Multicomponent — hydantoin synthesis
Bucherer-Bergs reaction
How the Bucherer-Bergs reaction works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Ketone, KCN, (NH₄)₂CO₃. Conditions: EtOH/H₂O, 60–70 °C (sealed vessel). Bonds formed: C–CN; C–N; C(=O)–N; ring; bonds broken: C=O (ketone); C≡N π. Stereochemistry: Quaternary C5; racemic unless prochiral control. Rate and selectivity: Cyanide addition and carbamate cyclization are fast in the buffered medium.
At a glance
Step 1: Imine, then α-aminonitrile
A ketone condenses with ammonium carbonate to form an imine/aminonitrile-forming sequence; cyanide (from KCN) adds to the resulting iminium, giving an α-aminonitrile — the same first steps as the Strecker synthesis.
Step 2: Carbamate formation, ring closure
The aminonitrile's amine nitrogen attacks a molecule of CO₂ or carbonate, and the nitrile nitrogen cyclizes onto that same carbon, closing a five-membered ring — two intramolecular additions in sequence.
Step 3: Rearrangement to the hydantoin
Tautomerization gives a hydantoin (a cyclic urea-amide) directly from a simple ketone — this one-pot method is still used industrially to manufacture the anticonvulsant drug phenytoin.
Abbreviations and terms
- EtOH
- Ethanol. Polar protic solvent.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
How it compares with related reactions
| Bucherer-Bergs reaction | Biginelli reaction | Groebke-Blackburn-Bienaymé reaction | |
|---|---|---|---|
| Reagents | Ketone, KCN, (NH₄)₂CO₃ | Aldehyde, urea, ethyl acetoacetate, HCl or Lewis acid | 2-aminopyridine, aldehyde, isocyanide |
| Conditions | EtOH/H₂O, 60–70 °C (sealed vessel) | EtOH, reflux (or neat, 90 °C) | cat. Sc(OTf)₃ or AcOH, MeOH, 25–60 °C |
| Stereochemistry | Quaternary C5; racemic unless prochiral control | C4 stereocentre formed (racemic unless chiral acid catalyst) | None (aromatic product) |
| Rate / selectivity | Cyanide addition and carbamate cyclization are fast in the buffered medium | Iminium formation or its Mannich-type capture is rate-limiting | Iminium formation then isocyanide addition; ring closure is fast |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Bucherer-Bergs reaction?
Ketone, KCN, (NH₄)₂CO₃. Conditions: EtOH/H₂O, 60–70 °C (sealed vessel).
Which bonds are formed and which are broken?
Formed: C–CN; C–N; C(=O)–N; ring. Broken: C=O (ketone); C≡N π.
What is the stereochemical outcome?
Quaternary C5; racemic unless prochiral control
What controls the rate or the selectivity?
Cyanide addition and carbamate cyclization are fast in the buffered medium
Study guides that help with this reaction
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go