Synthesis of N,N‐Bis(dialkoxyphosphinoylmethyl)‐ and N,N‐Bis(diphenylphosphinoylmethyl)‐β‐ and γ‐amino acid Derivatives by the Microwave‐Assisted Double Kabachnik–Fields Reaction

The title compounds were synthesized by the microwave‐assisted, mostly solvent‐free bis Kabachnik–Fields condensation of β‐alanine and γ‐aminobutyric acid or their esters with formaldehyde and >P(O)H species, such as dialkyl phosphites and diphenylphosphine oxide.     

The Kabachnik–Fields and Pudovik Reactions on the Basis of E,Z‐Citral and Its Imines and (R,S)‐Citronellal

The Kabachnik–Fields reaction of E,Z‐citral with diethyl phosphite in the presence of isobutylamine has been found to form α‐aminophosphonates. The Pudovik reactions of diethyl phosphite with prenyl imines prepared on the basis of E,Z‐citral with isobutylamine also allowed us to obtain the same α‐aminophosphonates. We have managed to synthesize α‐aminophosphonates by the reaction of O,O‐dialkyl trimethylsilyl phosphites with prenyl imines in the presence of water or diethylamine. α‐Aminophosphonates were also synthesized by the reaction of diethyl phosphite with (R,S)‐citronellal in the presence of alkylamines. α‐Aminophosphonates obtained showed bacteriostatic activity against Staphylococcus aureus and Bacillus cereus. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:36–42, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21060     

Convenient One‐Pot Synthesis of α‐Amino Phosphonates in Water Using p‐Toluenesulfonic Acid as Catalyst for the Kabachnik–Fields Reaction

The three‐component Kabachnik–Fields reaction of substituted salicylaldehydes, aromatic amine, and triphenyl phosphite in water was effectively catalyzed by p‐toluenesulfonic acid to give various α‐amino phosphonates in good yields. The catalyst is easily available and inexpensive, and the process is green and mild. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:110–115, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21071     

A study on the kabachnik‐‐fields reaction of benzaldehyde,cyclohexylamine, and dialkyl phosphites

The Kabachnik–Fields reaction of benzaldehyde, cyclohexylamine, and dimethyl phosphite carried out at 80°C in acetonitrile takes place via an imine (PhCN ^cHex) intermediate, as the monitoring by in situ Fourier transform IR spectroscopy suggested. The corresponding α‐hydroxyphosphonate was also formed in a quantity of 13% that was not converted to α‐aminophosphonate under the conditions applied. The outcome was similar to the Kabachnik–Fields reaction with diethyl phosphite as the P‐component. Molecular modeling and subsequent DFT calculations carried out under solventless conditions supported the experimental results and indicated the formation of a high number of ideally positioned H bonds as the key determinant for the conformation of the starting, intermediate, and product states. The relative energies of the possible intermediates were in accord with the observation that the formation of the α‐hydroxyphosphonate is a “dead‐end” route. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:171–178, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20767     

α‐Aminophosphonates and α‐Aminophosphine Oxides by the Microwave‐Assisted Kabachnik–Fields Reactions of 3‐Amino‐6‐methyl‐2 H‐pyran‐2‐ones

The microwave‐assisted Kabachnik–Fields reaction of a series of 3‐amino‐6‐methyl‐2H‐pyran‐2‐ones, paraformaldehyde, and dialkyl phosphites or diphenylphosphine oxide led to α‐aminophosphonates or α‐aminophosphine oxides, respectively. The α‑aminophosphonates were obtained under solvent‐free conditions, whereas the α‑aminophosphine oxides in acetonitrile. The novel products were characterized by NMR and mass spectral data. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:221–225, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21086     

NbCl5: an efficient catalyst for one‐pot synthesis of α‐aminophosphonates under solvent‐free conditions

NbCl₅ has been found to be a very effective catalyst for the synthesis of a variety of α‐aminophosphonates through the Kabachnik–Fields reaction of carbonyl compound, amine and diethyl phosphite under solvent‐free conditions. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of ω‐phosphonated poly(ethylene oxide)s through the combination of kabachnik–fields reaction and “click” chemistry

