Methyl Phenyl Phosphinate Research Articles

Catalyst-free Hydrophosphinylation of Isocyanates and Isothiocyanates under Low-Added-Solvent Conditions

A catalyst-free, low-solvent method for the hydrophosphinylation of isocyanates and isothiocyanates is reported. A range of phosphorus nucleophiles including secondary phosphine oxides HP(O)R2 (R = Ph, iPr), phosphites HP(O)(OR)2 (R = Me, Et), and methyl phenylphosphinate were tested. The procedure tolerated isocyanates and isothiocyanates featuring a wide range of substituents and, with use of 4 equiv of 2-methyltetrahydrofuran (2-MeTHF), solid substrates can be utilized. Twenty-five compounds were prepared with improved functional group tolerance compared to previous methods allowing access to new compounds (16 are novel). Facile scale up and simple reaction conditions make this a straightforward and practical methodology for obtaining phosphorus analogues of ureas and thioureas, which are challenging to synthesize by other methods.

Catalysis of the ethanolysis of aryl methyl phenyl phosphinate esters by alkali metal ions: transition state structures for uncatalyzed and metal ion-catalyzed reactions

This paper reports on a spectrophotometric kinetic study of the effects of the alkali metal ions Li+ and K+ on the ethanolysis of the aryl methyl phenyl phosphinate esters 3a-f in anhydrous ethanol at 25 degrees C. Rate data obtained in the absence and presence of complexing agents afford the second-order rate constants for the reaction of free ethoxide (k(EtO-)) and metal ion-ethoxide ion pairs (k(MOEt)). The sequence k(EtO-) < k(MOEt) is established for all the substrates, contrary to the generally observed reactivity order in nucleophilic substitution processes. The quantities deltaG(ip), deltaG(ts) and DeltaG(cat), which quantify the observed alkali metal ion effect in terms of transition state stabilization through chelation of the metal ion, give the order deltaG(ts) > deltaG(ip) for Li+ and K+. Hammett plots show significantly better correlation of rates with sigma and sigma(o) substituent constants than with sigma-, yielding moderately large rho(rho(o)) values that are consistent with a stepwise mechanism in which formation of a pentacoordinate (phosphorane) intermediate is the rate-limiting step. The range of the values of the selectivity parameter, rho(n) (= rho]/rho(eq)), 1.3-1.6, obtained for the uncatalyzed and alkali metal ion catalyzed reactions indicates that there is no significant perturbation of the transition state (TS) structure upon chelation of the metal ions. This finding is relevant to the mechanism of enzymatic phosphoryl transfer involving metal ion co-factors. The present results enable one to compare structural effects for nucleophilic reactions of several series of organophosphorus substrates. It is shown that the order of reactivity of the substrates: 4-nitrophenyl dimethyl phosphinate (2) > 3a > 4-nitrophenyl diphenyl phosphinate (1) is determined mainly by the steric effects of the alkyl/aryl substituents around the central P atom in the TS of the reaction.

Phosphylation kinetic constants and oxime‐induced reactivation in acetylcholinesterase from fetal bovine serum, bovine caudate nucleus, and electric eel

Kinetic constants for selected phosphonate and phosphinate inhibitors of fetal bovine serum acetylcholinesterase (FBS AChE; EC 3.1.1.7), bovine caudate nucleus AChE (BCN AChE), and eel AChE have been determined. Oxime reactivation of the phosphylated enzymes has also been evaluated. In general, a rank order with respect to organophosphorus compound (OP) inhibition of the enzymes was observed: soman (pinacolyl methylphosphonofluoridate) was found to be the most potent inhibitor, and 4-nitrophenyl methyl(phenyl)phosphinate (PMP) the least potent. On average the bimolecular rate constant for soman inhibition of eel AChE was nearly twofold greater (9.3 x 10(7) M-1 s-1) than that for FBS AChE (5.5 x 10(7) M-1 s-1) and nearly fourfold greater than that for BCN AChE (2.2 x 10(7) M-1 s-1). In addition, 4-nitrophenyl chloromethyl(phenyl)phosphinate (CPMP) inhibition of eel AChE on average was nearly 10-fold greater than FBS AChE and three orders of magnitude greater than BCN AChE. The oxime HI-6 reactivated soman phosphonylated enzymes to a considerably greater extent than other oximes, and FBS AChE was notably more responsive to HI-6 than to other oximes. The individual mean values of the ki for each inhibitor in each class (phosphonate or phosphinate) were different with respect to each AChE, which may be a reflection of differences in enzyme configuration, whereas the general rank order of inhibitor potency within each class, reflected by the ki, was similar with respect to each AChE, which may be related to similar active centers. In general, oxime potency and some rank order varied with each inhibitor and with each AChE, although there was some similarity in oxime rank order between the two mammalian AChEs. Overall, the data support the selection of FBS AChE as the enzyme of choice for in vitro testing of OP inhibitors and reactivators.

