Compound IIIa Research Articles

Brain permeable curcumin-based pyrazoline analogs: MAO inhibitory and antioxidant activity

In continuation of our past efforts developing curcumin-based pyrazoline analogs for human monoamine oxidase (hMAO) inhibitory activity, we report a new series of pyrazoline derivatives with the chloro group (electron-withdrawing) located on the 5-phenyl ring replaced with a bioisostere methyl group (electron-donating). All the synthesized compounds (II, IIIa–IIId) were tested for hMAO inhibitory activity. Compounds IIIa–IIId were found to be potent and selective inhibitors of hMAO-A. Surprisingly, compound II exhibited a greater change in selectivity from hMAO-A (6550.00±74.80 µM) to hMAO-B (1098.50±36.70 µM) as compared to its chloro counterpart. Among all methyl-substituted derivates, compound IIIa was found potent and selective towards hMAO-A: IC50=48.00 ±2.41 µM; hMAO-B: IC50= >20000.00 µM). The molecular-level interaction between compounds II and IIIa and the hMAO isoforms that contributed to potency was observed in terms of the ability to form an “aromatic cage”. However, selectivity was investigated using molecular docking and molecular dynamics (MD) simulations, where the binding free energy indicates that the R isoform of compound IIIa has ∼ 5 kcal/mol of stronger affinity towards hMAO system in comparison to the S isoform. The brain permeability [Pe (x10−6 cm s−1): 15.22±0.34] and powerful antioxidant property (DPPH: IC50= 7.36±0.56 µM; H2O2: IC50= 8.13±0.40 µM) of compound (IIIa) might be useful in neutralizing the free radical generated during oxidative deamination of neurotransmitters and dietary amines, which may help treat depressive illness and neurodegenerative disorders without toxicity.

WITHDRAWN: Design, molecular docking, synthesis and evaluation of new 5-aminoisatin derivatives as tyrosine kinase inhibitors

Abstract Two series of compounds derived from 5-aminoisatin were synthesized, Schiff bases IIa-c and ureido derivatives of 5-aminoisatin Schiff bases IIIa-c& IVa-c. The proposed compounds were successfully synthesized and purified; they were characterized and identified using: melting point, IR spectroscopy, 1H NMR and13C-NMR; The in vitro cytotoxic activity of these novel compounds was tested and molecular docking-based in silico tyrosine kinase selectivity via GOLD Suite (v.5.7.1); Our docking results and the experimental data (In vitro study) are in good accord since the compound IIIa shows the highest docking result and at the same time showing a promising cytotoxic activity among the tested compounds when tested against (A549) cancer cell lines by the MTT assay in comparison with erlotinib. Additionally, ADME studies were conducted to determine which of them are candidates for oral administration, as well as their absorption location, bioavailability, topological polar surface area, and drug-likeness.

Design, synthesis, antiproliferative activity, and cell cycle analysis of new thiosemicarbazone derivatives targeting ribonucleotide reductase

Thiosemicarbazones are potential anticancer agents. In this study, we designed and synthesized new thiosemicarbazone derivatives as anticancer agents. The antiproliferative activity of compounds (IIIa, IIIb, IIIe, IIIh, and IIIi) selected by The National Cancer Institute (USA) was investigated in vitro in 60 cancer cell lines. The initial results of the screening of these compounds revealed encouraging anticancer activity. The enzyme inhibitory activity of the compounds against ribonucleotide reductase was then evaluated. It was found that compounds IIIa, IIIe, and IIIh show the most potent inhibitory activity with IC50 (1.51, 2.41, and 2.85 μM, respectively). Flow cytometric analysis showed that compound IIIa induced apoptosis and cell cycle arrest in the G2/M phase. Additionally, according to the gene expression report, compound IIIa upregulated p53, BAX, and caspase-3 expression and down regulated Bcl-2 expression. Thus, IIIa exerted potent inhibitory activity against RNR and a strong pro-apoptotic effect by activating the intrinsic apoptotic pathway.

