S. A. Koshkin

Synthesis and acid-base properties of aminophosphine oxides on the basis of natural amino acids

In recent years aminophosphonate derivatives of the natural amino acids attracted a considerable interest because of their pronounced physiological activity and specific complexing properties [1, 2]. However, the phosphine oxide derivatives of amino acids, which can show high efficiency in liquid and membrane extraction processes [3], were not described up to day. Using the Kabachnik–Fields reaction [1] in a dioctylphosphine–formaldehyde–amino acid threecomponent system, we synthesized a series of αaminomethylphosphine oxides containing structural fragments of glycine (I), β-alanine (II), and its N-butyl derivative (III) of the general formula Oct2P(O)· CH2NR(CH2)nC(O)OH, R = Oct2P(O)CH2, n = 1 (I); R = Oct2P(O)CH2, n = 2 (II); R = C4H9, n = 2 (III).

Synthesis of α-Aminophosphine Oxides with Chiral Phosphorus and Carbon Atoms

Lipophilic α-aminophosphine oxides are good extractants for liquid and membrane extraction. Optically active α-aminophosphine oxides, containing chiral centers in their structure, can provide selective means for transfer of stereoisomers through supported liquid membranes. We have developed a method for synthesis of such carrier compounds based on a three-component Kabachnik–Fields reaction.

Synthesis of (S)-2-((Dioctylphosphoryl)methylamino)propionic Acid from Trimethylsilyl 2-(Trimethylsilylamino)propanoate

We previously showed [1] that the Kabachnik– Fields reaction in the system dioctylphosphine oxide– paraformaldehyde–amino acid leads to the formation of the corresponding N-(dioctylphosphorylmethyl)substituted amino acid derivatives. In particular, N-phosphorylmethyl derivatives of glycine, β-alanine, and N-butylglycine were synthesized in this way. Because of poor solubility of amino acids in organic solvents, the reactions were carried out in acetonitrile in the presence of the corresponding amino acid hydrochloride. We made an attempt to perform phosphorylation of (S)-α-alanine under similar conditions. However, the reaction in heterogeneous medium gave a mixture of monoand bisphosphorylation products. With a view to improve the selectivity, the Kabachnik– Fields reaction was carried out with dioctylphosphine oxide, paraformaldehyde, and trimethylsilyl (S)-2-(trimethylsilylamino)propanoate prepared by heating of (S)-α-alanine with excess hexamethyldisilazane over a period of 72 h under reflux. Heating of the reactants in boiling toluene in the presence of p-toluenesulfonic acid (reaction time 3 h) afforded 96% (according to the P–{H} NMR data) of silylated aminomethylphosphine oxide I. Silylamine I was treated with a hot 15% aqueous solution of sodium hydroxide, and the subsequent neutralization of sodium salt II with 10% aqueous HCl gave target acid III. (S)-2-{[(Dioctylphosphoryl)methyl](trimethylsilyl)amino}propionic acid (I). White amorphous substance. H NMR spectrum (CDCl3), δ, ppm: 0.21 s [9H, Si(CH3)3], 0.86 d (3H, CH3, JHH = 9 Hz), 1.25– 1.90 m (34H, C8H17), 2.88 d.d (2H, CH2P, JHH = 4, JPH = 18 Hz), 3.27 q (1H, CH, JHH = 9 Hz). P–{H} NMR spectrum (PhMe): δP 51.2 ppm, s. (S)-2-[(Dioctylphosphoryl)methylamino]propionic acid (III). White crystalline substance, mp 132°C. H NMR spectrum (CDCl3), δ, ppm: 0.87 d (3H, CH3, JHH = 9 Hz), 1.25–1.90 m (34H, C8H17), 2.89 d.d (2H, CH2P, JHH = 4, JPH = 18 Hz), 3.27 q (1H, CH, JHH = 9 Hz). P–{H} NMR spectrum (CH2Cl2): δP 52.4 ppm, s. The H and P–{H} NMR spectra were recorded on a Varian XL-300 spectrometer a t 300 and 122.4 MHz, respectively. This study was performed under financial support by the Russian Foundation for Basic Research (project no. 13-03-00 536).

Synthesis of new lipophilic phosphine oxide derivatives of natural amino acids and their membrane transport properties toward carboxylic acids

One-pot procedures were developed for the synthesis of lipophilic N-(dialkylphosphorylmethyl) derivatives of natural amino acids with high yields from dioctyl- or didecylphosphine oxide, formaldehyde, and amino acid in the presence of amino acid hydrochloride. The reactions with some amino acids were also effective under catalysis by crown ether. The structure of the isolated N-(dialkylphosphorylmethyl) and N,N-bis(dialkylphosphorylmethyl)amino acids was determined on the basis of 1H, 13C, and 31P NMR and mass spectra; the structure of (S)-N-[(dicyclohexylphosphoryl)methyl]-α-alanine was proved by X-ray analysis, and intermolecular association of its molecules in crystal was characterized. Membrane transport properties of the new phosphorylated amino acids with respect to polyfunctional carboxylic acids were studied, and factors responsible for the efficiency and selectivity of membrane transport of acid substrates were estimated. Selective extraction of glutaric acid through a liquid membrane containing N,N-bis[(dioctylphosphoryl)methyl]-β-alanine was revealed.