The synthesis of new ω‐phosphonic acid‐terminated poly(ethylene oxide) (PEOs) monomethyl ethers was investigated by the combination of Atherton–Todd or Kabachnik–Fields reactions and the “click” copper‐catalyzed 1,3‐dipolar cycloaddition of azides and terminal alkynes. The Atherton–Todd route fails to give the corresponding phosphonic acid‐terminated PEOs due to competitive cleavage of the P? N bond during the dealkylation step. In contrast, the Kabachnik–Fields route leads with very good yields to ω‐phosphonic acid‐PEO through “click” reaction of azido‐PEO onto dimethyl aminopropargyl phosphonate prepared by Kabachnik–Fields reaction between propargylbenzylimine and dimethyl phosphonate, followed by acidic hydrolysis. The reported methodology, precluding the use of anionic polymerization of ethylene oxide, leads to novel well‐defined phosphonic acid‐terminated PEOs from commercially available products in good yields. Moreover, such a strategy can be adapted to anchor phosphonic acid functionality onto a wide range of polymers. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

A catalyst-free synthesis of α-aminophosphonates in glycerol

A simple and efficient method is described using glycerol as a solvent in the catalyst-free synthesis of α-aminophosphonates in high purity. Products are prepared by the Kabachnik–Fields reaction from amines, phosphites, and carbonyl compounds. The method does not require a toxic catalyst.     

Synthesis of alkyl α‐aminomethyl‐phenylphosphinates and N,N‐bis(alkoxyphenylphosphinylmethyl)amines by the microwave‐assisted Kabachnik–Fields reaction

As a novel extension, the Kabachnik–Fields reaction was applied to the synthesis of alkyl α‐aminomethyl‐phenylphosphinates, and the double phospha‐Mannich reaction was utilized in the preparation of bis(alkoxyphenylphosphinylmethyl)amines. A total of 27 new aminophosphinate derivatives were synthesized by the microwave‐assisted solvent‐free condensation of alkyl phenyl‐H‐phosphinates, paraformaldehyde, and primary or secondary amines. The starting P‐species were also prepared under microwave conditions. The formation of the N‐methylated aminomethyl‐phenylphosphinate by‐products was also investigated.     

Microwave-assisted synthesis of α-aminophosphonates with sterically demanding α-aryl substituents

Abstract

A series of N-benzhydryl protected α-aminophosphonates with α-phenyl, α-(1-naphtyl), α-(9-anthryl) or α-(1-pyrenyl) substituents was synthesized by the Kabachnik–Fields condensation of diphenylmethylamine (benzhydrylamine), the corresponding aryl aldehyde and a dialkyl phosphite under MW irradiation. X-ray studies performed at low temperatures for a few of these α-aminophosphonates confirmed the presence of unusually short intramolecular C_α–H^δ+ ··· ^δ+H–C_peri contacts.     

TfOH/C-catalyzed one-pot three-component synthesis of α-amino phosphonates under solvent-free conditions

The TfOH/C was readily prepared via simple absorption of triflic acid onto activated charcoal. This solid acid was used as an efficient catalyst for the synthesis of α-aminophosphonates through the Kabachnik–Fields reaction of carbonyl compound, amine and diethyl phosphite under solvent-free conditions.     

Phenyl‐, benzyl‐, and unsymmetrical hydroxy‐methylenebisphosphonates as dronic acid ester analogues from α‐oxophosphonates by microwave‐assisted syntheses

The microwave (MW)‐assisted addition of dialkyl phosphites to α‐oxophosphonates was investigated and optimized under solventless conditions to provide the phenyl‐ and benzyl‐hydroxy‐methylenebisphosphonates efficiently by suppressing the rearrangement side reaction. Methyl‐hydroxy‐methylenebisphosphonates with mixed ester functionalities and an analogous diester‐diacid were also synthesized. It was found that the α‐oxophosphonates may also be converted to hydroxy‐methylenebisphosphonates and/or rearranged products without using dialkyl phosphite as the reagent and with the careful exclusion of water, simply on standing at room temperature, on thermal treatment, or on MW irradiation. These novel reactions taking place via the controlled decomposition of the precursor and resulting in the intermediate formation of dialkyl phosphite were also studied in detail. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:640–648, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20727     

Phosphorylated Aminoacetal in the Synthesis of New Acyclic,Cyclic, and Heterocyclic Polyphenol Structures

New phosphorylated aminoacetal has been synthesized by the Kabachnik–Fields reaction; its reactivity has been studied in acid‐catalyzed condensation with linear polyphenols (2‐methylresorcinol, resorcinol, pyrogallol) and the Mannich reaction with macrocyclic polyphenol (calix[4]resorcinol). It has been determined for the first time that acid‐catalyzed reaction of phosphorus‐containing acetal with resorcinol and its derivatives in ethanol in the presence of hydrochloric acid gives new phosphorylated piperazines in addition to the compounds of diarylmethane series. Condensation of macrocyclic polyphenol (calix[4]resorcinol) with formaldehyde and N‐((dihexylphosphoryl)methyl)‐2, 2‐dimethoxyethylamine (the Mannich reaction) has resulted in novel tetrasubstituted calixarene containing aminophosphine oxide and acetal groups on the “upper rim” of molecule.     

