Synthesis of Some Mixed Dialkyl Phosphites and their Use as Forerunners for Potential Chiral Phosphates

Abstract

Organophosphorus compounds containing a c h i d ccntrc at the P atom are of considerable interest fiom a stcreochemical point of view. Accordingly, trialkyl phosphates (RO)(RIO)(R20)P(0) (4) were synthesized starting from dialkyl phosphites. Thus: direct hydrolysis of dialkyl phosphites (ROhP(0)H (1) with tetraethylammonium hydroxide (20% aqueous solution), followed by extraction with dichloromethane affords the corresponding tetraethylammonium alkyl hydrogen phosphitcs (2). Good yields (q) of mixed dialkyl phosphites (3) were obtained on heating stoichiometric amounts of (2) and alkyl iodides in acetonitrile solution at 6O°C, for 6 hrs. Mixed dialkyl phosphites (3) were used in synthesis of some trialkyl phosphates (4) by PTC (see scheme).     

Novel Ylidic Phosphoryl Compounds from Halogenated Furan-2,5-Diones with Trivalent Phosphorus Esters: Application of this Approach to New Trisphosphonates Containing a Geminal Bisphosphonate Unit

Abstract

The reactions of trivalent phosphorus esters, including trialkyl phosphites, dialkyl phosphonites, and alkyl phosphinites, with 3-halo- and 3,4-dihalo-furan-2,5-diones has been shown to lead to the formation of novel phosphorus ylides possessing additional phosphoryl-containing groups. For the reaction of 3,4-dihalo-furan-2,5-diones with trialkyl phosphites, the products are trialkoxyphosphonium ylides containing an adjacent geminal bisphosphonate unit. These can be used to provide a convenient route to novel 2,3,3-tris(dialkoxyphosphoryl)-substituted propionate esters which can be hydrolyzed to give the corresponding novel trisphosphonic monocarboxylic acid.     

Reactions with aziridines XXI The (Michaelis-)arbusov reaction with N-acyl aziridines and other amidoethylations at phosphorus.

Heating trialkyl phosphites with N-acyl aziridines produces dialkyl 2-amidoethyl-phosphonates bearing one of the phosphite alkyl groups on nitrogen. Other alkoxy phosphines behave analogously. Dialkyl phosphites furnish the same type of products devoid of the N-alkyl group.     

Reaction of N-Phtalylamino Acid Chlorides with Trialkyl Phosphites

Abstract

Reaction of N-blocked amino acid chlorides with trialkyl phosphites is a first step in the synthesis of 2-amino-l-hydroxyalkylphosphonates. Quite surprisingly a very purl trialkyl phosphite is required m order to obtain the desired N-blocked 2-amino-1-oxoalkylphosphonate. Thus, the use of commercially rvailrble phosphites prolongation of the reaction time, or attempts for chromatographic purification of the formed oxophosphonate resulted m quite complicated mixture of products. We haw found that these products arise as a consequence of rearrangements of 1oxo-2. phtalylnmmoalLylphosphonates in a series of reactions which are promoted by that presence of dialkyl phosphite (standard impurity present m commercially availablt trialkyl phosphites) in the reaction medium.     

DIRECT FORMATION OF λ5-PHOSPHOLES FROM DIALKYL PHOSPHONITES AND DIMETHYL ACETYLENEDICARBOXYLATE

Abstract

The reaction of dialkyl phosphonites with dimethyl acetylenedicarboxylate proceeds via an analogous route to that previously established for the reaction of trialkyl phosphites although the intermediates are less stable. The five-coordinate phosphole (3; R = Et, R' = Ph) is sufficiently stable at -70°C to enable it to be converted to the oxo-phosphole (5; R' = Ph) by treatment with anhydrous hydrogen bromide.     

