Harry R. Hudson

ORGANOPHOSPHORUS COMPOUNDS AS POTENTIAL FUNGICIDES. PART II. AMINOALKANE-, GUANIDINOALKANE-, AND THIOUREIDOALKANE-PHOSPHONIC ACIDS: PREPARATION, SPECTROSCOPY, AND FUNGICIDAL ACTIVITY

Abstract A range of α-amino-, ω-amino-, α-guanidino-, and ω-guanidinoalkanephosphonic acids has been prepared for the purpose of studying their spectroscopic features and fungicidal activity. In addition, α-thioureido-octanephosphonic acid and thioureylene-1,1-bis(1-octanephosphonic acid) were isolated during the preparation of α-guanidino-octanephosphonic acid. 31P, 1H, and 13C nmr spectral data which were obtained for solutions of the amino-and guanidino-compounds in D2O or D2O/D2SO4, and for the thioureido compounds in DMSO-d 6, are discussed together with previously reported data for the aminophosphonic types. FAB mass spectrometry generally gives strong pseudomolecular ions [MH]+ for the zwitterionic amino-and guanidino-compounds with relatively simple fragmentations. Fungicidal activity of the α-aminophosphonic acids was found to be greater than for the ω-amino compounds, with maximum activity at a chain length of three carbon atoms when used as a seed dressing for the control of Drechslera spp. Mod...

Transition metal complexes of dialkyl α-hydroxyiminophosphonates, a novel class of metal complexes

A new range of dialkyl α-hydroxyiminophosphonates has been prepared and the first examples of metal complexes of this class of compound have been obtained; X-ray crystal structure analysis of the dichlorobis(diethyl E-(α)-hydroxyiminopropanephosphonate)nickel(II) complex shows a distorted octahedral coordination at the nickel atom giving two symmetry related diethyl-(E)-α-hydroxyiminopropanephosphonate ligands and two chlorine donors.

ω -Phosphinyl-α -Amino Acids: Synthesis, and Development towards Use as Therapeutic Agents

Literature publications (up to September 2006) concerning the synthesis of ?-phosphinyl-?-amino acids and their development towards use as therapeutic agents are reviewed. General and asymmetric methodologies for the preparation of straight-chain examples are described, including AP3-7 modulators of glutamate-responsive excitatory amino acid (EAA) receptors (i.e. ionotropic NMDA-, and metabotropic GrpIII mGlu-receptors), and the glutamate synthetase inhibitor phosphinothricin. Focusing primarily on the development of methods for introducing phosphonate and aminocarboxylate functions to the appropriate scaffold, approaches to conformationally constrained ?-phosphinyl-?-amino acids are also investigated, along with their relevance to the development of therapeutic regimens towards neurodegenerative disorders.

THE PREPARATION AND CHARACTERIZATION OF SOME FLUORINATED α-AMINOARYLMETHANEPHOSPHONIC ACIDS

Abstract α-Aminoarylmethanephosphonic acids have been prepared with a range of fluoro, fluoroalkyl, or fluoroalkoxy substituents in the benzene ring (4-F, 3-F, 2-F, 3,4-F2, F5, 4-CF3, 3-CF3, 4-CF3O, and 3-CF3O). These compounds have relatively low aqueous solubility and their NMR spectra (1H, 13C, 31P and 19F) were therefore recorded in D2O in the presence of an excess of alkali. Under these conditions, the ring substituents appear to have little effect on δH (15–18 ppm), or on the 1H and 13C parameters for the benzylic group (α-CH), which are mainly in the ranges observed for other types of α-aminoarylmethanephosphonic acids under alkaline conditions (δH, 3.8–4.0 ppm, 2 J PH 15.3–16.5 Hz; δc 57–58 ppm, 1 J PC 128–132 Hz). For those examples with fluorine in the ortho position (i.e., the 2-fluoro and pentafluoro derivatives) a slightly higher field chemical shift was observed for the benzylic carbon atom (δc 50–51 ppm). In the fast-atom bombardment mass spectra, pseudo-molecular ions, MH+, and ions result...

The Preparation and Anticancer Activity of Some Phosphorus Heterocycles

Methods for the preparation of some phosphorus heterocycles are reviewed, together with a preliminary report of their activity in vitro against the NCI 60-cell line panel of human tumour cells. The most active compound, a dimer of 3-methyl-1-(2,4,6-triisopropylphenyl)phosphole oxide, showed GI50 values in the micromolar region against leukaemia cell lines RPMI-8226 and SR, non-small cell lung cancer (NCI-H460), colon cancer (COLO 205), and melanoma (SK-Mel-5 and UACC-62).