Synthesis and evaluation of novel pyrimidyl thio methyl and pyrimidyl sulfinyl methyl benzimidazoles derivatives for their antiulcer activity

A series of novel pyrimidylthiomethyl benzimidazole ( IIa-c) and pyrimidylsulfinylmethyl benzimidazolles (III a-c ) have been synthesized and evaluated for their antiulcer activity, by the pylorus ligation of rats ( say method ). Compound IIa and IIIa when evaluated significantly decreased the gastric acid secretion, free acidity, as well as gastric ulcer in the pylorus ligated rats and the effects are dose dependent and comparable to omeprazole of the two compounds, the sulfinyl derivative IIIa is more effective then the thio analog IIa.

Docking, Screening, Synthesis of 4-hydroxy-6-methyl-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity

Auroneis a bicyclic ring where a benzene ring fused with a furanone. Docking is an efficient tool in the development of new lead molecules. Docking, virtual screening, ADMET prediction are prominent devices in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compound IIIA was found to be with potent activity.

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.

Effective method of β-keto sulfones synthesis

β-Keto sulfones are widely used in organic synthesis as reagents in Michael and Knoevenagel reactions [1–3], for preparation of vinyl sulfones [4], polyfunctional 4Н-pyrans [3], chalcones, alkynes, allenes, and compounds of other classes [1,5–9]. In this connection various approaches are developed to the synthesis of β-keto sulfones [10–18], but many among them require severe conditions, preparation of initial compounds, and the yields of products in these reactions are often low. Looking for an effi cient and cheap method of β-keto sulfones synthesis aiming at their application as methylene-active reagents in the preparation of 1,2,3-triazoles [19] we developed a procedure for the synthesis of β-keto sulfones with the use of available thiols I and β-haloketones II. The reaction of thiophenol (Ia) and 4-methylthiophenol (Ib) with β-haloketones IIа–IIh afforded β-keto sulfi des IIIа–IIIh. The oxidation of these compounds with hydrogen peroxide in acetic acid [20] did not result in selective formation of sulfones V, but gave a mixture of reaction products. This result may be ascribed to the concurrent reaction of the keto group oxidation analogously to Baeyer-Villiger reaction. For instance, the oxidation of compound IIIa with hydrogen peroxide in acetic acid at room temperature led to the formation of a mixture of β-keto sulfone Va and methylsulfonylbenzene in a ratio 2 : 1 [21]. Keto sulfi des may be oxidized with potassium permanganate [22], but at the oxidation β-keto sulfi des III in this way sulfones V formed in low yields. Considering these results we protected the keto group in compounds IIIа–IIIh by converting them in 1,3-dioxolanes IVа–IVh. At the oxidation of compounds IVа–IVh with hydrogen peroxide in acetic acid followed by treating the reaction mixture with water the target β-keto sulfones Vа–Vh formed in high yields (see the table).

An ecofriendly synthesis and DNA binding interaction study of some pyrazolo [1,5-a]pyrimidines derivatives

The DNA molecule is a target for plethora of anticancer and antiviral drugs that forms covalent and non-covalent adducts with major or minor groove of DNA. In present study we synthesized series of novel Pyrazolo [1,5-a]pyrimidine derivatives. The newly synthesized compounds were characterized by elemental analysis, IR, 1H NMR, and mass spectral data. The selected compounds were studied for interaction with Calf thymus DNA (CT-DNA) using electronic spectra, viscosity measurement and thermal denaturation studies. Further, molecular interactions were revealed for compound IIIa and IVa by computational methodologies. The preferred mode of ligand binding with double helical DNA as well as preferable DNA groove were explored by molecular docking in different DNA models.

Antimicrobial evaluation of some Mannich bases of acetophenones and representative quaternary derivatives.

