantoins (imidazolidine-2,4-diones) from natural plant products. The method achieved multiple production of α,α-disubstituted amino acid derivatives by direct chemical derivatization of ethyl acetate extracts of Curcuma zedoaria under Bucherer-Bergs reaction conditions. [2]
- Example 2: Biljana M. Šmit et al. assembled a fused bicyclic framework from readily available β-ketoesters and alkenyl halides in a three-step reaction sequence that combined the Bucherer-Bergs reaction and a final selenium-promoted intramolecular cyclization as key steps. [3]
Fig 2. Synthetic examples via Bucherer-Bergs reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 53-55.
- Tomohara, Keisuke, et al. Tetrahedron Letters, 2017, 58(32), 3143-3147.
- Šmit, Biljana M., et al. Tetrahedron, 2015, 71(7), 1101-1108.