Synthesis of 5,6-Dideoxy-5-phenylphosphinyl-l-galactopyranoses. The P-in-Ring Sugar Analogs of l-Fucose

Abstract 1,2-O-Isopropylidene-3-O-methyl-6-O-tosyl-β-d-arabino-hexofuranos-5-ulose (9a) and its 3-O-benzyl congener (9b) were prepared from 1,2:5,6-di-O-isopropylidene-β-d-altrofuranose in 4 steps. Addition of methyl phenylphosphinate to 9a and 9b in the presence of DBU, followed by reduction with Raney Ni, afforded (5R and 5S)-5,6-dideoxy-1,2-O-isopropylidene-5-[(methoxy)phenylphosphinyl]-3-O-methyl-β-d-arabino-hexofuranose(11a) and 3-O-benzyl congener (11b), respectively. The latter compound (11b) was debenzylated to 3-O-unsubstituted hexofuranose 11d. By reduction with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by acid hydrolysis, these key intermediates 11a, 11b, and 11d provided the title l-fucoses 13 (together with a minor proportion of d-altropyranoses 14) having as phenylphosphinylidene group in place of the ring oxygen. Compounds 13 and 14 were converted into per-O-acetyl derivatives for structural and conformational analysis by spectroscopy.

Evaluation of phosphinates as potential pretreatments for nerve agents

To assess the utility of phosphinates as pretreatments against nerve agents, experiments were conducted to determine whether oximes can reactivate phosphinate-inhibited guinea pig acetylcholinesterase (AChE) and whether the toxicity of phosphinates is reduced by treatment with atropine and/or oxime. Three phosphinates, 4-nitrophenyl methyl(phenyl) phosphinate (MPP), 4-nitrophenyl chloromethyl(phenyl) phosphinate (CMPP), and 4- nitrophenyl 2-methoxyphenyl(methyl) phosphinate (MPMP), were used in these experiments. In the first group of experiments, 2-PAM or HI-6 was administered, im 2 minafter peak inhibition of whole blood AChE activity by the phosphinates. Both oximes significantly reactivated MPP- or CMPP-inhibited AChE; however, HI-6 was the better reactivator in both cases. Oximes were ineffective against MPMP. Efficacy studies revealed that neither HI-6 nor 2-PAM potentiated the toxic effects of MPP or CMPP and that atropine/oxime therapy provided greater protection (up to 100 LD50s) against either phosphinate than any single therapy. The reactivation and efficacy data, especially for CMPP, support the concept that oxime sensitive phosphinates may be useful as pretreatments against nerve agent intoxication.

Asymmetric synthesis of phosphinates, phosphine oxides and phosphines by Michaelis Arbuzov rearrangement of chiral oxazaphospholidine

A general approach to asymmetric synthesis of high optically active tertiary organophosphorus compounds is described. Oxazaphospholidine 3 reacts with alkyl halide to give regio and stereoselectively the corresponding phosphinamide 4 . Methyl phenyl phosphinamide 4a is used for the preparation of methyl phenyl phosphinate 5a with ee > 96%. The preparation of (+) and (−) - PAMP or DIPAMP from 3 is described.

New methods for probing the chirality of 18O-labelled phosphinic acids

The chirality of singly 18O-labelled methyl(phenyl)phosphinic acid can be probed by conversion into the diastereoisomeric myrtenyl esters by the action of myrtenyl bromide on the potassium salt of the acid in Me2SO in the presence of 18-crown-6. The Mitsunobu reaction applied to the esterification of singly labelled methyl(phenyl)phosphinic acid with myrtenol gives some doubly labelled ester. The minor retention of configuration at phosphorus that occurs in the alkaline hydrolysis of (SP)-methyl methyl(phenyl)phosphinate is due to racemisation of the ester by methoxide ion formed in the hydrolysis. Alkaline hydrolysis of the corresponding (SP)-menthyl ester occurs with > 98% inversion of configuration at phosphorus.

