Multi component reaction

1. Kabachnik-Fields reaction
Multi-Component Reaction
Presented by:
Santosh Kumar Sahoo
NIPER Hyderabad

2. Flow of Presentation
2
Kabachnik-Fields Reaction
Introduction
Substrate Scope
Mechanism
Variations
Applications
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3. Introduction
3
• Multi Component Reactions (MCRs) are convergent reactions.
•MCRs 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.
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4. Kabachnik-Fields Reaction
This MCR was discovered in 1952 independently by Martin I. Kabachnik & Ellis K. Fields
Synthetic targets as phosphorus
analogues of α-aminoacids
Enzyme inhibitors, antibiotics,
pharmacological agents
Involves synthesis of α-amino phosphonates which is a one-pot, three-
component reaction using carbonyl compound, amine and dialkyl phosphite.
Conditions
Amines like Primary or Secondary
Aldehydes like formaldehyde and benzaldehyde
Ketones like acetone, acetophenone and cyclohexanone
symmetrical dialkyl phosphites
Solvents like benzene, toluene, isopropanol
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5. 5
Amine
Carbonyl
Dialkyl
phosphites
α- Amino
phosphonate
Substrate Scope
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Russian Chemical Reviews , 1998, 67 , 857-882.

6. 6
Mechanism
Alkylamino Alkyl
phosphonic acid
dialkyl ester
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7. Amino-component
Ammonia, it’s silylated derivatives
aliphatic, aromatic
heterocyclic amines
dicyanoethylamine
trans-1,2- diaminocyclohexane
Aminoadamantanes
Aminopyridines
Aminotetrazoles
Aminobenzofurazanes
crosslinked aminoacids
Carbonyl-component
Mainly Aldehydes
e. g., salicylaldehyde
3-indol-aldehydes
Rarely Ketones are used
Phospho-containing component
P-H containing compounds
HP(O)(OH)2, H3PO2
H2P(O)OR, R2PHO
(RO)4P-H, P(OR)3
Catalysis
Energy → microwave irradiation itself or in combination with catalyst,
Ionic liquids as solvents, Ultrasonic radiation
Use of appropriate dehydrating agents e.g. MgSO4, molecular sieves
Use of catalysts Lewis acids are effective catalysts; make carbonyl group more electrophilic
Water deactivates the Lewis acid→Overcame by co-use of catalyst with dehydrating agent
or by application of catalysts being stable in water, Like some rare earth metal triflates.
e.g. lanthanide triflates/MgSO4, metal triflates/no solvent, scandium (tris-dodecyl sulfate),
TaCl5-SiO2, Ln(OTf)3 –ionic liquid, Lanthanide triflates/ionic liquids, SmI2, AlCl3.
Variations in Conditions and catalysis
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8. Tetrahedron Letters. 2001, 42, 8211–8213
Microwave-assisted synthesis and solvent-free conditions
Bull. Korean Chem. Soc. 2002,23, 667-668
d = thermal condition 120° C, 2 hr
Microwave-assisted in Ionic Liquid
Catalyzed by Magnesium Perchlorate
J. Org. Chem. 2007, 72, 1263-1270
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9.  Catalytic enantioselective hydrophosphonylation
of preformed imines by using chiral phosphoric acid
derivatives
Angew. Chem. Int. Ed. 2008, 47, 5079 –5081
From Aryl Azides under Solvent-Free Conditions
Synthesis 2013, 45, 2545–2550
Cu np weaken P-H bond,
aid in addition to Imine
Catal. Sci. Technol., 2011, 1, 426–430
Aldehydes possessing electron withdrawing
group And Amines possessing electron
donating group exhibited good reactivity
Cu-nanoparticles as heterogeneous catalyst for A2-P coupling
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10. Four-component Kabachnik-Fields synthesis
One pot reaction
Reaction Sequence
A+B→+C → +D
RSC Adv., 2015,5, 99148-99152
Quaternary ammonium salts,
which are environmental friendly,
inexpensive, and recyclable
Synthesis 2015, 47, 1869–1876
Green Procedure with Quaternary Ammonium
Salts as Efficient and Recyclable Reaction Media
10

11. Enantiomerically Enriched α-Amino Phosphonic
Acid Derivatives by Organocatalytic Asymmetric
Hydrophosphonylation of Imines
J. Org. Chem. 2006, 71, 6269-6272Catalyst and solvent-free,
ultrasound promoted rapid synthesis
Tetrahedron Letters, 2012, 53, 5497–5502
Application of Bis(trimethylsilyl) Phosphonite
Synthesis, 2011, 3, 0437–044211 niper H

12. leucine aminopeptidase
(LAP) Inhibitor
protein modification, activation
Anticancer
Journal of Medicinal Chemistry, 2003, 46, 2641-2655
ApplicationsAntibacterial
Anticancer
J. Org. Chem. 1994,59, 5784-5
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13. Anti-leishmanial Activity
Interfere with ether–lipid
Metabolism or glycosylphosphatidyl
Inosital anchor biosynthesis
Med. Chem. Commun., 2014, 5, 665-670
J Plant Growth Regul, 1995, 14:199-203
Polymer synthesis
Polym. Chem., 2014, 5, 1857-1862
Anti-leishmaniasis As Herbicides
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14. Inhibitors of the aspartic proteases pepsin
(Mammalian) and penicillo-pepsin (Bacterial)
J. Org. Chem., 1990, 55, 6268-6274
Inhibitors of HIV-Protease
Angew. Chem. Int. Ed. 1993, 32, 1720-1722
Thrombin Inhibitors
Thrombin, a trypsin-like serine protease, is the
final enzyme in the blood coagulation cascade,
and is an ideal target for the development of an
anticoagulant protease inhibitor.
Tetrahedron Letters,1991, 32, 7333-7336.14 niper H

15. THANK YOU