Zirconium(IV) compounds as efficient catalysts for synthesis of alpha-aminophosphonates

Zirconium(IV) compounds are reported as excellent catalysts for a three-component one-pot reaction of an amine, an aldehyde or a ketone, and a di/trialkyl/aryl phosphite to form alpha-aminophosphonates under solvent-free conditions at rt. Among the various zirconium compounds, ZrOCl2 x 8 H2O and ZrO(ClO4)2 x 6 H2O were most effective. The reactions were faster with dialkyl/diaryl phosphites than with trialkyl/triaryl phosphites. No O-Me cleavage occurs with aryl methyl ether and methyl ester groups. alpha,beta-Unsaturated carbonyl moiety does not undergo conjugate addition with the phorphorous moiety.     

Calix[4]arenes bearing α‐amino‐ or α‐hydroxyphosphonic acid fragments at the upper rim

By the reaction of para‐formylcalix[4]arenes 1–6 with trialkyl phosphites in the presence of dry hydrogen chloride, calix[4]arenes 7–13 possessing dialkylphosphoryl‐hydroxymethyl groupings at the upper rim were synthesized. Calix[4]arenes 18–23 functionalized with dialkylphosphoryl‐alkyl(aryl)aminomethyl groups were obtained by sodium‐promoted addition of dialkyl phosphites to C=N bonds of para‐iminocalix[4]arenes 14–17 . The consecutive treatment of α‐hydroxy‐ or α‐aminophosphonic acid dialkyl esters of calix[4]arenes 7, 10, 18 , and 21 with bromotrimethylsilane and methanol gave dihydroxyphosphoryl derivatives of calix[4]arenes 24–27 . It was shown that calix[4]arenes bearing at the macrocyclic upper rim hydroxymethylphosphonic fragments, as well as bis‐hydroxymethyl(aminomethyl)phosphonic fragments, are able to undergo self‐assembly with formation of dimeric OH···O=P hydrogen bonded associates. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:58–67, 2001     

A Synthesis of Dialkyl Phosphorylsuccinates from the Reaction of NH-Acids with Dialkyl Acetylenedicarboxylates in the Presence of Trialkyl(aryl) Phosphites

Summary. The reaction of dialkyl acetylenedicarboxylates with trialkyl(aryl) phosphites in the presence of isatin, phthalimide, indole, or pyrrole leads to stable dialkyl(aryl) phosphorylsuccinates in excellent yields.     

One-pot synthesis of phosphorylsuccinates and triphenylphosphanylidenesuccinates containing a thioamido group

Abstract

Stable substituted dialkyl phosphorylsuccinates were synthesized, as a mixture of two diastereoisomers, in high yields using one-pot reaction of dialkyl acetylenedicarboxylates, trialkyl phosphites, and thioamides in CH₂Cl₂ at room temperature. Using triphenylphosphine instead of phosphites, afforded stabilized triphenylphosphanylidenesuccinates. DFT calculations at B3LYP/6-31?+?G(d) level indicated that among four possible conformational diastereoisomers of dimethyl 2-(dimethoxyphosphoryl)-3-ethanethioamidosuccinate, the (2R,3S) and (2S,3S) diastereomers are the most stable forms.     

A Synthesis of Phosphorylated 2,4-Dioxothiazolidine Derivatives

Abstract

The zwitterionic 1:1 intermediates generated from trialkyl phosphites and dialkyl acetylenedicarboxylates are trapped by 2,4-thiazolidinedione and 5-arylidene- 2,4-thiazolidinediones to produce dialkyl 2-(2,4-dioxothiazolidin-3-yl)-3-(dialkoxyphosphoryl) succinates and dialkyl 2-(5-arylidene-2,4-dioxothiazolidin-3-yl)-3-(dialkoxyphosphoryl) succinates in good yields.

GRAPHICAL ABSTRACT     

Asymmetric synthesis of α-substituted alkylphosphonates based on symmetrical dialkyl phosphites

Chiral C₂-symmetrical dialkyl phosphites and C₃-symmetrical trialkyl phosphites, derived from (−)-borneol, (−)-menthol, and 1,2∶5,6-di-O-isopropylidene-α-d-glucofuranose, were studied as the starting reagents for the preparation of chiral organophosphorus compounds. The reactions of C₂-symmetrical dialkyl phosphites and C₃-symmetrical trialkyl phosphites with aldehydes and amines or aldehydes are accompanied by asymmetrical induction at the α-carbon atom to yield optically active α-aminoalkylphosphanates or α-hydroxyalkylphosphonates, respectively. The stereoselectivity of the reaction depends on the structure of the starting compounds and the reaction conditions. Translated fromIzvestiya Akademii, Nauk, Seriya Khimicheskaya, No. 8, pp. 1588–1593, August, 1999.     

