Multi-Component Reaction

Kabachnik--Fields reaction
Kabachnik

Presented by:

Santosh Kumar Sahoo

Research Scholar
NIPER Hyderabad

Flow of Presentation
Kabachnik-Fields Reaction
Introduction
Substrate Scope
Mechanism
Variations
Applications
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Introduction
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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Kabachnik-Fields Reaction
This MCR was discovered in 1952 independently by Martin I. Kabachnik & Ellis K. Fields

Involves synthesis of -amino phosphonates which is a one-pot, threecomponent reaction using carbonyl compound, amine and dialkyl phosphite.

Synthetic targets as phosphorus

analogues of
-aminoacids
Enzyme inhibitors, antibiotics,
Conditions
pharmacological agents
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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Substrate Scope

C-Modification
Base,Alkylation or
Conjugate Addition

Dialkyl
phosphites

- Amino
phosphonate

Carbonyl

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Russian Chemical Reviews , 1998, 67 , 857-882.

Amine
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Mechanism
O
P
R5
H
O
O
R4

R5
O
H

O
P O

R3

R4

R2
R1
Aminoalkylation of
hydrophosphoryl
compounds
O
P
R
H
O 5
O
R4

O R
3 OH
R4 O P
O R
2
R5
R1 NH2

Alkylamino Alkyl
phosphonic acid
dialkyl ester

Replacement of the
hydroxy group by
the amino group.
nucleophilic amination
High Temperature

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Variations in Conditions and catalysis

Amino-component
Ammonia, its silylated derivatives
aliphatic, aromatic
heterocyclic amines
dicyanoethylamine
trans-1,2- diaminocyclohexane
Aminoadamantanes
Aminopyridines
Aminotetrazoles
Aminobenzofurazanes
crosslinked aminoacids

Phospho-containing component
P-H containing compounds
HP(O)(OH)2, H3PO2
H2P(O)OR, R2PHO
(RO)4P-H, P(OR)3
Carbonyl-component
Mainly Aldehydes
e. g., salicylaldehyde
3-indol-aldehydes
Rarely Ketones are used

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 acidOvercame 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.
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Microwave-assisted synthesis and solvent-free conditions

Microwave-assisted in Ionic Liquid

Tetrahedron Letters. 2001, 42, 82118213

d = thermal condition 120 C, 2 hr

Catalyzed by Magnesium Perchlorate

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Bull. Korean Chem. Soc. 2002,23, 667-668

J. Org. Chem. 2007, 72, 1263-1270

 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

Cu-nanoparticles as heterogeneous catalyst for A2-P coupling

Synthesis 2013, 45, 25452550

Aldehydes possessing electron withdrawing

group And Amines possessing electron
donating group exhibited good reactivity

Cu np weaken P-H bond,

aid in addition to Imine
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Catal. Sci. Technol., 2011, 1, 426430

Four-component Kabachnik-Fields synthesis

One pot reaction
Reaction Sequence
A+B+C +D

RSC Adv., 2015,5, 99148-99152

Green Procedure with Quaternary Ammonium
Salts as Efficient and Recyclable Reaction Media
Quaternary ammonium salts,
which are environmental friendly,
inexpensive, and recyclable

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Synthesis 2015, 47, 18691876

Enantiomerically Enriched -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, 54975502

Application of Bis(trimethylsilyl) Phosphonite

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Synthesis, 2011, 3, 04370442

Applications

Antibacterial
H
N

H2N

OH
O
P
OH

O
Alafosfolin L-Ala-L-(P-Ala)
L-Ala
H2N

HOOC
N
COOH
Tetrahydrodipicolinic acid

Transport
Cleavage
OH
O
P
OH

L-(P-Ala)

DAP Dehydrogenase
DAP Epimerase
O

HO

OH
NH2

NH2

diaminopimelic acid (DAP)

DAP Decarboxylase

Inhibition of Alanine Racemase

Anticancer

J. Org. Chem. 1994,59, 5784-5793

leucine aminopeptidase
(LAP) Inhibitor
protein modification, activation
Anticancer

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Journal of Medicinal Chemistry, 2003, 46, 2641-2655

Anti-leishmaniasis

As Herbicides

Anti-leishmanial Activity
Interfere with etherlipid
Metabolism or glycosylphosphatidyl
Inosital anchor biosynthesis
Med. Chem. Commun., 2014, 5, 665-670
Polymer synthesis

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J Plant Growth Regul, 1995, 14:199-203

Polym. Chem., 2014, 5, 1857-1862

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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

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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.

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