H-phosphinic Acids Research Articles

Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction.

Aminoalkyl-H-phosphinic acids, also called aminoalkylphosphonous acids, are investigated as biologically active analogues of carboxylic amino acids and/or as valuable intermediates for synthesis of other aminoalkylphosphorus acids. Their synthesis has been mostly accomplished by phospha-Mannich reaction of a P–H precursor, an aldehyde and an amine. The reaction is rarely clean and high-yielding. Here, reaction of H3PO2 with secondary amines and formaldehyde in wet AcOH led to aminomethyl-H-phosphinic acids in nearly quantitative yields and with almost no by-products. Surprisingly, the reaction outcome depended on the basicity of the amines. Amines with pKa > 7–8 gave the desired products. For less basic amines, reductive N-methylation coupled with oxidation of H3PO2 to H3PO3 became a relevant side reaction. Primary amines reacted less clearly and amino-bis(methyl-H-phosphinic acids) were obtained only for very basic amines. Reaction yields with higher aldehydes were lower. Unique carboxylic–phosphinic–phosphonic acids as well as poly(H-phosphinic acids) derived from polyamines were obtained. Synthetic usefulness of the aminoalkyl-H-phosphinic was illustrated in P–H bond oxidation and its addition to double bonds, and in selective amine deprotection. Compounds with an ethylene-diamine fragment, e.g. most common polyazamacrocycles, are not suitable substrates. The X-ray solid-state structures of seventeen aminoalkyl-phosphinic acids were determined. In the reaction mechanism, N-hydroxyalkyl species R2NCH2OH and [R2N(CH2OH)2]+, probably stabilized as acetate esters, are suggested as the reactive intermediates. This mechanism is an alternative one to the known phospha-Mannich reaction mechanisms. The conditions can be utilized in syntheses of various aminoalkylphosphorus compounds.

From Oxygen to Sulfur and Back: Difluoro -H-phosphinothioates as a Turning Point in the Preparation of Difluorinated Phosphinates: Application to the Synthesis of Modified Dinucleotides.

A simple, two-step procedure to convert α,α-difluorinated H-phosphinic acids into the corresponding H-phosphinothioates is described. The usefulness of these species is demonstrated by their transformation into difluorinated phosphinothioyl radicals and their addition onto alkenes. Additionally, sequential treatment of H-phosphinothioates by a strong base and a primary alkyl iodide constitutes an alternate route to the formation of the C-P bond. Both methods efficiently deliver difluorinated phosphinothioates. Similar reactions carried out with the fully oxygenated counterparts clearly indicate the superiority of the sulfur-based species and emphasize the crucial role played by sulfur in the construction of the second C-P bond. Oxidation easily transforms the thereby obtained phosphinothioates into the corresponding phosphinates. The whole strategy is applied to the stereoselective preparation of dinucleotide analogues featuring either a difluorophosphinothioyl or a difluorophosphinyl unit linking the two furanosyl rings.

Palladium-Catalyzed Allylation/Benzylation of H-Phosphinate Esters with Alcohols.

The Pd-catalyzed direct alkylation of H-phosphinic acids and hypophosphorous acid with allylic/benzylic alcohols has been described previously. Here, the extension of this methodology to H-phosphinate esters is presented. The new reaction appears general, although its scope is narrower than with the acids, and its mechanism is likely different. Various alcohols are examined in their reaction with phosphinylidene compounds R1R2P(O)H.

Rapid and Efficient Microwave-Assisted Hydrophosphinylation of Unactivated Alkenes with H-Phosphinic Acids without Added Metal or Radical Initiator

A microwave-assisted hydrophosphinylation of unactivated alkenes with phosphinic acid and its derivatives under metal-free and initiator-free conditions is reported. Such hydrophosphinylations are operationally simple, use aqueous hypophosphorus acid, H-phenylphosphinic acid, and H-alkylphosphinic acids, and seem to proceed by a radical mechanism. Good isolated yields were obtained using a reasonable excess of the appropriate reagent.

The influence of the combination of carboxylate and phosphinate pendant arms in 1,4,7-triazacyclononane-based chelators on their 68Ga labelling properties.