Synthesis of new N -phosphorylmethyl amino acid derivatives. Steric structure of 2-[( S )- N -dicyclohexylphosphorylmethylamino] propanoic acid

Membrane extraction study of a number of natural hydroxy and amino acids with dipentyl 1-(benzylamino)cyclopentylphosphonate showed a quite high rate of transfer of these acid substrates, which was rationalized by complementary carrier–substrate interaction with formation of a stable complex [1]. Lipophilic α-amino phosphine oxides turned out to be equally efficient as carriers of simple organic acids; however, in the case of polyfunctional substrates, the transmembrane mass transfer with both types of extractants was insignificant because of shortage of coordination centers [2]. Obviously, receptor properties of α-amino phosphine oxides could be enhanced via introduction of a carboxy group which strongly tends to form hydrogen bonds. It seemed quite convenient to synthesize such compounds from structurally diverse natural amino acids. However, their use led to poor yields in Kabachnik–Fields reactions and in addition reactions of P–H compounds to imines (Pudovik reaction), which underlie general methods for the synthesis of α-amino phosphine oxides [3, 4]. We previously reported successful syntheses of N,N-bis(phosphorylmethyl) derivatives of glycine and β-alanine [5], as well as of N-(phosphorylmethyl)-(S)alanine derivative [6], from the corresponding amino acids via Kabachnik–Fields reaction. In this communication we describe a three-component version of this reaction with equimolar amounts of β-alanine or (S)-alanine hydrochloride, formaldehyde, and dihexylor dicyclohexylphosphine oxide. The reactions were carried out by heating the reactants for 3 h in boiling acetonitrile. According to ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 4, pp. 596–598.

Reaction of 3-methylbuta-1,2-dien-1-ylphosphonates with benzimidazole and 2-aminobenzimidazole

We previously showed that reactions of allenyland vinylphosphonates with imidazole involve addition of the imidazole nitrogen atom to the β-carbon atom of the unsaturated substrate with formation of alkenyland alkylphosphonates functionalized with nitrogencontaining pharmacophoric fragment [1]. The addition products were found to exhibit a strong bactericidal activity against such pathogenic microorganisms as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. While continuing studies in this line we examined the reaction of diethyl and diisopropyl 3-methylbuta1,2-dien-1-ylphosphonates with benzimidazole and 2-aminobenzimidazole with a view to obtaining new biologically active compounds. An equimolar mixture of diethyl 3-methylbuta-1,2-dien-1-ylphosphonate and benzimidazole was heated for 15 h at 70–75°C, and the upper oily layer was separated and repeatedly washed with hexane until constant nD value. We thus isolated compound 1 as a yellow thick oily material. The minor bottom layer was washed in succession with hexane and diethyl ether to isolate unreacted benzimidazole as colorless crystals with mp 169–170°C (published data [2]: mp 171–173°C). The P NMR spectrum of 1 contained only one signal at δP 24.6 ppm, indicating formation of a single addition product. The following signals were observed in the H NMR spectrum of 1, δ, ppm: 1.07 t (3H, CH3CH2O, JHH = 6.9 Hz), 1.31 t (3H, CH3CH2O, JHH = 7.0 Hz), 1.49 d (3H, CH3C=, JPH = 6.0 Hz), 2.00 d (3H, CH3C=, JPH = 4.5 Hz), 2.98 d.d (1H, PCH2, JPH = 20.7, JHH = 15.7 Hz), 3.18 d.d (1H, PCH2, JPH = 20.7, JHH = 15.7 Hz), 3.98 m (4H, OCH2), 7.30–7.98 m (4H, Harom). The presence in the H NMR spectrum of doublets of doublets at δ 2.98 and 3.18 ppm with a H–P coupling constant JPH of 20.7 Hz, which are typical of methylene group attached to phosphorus, indicated that the benzimidazole nitrogen atom added to the β-carbon atom of 3-methylbuta-1,2-dienylphosphonate with formation of diethyl 2-(1H-benzimidazol-1-yl)-3methylbut-2-en-1-ylphosphonate (1). Yield 67%, nD = 1.5292. Found, %: C 60.01; H 6.97. C16H23N2O3P. Calculated, %: C 59.62; H 7.14. Theoretically possible isomerization of adduct 1 into diethyl 2-(1H-benz-