THE PREPARATION OF DIMETHYL PHOSPHOROCHLORIDITE AND ITS HOMOLOGS FROM TRIALKYL PHOSPHITES AND DICHLOROTRIPHENYLPHOSPHORANE

Abstract

A novel convenient synthesis of dialkyl phosphorochloridites based on the reaction of trialkyl phosphites with dichlorotriphenylphosphorane has been described. In this way the commonly used dialkyl phosphorochloridites (3a–e) were prepared in satisfactory yields. Their identity was confirmed by ³¹P-NMR spectroscopy as well as by their refractive index.     

Solvent-free reaction of some 1,2-diaza-1,3-butadienes with phosphites: environmentally friendly access to new diazaphospholes and E-hydrazonophosphonates

[structures: see text] The present article describes the reaction between 1,2-diaza-1,3-butadienes and trialkyl phosphites, under an atmosphere of nitrogen and under solvent-free conditions, to give alkyl 3,3-dialkoxy-2H-1,2,3lambda5-diazaphosphole-4-carboxylates that, in turn, are converted into corresponding E-hydrazonophosphonates by treatment with THF:water (95:5). These latter compounds are obtained directly by the reaction of 1,2-diaza-1,3-butadienes with trialkyl phosphites in the presence of air. These compounds are useful for the further preparation of dialkyl (5-methyl-3-oxo-2,3-dihydro-1H-4-pyrazolyl)phosphonates and 2-dialkoxyphosphoryl-1,2,3-thiadiazoles.     

Cycloaromatization Reaction of 4‐Alkoxy‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐Diaminotoluene: The Unexpected Regioselective Synthesis of 2,4,7,8‐Tetrasubstituted Quinolines

This article reports a convenient and general method for the regioselective synthesis of a new series of 2‐alkyl(aryl)‐8‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines in 86–93% yields, from cycloaromatization reactions of N‐(oxotrifluoroalkenyl)‐2,6‐diaminotoluenes in a strongly acidic medium polyphosphoric acid and absence of solvent. The enaminoketone intermediates were easily isolated from the reaction of 4‐alkoxy‐4‐alkyl(aryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones [CF₃C(O)CH═C(R)OR¹, where R = H, Me, Ph, 4‐FPh, 4‐BrPh, 4‐MePh, and R¹ = Me, Et] with 2,6‐diaminotoluene (2,6‐DAT) in methanol under mild conditions, in 46–70% yields. Another synthetic route also allowed the regioselective synthesis of 2‐aryl(heteroaryl)‐4‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines from direct cyclocondensation reactions of 4‐alkoxy‐4‐aryl(heteroaryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐diaminotoluene in methanol under mild conditions, in 21–36% yields.     

Reactions of phosphite esters and trisdialkylaminophosphines with 5‐substituted 1,3,4‐thiadiazol derivatives

5‐{[(1E)‐(4‐methoxyphenyl)methylene]amino}‐1,3,4‐thiadiazole‐2‐thiol ( 1a ) reacts with trialkyl phosphites ( 2a–c ) to give the respective dialkyl phosphonate adducts ( 4a–c ). On the other hand, the reactions of trisdialkylaminophosphines ( 3a,b ) with 1a , 5‐{[(1E)‐(4‐phenyl)methylene]amino}‐1,3,4‐thiadiazole‐2‐thiol ( 1b ) yield the corresponding open dipolar structures 6a–c . In the case of the reaction of triethyl phosphite ( 2a ) with 1b , both the dialkyl phosphonate adduct ( 7 ) and the dipolar product ( 8a ) are obtained. Moreover, triisopropyl phosphite ( 2c ) reacts with 1b to give both the S‐alkyl and the N‐alkyl phosphonate adducts ( 9a,b ), respectively. Mechanisms are proposed to explain the formation of the new products, and their structures were confirmed on the basis of elemental analysis and spectral studies. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:594–601, 2001     

