INTRODUCTION:

In chemistry, a multi-component reaction (or MCR) is a chemical reaction where three or more compounds react to form a single product.¹By definition, multicomponent reactions are those reactions whereby more than two reactants combine in a sequential manner to give highly selective products that retain majority of the atoms of the starting material. The challenge is to conduct an MCR in such a way that the network of pre-equilibrated reactions channel into the main product and do not yield side products. The result is clearly dependent on the reaction conditions: solvent, temperature, catalyst, concentration, the kind of starting materials and functional groups. Such considerations are of particular importance in connection with the design and discovery of novel MCRs.²

History of Multicomponent Reactions:

Multicomponent reactions have been known for over 150 years. The first documented multicomponent reaction was the Strecker synthesis of α-amino cyanides in 1850 from which α-amino acids could be derived. A multitude of MCRs exist today, of which the isocyanide based MCRs are the most documented. Other MCRs include free-radical mediated MCRs, MCRs based on organoboron compounds and metal-catalyzed MCRs.

Isocyanide based MCRs are most frequently exploited because the isocyanide is an extraordinary functional group. It is believed to exhibit resonance between its tetravalent and divalent carbon forms. This induces the isocyanide group to undergo both electrophilic and nucleophilic reactions. The two most important isocyanide-based multicomponent reactions are the Passerini 3-component reaction to produce α-acyloxy carboxamides and the Ugi 4-component reaction, which yields the α-acylamino carboxamides.³

Ø Strecker reaction ,1850 (1838 by Laurent and Gerhardt, 1850 by stecker)

Ø Hantzsch reaction , 1882 (by Hantzsch )

Ø Biginelli reaction , 1891 (by Biginelli )

Ø Mannich reaction , 1912 (by Mannich )

Ø Passerini reaction ,1921 (by passerine )

Ø Ugi reaction ,1959 ( by Ugi )

Ø Organometallic MCRs

Ø Miscellaneous MCRs

Figure: A. Dömling, Org. Chem. Highlights 2004, April 5.

Types Multicomponent Reactions:

Examples of three component reactions:

· Alkyne trimerisation

· Biginelli reaction

· Bucherer–Bergs reaction

· Gewald reaction

· Hantzsch pyridine synthesis

· Kabachnik–Fields reaction

· Mannich reaction

· Passerini reaction

· Pauson–Khand reaction

· Strecker amino acid synthesis

· Petasis reaction

Examples of four component reactions:

· Ugi reaction

· Asinger reaction

Alkyne trimerisation

An alkyne trimerisation reaction is a [2+2+2] cyclization reaction in which three alkyne molecules react to form an aromatic compound. The reaction is 'pseudo' pericyclic since it has not been observed to occur without the assistance of metal catalysis; and the metal catalyst assembles the ring stepwise via intermediates which are not directly in between (in a geometric sense) the starting material and products.⁴

Biginelli reaction:

The combination of an aldehyde , β-keto ester , and urea under acid catalysis to give adihydropyrimidine was first reported by Pietro Biginelli in 1893.⁵ Referred to as the Biginelli reaction, this one-pot condensation reaction generates compounds with pharmacological activity, including calcium channel modulation, mitotic kinesin inhibition, and antiviral and antibacterial activity.⁶

Bucherer-Bergs reaction:

The Bucherer-Bergs reaction is the chemical reaction of carbonyl compounds (or cyanohydrins) with ammonium carbonate and potassium cyanide to give hydantoins. The reaction is named after Hans Theodor Bucherer.⁷The hydantoin nucleus has many pharmacological effects⁸ and is found in several clinically important medicines (e.g., nilutamide,⁹ phenytoin¹⁰). TheBucherer–Bergs reaction provides perhaps the best method fortheir preparation.^11,12

Gewald reaction:

The Gewald reaction is an organic reaction involving the condensation of a ketone (or aldehyde when R₂ = H) with a α-cyanoester in the presence of elemental sulfur and base to give a poly substituted 2-amino-thiophene.¹³ Moreover, they were found to have various biological applications, such as a potent apoptosis inducer;^14(a)a potential anti-inflammatory^(b) and anti-osteoporosis agent.^(c) the Gewald reactionwas mediated by excess amount of base, such as morpholine, diethylamine, triethylamine, KFealumina, etc. Many modifications of this reaction

have been developed recently, including using solid support,¹⁵ microwave irradiation combined with insoluble polymer support¹⁶ or soluble polymer support,¹⁷ In the course of our current research, we developed a facile and practical method to conduct one-pot Gewald reaction using catalytic amount of imidazole, which could give the desired products in moderate to high yield.

Hantzsch synthesis:

The first synthesis of a 1,4-dihydropyridines (1,4-DHPs) via a three component cyclocondensation reaction of acetoacetic ester, aldehyde and ammonia was reported by Arthur Hantzsch in 1882.¹⁸ 1,4-DHPs have now been recognised as vital drugs in treatment of angina and hypertension. Some of the representatives (nifedipine¹⁹, felodipine²⁰, nicardipine²¹and amlodipine.²²

Kabachnik-Fields Reaction:

This three-component coupling of a carbonyl, an amine and a hydrophosphoryl compound leads to α-aminophosphonates. The Kabachnik-Fields Reaction is very important in drug discovery research for generating peptidomimetic compounds.The synthesis of α-aminophosphonates exhibiting high bio-activity such as inhibition of synthase²³ HIV protease,²⁴ renin,²⁵ inhibitors of enzymes, neuroactive compounds, and plant growth regulators.²⁶

Mannich reaction:

The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after Chemist Carl Mannich.²⁷

Passerini reaction:

