Multicomponent reaction
Ugi reaction
How the Ugi 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: Amine, aldehyde, carboxylic acid, isocyanide. Conditions: MeOH or TFE, 0.5–2 M, 25 °C. Bonds formed: C–C; C–N (amide ×2); N–C(acyl); bonds broken: C=O π; O–H; isocyanide divalent C. Stereochemistry: Racemic α-centre unless chiral amine/aldehyde used. Rate and selectivity: Imine formation is pre-equilibrium; Mumm acyl transfer is irreversible and drives the reaction.
At a glance
Step 1: Imine, then protonation to the iminium
An amine and an aldehyde condense to form an imine (the same Schiff-base chemistry covered earlier), which is then protonated by a carboxylic acid to form an electrophilic iminium ion.
Step 2: Isocyanide adds; carboxylate traps the nitrilium
An isocyanide's nucleophilic terminal carbon attacks the iminium carbon, and the resulting nitrilium ion is trapped by the carboxylate — the same nitrilium-trapping logic as the Passerini reaction, just with an amine component added first.
Step 3: Mumm rearrangement
A Mumm rearrangement delivers the final product: a dipeptide-like scaffold built from four separate starting materials in one flask — the Ugi reaction is one of the most efficient ways known to rapidly build molecular complexity for drug discovery libraries.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- M
- Metal. A generic metal centre.
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- TFE
- Fluorinated alcohols. Strongly H-bond-donating, non-nucleophilic solvents that stabilise cations.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
How it compares with related reactions
| Ugi reaction | Passerini reaction | Bucherer-Bergs reaction | |
|---|---|---|---|
| Reagents | Amine, aldehyde, carboxylic acid, isocyanide | Carboxylic acid, aldehyde or ketone, isocyanide | Ketone, KCN, (NH₄)₂CO₃ |
| Conditions | MeOH or TFE, 0.5–2 M, 25 °C | Aprotic solvent (CH₂Cl₂), high concentration, 25 °C | EtOH/H₂O, 60–70 °C (sealed vessel) |
| Stereochemistry | Racemic α-centre unless chiral amine/aldehyde used | Racemic α-stereocentre (unless chiral components) | Quaternary C5; racemic unless prochiral control |
| Rate / selectivity | Imine formation is pre-equilibrium; Mumm acyl transfer is irreversible and drives the reaction | Third-order overall: faster at high concentration, slowed by polar protic solvents | Cyanide addition and carbamate cyclization are fast in the buffered medium |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Ugi reaction?
Amine, aldehyde, carboxylic acid, isocyanide. Conditions: MeOH or TFE, 0.5–2 M, 25 °C.
Which bonds are formed and which are broken?
Formed: C–C; C–N (amide ×2); N–C(acyl). Broken: C=O π; O–H; isocyanide divalent C.
What is the stereochemical outcome?
Racemic α-centre unless chiral amine/aldehyde used
What controls the rate or the selectivity?
Imine formation is pre-equilibrium; Mumm acyl transfer is irreversible and drives the reaction
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