multicomponent raction

MulticoMponent reactions for
the synthesis of pyrroles
Under The Supervision Of:
Dr. Shafiullah
Presented By:
Shaheen Siddiqui
Roll No:2012 OCHM15
EN.NO:GD9318

• Introduction
• Multicomponent reactions : Definition And Importance
• Importance of Pyrrole-Examples
• Advantage of Multicomponent Reactions over other
Reactions
• Synthesis of Pyrrole by different methods
• Application
• Conclusion
• References

•Present-day requirements for new synthetic methods go far beyond the
traditional ones and can be summarized as follows:
1. Use of simple and readily available starting materials.
2. Experimental simplicity.
3. Possibility of automation.
4. Favourable economic factors, including the cost of raw
materials, human resources and energy.
5. Low environmental impact: use of environmentally
friendly solvents, atom economy
For this reason, the creation of molecular diversity and complexity from
simple and readily available substrates is one of the major current challenges
of organic synthesis, and hence the development of processes that allow the
creation of several bonds in a single operation has become one of its more
attractive goals

•Multicomponent reactions (MCRs) are convergent chemical
processes where three or more reagents are combined in such a
way that the final product retains significant portions of all starting
materials
•They lead to the connection of three or more starting materials in
a single synthetic operation with high atom economy and bond-forming
efficiency, thereby increasing molecular diversity and
complexity in a fast and often experimentally simple fashion

•Most important simple heterocyclic compound, found in a
broad range of natural products, drug molecules and also of
growing relevance in materials science
•Present as a structural fragment of heme and chlorophyll, two
pigments essential for life
•Present in a large number of bioactive compounds including
HIV fusion inhibitors and antitubercular compounds
•Glucose sensors based on polypyrrole-latex materials and
polypyrrole materials for the detection and discrimination of
volatile organic compounds

•Based on the reaction between a β-enaminone and a α-haloketone
•Original Hantzsch method was restricted to the use of
ethyl β-aminocrotonate.
•Later on extented to include R2 substituents other than methyl and
also the case of R5 = H
•Yields for these reactions were normally below 50%

• Phenacyl bromide, acetylacetone and a variety of amines
and β-cyclodextrin were heated in water at 60–70⁰C, the
corresponding 1,5-diarylpyrroles were obtained in good
to excellent yields(77% average)

•The reaction involved generating the supramolecular inclusion
complex between β-cyclodextrin and phenacyl bromide in water at
50 C, followed by addition of ᵒ the other reagents and stirring at
60–70 ᵒC
• The role of cyclodextrin was assumed to be the activation of
phenacyl bromide through hydrogen bonding interactions of its
bromine atom with hydroxy substituents in the cyclodextrin rim

•Three component reaction among β-dicarbonyl compounds, arylglyoxals
and ammonium acetate in water, which affords 4-hydroxy-5-arylpyrroles
in variable yields
•β-ketoesters were employed as the dicarbonyl component

•β- ketoester undergoes keto-enol tautomerisation followed by aldol
addition to arylglyoxals giving 1,4-dicarbonyl intermediate 1
•It is then followed by a Paal–Knorr-type cyclization and double
dehydration to yield the desired product

•Four-component reaction between acetylenedicarboxylates, succinimide
or maleimide and two molecules of an isonitrile in refluxing
dichloromethane.
•Pyrroles are obtained in good to excellent yields
•Average yield is 78%

•In pathway b, an initial addition of the isonitrile to the
electron-defficient alkyne takes place to give species 13
• Reaction of 13 with second molecule of isonitrile affords
bis-ketenimine 14
•Its reaction with the imide component followed by
cyclisation gives the desired product,pyrrole
•Use of sterically hindered isonitriles (e.g. tert-butyl isonitrile)
prevented the generation of 14 because of steric hindrance
•Intermediate 13 deprotonates the imide to give intermediate
15, and this is followed by a Michael addition that leads to
product 16

•Three-component reaction between primary amines, alkyl
acetoacetates and fumaryl chloride
•Pyrrole derivatives thus obtained contain a 5-chloro substituent,
together with carboxylic ester and carboxymethyl functional groups
•Reaction occur at room temperature
• Average yield is 78%

• Formation of β-enaminone 2, followed by its Michael addition
onto a molecule of fumaryl chloride to afford 3
•Intramolecular attack of the enamine nitrogen onto the acyl
chloride function leading to the generation of the five-membered
ring
•Loss of H2O and HCl give the desired product

•Four-component coupling of aldehydes, amines and nitroalkanes in
the presence of a catalytic amount of samarium trichloride at 60⁰C
which affords tetrasubstituted pyrroles
•Moderate yield is obtained

•Initial formation of the imine 28 from the starting
amine and one molecule of aldehyde
•Samarium-catalyzed aldol-type self-condensation of
28 affords the α,β-unsaturated imine 29, which is
attacked by the nitroalkane in a conjugate fashion to
yield intermediate 30
•An intramolecular proton transfer followed by
cyclization affords a new intermediate 31, which then
evolves to the final aromatic pyrrole following loss of
water and HNO

•Entry to munchnones via an acylamino chromium carbene
complex followed by a 1,3-dipolar cycloaddition with
acetylenedicarboxylates that yields pyrroles
•Average yield is 48%

•Acylation of the starting aminocarbene chromium complex
with benzoyl chloride to give an acylaminocarbene complex
54
•Insertion of carbon monoxide to give a ketene complex 55
•Ketene cyclizes to a metal-free Munchnone 56,that could be
isolated if desired, with the demetalation facilitated by the
presence of CO
•1,3-dipolar cycloaddition to the alkyne followed by loss of a
molecule of carbon dioxide, yields the final pyrrole

•Multicomponent reactions are particularly well suited for diversity
oriented synthesis
•Very powerful for synthesis aimed at carrying out structure–activity
relationship (SAR) studies of drug-like compounds, which are an
essential part of the research performed in pharmaceutical and
agrochemical companies
•For all these reasons, the development of new multicomponent reactions
is rapidly becoming one of the frontiers of organic synthesis
•Recent years have witnessed a steady growth in the development of
MCRs that lead directly to heterocycles, the most important single class
of compounds in the development of bioactive substances

•Pyrrole derivatives have great relevance in many fields of
chemistry, and we have shown that Multicomponent
Reactions are an excellent, multipurpose approach to Pyrrole
synthesis
•Besides the development of new reactions or improved
conditions for the classical ones, future developments in this
field will probably involve the application of
multicomponent-based strategies to target-oriented synthesis
•Very useful area of organic synthesis

• Multicomponent Reactions, ed. J. Zhu and H. Bienayme´ , Wiley-
VCH, 2005
• For a symposium in print on MCRs, see: Tetrahedron Symposia-in-
Print, ed. I. Marek, 2005, vol. 67, p. 11299
• F. Palacios, D. Aparicio, J. M. de los Santos and J. Vicario,
Tetrahedron, 2001, 57, 1961
• C. Cao, Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2003, 125, 2880
•D. J. St Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129, 12366
• D. J. St Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129,
12366

multicomponent raction

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