Ugi reaction

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. [cite journal | author = Ugi, I; Meyr, R.; Fetzer, U.; Steinbrückner, C.
title = Versuche mit Isonitrilen
journal = Angew. Chem.
year = 1959 | volume = 71 | pages = 386|doi=10.1002/ange.19590711110] [cite journal
author = Ugi, I; Steinbrückner, C.
title = Über ein neues Kondensations-Prinzip
journal = Angew. Chem.
year = 1960 | volume = 72 | pages = 267–268|doi = 10.1002/ange.19600720709] [cite journal
author = Ugi, I.
title = The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions
journal = Angewandte Chemie International Edition in English
year = 1962 | volume =1 | issue = 1 | pages = 8–21
doi = 10.1002/anie.196200081] The reaction is named after Ivar Karl Ugi, who first published this reaction in 1962.

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 chemical yield in general are high. Recent research has shown that the Ugi reaction is accelerated in water. [cite journal
author = Pirrung, M. C.; Sarma, K. D.
title = Multicomponent Reactions Are Accelerated in Water
journal = Journal of the American Chemical Society
year = 2004
volume =126
pages = 444–445
doi = 10.1021/ja038583a]

Several reviews have been published. [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)] [cite journal
author = Ugi, I.; Werner, B.; Dömling, A.
title = The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries
journal = Molecules
year = 2003
volume =8
url = http://www.mdpi.org/molecules/papers/80100053.pdf
pages = 53–66
doi = ] [Banfi, L., and Riva, R. (2005). "The Passerini Reaction". Organic Reactions, Vol. 65 L. E. Overman Ed. Wiley. (ISBN 0-471-68260-8)] [cite journal
author = Tempest P.A.
title = Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction
journal = Current Opinion in Drug Discovery & Development
volume = 8
issue = 6
pages = 776–788
year = 2005 ] [cite journal
author = Ugi I., Heck S.
title = The multicomponent reactions and their libraries for natural and preparative chemistry
journal = Combinatorial Chemistry & High Throughput Screening
volume = 4
issue = 1
pages = 1–34
year = 2001 ] [cite journal
author = Bienayme H, Hulme C, Oddon G, Schmitt P
title = Maximizing synthetic efficiency: Multi-component transformations lead the way
journal = Chemistry- a European Journal
volume = 8
issue = 16
pages = 3321–3329
year = 2000
doi = 10.1002/1521-3765(20000915)6:18<3321::AID-CHEM3321>3.0.CO;2-A] [cite journal
author = Dömling A., Ugi I.
title = Multicomponent Reactions with Isocyanides
journal = Angewandte Chemie International Edition in English
volume = 39
issue = 18
pages = 3168–3210
year = 2000
doi = 10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U ]

Reaction mechanism

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.Fact|date=February 2007

The reaction can also be performed with a pre-formed imine. This results in an increased yield.Fact|date=February 2007

One plausible reaction mechanism is depicted below: [ cite journal
author = S. E. Denmark and Y. Fan
title = Catalytic, Enantioselective α-Additions of Isocyanides: Lewis Base Catalyzed Passerini-Type Reactions
journal = Journal of Organic Chemistry
year = 2005
volume = 70
issue = 24
pages = 9667–9676
doi = 10.1021/jo050549m]

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

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 ["Complexity-Enhancing Acid-Promoted Rearrangement of Tricyclic Products of Tandem Ugi 4CC/Intramolecular Diels-Alder Reaction"Alexei 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] 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 ["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] .

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

Combination of amine and carboxylic acid

Several groups have used β-amino acids in the Ugi reaction to prepare β-lactams. [cite journal
author = Gedey, S.; Van der Eycken, J.; Fülöp, F.
title = Liquid-Phase Combinatorial Synthesis of Alicyclic β-Lactams via Ugi Four-Component Reaction
journal = Organic Letters
year = 2002
volume = 4
pages = 1967&ndash;1969
doi = 10.1021/ol025986r] 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." [cite journal
author = Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W.
title = Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid
journal = Journal of Organic Chemistry
year = 1999
volume = 64
pages = 1074&ndash;1076
doi = 10.1021/jo982192a] have combined aldehydes with carboxylic acids and used the Ugi reaction to create lactams of various sizes. Short "et al." [cite journal
author = Short K. M., Mjalli A. M. M.
title = A solid-phase combinatorial method for the synthesis of novel 5- and 6-membered ring lactams
journal = Tetrahedron Letters
year = 1997
volume = 38
pages = 359–362
doi = 10.1021/ol048791n] 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 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:
* Isoquinolines from Ugi and Heck reactions. [ cite journal
author = Xiang, Z.; Luo, T.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z.
title = Novel Pd-II-mediated cascade carboxylative annulation to construct benzo [b] furan-3-carboxylic acids
journal = Organic Letters
year = 2004
volume = 6
pages = 3155–3158
doi = 10.1021/ol048791n]

Pharmaceutical industry

Crixivan can be prepared using the Ugi reaction. [cite journal
author = Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.; Reider, P. J.
title = An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan piperazine intermediate
journal = Tetrahedron Letters
year = 1998
volume =39
pages = 6823–6826
doi = 10.1016/S0040-4039(98)01484-1]

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

ee also

*Passerini reaction

References