Direct Deoxygenation of the Hydroxy Group of Methyl 1-Hydroxyalkyl-(phenyl)-phosphinates using Diphosphorus Tetraiodide

The hydroxy group of methyl 1-hydroxyalkyl-(phenyl)-phosphinates 3, prepared from methyl phenylphosphinate 1 and aldehydes or ketones 2, is directly deoxygenated on treatment with diphosphorus tetraiodide to give the methyl alkyl-(phenyl)-phosphinates 4.

Synthesis of 1,2,4-tri- O-acetyl-5-deoxy-3- O-methyl-5- C-[( R)- and -( S)-phenylphosphinyl]-β- d-ribopyranose

5-Deoxy-1,2- O-isopropylidene-5- C-(methoxyphenylphosphinyl)-3- O-methyl-α- d-ribofuranose ( 4) was prepared from 1,2- O-isopropylidene-3- O-methyl-α- d- ribo-pentodialdo-1,4-furanose by an addition reaction with methyl phenylphosphinate, followed by deoxygenation of the terminal HOCHP group of the adduct by successive reaction with 1,1′-thiocarbonyldiimidazole and tributyltin hydride. Treatment of 4 with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by deacetonation with mineral acid, and acetylation with acetic anhydride—pyridine, gave mainly the two title compounds, which were isolated by column chromatography on silica gel, and characterized by 90-MHz, 1H-n.m.r.-spectral analysis.

A new route for formation of the carbon-phosphorus bond, and synthesis of 1,2,4-tri- O-acetyl-5-deoxy-3- O-methyl-5- C-[( R)- and ( S)-phenylphosphinyl]-α- and -β- d-xylopyranose

Deoxygenation at the carbon atom α to the phosphorus atom of 1,2- O-isopropylidene-5- C-(methoxyphenylphosphinyl)-3- O-methyl-α- d-xylofuranose ( 7), prepared from 1,2- O-isopropylidene-3- O-methyl-α- d- xylo-pentodialdo-1,4-furanose by reaction with methyl phenylphosphinate, was performed by successively treating 7 with 1,1′-(thiocarbonyl)diimidazole (TCDI) and tributyltin hydride. Treatment of the resulting 5-deoxy-1,2- O-isopropylidene-5- C-(methoxyphenylphosphinyl)-3- O-methyl-α- d-xylofuranose with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by mineral acid, and then acetic anhydride in pyridine, gave the four title compounds, which were separated by column chromatography on silica gel and recrystallization, and characterized by 1H-n.m.r.-spectral analysis and their optical rotations.

Organophosphorus compounds. XIX. Synthesis of 2,3-Dihydro-1 H-1,2-benzazaphosphole 2-oxides, variously substituted on nitrogen and phosphorus, by N-P cyclization of zwitterionic intermediates

2-Phenyl-2,3-dihydro-1H-1,2-benzazaphosphole 2-oxide (7a) was prepared by thermolysis of the corresponding zwitterionic amino phosphinic acid (4), or its hydrochloride salt (1). Thermolysis of methyl (2-aminobenzy1)phenylphosphinate (5a) was accompanied by intermolecular O→N transmethylation to give, after cyclization, l-methyl-2-phenyl-2,3-dihydro-1H-1,2-benzazaphosphole 2-oxide (9a); similarly, the ethyl ester (5b) gave the N-ethyl heterocycle (9b). Reaction of 2-phthalimidobenzyl bromide (13a) with diethyl methylphosphonite (14b) gave ethyl (2-phthalimidobenzy1)methylphosphinate (15a). Hydrolysis of (15a) afforded (2-aminobenzyl)- methylphosphinic acid (16), and thermolysis of this produced 2-methyl-2,3-dihydro-lH-1,2-benzaza- phosphole 2-oxide (18a). 1-Methyi-2-methoxy-2,3-dihydro-1H-l,2-benzazaphosphole 2-oxide (24) was synthesized in an analogous manner. Base catalysed N-alkylation of the benzazaphosphole derivatives (7a) and (18a) was readily achieved, and the interconversion of 2-oxides and 2-sulfides was accomplished by conventional methods.