The Passerini reaction, a three-component condensation reaction of carboxylic acid, aldehyde and isocyanide constructing an α-acyloxycarboxamide in a single step, was first discovered by Passerini about 80 years ago.²⁸ Since then, this reaction has been widely used in synthetic and medicinal chemistry.²⁹

Pauson-Khand Reaction:

The preparation of 5-membered rings has been a subject of intensive research for organic chemists Of the many reported methods, transition metal-mediated coupling of three components, alkyne, alkene, and carbon monoxide, is a unique synthetic arsenal in the preparation of cyclopentenones.Since the very first report mediated by cobalt carbonyls by Pauson and Khand in 1973 (hereafter, PKR or PK-type reaction), numerous improvements of the prototype of the reaction and the variations employing other metals have been reported.³⁰

Strecker reaction:

The Strecker amino acid synthesis, devised by Adolph Strecker, is a series of chemical reactions that synthesize an amino acid from an aldehyde (or ketone). The aldehyde is condensed with ammonium chloride in the presence of potassium cyanide to form an α aminonitrile, which is subsequently hydrolyzed to give the desired amino-acid. A practical synthesis of optically active arylglycines via catalytic asymmetric Strecker reaction.³¹

Petasis reaction :

A new synthetic method, involving vinyl boronic acids as nucleophiles in Mannich type reactions was developed by Petasis for the preparation of various allylamines.³² Later on, this approach was extended to the preparation of non-natural amino acids. Thus, a trimolecular condensation involving diverse 3-indolyl boronic acids (A), glyoxalic acid (B), and a chiral amine (C) allowed the preparation of N-substituted-indolylglycines (D) with excellent diastereoselectivity.³³

Ugi reaction:

The Ugi four-component coupling reaction is representative among this class of reactions. The Ugi reaction is a coupling reaction between aldehyde,amine, isocyanide, and carboxylic acid to give a-acylaminoamide in one step. Recently, efforts have been made for tandem or sequential reactions to synthesize more complex molecules in combination with the Ugi reaction.^34,35 The reaction is usually conducted in a polar protic solvent such as methanol, and some success in water has recently been shown.³⁶Major advances in the scope of the Ugi reaction have occurred only within the last 20 years, mainly because of the limited availability of isocyanides and poor stereocontrol. In the mid 1900’s, only a few isocyanides were available. Today, about 380 isocyanides are commercially available.³⁷

Asinger reaction:

The Asinger-reaction was invented in 1956 by Friedrich Asinger³⁸. The Asinger-reaction is a multicomponent reaction and is classified as A-4CR (short for Asinger-4 component reaction), An α-halogenated carbonyl-component reacts with sodium-hydrogensulfide NaSH and forms in situ a Thiole. The thiole reacts directly with another carbonyl-component and ammonia to form Thiazolines. The reaction works also by using sulphur, an in α–position substitutable ketone, a further carbonyl-component and ammonia under formation of mixtures³⁹. The formation of 3-Thiazolines also occurs by using α-thioaldehyde or α-thioketone and ammonia⁴⁰. The chemical industry developed based on the Asinger-reaction multi stage processes for the production of pharmaceuticals like D-Penicillamine⁴¹ and the aminoacid DL-cysteine⁴²

APPLICATION OF MULTI- COMPONENT REACTION:

A) Antituberculosis-agents: (Synthesized the Ugi reaction)⁴³

B) Hepatitis agents:(Synthesized by the Ugi reaction)⁴³

C) Antiviral and antileishmanial agents: (Synthesized by the Ugi reaction)⁴³

D) Antimalarial agents : (Synthesized by the Ugi reaction)⁴³

E) Enzyme-inhibitors(HIV-protease): (Synthesized by the passerine reaction)⁴³

F) Antiviral-agents(HIV): (Synthesized by blackburn followed by cyclization)⁴³

G) Enzyme inhibitors (β- Secretase): (Synthesized by an MCR employing KoCN⁴⁴

H) Enzyme-inhibitors(calpain): (Synthesized by the passerine reaction)⁴⁴

I) Antimalarial agents: (synthesized by one- pot multicomponent under microwave irradiation)⁴⁵

J) Synthesis of new 3^’- Indolyl substituted hetrocycles under microwave irradiation. Following are examples of 3^’- Indolyl substituted hetrocycles.⁴⁶

K) Ion-Channel blocker(T- type Ca⁺²): (Synthesized by the Ugi reaction)

L) Anticancer and Antimicrobial activities: (synthesized by multicomponent reaction of isocynide based , give a good yields and short reaction time)

M) Fungicide: (synthesized by Ugi and Passerine reaction)

N) Protein- Protein interactions: (Snthesized by van leuser reaction)

O) GPCR-modulator(mGluR₅): (Synthesized by the Blackburn reaction)

P) Ion-Channel blocker(T- type Ca⁺²): (Synthesized by the Ugi reaction)

CONCLUSION:

MCRs continue to provide rapid access to novel chemotypes concurrently allowing exploration of large chemical space. Although in the past decade we have started to see numerous applications of MCRs in drug discovery the potential benefits of MCR chemistry have not been fully realized. Particularly, variations and post-MCR methodologies to access more restricted scaffolds remain still a largely untapped field for exploring biological space. However, as was illustrated in this review, several groups were able to obtain MCR-derived compounds with good pharmacokinetic properties.Furthermore, research teams with limited human and financial resources benefit tremendously by MCRapproaches as they can advance their programs in a very effective way. It is expected that in the next couple of years we will see even more examples of MCR drug discovery as compound from numerous method which are already developed and provide valuable hits for drug discovery programs.

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Received on 14.09.2011 Modified on 10.10.2011

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