V. V. Ragulin

Amidoalkylation of hydrophosphoryl compounds

A new mild procedure of the amidoalkylation of hydrophosphoryl compounds in a mixture of acetic anhydride and acetyl chloride was developed as a convenient method of constructing the α-aminophosphoryl fragment of the pseudo-α,α′-dipeptide molecule. The reaction intermediates N,N′-benzylidene- and N,N′-alkylidenebiscarbamates were detected, isolated, and identified. The report presents the results of studying the direct interaction of hydrophosphoryl compounds previously synthesized with biscarbamates in acetic anhydride and other solvents, the influence of the structure of phosphorus component and biscarbamate, and the effect of acid catalysis on the course of this two-component reaction. A new version of the mechanism of the three-component reaction of amidoalkylation of hydrophosphoryl compounds is suggested: it is regarded as a multistage process involving the stage of biscarbamate formation followed by the stage of Arbuzov-type reaction with the intermediate formation of acyliminium cation and P-OAc derivative with trivalent phosphorus.

Acetals and N,N′-alkylidenebiscarbamates in the synthesis of N-protected α-aminophosphinic acids

A convenient procedure of the amide version of the Kabachnik–Fields reaction is a promising approach to the synthesis of N-protected α-aminophosphorylic compounds. The amidoalkylation originally suggested for the phosphorous chlorides in acetic acid (the Oleksyszyn reaction) [1] was later modified to the amidoalkylation of dialkylphosphites in acetyl chloride or in a mixture of acetic acid and thionyl chloride involving the carbonyl compounds and amides [2].

A method of synthesis of phosphinic acids on the basis of hypophosphites: VII. Synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid

A method of synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid from hypophosphites is suggested. Silyl phosphonites formed by in situ addition of bis-(trimethylsilyl) hypophosphite to the corresponding α-substituted acrylates, styrene, or vinyl phosphonate used as unsaturated components in the synthesis react in situ with N-(ω-bromoalkyl)phthalimides by an Arbuzov reaction scheme, affording ω-(phthalimido)alkylphosphinic acids possessing β-substituted β-(alkoxycarbonyl)ethyl, β-phenylethyl, or β-(diethoxyphosphinoyl)ethyl substituents. Acid hydrolysis of these reaction products gives the target aminophosphinic acids: phosphinic analogs of γ-aminobutyric acid.

Synthesis of phosphinic acids on the basis of hypophosphites: VI. General methods for synthesis of pseudo-γ-glutamylpeptides

A general method for synthesis of 2-substituted pseudo-γ-glutamylpeptides, namely, [2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)propyl]phosphinic acids I which are phosphinic acid analogs of γ-glutamylpeptides. Bis(trimethylsilyl) hypophosphite (IV) formed from ammonium hypophosphite (II) in situ was added to the respective α-substituted acrylate to form bis(trimethylsilyl) [2-R-2-(alkoxycarbonyl)ethyl]-phosphonites V. Treatment of compounds V in situ with excess dibromoethane followed by alcoholysis gave [2-R-2-(alkoxycarbonyl)ethyl](2-bromoethyl)phosphinic acids VI which without isolation were treated with excess triethyl orthoformate. The simultanious esterification and dehydrobromination led to [2-R-2-(alkoxy-carbonyl)ethyl](vinyl)phosphinates III which were isolated and characterized. The Michael addition of diethyl acetamidomalonate to vinylphosphinates III followed by acid hydrolysis of phosphinates VII without their isolation resulted in formation of target [2-R-2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)]proly]phosphinic acids-pseudo-γ-glutamylpeptides I.

Acyloxy derivatives of trivalent phosphorus in amidoalkylation of hydrophosphoryl compounds

In order to model the previously suggested mechanism of the P-C bond formation via the Arbuzov reaction, we have studied the interaction of diethylacylphosphite (prepared beforehand as well as generated in situ from tetraethylpyrophosphite) with the in situ generated acyliminium cation. Various conditions of in situ generation of acylphosphite derivatives of P(III) from hydrophosphoryl compounds and acyliminium ions from N,N′-alkylidenebiscarbamates have been investigated: solvent nature, acid catalyst, and the reagents mixing order). The results obtained have confirmed the suggested mechanism of three-component reaction of amidoalkylation of hydrophosphoryl compounds with the formation of P-C bond via the Arbuzov reaction of in situ formed intermediates.

Method of synthesis of phosphinic acids based on hypophosphites: VIII. Synthesis of α-aminoalkylphenethylphosphinic acids

Development of methodology of double Arbuzov rearrangement based on hypophosphites allows a one-pot formation of two unsymmetrical phosphorus-carbon bonds by the Michael-Pudovik type reaction of stepwise addition of the intermediately forming silyl esters of trivalent phosphorus to different unsaturated compounds. A procedure was developed of the synthesis of α-aminoalkylphenethylphosphinic acids. Bis-(trimethylsilyl)phenethylphosphonite formed as a result of the addition of bis(trimethylsilyl)hypophosphite to styrene in situ was added without isolation from the reaction mixture to Schiff bases obtained preliminary from benzylamine or diphenylmethylamine and various aldehydes. The subsequent removal of N-protecting groups by hydrogenation or acidic hydrolysis gave a number of new α-aminoalkylphenethylphosphinic acids.