Synthesis of 4,5-dideoxy-4- C-[( R,S)-phenylphosphinyl]- d-ribo- and l-lyxo-furanose and their 1,2,3-triacetates

2,3- O-Isopropylidene- d-ribose diethyl dithioacetal, prepared from d-ribose, was converted in three steps into the corresponding dimethyl acetal, which was monotosylated at O-5, and the ester oxidized at C-4 with pyridinium chlorochromate; addition of methyl phenylphosphinate to the resulting pentos-4-ulose derivative then provided (4 R,S)-4,5-anhydro-2,3- O-isopropylidene-4- C-[( R,S)-(methoxy)phenylphosphinyl]- d- erythro-pentose dimethyl acetal. Hydrogenation of this compound in the presence of Raney Ni, followed by reduction with SDMA, hydrolysis, and acetylation, yielded the title compounds (seven kinds), the structures of which were established on the basis of their 400-MHz, 1H-n.m.r. and mass spectra. A general dependence of the 2 J PH and 3 J PH values on the OPCH and PCCH dihedral angles provided an effective method for the assignment of the configurations and conformations of these 4-deoxy-4-phosphinyl-pentofuranoses.

Synthesis of 1,2,4-tri- O-acetyl-3,6-di- O-benzyl-5-deoxy-5- C-[( S)-phenylphosphinyl]-β- d-glucopyranose: The first gluco type of hexopyranose derivative having phosphorus in the hemiacetal ring

Oxidation of 3,6-di- O-benzyl-1,2- O-isopropylidene-α- d-glucofuranose with pyridinium chlorochromate in the presence of molecular sieves, followed by conversion into the p-tolylsulfonylhydrazone, addition of methyl phenylphosphinate, and reduction with sodium borohydride, provided the key intermediate, namely, 5( R, S)-3,6-di- O-benzyl-5-deoxy-1,2- O-isopropylidene-5- C-[(methoxy)phenylphosphinyl]-α- d- xylo-hexofuranose, in 23% overall yield. Treatment of this compound with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of mineral acid and acetic anhydride, yielded the crystalline title compound, the structure of which was established on the basis of mass and 400-MHz, 1H-n.m.r. spectra. A general dependence of 2 J PH values on the OPCH dihedral angles effectively served for assigning the configuration of C-1, C-5, and the ring-phosphorus atom of the present product and other such 5- C-phosphinylhexopyranoses.

A phosphorus-31 magnetic resonance study of ligand exchange on Hexakis[methyl methyl(phenyl)phosphinate]yttrium(III) ion and the solution chemistry of related yttrium(III) species

A 31P n.m.r, study shows that the species [YLn3+ where n = 4,5,6 for L = OP(NMe2), or OPPh3 n = 5,6 for L = OPMe(0Me)Ph are the major yttrium(III) species formed with these ligands in CD2CI2 solution. A detailed ligand exchange study of the latter species shows the rate law to be: exchange rate = 6(kl+k2[OPMe(OMe)Ph])[Y(OPMe(OMe)Ph)63+] where k1(215 K) = 312�13 s-1, ΔH1‡ = 3l·4 � 1.4 kJmol-1, ΔS1‡ = -48·4�6.6 J K-1 mol-1, k2(215 K) = 455 � 31 dm3 mol-1 s-1, ΔH2‡ = 35·2�2.8 kJmol-1 and ΔS2‡ = -27·6 � 12·7 JK-1 mol-1, where the k1 and k2 terms are assigned to D and A mechanisms respectively. The rate of OP(OMe)3 and OPMe(OMe)2 exchange on yttrium(III) is found to be in the fast exchange limit of the n.m.r. time scale and thus the coordination numbers of the yttrium(III) species formed with these ligands are not directly determined in solution. Qualitatively it appears that the coordination number and the lability of the yttrium(III) species increases as the size of the ligand decreases. The isolation of the crystalline species [Y(OP(NMe2)3)5ClO4](ClO4)2, [Y(OPPh3)4](ClO4)3, [Y(OPMe(OMe)Ph)6] (ClO4)3, [Y(OP(OMe)3)6](ClO4)3 and [Y(OPMe(OMe)2)6](ClO4)3 is reported.

