Multi Component Reactions

Multi Component Reactions (MCR) is an important topic in organic chemistry come under the heading Green Chemistry.
MCRs are very useful for preparation of desire molecule in medicinal chemistry.

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WHY LOOK AT MULTICOMPONENT
REACTIONS (MCRs)?
MCRs
Natural
Products
Drug
Discovery
Scaffold
Generation
MULTI-
COMPONENT
REACTIONS
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http://www.abcam.com/ps/datasheet/images/18251-final.jpg

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OUTLINE
•What is an ideal reaction?
•Definition of Multicomponent Reactions (MCRs)
•Comparison of MCRs with Multistep Reactions
•History of MCRs
•Types of Multicomponent Reactions
•PasseriniReacton
•UgiReaction
•BiginelliReaction
•Conclusion

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WHAT IS AN IDEAL REACTION?
Ideal
Reaction
Simple
100% Yield
Ready
available
starting
materials
Eco-Friendly
Resource
Effective
One Pot
Reference: Wender, P. A.; Handy, S; Wright, D. L; Towards the ideal synthesis. Chem. Ind.
1997, 765.

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DEFINITION OF MULTICOMPONENT
REACTIONS (MCRs)
•Reactions in which more than two starting compounds
react to form a product in such a way that the majority
of the atoms of the starting material can be found in
the productare called multicomponentreactions.
PRODUCT
3
2
1
Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.

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•Multistep Reactions
–Divergent Reactions
–One step after another
–Low Efficiency
–Low Diversity per Step
Multicomponent Reactions
ConvergentReactions
Reaction in onepot
Higher Efficiency
HighDiversity per Step
A + B A-B
+ C
A-B-C
P +Q+R
P-Q-R
A + B
C
D
E
F
G
H
I
P Q
R
P-Q-R

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TYPE OF
REACTION
GENERAL REACTION SCHEME
TYPE I
e.g. Certain types of Strecker Reaction
TYPEII
e.g. Passerini Reaction and UgiReactions
TYPE III
e.g. Generally seen in biological systems
Reference: Ugi, I. et al. Molecules2003, 8, 53-66.

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•IsocyanideBased MCRs
–PasseriniReaction
–UgiReaction

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•First isocyanide
based MCR
•Developed in
1921 by Mario
Passerini
•Simple 3
component
reaction
References: 1. Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
2. Domling, A. Chem. Rev. 2006, 106, 17-89.
1881-1962
α-acyloxycarboxamides
Mario Passerini

10. Reference: Banfi, L. et. al. Organic Reactions; CharetteA. B. ed. Wiley, New York, 2005,
vol. 65, p 1.
10

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•Synthesis of analogs of Azinomycin–a DNA binding
and alkylatingantibiotic by Armstrong et al.
Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.
Acid component
Aldehydecomponent
Isocyanide component

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The reaction
Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.

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•IsocyanideBased MCRs
–Passerini Reaction
–Ugi Reaction

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•Developed in 1959 by
Ivar Ugi
•The most studied and
used MCR
•Involves an isocyanide,
a carboxylic acid, an
amine and a carbonyl
compound to yield
α-aminoacylamides
α-acylamino
carboxamides
1930 -2005
References: Domling, A. Chem. Rev. 2006, 106, 17-89.
Ivar Ugi

15. Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
15

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•Synthesis of toxin Dysideninfrom the sponge Dysidea
herbacea
Reference: De Laszlo, S. E. et al. J. Am. Chem. Soc.1985, 107, 199-203.

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Fukuyama et al. have reported the synthesis of a marine tunicate,
Ecteinascidin743, which has extremely potent antitumor acitivity, using
the Ugireaction as a key step.

18. Reference: Domling, A. et al, Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
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Majority of the variations
can be made
at the carboxylic acids.
For eg. Use of cyanic
acids, hydrogen
thiocyanate, hydrazoic
acid
Few changes can be made to the
amine.
Derivatives of ammonia such as
hydrazine, hydrazidesor
hydroxylaminescan be used.

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•Overlap between Ugi reaction and Passerini reaction
–Side products of each other
–Limited use of amines in Passerini Reaction
–Lower yields
Reference: Banfi, L. et. al. Organic Reactions; CharetteA. B. ed. Wiley, New York, 2005,
vol. 65, p 1.
Ugi Reaction
Passerini Reaction

20. •Developed in 1893 by Italian Chemist, PietroBiginelli.
•A classical non-isocyanide-based multicomponent
process.
•Involves an acid catalysedcondensation of β-keto
esters, aldehyde and urea (or thiourea) in alcohol gives
Dihydropyrimidinones.
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•They have been found to exhibit a wide spectrum of biological effects
including antiviral, antitumor, antibacterial and anti-inflammatory
activities.
•A batzelladinealkaloids A and B which are efficient HIV gp-120-CD4
inhibitors

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PAST PRESENT FUTURE
Over 150Years of development

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