Comparative Studies on the Amidoalkylating Properties of N-(1-Methoxyalkyl)Amides and 1-(N-Acylamino)Alkyltriphenylphosphonium Salts in the Michaelis–Arbuzov-Like Reaction: A New One-Pot Transformation of N-(1-Methoxyalkyl)Amides into Phosphonic or Phosphinic Analogs of N-Acyl-α-Amino Acids

Abstract

It was demonstrated that N-(1-methoxyalkyl)amides do not react with trimethyl phosphite under neutral or basic conditions. The treatment of N-(1-methoxyalkyl)amides with trialkyl phosphites or dialkyl phosphonites, triphenylphosphonium tetrafluoroborate, and Hünig's base caused immediate formation of the corresponding 1-(N-acylamino)-alkyltriphenylphosphonium tetrafluoroborates, followed by the slow Michaelis–Arbuzov-like reaction of phosphonium salt with phosphites or phosphonites to α-(N-acylamino)-alkanephosphonic or α-(N-acylamino)alkanephosphinic acid esters, respectively. A plausible mechanism of the considered transformations, assuming an equilibrium between N-(1-alkoxyalkyl)amide, triphenylphosphonium tetrafluoroborate, 1-(N-acylamino)alkyltriphenyl-phosphonium salt, N-acylimine, and N-acyliminium salts, is discussed.     

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     

Synthesis of Tetrazoloquinoline‐Based Mono‐ and Bisphosphonate Esters as Potent Anti‐Inflammatory Agents

Several new α‐alkoxy‐ and α‐hydroxyphosphonate derivatives of tetrazole‐quinolines were synthesized from the reaction of 2‐azidoquinolines 3‐carboxaldehyde 1a,b with trialkyl phosphites and dialkyl phosphites. On the other hand, azaphospholes 12a,b were obtained by treating 1a,b with tris(dimethylamino)phosphine. Furthermore, Perkin‐type condensation of 1a,b and tetraethyl methylenebisphosphonate provided the corresponding tetrazoloquinoline‐based bisphosphonate esters 14a,b . Based on the prediction results (PASS program), the anti‐inflammatory activity of the prepared compounds was determined in vivo by the acute carrageenin‐induced paw edema in rats. Many of the new compounds exhibit considerable anti‐inflammatory properties at a dose of 50 mg/kg body weight. Especially 14a and 14b revealed remarkable activities compared with indomethacin, which was used as a reference standard in this study.     

Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism

Oxidative addition and reductive elimination are the central steps in new palladium-catalyzed chemistry that forms C–N and C–O bonds in arylamines and ethers. In the potential mechanism shown on the right the amine is formed by reductive elimination from a four-coordinate, 16-electron amido aryl complex. The use of a chelating ligand such as 1,1′-bis(diphenylphosphanyl)ferrocene (DPPF) reduces the occurrence of the competing β-hydrogen elimination. X=Br, I; R, R′=alkyl, aryl.     

Investigations of the Chemistry of Alkyl Phosphites Toward Nitrogen-Containing Compounds: Efficient Approaches to α-Amino-, β-Amino-, and/or Enaminophosphonates

Abstract

In this study, we report recent investigations of the chemical reactivity of alkyl phosphites, mainly trialkyl and dialkyl phosphites, with molecules containing different nitrogen-containing compounds reported by us and other research groups over the past 25 years. Previous ground-breaking important reports are also considered. The reviewed investigations in this article are grouped according to only the type of the nitrogen-functional groups [amines (primary, secondary, and tertiary amines), imines, amides, thioamides, nitriles, isocyanates, isothiocyanates, oximes, hydrazones, diazo, and azides] and not according to the site of attack or the final products. Furthermore, the present review article focuses on the synthesis of α-amino-, β-amino-, and/or enaminophosphonates. These compounds have important roles in pharmaceutical chemistry.