In order to compare the coordination properties of 1,4,7-triazacyclononane (tacn) derivatives bearing varying numbers of phosphinic/carboxylic acid pendant groups towards 68Ga, 1,4,7-triazacyclononane-7-acetic-1,4-bis(methylenephosphinic) acid (NOPA) and 1,4,7-triazacyclononane-4,7-diacetic-1-[methylene(2-carboxyethyl)phosphinic] acid (NO2AP) were synthesized using Mannich reactions with trivalent or pentavalent forms of H-phosphinic acids as phosphorus components. Stepwise protonation constants logK1–3 12.06, 3.90 and 1.95, and stability constants with GaIII and CuII, logKGaL 24.01 and logKCuL 16.66, were potentiometrically determined for NOPA. Both ligands were labelled with 68Ga and compared with NOTA (tacn-N,N′,N″-triacetic acid) and NOPO, a TRAP-type [tacn-N,N′,N″-tris(methylenephosphinic acid)] chelator. At pH 3, NOPO and NOPA showed higher labelling efficiency (binding with lower ligand excess) at both room temperature and 95 °C, compared to NO2AP and NOTA. Labelling efficiency at pH = 0–3 correlated with a number of phosphinic acid pendants: NOPO >> NOPA > NO2AP >> NOTA; however, it was more apparent at 95 °C than at room temperature. By contrast, NOTA was found to be labelled more efficiently at pH > 4 compared to the ligands with phosphinic acids. Overall, replacement of a single phosphinate donor with a carboxylate does not challenge 68Ga labelling of TRAP-type chelators. However, the presence of carboxylates facilitates labelling at neutral or weakly acidic pH.

Enantioselective Synthesis of H-Phosphinic Acids Bearing Natural Amino Acid Residues

The first systematic study on the asymmetric synthesis of H-phosphinic acids bearing natural protein amino acid residues was reported on the basis of the asymmetric addition of ethyl diethoxymethylphosphinate to N-tert-butanesulfinyl imines. Good yields and moderate to high enantioselectivities were obtained. Reliable methods were developed for the elucidation of the stereochemistry of these phosphinic acids and derivatives thereof. The transformation of the side chains of these analogues was studied. Methods for the conversion of the α-aminophosphinates to oligopetides were reported.

ChemInform Abstract: Synthesis of Disubstituted Phosphinates via Palladium‐Catalyzed Hydrophosphinylation of H‐Phosphinic Acids.

AbstractAll products are isolated without any chromatography.

Temporary Protection of H-Phosphinic Acids as a Synthetic Strategy.

H-Phosphinates obtained through various methodologies are protected directly via reaction with triethyl orthoacetate. The resulting products can be manipulated easily, and various synthetic reactions are presented. For example, application to the synthesis of aspartate transcarbamoylase (ATCase) or kynureninase inhibitors are illustrated. Other reactions, such as Sharpless' asymmetric dihydroxylation, or Grubbs' olefin cross-metathesis are also demonstrated.

Allylic Phosphinates via Palladium-Catalyzed Allylation of H-Phosphinic Acids with Allylic Alcohols

A novel catalytic allylation of H-phosphinic acids is described. Using Pd/xantphos (2 mol %), H-phosphinic acids react directly with allylic alcohols to produce P-allylated disubstituted phosphinic acids.

Palladium-Catalyzed Reactions of Hypophosphorous Compounds with Allenes, Dienes, and Allylic Electrophiles: Methodology for the Synthesis of Allylic H-Phosphinates

Hypophosphorous compounds (MOP(O)H(2), M = H, R(3)NH) effectively participate in metal-catalyzed C-P bond-forming reactions with allenes, dienes, and activated allylic electrophiles under mild conditions. The catalytic system Pd(2)dba(3)/xantphos is crucial to avoid or minimize the competitive reductive transfer-hydrogenation pathway available to hypophosphorous acid derivatives. Further investigation into the allylation mechanism provided access to the analogy allylic acetate-allylic phosphinate, which then led to the development of a Pd-catalyzed rearrangement of preformed allylic phosphinates esters and, ultimately, to a catalytic dehydrative allylation of hypophosphorous acid with allylic alcohols. The reactions disclosed herein constitute efficient synthetic approaches, not only to prepare allylic H-phosphinic acids but also their esters via one-pot tandem processes. In addition, the potential of H-phosphinates as useful synthons for the preparation of other organophosphorus compounds is demonstrated.

