The Kabachnik–Fields Reaction: Mechanism and Synthetic Use

Abstract

The Kabachnik–Fields (phospha-Mannich) reaction involving the condensation of primary or secondary amines, oxo compounds (aldehydes and ketones) and >P(O)H species, especially dialkyl phosphites, represents a good choice for the synthesis of α-aminophosphonates that are of significant importance due to their biological activity. In general, these three-component reactions may take place via an imine or an α-hydroxy-phosphonate intermediate. The monitoring of a few Kabachnik–Fields reactions by in situ Fourier transform IR spectroscopy has indicated the involvement of the imine intermediate that was also justified by theoretical calculations. The Kabachnik–Fields reaction was extended to >P(O)H species, comprising cyclic phosphites, acyclic and cyclic H-phosphinates, as well as secondary phosphine oxides. On the other hand, heterocyclic amines were also used to prepare new α-amino phosphonic, phosphinic and phosphine oxide derivatives. In most cases, the synthesis under solvent-free microwave (MW) conditions is the method of choice. It was proved that, in the cases studied by us, there was no need for the use of any catalyst. Moreover, it can be said that sophisticated and environmentally unfriendly catalysts suggested are completely unnecessary under MW conditions. Finally, the double Kabachnik–Fields reaction has made available bis(phosphonomethyl)amines, bis(phosphinoxidomethyl)amines and related species. The bis(phosphinoxidomethyl)amines serve as precursors for bisphosphines that furnish ring platinum complexes on reaction with dichlorodibenzonitriloplatinum.

On the discovery and development of tandem 1,4- and 1,2-addition of phosphites to 1-azadienes

“…When dimethyl (1-amino-1-phenylmethyl)phosphonate (17) was N-silylated using TMSCl and subsequently treated with a large excess of diethyl trimethylsilyl phosphite, diethyl phosphonate 18 was mainly recovered along with small amounts of 17. When the same experiment was repeated without silylation and using diethyl phosphite, no exchange at all occurred.…”

“…The best result was obtained with a minimal amount of CH 2 Cl 2 under reflux conditions (entry 14). However, the formed The reactions with pyridazine (entries [16][17][18][19][20] were performed with a minimal amount of solvent in analogy with the results obtained with pyrimidine under these reaction conditions. The best results were obtained under reflux conditions and sequential addition of P(OMe) 2 OTMS (entry 16).…”

Recent Advances in H-Phosphonate Chemistry. Part 2. Synthesis of C-Phosphonate Derivatives

“…This reaction is usually carried out with equimolar amounts of reactants with or without removal of water (e.g., molecular sieves, azeotropic distillation), and with or without a catalyst. The most significant modifications recently introduced consist of using microwave irradiation as an energy source [26,27], ionic liquids as a reaction medium [13], and different types of catalysts [28]. Some mechanistic aspects of this reaction have also been investigated [14,28].…”

Synthesis of α-aminophosphonates using solvate ionic liquids

“…12 The imine species can be generated in situ, as part of a three-component reaction, or preformed and added to the phosphite, both methodologies have been presented in the literature. 12 Additionally, several reports employ excess of the amine or dialkyloxy-phosphite (in some cases both) which limits the broad appeal of this reaction.…”

“…5,11,12 They are considered phosphorus analogues to a-amino acids and the phosphorus' geometry has served as a useful tool in medicinal chemistry.…”