The Ugi reaction is a

multi-component reaction In chemistry, a multi-component reaction (or MCR), sometimes referred to as a "Multi-component Assembly Process" (or MCAP), is a chemical reaction where three or more compounds react to form a single product. By definition, multicomponent reaction ...

organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...

involving a

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

, an

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

, an

isocyanide An isocyanide (also called isonitrile or carbylamine) is an organic compound with the functional group –. It is the isomer of the related nitrile (–C≡N), hence the prefix is ''isocyano''.IUPAC Goldboo''isocyanides''/ref> The organic fragme ...

and a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

to form a bis-

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

. The reaction is named after

Ivar Karl Ugi Ivar Karl Ugi (9 September 1930 in Saaremaa, Estonia – 29 September 2005 in Munich) was an Estonian-born German chemist who made major contributions to organic chemistry. He is known for the research on multicomponent reactions, yielding the U ...

, who first reported this reaction in 1959. UGI Reaction Ü V

The Ugi reaction is

exothermic In thermodynamics, an exothermic process () is a thermodynamic process or reaction that releases energy from the system to its surroundings, usually in the form of heat, but also in a form of light (e.g. a spark, flame, or flash), electricity (e ...

and usually complete within minutes of adding the isocyanide. High concentration (0.5M - 2.0M) of reactants give the highest yields. Polar, aprotic

solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...

s, like DMF, work well. However,

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

and

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

have also been used successfully. This uncatalyzed reaction has an inherent high

atom economy Atom economy (atom efficiency/percentage) is the conversion efficiency of a chemical process in terms of all atoms involved and the desired products produced. The simplest definition was introduced by Barry Trost in 1991 and is equal to the ratio ...

as only a molecule of water is lost, and the

chemical yield In chemistry, yield, also referred to as reaction yield, is a measure of the quantity of moles of a product formed in relation to the reactant consumed, obtained in a chemical reaction, usually expressed as a percentage. Yield is one of the pr ...

in general is high. Several reviews have been published. Due to the reaction products being potential protein mimetics there have been many attempts to development an

enantioselective In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

Ugi reaction, the first successful report of which was in 2018.

Reaction mechanism

One plausible

reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage of ...

is depicted below: UgiReactionMechanism

Amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

1 and

2 form the

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

3 with loss of one equivalent of water. Proton exchange with

4 activates the

iminium In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology. Structure Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...

ion 5 for

nucleophilic addition In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions di ...

of the isocyanide 6 with its terminal carbon atom to

nitrilium A nitrilium ion is a nitrile that has been protonated, CNHsup>+, or alkylated, CNR′sup>+. Synthesis Nitriles are only weakly basic and are poor nucleophiles, but they will attack very reactive electrophiles such as carbocations. 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 The Mumm rearrangement is an organic reaction and a rearrangement reaction. It describes a 1,3(O-N) acyl transfer of an acyl imidate or isoimide group to an imide. The reaction is of relevance as part of the Ugi reaction The Ugi reaction is ...

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 The Passerini reaction is a chemical reaction involving an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form a α- acyloxy amide. This addition reaction is one of the oldest isocyanide-based multicomponent reactions (IMCR) and wa ...

(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 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 Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...

. In this reaction the Mumm rearrangement in the final step is replaced by the

Smiles rearrangement The Smiles rearrangement is an organic reaction and a rearrangement reaction named after British chemist Samuel Smiles. It is an intramolecular nucleophilic aromatic substitution of the type: where X in the arene compound can be a sulfone, a ...

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

Combination of amine and carboxylic acid

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 acid

Zhang ''et al.'' have combined aldehydes with carboxylic acids and used the Ugi reaction to create

lactam A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words ''lactone'' + ''amide''. Nomenclature Greek prefixes in alphabetical order indicate ring size: * α-Lactam (3-atom rings) * β-Lacta ...

s of various sizes. Short ''et al.'' 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 Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...

, 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. Examples of Ugi reaction combinations: *

Isoquinoline Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquin ...

s from Ugi and

Heck reaction The Heck reaction (also called the Mizoroki–Heck reaction) is the chemical reaction of an unsaturated halide (or triflate) with an alkene in the presence of a base and a palladium catalyst (or palladium nanomaterial-based catalyst) to form a s ...

Pharmaceutical industry

Crixivan can be prepared using the Ugi reaction. Additionally, many of the ''caine''-type anesthetics are synthesized using this reaction. Examples include

lidocaine Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...

and

bupivacaine Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease feeling in a specific area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural space. It ...

References

{{DEFAULTSORT:Ugi Reaction Carbon-carbon bond forming reactions Multiple component reactions Name reactions Amide synthesis reactions