Ugi reaction

Reaction mechanism

One plausible reaction mechanism is depicted below:

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. All reaction steps are reversible except for the Mumm rearrangement, which drives the whole reaction sequence.

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. This reaction can take place concurrently with the Ugi reaction, acting as a source of impurities.

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 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.

Another combination (with separate workup of the Ugi intermediate) is one with the Buchwald–Hartwig reaction. In the Ugi–Heck reaction a Heck aryl-aryl coupling takes place in a second step.

Combination of amine and carboxylic acid

Several groups have used β-amino acids in the Ugi reaction to prepare β-lactams. 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. have combined aldehydes with carboxylic acids and used the Ugi reaction to create lactams of various sizes. Short et al. 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 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.

Pharmaceutical industry

Crixivan can be prepared using the Ugi reaction.

Additionally, many of the caine-type anesthetics are synthesized using this reaction. Examples include lidocaine and bupivacaine.

References

References

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6. (1991). "Comprehensive Organic Synthesis". Pergamon.
7. (2003). "The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries". [[Molecules (journal).
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14. (September 2018). "Asymmetric phosphoric acid-catalyzed four-component Ugi reaction". Science.
15. (November 2005). "Catalytic, enantioselective alpha-additions of isocyanides: Lewis base catalyzed Passerini-type reactions". The Journal of Organic Chemistry.
16. (December 2006). "Complexity-enhancing acid-promoted rearrangement of tricyclic products of tandem Ugi 4CC/intramolecular Diels-Alder reaction". The Journal of Organic Chemistry.
17. (August 2006). "Direct access to heterocyclic scaffolds by new multicomponent Ugi-Smiles couplings". Organic Letters.
18. (September 2006). "Rapid access to oxindoles by the combined use of an Ugi four-component reaction and a microwave-assisted intramolecular Buchwald-Hartwig amidation reaction". Organic Letters.
19. (2006). "Synthesis of functionalized quinolines via Ugi and Pd-catalyzed intramolecular arylation reactions". Journal of Combinatorial Chemistry.
20. Second part [[Microwave chemistry. microwave]] accelerated reaction with [[Tris(dibenzylideneacetone)dipalladium(0). Pd(dba)₂]] and [[Organophosphorus. phosphine]] ligand Me-Phos
21. The Heck step takes place with [[palladium(II) acetate]], [[1,1'-Bis(diphenylphosphino)ferrocene. dppf]] ligand [[potassium carbonate]] and [[tetra-n-butylammonium bromide]] in [[dimethylformamide]]
22. (February 1999). "Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid". The Journal of Organic Chemistry.
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25. (1998). "An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan piperazine intermediate". [[Tetrahedron Letters]].