Synthesis and antiviral activity of adamantyl-containing phosphonous and phosphinic acids

The method of adamantly-containing phosphonous and phosphinic acids preparation, based on radical addition of hypophosphorous acid and sodium hypophosphite to unsaturated derivatives of adamantane, has been developed. Unsymmetrical phosphinic acids have been prepared by reacting bistrimetylsilyl esters of phosphonous acids with halides. The obtained phosphinic acids exhibit antiviral activity against herpes simplex virus, influenza A (H5N1), respiratory syncytial virus, and adenovirus.     

A method of synthesis of phosphinic acids on the basis of hypophosphites: VII. Synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid

A method of synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid from hypophosphites is suggested. Silyl phosphonites formed by in situ addition of bis-(trimethylsilyl) hypophosphite to the corresponding α-substituted acrylates, styrene, or vinyl phosphonate used as unsaturated components in the synthesis react in situ with N-(ω-bromoalkyl)phthalimides by an Arbuzov reaction scheme, affording ω-(phthalimido)alkylphosphinic acids possessing β-substituted β-(alkoxycarbonyl)ethyl, β-phenylethyl, or β-(diethoxyphosphinoyl)ethyl substituents. Acid hydrolysis of these reaction products gives the target aminophosphinic acids: phosphinic analogs of γ-aminobutyric acid.     

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.     

Synthesis of alkyl-H-phosphinic acid alkyl esters from red phosphorus and alkyl bromides

Alkyl-H-phosphinic acid alkyl esters are synthesized in 65–71% yield via chemoselective reaction of alkyl bromides with available alkyl-H-phosphinic acids (60–65 °C, Et3N). The latter are prepared, in turn, by direct phosphorylation of alkyl bromides with red phosphorus under phase-transfer conditions.     

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.     

Decarboxylative Conjunctive Cross‐coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross‐coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross‐coupling cascade of vinyl boronic esters. Excellent functional‐group tolerance is displayed, and application of a range of carboxylic acids, including secondary α‐amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross‐coupling was also applied to the synthesis of sedum alkaloids.     

Preparation of phosphinic acids: Michael additions of phosphonous acids/esters to conjugated systems.

A very mild and facile method for the preparation of phosphinic acids via Michael addition of phosphonous acids as well as esters, through an intermediate silyl alkyl phosphonite, to activated conjugated systems is described.     

Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single‐electron reduction of an α‐boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α‐amino, α‐oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron‐containing molecules of potential biological importance.     

Efficient esterification of carboxylic acids and phosphonic acids with trialkyl orthoacetate in ionic liquid

An operationally simple, inexpensive, efficient, and environmentally friendly esterification of various carboxylic acids, phosphonic acids, and phosphinic acids with triethyl orthoacetate or trimethyl orthoacetate under neutral conditions in a typical room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate, was successfully carried out to provide the corresponding ethyl esters or methyl esters in high yields.     

Method of synthesis of phosphinic acids based on hypophosphites: VIII. Synthesis of α-aminoalkylphenethylphosphinic acids

Development of methodology of double Arbuzov rearrangement based on hypophosphites allows a one-pot formation of two unsymmetrical phosphorus-carbon bonds by the Michael-Pudovik type reaction of stepwise addition of the intermediately forming silyl esters of trivalent phosphorus to different unsaturated compounds. A procedure was developed of the synthesis of α-aminoalkylphenethylphosphinic acids. Bis-(trimethylsilyl)phenethylphosphonite formed as a result of the addition of bis(trimethylsilyl)hypophosphite to styrene in situ was added without isolation from the reaction mixture to Schiff bases obtained preliminary from benzylamine or diphenylmethylamine and various aldehydes. The subsequent removal of N-protecting groups by hydrogenation or acidic hydrolysis gave a number of new α-aminoalkylphenethylphosphinic acids.     

A mild, one-pot preparation of 1,3,4-oxadiazoles

A mild and efficient one-pot protocol for the synthesis of 1,3,4-oxadiazoles from carboxylic acids and acylhydrazides was developed. Diacylhydrazide formation via HATU coupling followed by addition of Burgess reagent afforded the corresponding 1,3,4-oxadiazoles in 63-96% yields at room temperature. The reaction conditions are tolerant of a variety of functional groups, including esters, nitriles, alkynes, olefins, alkyl halides, phenols, carbamates and sulfonamides.     

Visible-light-driven external-photocatalyst-free alkylative carboxylation of alkenes with CO_2

Herein, we report a novel protocol for visible-light-driven alkylative carboxylation of alkenes with CO_2 in the absence of external photocatalyst. Under the irradiation of visible light, a variety of 4-alkyl-1,4-dihydropyridines(alkyl-DHPs) serve as not only alkyl radical precursors but also photoexcited reductants probably with the potential to reduce benzyl radicals. Several styrenes and acrylates are applicable in this reaction to give structurally diverse carboxylic acids in good to excellent yields. These reactions feature mild reaction conditions(1 atm of CO_2, room temperature, visible light, photocatalyst-and transition metalfree), good functional group tolerance, easy scalability, as well as high regio-, and chemo-selectivity. Mechanistic investigations provide evidence that alkyl radical, benzyl radical and carbanion might be involved in this reaction, providing a novel strategy for CO_2 utilization.     