Synthesis and structure of aminomethylphosphabetaines

It is known that some dialkyl aminoalkylphosphonates in solution spontaneously undergo intramolecular O→N migration of alkyl group with formation of zwitterionic alkyl ammonioalkylphosphonates which may be regarded as synthetic analogs of phosphonoand phospholipids capable of acting as monoand multidentate ligands in donor–acceptor complexes with some Lewis acids [1]. While searching for efficient and selective liquid and membrane extractants for various substrates, we have developed a new convenient procedure for the synthesis of phosphabetaines. This procedure implies N-alkylation of potassium alkyl aminomethylphosphonates prepared by hydrolysis of the corresponding dialkyl aminomethylphosphonates with aqueous sodium hydroxide. Alkyl hydrogen aminomethylphosphonates (RO)(OH)P(O)CH2NR′R′ were synthesized in almost quantitative yield (according to the P NMR data) by the Kabachnik–Fields reaction [2] and were converted without isolation and special purification into potassium salts I–III. The latter were purified by treatment with ethyl acetate; nonpolar organic impurities were thus removed, whereas salts I–III did not dissolve. If this procedure was inefficient, the salts were dissolved in methanol, and small amount of dilute hydrochloric acid was added to the solution. Solid impurities were filtered off, and the alkyl hydrogen phosphonate was converted again into potassium salt by adding an equimolar amount of 50% aqueous potassium hydroxide. Quaternization of potassium salts with benzyl chloride gave zwitterionic ammoniomethylphosphonates IV–VI as well shaped crystals, which can be readily purified by recrystallization from methanol or ethyl acetate. The structure of IV–VI was determined on the basis of their IR and H and P NMR spectra, and the structure of ethyl [benzyl(dipropyl)ammoniomethyl]phosphonate (IV) was proved by the X-ray diffraction data. More detailed information on the structure and properties of new phosphabetaines will be reported elsewhere. The synthesis of dialkyl aminomethylphosphonates was described in [2]. Potassium ethyl [(dipropylamino)methyl]phosphonate (I). Yield 75%, mp 188°C. IR spectrum (mineral oil), ν, cm: 1104 (P=O), 1061 (P–O–C). H NMR spectrum (CDCl3, 300 MHz), δ, ppm: 0.86 t (3H, CH3CH2, JHH = 7.28 Hz), 1.23 t (6H, CH3, JHH = 7.04 Hz), 1.39–1.52 m (4H, NCH2CH2), 2.52–2.65 d.d (2H, PCH2) and t (4H, NCH2); 3.86–3.95 m (OCH2). P NMR spectrum (dioxane, 122.4 MHz): δP 20.4 ppm. Potassium butyl [(dibutylamino)methyl]phosphonate (II). Yield 78%, mp 205°C. IR spectrum (mineral oil), ν, cm: 1194 (P=O), 1061 (P–O–C). H NMR spectrum (CDCl3, 300 MHz), δ, ppm: 0.95 t (9H, CH3, JHH = 7.24 Hz), 1.23–1.67 m (12H, CH2), 2.57–2.74 t (NCH2), 2.69 d (2H, PCH2, JPH = 12.80 Hz), 3.81–3.91 m (2H, OCH2). P NMR spectrum (dioxane, 122.4 MHz): δP 21.3 ppm. Potassium 3-methylbutyl [(dibutylamino)methyl]phosphonate (III). Yield 80%, mp 198°C. IR specI, IV, R = Et, R′ = Pr; II, V, R = R′ = Bu; III, VI, R = iso-C5H11, R′ = Bu. ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 4, pp. 625–626.

Synthesis of lipophilic N-phosphorylmethylated amino acids and their membrane-transport properties towards some organic acids

GRAPHICAL ABSTRACT ABSTRACT One-pot procedures were developed for the synthesis of lipophilic N-(dialkylphosphorylmethyl) derivatives of natural amino acids with high yields from dioctyloxide, formaldehyde, and an amino acid in the presence of amino acid hydrochloride. Membrane transport properties of the new phosphorylated amino acids towards polyfunctional carboxylic acids were studied. It was found that N,N-bis[(dioctylphosphoryl)methyl]-β-alanine is a selective extractant for glutaric acid.

Synthesis of a new quaternary phosphonium salt: NMR study of the conformational structure and dynamics.

A novel phosphonium salt based on pyridoxine was synthesized. Conformational analysis of the compound in solution was performed using dynamic NMR experiments and calculations. The obtained results revealed some differences in the conformational transitions and the energy parameters of the conformational exchange of the studied compound in comparison to previously reported data for other phosphorus‐containing pyridoxine derivatives. It was shown that increasing the substituent at the C‐11 carbon leads to greater differences in the populations of stable states and the corresponding equilibrium energies. Copyright

Synthesis and structure of complexes of N-(diphenylphosphoryl)methyl-N-methylaminoacetic acid with ions of cooper(II) and nickel(II)

Recently we developed a method of synthesis of lipophilic N-phosphorylmethyl derivatives of methylaminoacetic acid (sarcosine) basing on three-component Kabachnik-Fields reaction involving dialkylphosphinous acids, formaldehyde, and sarcosine, and demonstrated the capability to use the new types of aminophosphorous transporters for membrane extraction of twoand three-charged ions of some metals [1]. We found it necessary and important to establish the structure of obtained metal derivatives of phosphorylmethylated amino acids and therefore we synthesized cooper and nickel salts of N-[(diphenylphosphoryl)-methyl]-Nmethylaminoacetic acid and determined their spatial structure by physical methods.