Reactions of N‐phthalylamino acid chlorides with trialkyl phosphites

Reaction of commercially available trialkyl phosphites with N‐phthalylamino acids gave mixtures of seven products, whereas the same reaction carried out with pure triethyl phosphite yielded only the desired 2‐(N‐phthalylamino)‐1‐oxoalkanephosphonates. These compounds underwent rearrangement to the same types of products that were obtained with the commercial phosphites. This latter series of reactions was promoted by the presence of dialkyl phosphites. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:232–239, 2000     

Phosphonylmethylaminocyclopentane‐1‐carboxylic acid

Phosphonylmethylaminocyclopentane‐1‐carboxylic acid was synthesized using Kabachnik–Fields reaction conditions in high yield and was characterized by NMR (¹H, ³¹P, and ¹³C) and FAB spectroscopy. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:229–230, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10124     

Synthesis of 1,4‐phenylene‐bis‐aminomethanephosphonates: The stereochemical aspect

The synthesis of new 1,4‐phenylene‐bis‐(N‐alkylaminomethane)‐bis‐phosphonates 3Aa–3Da by the addition of dialkyl or diaryl phosphites to the azomethine bond of 1,4‐phenylene Schiff bases is reported. Some NMR studies on the stereochemistry of dialkyl phosphite addition to terephthalic bis‐imines showing the exclusive formation of the meso‐form are presented. The mechanism and the origin of such a high stereoselectivity are discussed. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:144–151, 2000     

Highly efficient metal-free one-pot synthesis of α-aminophosphonates through reduction followed by Kabachnik–fields reaction using three-component system

One-pot synthesis of α-aminophosphonates directly from aryl nitro compounds, aldehydes/ketones, and diethyl phosphite using sodium dithionite through reduction and followed by Kabachnik–Fields reaction under metal-free conditions is reported. The major advantages are excellent yield, high chemoselectivity, neutral reaction medium, and simple experimental procedure. This methodology consists of the following steps: 1) amine formation from nitro compound, 2) imine formation from amine and aldehyde/ketone, 3) phosphate addition to imine.     

Synthesis of new racemic and optically active N‐phosphonoalkyl bicyclic β‐amino acids via the kabachnik–fields reaction as potential biologically active compounds

Novel racemic and optically active constrained N‐phosphonoalkyl bicyclic β‐amino acids have been synthesized via the Kabachnik–Fields reaction of the (RS) or (R)‐1‐aminobicyclo[2.2.2]octane‐2‐carboxylic acids with paraformaldehyde and benzaldehyde, and the dimethyl‐H‐phosphonate. The structure of obtained compounds was characterized by NMR (¹H, ¹³C, and ³¹P), LC/MS, and X‐ray diffraction analyses. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:123–130, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20759     

Nucleophilic Addition to Carbonyl Compounds. Competition Between Hard (Amine) and Soft (Phosphite) Nucleophile

Abstract

In the reaction mixture of carbonyl compound, amine and diethyl phosphite several different reactions are observed. The formation of aminophosphonate (Kabachnik- Fields reaction) is frequently accompanied with the formation of hydroxyphosphonate (Pudovik reaction) or product of its rearrangement. ^1–3 This is due to the presence of one electrophile (carbonyl compound) and two nucleophiles (amine and phosphite) in the reaction mixture, which may compete for the electrophilic center.     

Phosphosulfonic acid‐catalyzed green synthesis and bioassay of α‐aryl‐α′‐1,3,4‐thiadiazolyl aminophosphonates

A series of new α‐aminophosphonates containing 1,3,4‐thiadiazole moiety (4a–l) were synthesized via a simple, efficient, and one‐pot three‐component Kabachnik–Fields reaction of 2‐amino‐5‐ethyl‐1,3,4‐thiadiazole with various aryl/heteroaryl aldehydes and diethylphosphite under solvent‐free microwave irradiation conditions using phosphosulfonic acid, as a reusable and heterogeneous solid acid catalyst. All the title compounds were screened for radical scavenging activity by DPPH and H₂O₂ methods, and antimicrobial activity against bacteria (Gram‐positive and Gram‐negative) and fungi using the disc diffusion technique. They exhibited potent in vitro antioxidant and moderate antimicrobial activity.