The structure of methyl (1-hydroxy-1-phenylethyl)phenylphosphinate, the product of sterically controlled Grignard addition to the carbonyl group of an α-ketophosphine oxide

The structure of methyl (1-hydroxy-1-phenylethyl)phenylphosphinate, the product of sterically controlled Grignard addition to the carbonyl group of an α-ketophosphine oxide

Addition reactions of glycosid-4-uloses and related compounds with some phosphorus compounds

Methyl 6-deoxy-2,3- O-isopropylidene-α- l- lyxo-hexopyranosid-4-ulose ( 2) was treated with methyl phenylphosphinate in the presence of triethylamine, to give mainly methyl 6-deoxy-2,3- O-isopropylidene-4- C-[(methoxy)phenylphosphinyl]-α- l-talopyranoside. Treatment of compound 2 with dimethyl and diethyl phosphonate under the same reaction conditions also afforded adducts having the l- talo configuration. The reaction of (6- S)-tetrahydro-6-methoxypyran-3-one with dimethyl phosphonate and methyl phenylphosphinate, respectively, gave the corresponding adducts in good yields. The reaction of methyl 2,3- O-isopropylidene-α,β- l- erythro-pentopyranosid-4-ulose and 2,3,5-tri- O-benzyl- aldehydo- l- threo-pentos-4-ulose 1-(dimethyl acetal) with methyl and phenyl phenylphosphinate also gave the corresponding adducts. These results suggest that the substituents on the sugar skeleton play an important role in the addition of phosphorus compounds.

Spontaneous and induced reactivation of eel acetylcholinesterase inhibited by three organophosphinates

This paper constitutes the first report on the spontaneous reactivation of a cholinesterase following inhibition by an organophosphinate. The spontaneous reactivation of eel acetylcholinesterase following inhibition by p-nitrophenyl diphenylphosphinate (DPP), p-nitrophenyl methyl(phenyl)phosphinate (MPP), and p-nitrophenyl dimethylphosphinate (DMP) at 25.0°C in 0.10 M 3-( N-morpholino)propanesulfonic acid buffer of pH 7.60 reflected the following order of activity: MPP > DPP > DMP. Hydrolysis studies of the phosphinate esters under these conditions exhibited the same order of reactivity. Kinetic studies on the spontaneous reactivation of methyl(phenyl)phosphinylated eel acetylcholinesterase at pH 7.60 and pH 9.10 showed a 100% recovery of enzymatic activity, thus demonstrating the absence of aging. The absence of aging was further supported by oxime-induced reactivation studies.

Reaction of methyl phenylphosphinate with tetracyclone in the presence of bases

In the presence of amines methyl phenylphosphinate reacts to form products only of 1,6 addition to the conjugated system of tetracyclone.

Reaction of tetracyclone with methyl phenylphosphinate in the presence of catalysts

1. Methyl phenylphosphinate reacts with tetracyclone in the absence of catalysts according to a scheme involving 1,4 and 1,6 addition of the conjugated cyclone system to form methyl 2,3,4,5-tetraphenyl-4-cyclopenten-1-one-3-phenylphosphinate and 2,3,4,5 -tetraphenyl-3-cyclopenten-1-one-2-phenylphosphinate, respectively. 2. Upon heating, the 1,6 adduct is prototropically isomerized to form methyl 2,3,4,5-tetraphenyl-4-cyclopenten-1-one-2-phenylphosphinate and simultaneously dissociates back to the original components, which again react to form the thermodynamically more stable 1,4 adduct. 3. Theβ- andγ-conjugated keto phosphinates with a cis configuration of the methylidyne proton and the phosphinate group have been isolated in the form of pairs of diastereomers with respect to the asymmetric phosphorus and carbon atoms.

Organophosphorus intermediates. Part III. The base-catalysed addition of methyl phenylphosphinate, dimethyl phosphonate, and diphenylphosphine oxide to tetraphenylcyclopentadienone

Methyl phenylphosphinate adds to tetraphenylcyclopentadienone (tetracyclone) in the presence of base with initial formation of a stable enolate anion (1), which on protonation gives 1,4-Michael addition products of predominantly cis-geometry. Dimethyl phosphonate behaves similarly but gives, in addition, considerable quantities (35%) of enol phosphates which are believed to arise by attack of the tervalent tautomer of the diester at carbonyl oxygen atom. Diphenylphosphine oxide adds in a 1,6-manner to the ketone in the presence of base.The enolate anions (1) are oxidised by an excess of tetracyclone to a stable radical species.The mechanism of nucleophilic attack on tetracyclone is discussed and the data obtained in this and previous studies in this series are used to assign structures to the complex mixture of products obtained in the reaction of phenylphosphinic acid, phenylphosphonous bismorpholinamide, and tetracyclone.