This three-component coupling of a carbonyl, an amine and a hydrophosphoryl compound leads to α-aminophosphonates. The Kabachnik-Fields Reaction is very important in drug discovery research for generating peptidomimetic compounds.
Early protocols were limited to simple starting materials (for example aldehydes) but newer methods permit reactions to take place even with sterically demanding starting materials.
Mechanism of the Kabachnik-Fields Reaction
The pathway of the Kabachnik-Fields reaction depends on the nature of the substrates. The amine and hydrophosphoryl compound form a complex in which either one of the partners may react with the carbonyl compound. Often, the basicity of the amine determines the reaction pathway. Weakly basic amines such as anilines, which can act as proton donors, favour the formation of an imine, whereas alkylamines such as cyclohexylamines do not form imines:
If additional catalysts are used, both acids and bases can have a positive influence on the reaction rate. Sometimes, the chemical yield and the diastereoselectivity of the formation of α-aminophosphonates are higher in two-component systems using preformed imines. In this case, due to the phosphonate <-> phosphite tautomerism, the addition to the imine could occur by either a four- or five-membered transition state:
A more detailed discussion of the mechanism of the Kabachnik-Fields reaction, its synthetic potential and the biological activity of the α-aminophosphonates can be found in a review by R. A. Cherkasov and V. I. Galkin (Russ. Chem. Rev. 1998, 67, 857-882. DOI)
An interesting recent publication of an enantioselective transformation using quinine as an organocatalyst suggests the following transition state:
As this example shows a high degree of complexity, one can imagine that the design of an enantioselective three-component reaction would be somewhat more difficult, and it is clear that some basic investigation into the stereocontrol of the Kabachnik-Fields reaction is still needed.
An Extremely Efficient Three-Component Reaction of Aldehydes/Ketones, Amines, and Phosphites (Kabachnik-Fields Reaction) for the Synthesis of α-Aminophosphonates Catalyzed by Magnesium Perchlorate
S. Bhagat, A. K. Chakraborti, J. Org. Chem., 2007, 72, 1263-1270.
A facile and highly efficient route to α-amino phosphonates via three-component reactions catalyzed by Mg(ClO4)2 or molecular iodine
J. Wu, W. Sun, H.-G. Xia, X. Sun, Org. Biomol. Chem., 2006, 4, 1663-1666.
A Novel Catalytic Three-Component Synthesis (Kabachnick-Fields Reaction) of α-Aminophosphonates from Ketones
E. D. Matveeva, T. A. Podrugina, E. V. Tishkovskaya, L. G. Tomilova, N. S. Zefirov, Synlett, 2003, 2321-2324.
Direct Access to Enantiomerically Enriched α-Amino Phosphonic Acid Derivatives by Organocatalytic Asymmetric Hydrophosphonylation of Imines
D. Pettersen, M. Marcolini, L. Bernardi, F. Fini, R. P. Herrera, V. Sgarzani, A. Ricci, J. Org. Chem., 2006, 71, 6269-6272.
Thiourea-Catalyzed Enantioselective Hydrophosphonylation of Imines: Practical Access to Enantiomerically Enriched α-Amino Phosphonic Acids
G. D. Joly, E. N. Jacobson, J. Am. Chem. Soc., 2004, 126, 4102-4103.