A novel synthesis of bis-(α-hydroxyalkyl)phosphinic acids involving microwave irradiation

A simple, efficient, and general method has been developed for the synthesis of bis-(α-hydroxyalkyl)phosphinic acids from hypophosphorous acid using microwave irradiation. Bis-(α-hydroxyalkyl)phosphinic acids were obtained in high yield under mild conditions by reaction of hypophosphorous acid with aldehydes under microwave irradiation.     

Photoinitiated free radical carbonylation enhanced by photosensitizers

[reaction: see text] The enhancing effect of several photosensitizers in photoinitiated radical carbonylation is demonstrated and applied to accelerate the synthesis of compounds labeled with short-lived 11C. With the sensitizers, the synthesis of [carbonyl-11C]esters and acids from alkyl iodides, [11C]carbon monoxide, alcohols, and water provided up to 75-85% decay-corrected radiochemical yields in 6-min reactions under mild conditions. Acetone was used as a sensitizer in preparing 13C-substituted 1,10-decanedicarboxylic acid from (13C)carbon monoxide.     

Über eine Reaktion von o-Hydroxybenzylalkoholen mit Estern von Säuren des Phosphors mit der Koordinationszahl 3

Abstract

o-Hydroxybenzyl alcohol reacts with trimethyl phosphite under smooth conditions to o-hydroxyphenylmethane phosphonic acid dimethyl ester. This unusual reaction is of widest applicability. Derivatives of o-hydroxybenzyl alcohol independent of type, number or position of substituents in the ring, react with alkyl esters of phosphorous, phosphonous or phosphinous acids in an analogous process, forming the corresponding o-hydroxyphenylmethane phosphonic or phosphinic esters or phosphine oxides.     

Kinetics of the hydrolysis of ethers of bis(chloromethyl)phosphinic acid

Conclusions A study was made of the hydrolysis kinetics of some esters of bis(chloromethyl)phosphinic acid in water at 75–95°. The reaction rate depends on the nature of the alcohol radical, and for the alkyl radicals is determined by the steric factor.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 1654–1655, September, 1966.     

Phosphorus Analogues of Homoproline

Abstract

Aminophosphonic and aminophosphinic acid analogs of most of the natural amino acids have been synthesized recently (1). We describe here the synthesis of phosphonic and phosphinic analogs of the natural iminocarboxylic acid homoproline. The compounds were obtained by the iminoalkylation of P(O)H-containing organophosphorus compounds with the trimer of tetrahydropyridine. This trimer adds three equivalents of dialkyl phosphite or monoalkyl alkyl(ary1) phosphonite to form the esters of piperidine-2-phosphonic or piperidine-2-alkyl (ary1)phosphinic acids. Hydrolysis of the esters in acidic medium leads to the phosphorus analogs of homoproline.     

Kinetics and mechanism of the hydrolysis of esters of hydroxymethylphosphonic and hydroxymethylethylphosphinic acids

Conclusions The reactivity of ethyl esters of phosphonic and phosphinic acids containing a hydroxymethyl group at the phosphorus atom in their reaction with hydroxide anion is usually high as a consequence of intramolecular catalysis of the cleavage of the ester bond involving the ionized OH group. The spontaneous hydrolysis of these esters proceeds according to a mechanism analogous to that for other alkyl esters of tetracoordinated phosphorus acids.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2139–2140, September, 1985.     

Progress towards metal-free radical alkylations of quinones under mild conditions

A new method for the radical alkylation of quinones is reported. Lewis basic nitrogen additives increase the efficacy of quinone alkylations from carboxylic acids using catalytic AgNO₃ and Selectfluor as a mild oxidant. Electrochemical data suggests that certain Lewis basic additives are capable of directly reducing Selectfluor through a single-electron transfer, presumably via a charge-transfer complex. This process yields intermediates capable of promoting oxidative decarboxylation of alkyl carboxylic acids without an added metal initiator. Using this strategy, we have demonstrated progress towards a metal-free C–H quinone alkylation reaction that proceeds at room temperature under mild conditions.     

Asymmetric synthesis of alpha-amino acids based on carbon radical addition to glyoxylic oxime ether

The first asymmetric synthesis of alpha-amino acids based on diastereoselective carbon radical addition to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from i-PrI, Bu(3)SnH, and Et(3)B in CH(2)Cl(2) at 25 degrees C, to achiral glyoxylic oxime ether 1 proceeded regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 degrees C, in contrast to the unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxiliary. The stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at -78 degrees C afforded a 96:4 diastereomeric mixture, 7a, of the C-isopropylated product. The reductive removal of the benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO)(6) and the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural alpha-amino acids. Even in the absence of Bu(3)SnH, treatment of 6 with alkyl iodide and Et(3)B at 20 degrees C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et(2)Zn as a radical initiator, instead of Et(3)B, was also effective for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2, 2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr(2) gave excellent chemical yield of the valine derivative 2 in 52% ee.