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Kabachnik fields reaction- Variations, Applications
The Kabachnik-Fields reaction is a multi-component reaction that involves the synthesis of α-amino phosphonates from a carbonyl compound, amine, and dialkyl phosphite. It was discovered independently in 1952 by Martin I. Kabachnik and Ellis K. Fields. The reaction produces α-amino phosphonate products in a one-pot reaction under mild conditions. Variations to the traditional Kabachnik-Fields reaction include using different substrates, catalysts, solvents and conditions such as microwave irradiation or solvent-free systems. The α-amino phosphonate products have applications as enzyme inhibitors, antibiotics, and in polymer synthesis.
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- 1. Kabachnik-Fields reaction Multi-Component Reaction Presentedby: Santosh Kumar Sahoo NIPER Hyderabad
- 2. Flow of Presentation 2 Kabachnik-FieldsReaction Introduction Substrate Scope Mechanism Variations Applications 11/13/2016niper H
- 3. Introduction 3 • Multi ComponentReactions (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. 11/13/2016niper H
- 4. Kabachnik-Fields Reaction This MCRwas 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 11/13/20164 niper H
- 5. 5 Amine Carbonyl Dialkyl phosphites α- Amino phosphonate Substrate Scope 11/13/2016niperH Russian Chemical Reviews , 1998, 67 , 857-882.
- 6. 6 Mechanism Alkylamino Alkyl phosphonic acid dialkylester 11/13/2016niper H
- 7. Amino-component Ammonia, it’s silylatedderivatives 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 11/13/20167 niper H
- 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 8 niper H
- 9. Catalytic enantioselectivehydrophosphonylation 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 11/13/20169
- 10. Four-component Kabachnik-Fields synthesis Onepot 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-AminoPhosphonic Acid Derivatives by Organocatalytic Asymmetric Hydrophosphonylation of Imines J. Org. Chem. 2006, 71, 6269-6272Catalyst 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 proteinmodification, activation Anticancer Journal of Medicinal Chemistry, 2003, 46, 2641-2655 ApplicationsAntibacterial Anticancer J. Org. Chem. 1994,59, 5784-5 12 niper H
- 13. Anti-leishmanial Activity Interfere withether–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 11/13/201613 niper H
- 14. Inhibitors of theaspartic 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
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