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.[5][6][7][8][9][10][11][12][excessive citations]
Due to the reaction products being potential protein mimetics there have been many attempts to development an enantioselective Ugi reaction,[13] the first successful report of which was in 2018.[14]
Amine1 and ketone2 form the imine3 with loss of one equivalent of water. Proton exchange with carboxylic acid4 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.
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 intramolecularDiels-Alder reaction[16] 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.[17]
Several groups have used β-amino acids in the Ugi reaction to prepare β-lactams.[22]
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:
An example of the use of the Ugi reaction to form a beta-lactam
Combination of carbonyl compound and carboxylic acid[edit]
Zhang et al.[23] have combined aldehydes with carboxylic acids and used the Ugi reaction to create lactams of various sizes. Short et al.[24] have prepared γ-lactams from keto-acids on solid-support.
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.
^Ugi I, Lohberger S, Karl R (1991). "The Passerini and Ugi Reactions". Comprehensive Organic Synthesis. Vol. 2. Oxford: Pergamon. pp. 1083–1109. ISBN0-08-040593-2.
^Banfi L, Riva R (2005). "The Passerini Reaction". In Overman LE (ed.). Organic Reactions. Vol. 65. Wiley. ISBN0-471-68260-8.)
^Tempest PA (November 2005). "Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction". Current Opinion in Drug Discovery & Development. 8 (6): 776–88. PMID16312152.
^Ugi I, Heck S (February 2001). "The multicomponent reactions and their libraries for natural and preparative chemistry". Combinatorial Chemistry & High Throughput Screening. 4 (1): 1–34. doi:10.2174/1386207013331291. PMID11281825.
^Wang Q, Wang DX, Wang MX, Zhu J (May 2018). "Still Unconquered: Enantioselective Passerini and Ugi Multicomponent Reactions". Accounts of Chemical Research. 51 (5): 1290–1300. doi:10.1021/acs.accounts.8b00105. PMID29708723.
^Denmark SE, Fan Y (November 2005). "Catalytic, enantioselective alpha-additions of isocyanides: Lewis base catalyzed Passerini-type reactions". The Journal of Organic Chemistry. 70 (24): 9667–76. doi:10.1021/jo050549m. PMID16292793.
^Ilyin A, Kysil V, Krasavin M, Kurashvili I, Ivachtchenko AV (December 2006). "Complexity-enhancing acid-promoted rearrangement of tricyclic products of tandem Ugi 4CC/intramolecular Diels-Alder reaction". The Journal of Organic Chemistry. 71 (25): 9544–7. doi:10.1021/jo061825f. PMID17137394.
^El Kaim L, Gizolme M, Grimaud L, Oble J (August 2006). "Direct access to heterocyclic scaffolds by new multicomponent Ugi-Smiles couplings". Organic Letters. 8 (18): 4019–21. doi:10.1021/ol061605o. PMID16928063.
^Bonnaterre F, Bois-Choussy M, Zhu J (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. 8 (19): 4351–4. doi:10.1021/ol061755z. PMID16956224.
^Ma Z, Xiang Z, Luo T, Lu K, Xu Z, Chen J, Yang Z (2006). "Synthesis of functionalized quinolines via Ugi and Pd-catalyzed intramolecular arylation reactions". Journal of Combinatorial Chemistry. 8 (5): 696–704. doi:10.1021/cc060066b. PMID16961408.
^
Gedey S, Van der Eycken J, Fülöp F (May 2002). "Liquid-phase combinatorial synthesis of alicyclic beta-lactams via Ugi four-component reaction". Organic Letters. 4 (11): 1967–9. doi:10.1021/ol025986r. PMID12027659.
^Zhang J, Jacobson A, Rusche JR, Herlihy W (February 1999). "Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid". The Journal of Organic Chemistry. 64 (3): 1074–1076. doi:10.1021/jo982192a. PMID11674195.
^Xiang Z, Luo T, Lu K, Cui J, Shi X, Fathi R, et al. (September 2004). "Concise synthesis of isoquinoline via the Ugi and Heck reactions". Organic Letters. 6 (18): 3155–8. doi:10.1021/ol048791n. PMID15330611.
^Rossen K, Pye PJ, DiMichele LM, Volante RP, Reider PJ (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.
