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. The reaction is named after Ivar Karl Ugi, who first reported this reaction in 1959.
|Named after||Ivar Karl Ugi|
|Reaction type||Coupling reaction|
|Organic Chemistry Portal|
|RSC ontology ID|
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 the chemical yield in general is high. Several reviews have been published.
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.
The reaction can also be performed with a pre-formed imine. This results in an increased yield.
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.
Combination of reaction componentsEdit
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.
|Ugi–Diels–Alder reaction||Ugi–Smiles reaction|
|Ugi–Buchwald–Hartwig reaction ||Ugi–Heck reaction |
Combination of amine and carboxylic acidEdit
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 acidEdit
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:
- Ugi, I; Meyr, R.; Fetzer, U.; Steinbrückner, C. (1959). "Versuche mit Isonitrilen". Angew. Chem. 71 (11): 386. doi:10.1002/ange.19590711110.
- Ugi, I; Steinbrückner, C. (1960). "Über ein neues Kondensations-Prinzip". Angew. Chem. 72 (7–8): 267–268. doi:10.1002/ange.19600720709.
- Ugi, I. (1962). "The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions". Angewandte Chemie International Edition in English. 1 (1): 8–21. doi:10.1002/anie.196200081.
- Ugi Multicomponent Reaction André Boltjes, Haixia Liu, Haiping Liu, and Alexander Dömling Org. Synth. 2017, 94, 54 doi:10.15227/orgsyn.094.0054
- Ugi, I., Lohberger S., Karl R. The Passerini and Ugi Reactions, Chapter 4.6, Comprehensive Organic Synthesis 1991, 2, 1083-1109. ISBN 0-08-040593-2, Pergamon, Oxford, 10196 pages (Review)
- Ugi, I.; Werner, B.; Dömling, A. (2003). "The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries" (PDF). Molecules. 8: 53–66. doi:10.3390/80100053.
- Banfi, L., and Riva, R. (2005). The Passerini Reaction. Organic Reactions, Vol. 65 L. E. Overman Ed. Wiley. (ISBN 0-471-68260-8)
- Tempest P.A. (2005). "Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction". Current Opinion in Drug Discovery & Development. 8 (6): 776–788.
- Ugi I.; Heck S. (2001). "The multicomponent reactions and their libraries for natural and preparative chemistry". Combinatorial Chemistry & High Throughput Screening. 4 (1): 1–34.
- Bienayme H, Hulme C, Oddon G, Schmitt P (2000). "Maximizing synthetic efficiency: Multi-component transformations lead the way". Chemistry: A European Journal. 8 (16): 3321–3329. doi:10.1002/1521-3765(20000915)6:18<3321::AID-CHEM3321>3.0.CO;2-A.
- Dömling A.; Ugi I. (2000). "Multicomponent Reactions with Isocyanides". Angewandte Chemie International Edition in English. 39 (18): 3168–3210. doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U.
- Wang, Qian; Wang, De-Xian; Wang, Mei-Xiang; Zhu, Jieping (30 April 2018). "Still Unconquered: Enantioselective Passerini and Ugi Multicomponent Reactions". Accounts of Chemical Research. 51 (5): 1290–1300. doi:10.1021/acs.accounts.8b00105.
- Zhang, Jian; Yu, Peiyuan; Li, Shao-Yu; Sun, He; Xiang, Shao-Hua; Wang, Jun (Joelle); Houk, Kendall N.; Tan, Bin (13 September 2018). "Asymmetric phosphoric acid–catalyzed four-component Ugi reaction". Science. 361 (6407): eaas8707. doi:10.1126/science.aas8707.
- S. E. Denmark & Y. Fan (2005). "Catalytic, Enantioselective α-Additions of Isocyanides: Lewis Base Catalyzed Passerini-Type Reactions". Journal of Organic Chemistry. 70 (24): 9667–9676. doi:10.1021/jo050549m. PMID 16292793.
- Complexity-Enhancing Acid-Promoted Rearrangement of Tricyclic Products of Tandem Ugi 4CC/Intramolecular Diels-Alder ReactionAlexei Ilyin, Volodymyr Kysil, Mikhail Krasavin, Irina Kurashvili, and Alexandre V. Ivachtchenko J. Org. Chem.; 2006; 71(25) pp 9544 - 9547; (Note) doi:10.1021/jo061825f
- Direct Access to Heterocyclic Scaffolds by New Multicomponent Ugi-Smiles Couplings Laurent El Kaim, Marie Gizolme, Laurence Grimaud, and Julie Oble Org. Lett.; 2006; 8(18) pp 4019 - 4021; (Letter) doi:10.1021/ol061605o
- Rapid Access to Oxindoles by the Combined Use of an Ugi Four-Component Reaction and a Microwave-Assisted Intramolecular Buchwald-Hartwig Amidation Reaction Florence Bonnaterre, Michèle Bois-Choussy, and Jieping Zhu Org. Lett.; 2006; 8(19) pp 4351–4354; (Letter) doi:10.1021/ol061755z
- Synthesis of Functionalized Quinolines via Ugi and Pd-Catalyzed Intramolecular Arylation Reactions Zhibo Ma, Zheng Xiang, Tuoping Luo, Kui Lu, Zhibin Xu, Jiahua Chen, and Zhen Yang J. Comb. Chem; 2006; 8(5) pp 696–704; (Article) doi:10.1021/cc060066b
- Second part microwave accelerated reaction with Pd(dba)2 and phosphine ligand Me-Phos
- The Heck step takes place with palladium(II) acetate, dppf ligand potassium carbonate and tetra-n-butylammonium bromide in dimethylformamide
- Gedey, S.; Van der Eycken, J.; Fülöp, F. (2002). "Liquid-Phase Combinatorial Synthesis of Alicyclic β-Lactams via Ugi Four-Component Reaction". Organic Letters. 4 (11): 1967–1969. doi:10.1021/ol025986r.
- Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. (1999). "Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid". Journal of Organic Chemistry. 64 (3): 1074–1076. doi:10.1021/jo982192a. PMID 11674195.
- Short K. M.; Mjalli A. M. M. (1997). "A solid-phase combinatorial method for the synthesis of novel 5- and 6-membered ring lactams". Tetrahedron Letters. 38 (3): 359–362. doi:10.1016/S0040-4039(96)02303-9.
- Xiang, Z.; Luo, T.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. (2004). "Concise synthesis of isoquinoline via the Ugi and Heck reactions". Organic Letters. 6 (18): 3155–3158. doi:10.1021/ol048791n. PMID 15330611.
- Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.; Reider, P. J. (1998). "An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan piperazine intermediate". Tetrahedron Letters. 39 (38): 6823–6826. doi:10.1016/S0040-4039(98)01484-1.
- Ugi reaction - Synthetic protocols from organic-reaction.com