The Ugi reaction isexothermic and usually complete within minutes of adding the isocyanide. High concentration (0.5M - 2.0M) of reactants give the highest yields. Polar, aproticsolvents, likeDMF, work well. However,methanol andethanol have also been used successfully. This uncatalyzed reaction has an inherent highatom economy as only a molecule of water is lost, and thechemical 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 potentialprotein mimetics there have been many attempts to development anenantioselective Ugi reaction,[13] the first successful report of which was in 2018.[14]
Amine1 andketone2 form theimine3 with loss of one equivalent of water. Proton exchange withcarboxylic acid4 activates theiminium ion5 fornucleophilic addition of the isocyanide6 with its terminal carbon atom tonitrilium ion7. A second nucleophilic addition takes place at this intermediate with the carboxylic acid anion to8. The final step is aMumm rearrangement with transfer of the R4 acyl group from oxygen to nitrogen. All reaction steps arereversible except for the Mumm rearrangement, which drives the whole reaction sequence.
In the relatedPasserini 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 anintramolecularDiels-Alder reaction[16] in an extended multistep reaction.
A reaction in its own right is theUgi–Smiles reaction with the carboxylic acid component replaced by aphenol. In this reaction the Mumm rearrangement in the final step is replaced by theSmiles 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 4:1diastereomeric mixture:
An example of the use of the Ugi reaction to form abeta-lactam
Combination of carbonyl compound and carboxylic acid
Zhanget al.[23] have combined aldehydes with carboxylic acids and used the Ugi reaction to createlactams of various sizes. Shortet 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 ofcombinatorial 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.
^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.
^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.
