What Is Ugi Reaction?
The Ugi reaction (or Ugi four-component reaction, U-4CR), discovered by Prof. Ivar Karl Ugi in 1959, stands as a paradigm of multi-component reactions (MCRs). This one-pot, atom-economical process converges four distinct components—an amine, a carbonyl compound (aldehyde or ketone), an isocyanide, and a carboxylic acid—to efficiently generate a highly functionalized α-acylaminoamide scaffold.
This transformation is remarkably efficient, forming two amide bonds (C-N and C-O) and one stereogenic center (if using chiral inputs) in a single operation, with water as the only byproduct. The product is a peptide-like structure, making it exceptionally relevant to medicinal chemistry.
- Reagents: Often methanol or another polar solvent. No catalyst is typically required.
- Reactants: Amines, carbonyl compounds, isocyanides, and carboxylic acid.
- Products: α-acylamino amides (bis-amides).
- Reaction Type: Multi-component reaction.
- Related Reactions: Passerini reaction, Mumm rearrangement.
Fig 1. Ugi reaction and its mechanism. [1]
Mechanism of Ugi Reaction
The mechanism of the Ugi reaction is a complex, yet elegant, sequence of equilibrating steps. Amines and aldehydes react with acids to form imines. The carbon atom of the isonitrile attacks the imine to form an intermediate, which is then attacked by the acid anion. This is followed by transfer of the acyl group through rearrangement, to form the Ugi product. The first few steps in this sequence are reversible. The driving force of the whole reaction is the final step, in which the acyl group transfer takes place, and forms a thermodynamically stable amide.
- Imine formation: The amine and aldehyde/ketone condense to form an imine (or iminium ion).
- Nitrilium formation and attack: The isocyanide attacks the iminium ion, forming a nitrilium ion intermediate.
- Carboxylate addition and rearrangement: The carboxylic acid attacks the nitrilium intermediate; a subsequent intramolecular acyl transfer (Mumm rearrangement) yields the bis-amide product.
Experimental Tips
The Ugi reaction features a large scope of substrates. The acid component can be carboxylic acids as well as inorganic acids such as cyanic acid, hydrosulfuric acid and hydrazine, or even secondary ammonium salts. The amine component can be a primary or secondary amine, as well as hydrazine, hydroxylamine, and urea. For example, studies have reported the use of carbon dioxide as the acid component in the Ugi reaction. Carbon dioxide reacts with methanol to generate monomethyl carbonate in situ, which then reacts with n-butylamine, isopropanal, and cyclohexenyl isonitrile to produce a Ugi product containing a carbonic acid amide. Other studies have reported the use of a secondary diamine as the amine component in the Ugi reaction to produce a product containing a tertiary amine and two amide bonds.
The advantage of using the Ugi reaction for peptide bond synthesis lies in its ability to transform peptide bonds from intermolecular reactions to concentration-independent intramolecular reactions when linking two relatively large peptides. However, the conventional condensation methods require condensing and activating of acyl reagents, and as a result there is a risk of racemization of amino acid. On the other hand, the Ugi reaction takes place under relatively mild conditions.
When the two functional groups required for the Ugi reaction are present in the same molecule, the reaction of this bifunctional compound with the other two components can be used to form a wide range of nitrogen containing heterocyclic compounds.
Application Examples of Ugi Reaction
- Example 1: Joanne Tan et al. used a multicomponent Ugi reaction with boryl isocyanide to synthesize peptide mimetics α-aminoboronic acid, and simultaneously used de novo virtual screening to effectively analyze and screen all possible α-aminoboronic acid candidates. By integrating these two technologies, they successfully identified three α-aminoboronic acids that are potent inhibitors of hClpP and hClpXP with IC50 values in the low micromolar range. [2]
- Example 2: Janeta Popovici-Muller et al. reported the synthesis of the isocitrate dehydrogenase 1 (IDH1) inhibitor ivosidenib (Tibsovo), in which the Ugi reaction is a key step in the synthesis of this inhibitor. [3]
Fig 2. Synthetic examples via Ugi reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 547-551.
- Tan, Joanne, et al. Journal of Medicinal Chemistry 62.13 (2019): 6377-6390.
- Popovici-Muller, Janeta, et al. ACS medicinal chemistry letters 9.4 (2018): 300-305.
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