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.
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
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:
Combination of carbonyl compound and carboxylic acid
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.
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.
Recently, a breakthrough has been made in the field of covalent organic frameworks (COFs), where Ugi reaction is being utilized to introduce different functional handles into the COFs by post-synthetic modification.[25] With this new promising strategy, it is believed a library of COFs can be prepared with useful functional handles for various important applications.
^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.
^Volkov A, Mi J, Lalit K, Chatterjee P, Jing D, Carnahan SL, Chen Y, Sun S, Rossini AJ, Huang W, Stanley LM (March 2023). "General Strategy for Incorporation of Functional Group Handles into Covalent Organic Frameworks via the Ugi Reaction". Journal of the American Chemical Society. 145 (11): 6230–6239.
doi:
10.1021/jacs.2c12440.
PMID36892967.
S2CID257425598.
^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.