This document provides an overview of multi-component reactions (MCRs), including their history, advantages over multistep reactions, and examples such as the Passerini reaction, Ugi reaction, Biginelli reaction, and Mannich reaction. MCRs involve more than two starting materials reacting in one pot to form a product containing the majority of atoms from the reactants. They provide an efficient means of generating structural diversity and are important in drug discovery. Some of the earliest and most widely used MCRs are isocyanide-based reactions developed in the early 20th century.

1. MULTI-COMPONENT REACTIONS
Presented by:
MAHENDRA G.S.
M pharm
Dept of Pharmaceutical Chemistry
JSS College of Pharmacy
Mysuru.

2. CONTENTS :
 Introduction
 History And Development
 Multistep v/s Multicomponent
 Isocyanide based MCRs
 Biginelli reaction
 Mannich reaction
 Passerini reaction
 Ugi reaction

3. INTRODUCTION :
 Reactions in which more than two starting compounds react to form a product in
such a way that the majority of atoms of the starting material can be found in the
product are called Multicomponent reactions.
 Multi-component reactions (MCRs) play an important role in combinatorial
chemistry because of its ability to synthesize small drug-like molecules with several
degrees of structural diversity.
 These reactions is simplified purification, because all of the reagents are
incorporated into the final product.

4.  MCRs constitute an especially attractive synthetic strategy since they provide
easy and rapid access to large libraries of organic compounds with diverse
substitution patterns. As MCRs one pot reactions, they are easier to carry out
than multistep synthesis.
 The importance of MCRs for drug discovery has been recognized and
considerable efforts from both academic and industrial researchers have been
focussed especially on the design and development of multi-component
procedures for the generation of libraries of heterocyclic compounds.
 Isocyanide multicomponent reaction methodologies have applications
in most stages of the drug discovery process spanning lead discovery,
lead optimization and final drug manufacture.

5. HISTORYAND DEVELOPMENT :
 First 'officially' reported MCR was the Strecker synthesis of α-amino nitrile in 1850.
 A large portion of MCR chemistry has developed from isocyanides.
 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.
 The occurrence of isocyanides in natural products has also made it a useful functional
group.

6. MULTISTEP V/S MULTICOMPONENT
Multistep Reactions :
 Divergent Reactions
 One step after another
 Low Efficiency
 Low Diversity per Step
Multicomponent Reactions :
 Convergent Reactions
 Reaction in one pot
 Higher Efficiency
 High Diversity per Step

7. Isocyanide based MCRs
Passerini reaction
Ugi reaction

8. PASSERINI REACTION :
 First isocyanide based MCR.
 Developed in 1921 by Mario Passerini.
 Simple 3 component reaction.
 It involves an oxo component, an
isocyanide, an aldehyde and an acid in a
single step, the final product is acyloxy
amide.
Mario passerine (1881-1962)

9. MECHANISM OF PASSERINI REACTION
The Passerini Reaction proceeds rapidly if
the reaction is performed in aprotic solvents
at room temperature. High yields are obtained
with high concentrations of the starting
materials in the reaction mixture.
It involve the following steps:
1. Addition to protonated aldehyde
2. Addition to nitrilium ion
3. Acyl transfer
4. Tautomerization

10. UGI Reaction :
 Developed in 1959 by Ivar Ugi.
The most studied and used MCR.
Involves an isocyanide, a carboxylic
acid, an amine and an aldehyde
compound to yield α-aminoacyl
amides.
Ivar ugi (1930- 2005)

11. MECHANISM OF UGI REACTION
In the Ugi reaction, the initial reaction is the
formation of an imine. from the amine and
the ketone. Subsequent reaction of the imine
with the isocyanide and the carboxylic acid
gives intermediate.
which rearranges via an acyl transfer into
the bis-amide The exact mechanism of the
trimolecular reaction to form intermediate is
not known.
The reaction can also be performed with a
pre-formed imine. This results in an
increased yield.

12.  Amine and ketone form the imine with loss of one equivalent of water. Proton exchange
with carboxylic acid activates the iminium ion for nucleophilic addition of the
isocyanide with its terminal carbon atom to nitrilium ion.
 A second nucleophilic addition takes place at this intermediate with the carboxylic acid
anion to. 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.

13. BIGINELLI REACTION :
Developed in 1893 by Italian Chemist,
Pietro Biginelli.
A classical non-isocyanide based
multicomponent process.
 Involves an acid catalyzed condensation of
β-ketoesters, aldehyde and urea (or
thiourea) in alcohol gives
Dihydropyrimidinones.
PIETRO BIGIINELLI

14. MECHANISM OF BIGINELLI REACTION
 The reaction mechanism of the Biginelli
reaction is a series of bimolecular
reactions leading to the desired dihydro-
pyrimidinone.
 The first step in the mechanism is believed
to be the condensation between the
aldehyde and urea,with some similarities
to the mannich condensation.
 The iminium intermediate generated acts as
an electrophile to the nucleophilic addition
of the ketoester enol, and the keto
carbonylof the resulting adduct undergoes
condensation with the urea NH2 to give
cyclized product.

15. MANNICH REACTION
 Carl Ulrich Franz Mannich (March 8, 1877 in
Breslau-March 5, 1947 in Karlsruhe) was a German
Chemist.
 His areas of expertise were Keto bases, Alcohol bases,
Piperidine-Derivatives, Papaverine, Lactone and also
Digitalis-Glycoside.
 The Mannich reaction is the aminoalkylation reaction,
involving the condensation of an enolizable carbonyl
compound with a nonenolizable aldehyde (like
formaldehyde) and ammonia, or a primary or a
secondary amine to furnish a β-aminocarbonyl
compound, also known as Mannich base.
Ulrich franz mannich

16. MECHANISM OF MANNICH REACTION:
 The first step in the mechanism of
Mannich Reaction is the formation of
iminium ion from the reaction between
formaldehyde and amine.
 Then, it reacts with acid to form amino
methylated product after rearrangement.
 This reaction takes place under acidic
condition.
 Ammonia or primary or secondary amines
are used for the activation of
formaldehyde.

17. REFERENCES :
 https://www.slideshare.net/AnkushKularkar/multi-component-
reactions?qid=edce7526-2272-47bf-9177-
31aef13af64f&v=&b=&from_search=9
 http://www.sigmaaldrich.com/content/dam/sigma-
aldrich/docs/Aldrich/Brochure/al_chemfile_v6_n7.pdf
 http://www.diss.fu-
berlin.de/diss/servlets/MCRFileNodeServlet/FUDISS_derivate_000
000001635/02_IV2.pdf?hosts
 http://www.organic-chemistry.org/namedreactions/passerini-
reaction.shtm
 file:///C:/Users/user/Downloads/mannichreaction1-120915171941-
phpapp01%20(1).pdf
 https://en.wikipedia.org/wiki/Mannich_reaction