Synthesis of p-Aminophenyl Aryl H-Phosphinic Acids and Esters via Cross-Coupling Reactions: Elaboration to Phosphinic Acid Pseudopeptide Analogues of Pteroyl Glutamic Acid and Related Antifolates

The synthesis of suitably protected p-aminophenyl H-phosphinic acids and esters from the corresponding para-substituted aryl halides has been accomplished via the Pd-catalyzed cross-coupling reaction of anilinium hypophosphite, either in the absence or presence of a tetraalkyl orthosilicate, to provide the free H-phosphinic acid or the corresponding ester, respectively. Subsequent conjugate addition of either a PIII species or phosphorus anion, generated in situ from either the free H-phosphinic acid or ester, to a 2-methylene glutaric acid ester provided the aryl phosphinic acid analogue of p-aminobenzoyl glutamic acid. Alkylation of these suitably protected p-aminophenyl phosphinic acid esters with a 6-(bromomethyl)pteridine or the corresponding (bromomethyl)pyridopyrmidine, followed by hydrolytic removal of protecting groups, provided the target aryl phosphinic acid analogues of folic acid and related antifolates. Alternatively, for the synthesis of the folate or 5-deazafolate analogues on a slightly larger scale, reductive amination with either N2-acetyl or N2-pivaloyl-6-formylpterin or the corresponding formylpyridopyrmidine and the same suitably protected p-aminophenyl phosphinic acid esters, followed by removal of protecting groups, is preferred. In the course of this research, it was observed that the nucleophilicity of both the aniline nitrogen and various PIII species derived from p-aminophenyl phosphinic acid derivatives is significantly reduced compared to that of the unsubstituted counterpart.

A novel approach to phosphonic acids from hypophosphorous acid

A novel access to phosphonic acids via Pd-catalyzed tandem carbon–phosphorus bond formation–oxidation processes was developed. The procedures involve atom-economical and environmentally friendly functionalization reactions of hypophosphorous acid (H3PO2) and H-phosphinic acids [RP(O)(OH)(H)].

Advances in the Synthesis of H‐Phosphinic Acids and Esters

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Palladium-Catalyzed Dehydrative Allylation of Hypophosphorous Acid with Allylic Alcohols

A novel palladium-catalyzed allylation of H3PO2 with allylic alcohols is described. The phosphorus-carbon bond-forming reaction produces allylic-H-phosphinic acids and water, in the absence of additives. Primary H-phosphinic acids are obtained in excellent yields, whereas secondary H-phosphinic acids react sluggishly. A reusable polymer-supported catalyst is also described. The reaction provides an environmentally sound approach to H-phosphinic acids.

Prodrug forms of N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psiP(O)(OH)]-glutarate, a potent inhibitor of folylpoly-gamma-glutamate synthetase: synthesis and hydrolytic stability.

Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psiP(O)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to alpha-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond. N-Alkylation of the corresponding amides derived from p-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding gamma-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding gamma-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.

Environmentally Benign Synthesis of H‐Phosphinic Acids Using a Water‐Tolerant, Recyclable Polymer‐Supported Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Environmentally Benign Synthesis of H-Phosphinic Acids Using a Water-Tolerant, Recyclable Polymer-Supported Catalyst

[reaction: see text] A reusable polymer-supported hydrophosphinylation catalyst is described for the preparation of H-phosphinic acids. The polystyrene-based ligand is prepared in one step from commercially available compounds. The polymeric catalyst generally gives good yields for a variety of substrates and is water- and air-tolerant, although the scope of alkenes and alkynes which can be employed is somewhat narrower than with our original xantphos/Pd(2)dba(3) catalyst.

Direct synthesis of H-aryl and H-heteroarylphosphinic esters via palladium-catalyzed cross-coupling of alkylphosphinates

Aryl, heteroaryl, and benzylic electrophiles can be coupled to in situ-generated alkylphosphinates (ROP(O)H 2) in moderate to good yields using palladium catalysis. For the first time, electrophiles other than simple aryl iodides can be employed in an experimentally straightforward, one-pot reaction. The direct formation of H-phosphinic esters avoids the separate esterification of H-phosphinic (phosphonous) acids and is particularly useful in the case of nitrogen-containing heteroaromatics. The reaction significantly expands the scope of related palladium-catalyzed phosphorus-carbon bond-forming reactions. To cite this article: Z. Huang et al., C. R. Chimie 7 (2004).

Palladium‐Catalyzed Hydrophosphinylation of Alkenes and Alkynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Palladium-catalyzed hydrophosphinylation of alkenes and alkynes.

Various palladium catalysts promote the addition of hypophosphorous derivatives ROP(O)H(2) to alkenes and alkynes in good yields and under mild conditions. Particularly, Cl(2)Pd(PPh(3))(2)/2 MeLi, and Pd(2)dba(3)/xantphos allow for phosphorus-carbon bond formation instead of transfer hydrogenation. Commercial aqueous solutions of hypophosphorous acid can be employed successfully at ambient temperature. With styrene and terminal alkynes, the regioselectivity (linear versus branched products) can be controlled to some extent with the catalytic system employed. The methodology considerably extends upon previous routes for the preparation of H-phosphinic acids and other organophosphorus compounds.