Phosphonic acid derivatives, reaction

Other cyclizations at phosphorus have been observed when certain phosphinates were used in the acid-catalyzed Mannich reaction. As observed previously with various phosphonous acid derivatives, reaction of aliphatic phosphinic acids with primary amines favored the formation of 2 1 adducts (73). Thus, glycine and other a-amino acids reacted under the typical conditions with excess formaldehyde and alkyl phosphonous acids to give the bis-phosphinylmethyl adducts 125. 

Phosphonic and Phosphinic Acids and their Derivatives.—Further fundamental information on important reactions for preparing phosphonic acid derivatives has... 

Stable compounds which resemble the transition-state structure of a substrate in an enzymatic reaction are expected to behave as potent reversible inhibitors (1 ). Based on the X-ray crystallographic structure of the active site of carboxypeptidase A (CPA) (2), a mechanism was proposed in which a water molecule adds directly to the scissile carbonyl group of the substrate to give the tetrahedral intermediate 1, which collapses to products (3). We proposed to mimic this tetrahedral intermediate, similar to the transition state, with the stable tetrahedral phosphonic acid derivatives 2,... 

The discovery of the statin mevalonic acid synthesis inhibitors focused new attention on control of blood lipid levels as a measure to stave off heart disease. A number of compounds have been found that treat elevated lipid levels by other diverse mechanisms. The phosphonic acid derivative ibrolipim (9) is believed to lower those levels by accelerating fatty acid oxidation. The phosphoms-containing starting material 7 can in principle be obtained by the Arbuzov reaction of a protected from of p-bromomethylbenzoic acid (6) with triethyl phosphate. Removal of the protecting group and conversion of the acid to an acyl chloride then affords 7. Condensation of this intermediate with substituted aniline 8 leads to the hypolipidemic agent (9). ... 

In other developments, Lecat and Devaud ° have proposed an electrochemical reduction (Scheme 4) to recover triphenylphosphine from triphenylphosphine oxide produced, for example, in the Wittig reaction. Yields of up to 86% were obtained. Engel and Chakrabarty have reduced phosphoric and phosphonic chlorides to the corresponding monobasic phosphorous and phosphonous acid derivatives (equations 23 and 24), using NaBH4 in refluxing dioxane. Triphenylphosphine oxide is reportedly reduced to triphenylphosphine in 75% yield by the electron-transfer system Smh-THF-HMPA, at 65 °C. 

Diaryl methyl- and benzyl-phosphonates are conveniently prepared in high yields by heating mixtures of triaryl phosphites, methanol or benzyl alcohol, and a trace of methyl or benzyl halide. In a reaction that is usefully complementary to the previously reported formation of pyridine-2-phosphonic acid derivatives from sodium dialkyl phosphonates and //-methoxypyridinium compounds ( Organophosphorus Chemistry , Vol. 7, p. 111), N-triphenylmethylpyridinium tetrafluoroborate affords the pyridine-4-phosphonic dialkyl ester when heated with sodium dialkyl phosphonates. ... 

Noyori-type Ru-complexes, prepared by the combination of polar phosphonic acid-derived 10 and 11 with (R,R)-DPEN (1,2-diphenylethylenediamine), were also used to catalyze the asymmetric hydrogenation of aromatic ketones in an ionic liquid/iPrOH biphasic system (Scheme 7.3) [20]. The conversions and enantioselectivities were quite comparable to those obtained from homogeneous reaction in iPrOH. The Ru complex 10-DPEN immobilized in the ionic liquid layer could be recycled six times without any significant loss of enantioselectivity, albeit with a dramatic drop in activity after the third run. 

The reaction with Arsenazo III has been used in the study of extraction equilibria in the systems of REE and phosphonic acid derivatives [56]. 

Moskva, V.V., Maikova, A.I., and Razumov, A.I., Phosphonic and phosphonous acid derivatives. Part 64. Reaction of phosphites and arylphosphonates with orthoacetic ester, Zh. Obshch. Khim., 39, 2451, 1969 J. Gen. Chem. (Engl. Transl.), 39, 2391, 1969. 

A two-component catalyst system consisting of two different transition metal complexes (Rh-Pd) has been applied to the enantioselective allylation of diethyl 1-cyanoethylphosphonate. The reaction proceeds with high enantioselectivity to give optically active phosphonic acid derivatives (Scheme 6.11). ° ... 

Scheme 18). Phosphonic acid derivatives, e.g. (149), of prostaglandins Fia and p2a have been prepared by Arbusov reactions of the corresponding prostaglandin terminal iodides. The familiar difficulty of removing both phosphorus ester groups was encountered. 

Synthetic Methods.— Direct routes to phosphonic acid derivatives from olefins and phosphorus halides continue to be explored. In the presence of oxygen, phosphorus tribromide reacts with olefins by a radical mechanism in a manner analogous to the corresponding chloride, giving 2-bromoalkyl-l-phosphonyl dibromides. The reaction of phosphorus trichloride and per-chloryl fluoride with hex-1-ene gives moderate yields of (55), the direction of... 

As for all reactions which generate chlorophosphonium cations, in addition to furnishing phosphonic dichlorides by hydrolysis, the work-up can be modified to give other phosphonic acid derivatives and, for example, alcoholysis yields first the chloride esters, RP(0)(0R )C1, and then the diesters, RP(0)(0R )2 " -... 

