Ugi reaction
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The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide.[1][1][1] The reaction is named after Ivar Karl Ugi, who first published this reaction in 1962.
The Ugi reaction is exothermic and usually complete within minutes of adding the isocyanide. High concentration (0.5M - 2.0M) of reactants give the highest yields. Polar, aprotic solvents, like DMF, work well. However, methanol and ethanol have also been used successfully. This uncatalyzed reaction has an inherent high atom economy as only a molecule of water is lost and chemical yield in general are high. Recent research has shown that the Ugi reaction is accelerated in water.[1]
Several reviews have been published.[1][1][1][1][1][1][1]
Reaction mechanism
In the Ugi reaction, the initial reaction is the formation of an imine (1) from the amine and the ketone. Subsequent reaction of the imine with the isocyanide and the carboxylic acid gives intermediate 2, which rearranges via an acyl transfer into the bis-amide 3. The exact mechanism of the trimolecular reaction to form intermediate 2 is not known.[citation needed]The reaction can also be performed with a pre-formed imine. This results in an increased yield.[citation needed]
One plausible reaction mechanism is depicted below:[1]
Amine 1 and ketone 2 form the imine 3 with loss of one equivalent of water. Proton exchange with carboxylic acid 4 activates the iminium ion 5 for nucleophilic addition of the isocyanide 6 with its terminal carbon atom to nitrilium ion 7. A second nucleophilic addition takes place at this intermediate with the carboxylic acid anion to 8. The final step is a Mumm rearrangement with transfer of the R4 acyl group from oxygen to nitrogen. Note that in the related Passerini reaction (lacking the amine) the isocyanide reacts directly with the carbonyl group but other aspects of the reaction are the same. All reaction steps are reversible except for the Mumm rearrangement, which drives the whole reaction sequence.
Variations
Combination of reaction components
The usage of bifunctional reaction components greatly increases the diversity of possible reaction products. Likewise, several combinations lead to structurally interesting products. The Ugi reaction has been applied in combination with an intramolecular Diels-Alder reaction [1] in an extended multistep reaction.
A reaction in its own right is the Ugi-Smiles reaction with the carboxylic acid component replaced by a phenol. In this reaction the Mumm rearrangement in the final step is replaced by the Smiles rearrangement [1].
| Image:Ugi Diels Alder reaction.png | Image:Ugi-Smiles-reaction.png | |
| Ugi-Diels-Alder reaction | Ugi-Smiles reaction |
Another combination (with separate workup of the Ugi intermediate) is one with the Buchwald-Hartwig reaction [1]. In the Ugi-Heck reaction a Heck aryl-aryl coupling takes place in a second step [1]
| Image:Ugi Buchwald-Hartwig reaction.png | Image:Ugi-Heck-reaction.png | |
| Ugi-Buchwald-Hartwig reaction [1] | Ugi-Heck reaction [1] |
Combination of amine and carboxylic acid
Several groups have used β-amino acids in the Ugi reaction to prepare β-lactams.[1] This approach relies on acyl transfer in the Mumm rearrangement to form the four-membered ring. The reaction proceeds in moderate yield at room temperature in methanol with formaldehyde or a variety of aryl aldehydes. For example, p-nitrobenzaldehyde reacts to form the β-lactam shown in 71% yield as a 4:1 diastereomeric mixture:
Combination of carbonyl compound and carboxylic acid
Zhang et al.[1] have combined aldehydes with carboxylic acids and used the Ugi reaction to create lactams of various sizes. Short et al.[1] have prepared γ-lactams from keto-acids on solid-support.
Applications
Chemical libraries
The Ugi reaction is one of the first reactions to be exploited explicitly to develop chemical libraries. These chemical libraries are sets of compounds that can be tested repeatedly. Using the principles of combinatorial chemistry, the Ugi reaction offers the possibility to synthesize a great number of different compounds in one reaction, by the reaction of various ketones (or aldehydes), amines, isocyanides and carboxylic acids. These libraries can then be tested with enzymes or living organisms to find new active pharmaceutical substances. One drawback is the lack of chemical diversity of the products. Using the Ugi reaction in combination with other reactions enlarges the chemical diversity of possible products.
Examples of Ugi reaction combinations:
- Isoquinolines from Ugi and Heck reactions.[1]
Pharmaceutical industry
Crixivan can be prepared using the Ugi reaction.[1]
Additionally, many of the caine-type anesthetics are synthesized using this reaction. Examples include lidocaine and bupivacaine.
See also
References
de:Ugi-ReaktionAcknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