N-heterocyclic dronic acids: Applications and synthesis

Substituted hydroxymethylenebisphosphonic acid derivatives--either as dronic acids or their dronate sodium salts, are important pharmaceuticals in the treatment of diseases arising from excessive bone-resorption. Potential has also been identified in areas ranging from parasite-growth inhibition to immunological and cancer therapeutics. Representative clinically relevant N-heterocyclic derivatives include zoledronic and risedronic acids. The biochemical background and mechanism of action of these drugs are discussed, along with trends in structural development and future prospects. Synthetic routes to dronates are then summarized. The most popular route to valuable dronic acids involves the 3- component condensation of a substituted acetic acid, phosphorous acid, and phosphorus trichloride. However, the protocols recorded in the literature are very diverse. This review gives a critical account of reported methods, explores the contradictions and suggests a practical synthetic procedure after clarifying the inconsistencies described. Possible mechanisms of the reaction are also discussed.

CHEMICAL SHIFT NON-EQUIVALENCE IN THE NMR SPECTROSCOPY OF DIALKYL α-HYDROXYBENZYL-AND DIALKYL α-METHOXYBENZYLPHOSPHONATES AND THE CRYSTAL STRUCTURE OF DIMETHYL α-CHLOROMETHYL-αHYDROXYBENZYLPHOSPHONATE

Abstract Single crystal X-ray diffraction of dimethyl α-chloromethyl-α-hydroxybenzylphosphonate shows the compound to exist as hydrogen-bonded dimers in the solid state. In solution, 1H and 13C nmr spectroscopy reveal chemical shift non-equivalence of the corresponding nuclei in the two alkoxy groups of dialkyl α-hydroxybenzyl-and dialkyl α-methoxybenzylphosphonates, an effect that is attributed primarily to the presence of the chiral α-carbon atom, although restriction of rotation about the P—C α bond by intermolecular hydrogen-bonding may also be a factor in the α-hydroxy compounds. Chemical shift non-equivalence of the α-halogenomethyl protons in dimethyl α-halogenomethyl-α-hydroxyben-zylphosphonates is significantly greater for the chloro-than for the bromo-compound.

Quasiphosphonium intermediates. Part I. Preparation, structure, and nuclear magnetic resonance spectroscopy of triphenyl and trineopentyl phosphite–alkyl halide adducts

Experimental conditions for the preparation of triphenyl phosphite–alkyl halide adducts have been investigated. The long periods of heating necessary for reaction of the higher alkyl halides, especially the chlorides and bromides, leads to decomposition with the formation of halogenobenzenes and diphenyl alkylphosphonates, together in certain cases with halogenophosphites, dihalogenophosphites, and other phosphorus-containing compounds. At room temperature, trineopentyl phosphite reacts readily with iodomethane or bromomethane to afford crystalline Michaelis–Arbuzov intermediates, which decompose in solution to yield neopentyl halides without rearrangement of the alkyl group. 31P N.m.r. spectroscopy shows the adducts to have the phosphonium structure [(RO)3PR′]+X–(R = Ph or neopentyl), the chemical shifts lying in the range –40 to –50 p.p.m. from 85% H3PO4 and being independent of the nature of X (Cl, Br, or I). Molecular weight and conductivity measurements, together with the results of a study of the kinetics of decomposition for trineopentyl phosphite–methyl iodide, are consistent with the presence of ion pairs rather than dissociated ions in chloroform. 1H and 31P N.m.r. chemical shifts occur at slightly lower field for the phosphonium intermediates than for the corresponding diaryl (or dialkyl) alkylphosphonates. Long-range coupling between phosphorus and the α-, β-, and γ-protons is observed, that between phosphorus and the β-protons being greatest.

Quasiphosphonium intermediates—IV: Isolation and identification of intermediates in the arbuzov and perkow reactions of neopentyl esters of phosphorus(III) acids with α-halogenoacetophenones

Abstract Crystalline ketophosphonium bromides have been isolated as intermediates in the reactions of trineopentyl phosphite, dineopentyl phenylphosphonite, and neopentyl diphenylphosphinite with α-bromoacetophenone. Thermal decomposition in solution occurs in each case to yield neopentyl bromide and the corresponding Arbuzov product only. Rearrangement to the Perkow intermediate or product does not occur. An identifiable Perkow intermediate was separated from the reaction of neopentyl diphenylphosphinite with α-chloroacetophenone at O° and was shown to yield neopentyl chloride and the corresponding Perkow product by a first-order process in chloroform (t 1 2 ca 40min at 33°). It is suggested that the betaine formed by initial attack of phosphorus at the carbonyl carbon atom may be a common first intermediate in reactions that yield both Arbuzov and Perkow products

The Preparation of Dimethyl α -Hydroxyphosphonates and the Chemical Shift Non-Equivalence of Their Diastereotopic Methyl Ester Groups

Dimethyl α -hydroxyalkyl-, α -hydroxybenzyl-, α -hydroxyfurfuryl-, and α -hydroxy-α -thienylmethyl-phosphonates have been prepared in good yield by the alumina-catalyzed reaction of dimethyl phosphite with the corresponding alkanals, aryl aldehydes (or aryl methyl ketones), furfuraldehyde, and 2- or 3-thiophenecarboxaldehyde, respectively, thus confirming the general utility of this synthetic procedure. The 1H and 13C nmr spectra of the products exhibit characteristic chemical shift non-equivalence of the diastereotopic methyl ester groups, for which a tentative order of non-equivalence is reported and discussed.