In this procedure, the C-phosphorylated active methylene compound is first converted into its anion, through its reaction with KOBu BuLi, PhLi, NaH or even Et3N, and the anion is then acted upon by a sulphonyl azide the latter has been / -toluenesulphonyl azide in most recorded examples of the reaction. The first example of the adoption of this procedure to the synthesis of a phosphonic acid derivative appears to have been the conversion of triethyl phosphonoacetate into the diazo derivative (2). Since then, the procedure has been used to obtain A-substituted derivatives of the phosphonoacetamide corresponding to structure 2, but the primary amide itself undergoes further reaction to afford the C-phosphorylated 1,2,3-triazole (3)". Tetraethyl methylenebisphosphonate yields tetraethyl... 

The synthesis of phosphonic acid derivatives by the direct oxidation of those of the corresponding phosphonous acid has been afforded very little interest (Chapter 2, Section VI.c), unlike the more controllable synthesis of derivatives of the thio- or seleno-phos-phonic acid derivatives (Chapter 5, Section II.B.4). In the present instance, the oxidation of A -protected (fmoc) (l-aminoalkyl)phosphinic esters has been carried out with NaI04 with high yields. Quantitative yields of (aminoalkyl)phosphonic acids were obtained in oxidation reactions with bromine water and with HgCl2-H20. In an alternative approach (Scheme 59), the A -protected (cbz) ethyl(l-aminoalkyl)phosphinate is initially converted into a (l-aminoalkyl)phosphonous acid diester, which is then subjected to the Atherton procedure to achieve change in valence at phosphorus. ... 

One area of noteworthy activity during the year, if only because of the number of relevant publications, has been that concerning addition reactions of (diene)-phosphonic acid derivatives [particularly those of (l,2-propadiene)phosphonic... 

Phosphorus-containing compounds provide useful substrates for ozonolysis reactions as well and can provide several products depending on the reaction workup. Several biological uses exist for -amino-a-hydroxy phosphonic acid derivatives and they can be readily prepared by ozonolysis of Al-(ethoxycarbonyl)-/3-amino-Q -methylene phosphonic esters after reductive workup with sodium borohydride (eq 54). When the reaction mixture is treated with sodium hydroxide in MeOH, an anomalous ozonolysis reaction occurs and cleavage of the methylene as well as the carbon-phosphorus bond occurs to yield (V-(ethoxycarbonyl)-a-amino methyl carboxylic esters. 

The fused 1,2,3-triazolino-pyrrolidine 84 was obtained by oxidation of 2,3,4-tri-0-acetyl-5-azido-5-deoxy-D-xylose dibenzyl dithioacetal with MCPBA, the reaction involving intramolecular dipolar cycloaddition of the azido group onto a 1,2-double bond formed by loss of acetic acid. A similar product was obtained from the D-rt o-analogue. Nucleotide analogues based on hexenopyranosyl phosphonic acid derivatives with a nucleoside base moiety linked at C-4 are covered in Chapters 9 (Section 2.6) and 17. 

In this subsection, there will be described reactions of phosphonic acids derivatives occuring not only in the a-position to phosphorus atom which is characteristic for this group of compounds, but also on positions of both P-C and P-O-C phosphonate carbon chains. 

A wide range of a-amino phosphonic acid derivatives (213) have been synthesized with good enantioselectivities, in reactions of enamides or enecarbamates with iminophosphonates catalyzed (with a high turnover frequency) by a copper(ii) complex (214) (Scheme 82). ... 

A -Phosphinoyl and A -thiophosphinoyl ketimines, Ph-C(Me)=N-P(=X)Ph2 (X = O and S), have been hydrophosphonylated in high yield and ee using a copper(I) catalyst liganded with a chiral diphosphino ethane. In the case of the sulfur substrates, facile differentiated removal of the t/imphosphinoyl group affords a-amino phosphonic acid derivatives, Ph- C(Me)(NH2)-P(=0)(0Et)2, that is, phosphonic acid analogues of enantio-enriched a,a-disubstituted a-amino acids. The reaction also accommodates alkyl, cycloalkyl and alkenyl substituents in place of the phenyl. 

The trienamine-catalysed asymmetric Diels-Alder cycloaddition reaction of 2,4-dienals (77) with chiral phosphorous dienophiles (78) produced densely functionalized phosphonocyclohexene adducts (79) with excellent enantioselectivity (up to 99% ee) and good to high diastereoselectivity (up to >99 1) (Scheme 22). The thermal Diels-Alder reaction of l-phosphono-(3,4)-disubstituted-1,3-butadienes with maleimides and 4-phenyl-l,2,4-triazoline-3,5-dione produced polycyclic phosphonic acid derivatives. ... 

Various types of phosphorus reagents have been employed for asymmetric transformations of carbonyl compounds into alkenes [2, 4, 7-11]. Depending upon the structure of these reagents, different reaction names are given [3]. Phosphonium ylides and phosphine oxide are particularly popular, and are referred to as Wittig and Horner reagents, respectively. On the other hand, phosphonates and other phosphonic acid derivatives are termed Horner-Wadsworth-Emmons (HWE) reagents. In recent years, arsonium derivatives have often been used for similar reactions, and they are also covered herein. 

Two chiral phosphonic acid derivatives 19a,b, containing a stereogenic phosphorus atom connected to a mercaptoisoborneol moiety, were prepared as a mixture, and were then chromatographically separated. Their ability in asymmetric carbonyl olefination was examined in the reaction with 4-tert-butylcyclohexanone la [56). The two lithium carbanions reacted with the carbonyl group of the substrate to give opposite enantiomers 90a, although no remarkable degree of asymmetric induction was observed (up to 16% ee). 

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