1-Aryl-3-dimethylamino-1-propanone hydrochlorides Ia-f (series I) as mono-Mannich bases bis(beta-aroylethyl)ethylamine hydrochlorides IIa, IIb, IId, IIe (series II) as bis-Mannich bases, 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (structural isomer of bis derivatives IIIa-e, series III), and some of their representative quaternary salts (Ig, IIIf, IIIg) were synthesized. Antimicrobial activities of the compounds were evaluated against some bacteria and fungi. Series I and III showed antimicrobial activity against gram positive bacteria. All series demonstrated activity against fungi, however, they generally did not affect gram negative bacteria at the concentration range tested (2-64 micrograms/ml). Quaternisation procedure improved the bioactivity in compound IIIa for antibacterial activity and in compounds IIIa and IIIb for antifungal activity against Trichophyton rubrum and Mycosporium canis. There was no relationship between Hammett values of the aryl substituents and bioactivities in series III. The mono-Mannich bases of series I had better antimicrobial activities than bis-Mannich bases of series II. Compounds Ia, If, IIId had equal and compounds If and IIIf had higher antibacterial activities compared to the reference drug, streptomycin (CAS 57-92-1), against various gram positive bacteria. On the other hand, compounds Ia, IIIa, IIIc, IIIe, IIIf, and IIIg had equal and If, IIId, IIIf, IIIg had higher antifungal activity compared to the reference drug, amphotericin-B (CAS 1397-89-3), against various fungi. To conclude, the compounds of series III, having both marked antifungal and antibacterial activities, may serve as candidate compounds for further studies. Especially compound IIIf may serve as a model compound to develop new agents against dermatophytes.

Synthesis and antimicrobial activity of novel oxime derivatives of phenothiazine

A series of 4-methyl-2-oxo-pyranyl-phenothiazines ( IIIa - j ) followed by 4-methylpyrano-(2, 3-β)-phenothiazine-2(11 H )-one oxime ( IVa - j ) were synthesized by using 7-hydroxy-4-methylcoumarin ( I ). Further reaction of ( I ) was carried out with substituted aromatic amines ( a - j ) to convert into 7-arylamino-4-methyl-coumarin ( IIa - j ). Additionally ( IIa - j ) was treated with sulphur in presence of iodine to obtain a series of novel 4-methyl-2-oxo-pyranyl-phenothiazine ( IIIa - j ) derivatives, which on treatment with hydroxylamine hydrochloride afforded the title compounds i.e. 4-methylpyrano-(2,3-β)-phenothiazine-2(11 H )-one oxime ( IVa - j ). The structures of these compounds were confirmed by IR, NMR and Mass spectral analysis. The newly synthesized compounds were evaluated for antibacterial and antifungal activity. The results show that compound IIIa , IIIe , IIIh , IIIj, IVa , IVi and IVj exhibited moderate to good antibacterial and antifungal activity at 5-100 mcg/mL.

Synthesis of new heterocyclic enamines and their cyclization with oxalyl chloride

Substituted furan-2,3-diones are convenient synthons exhibiting high reactivity and unusual chemical behavior toward various reagents [1, 2]. Heterocyclic ensembles derived from these compounds were found to possess versatile biological activity [3]. Functionally substituted furan-2,3-diones can be synthesized by reaction of heterocyclic β-enaminoketones with oxalyl chloride [4–6]. By reaction of diaroylacetylenes Ia and Ib with biphenyl-3,3′,4,4′-tetraamine (II) according to the procedure described in [7] we obtained new heterocyclic enamines, 2,2′-(3,3′-diaryl-1,1′,2,2′-tetrahydro-6,6′-biquinoxaline-2,2′-diylidene)bis(1-arylethanones) IIIa and IIIb (Scheme 1). Heating of compounds IIIa and IIIb with oxalyl chloride in boiling anhydrous chloroform led to the formation of new representatives of the furan-2,3-dione series, 4,4′-(3,3′-diaryl-6,6′-biquinoxaline-2,2′-diyl)bis(5-aryl-2,3-dihydrofuran-2,3-diones) IVa and IVb (Scheme 2). Presumably, bis-furandiones IVa and IVb are formed via initial acylation of compounds IIIa and IIIb with oxalyl chloride at the exocyclic =CH fragments to give intermediate acyl chlorides [8] which are converted into hydroxyenimine structure with subsequent intramolecular cyclization. 2,2′-(3,3′-Diphenyl-1,1′,2,2′-tetrahydro-6,6′-biquinoxaline-2,2′-diylidene)bis(1-phenylethanone) (IIIa). A solution of 4.68 g (20 mmol) of compound Ia in 10 ml of acetonitrile was added to a solution of 2.14 g (10 mmol) of tetraamine II in 20 ml of acetonitrile, and the mixture was heated to the boiling point and cooled. The precipitate was filtered off and recrystallized from acetonitrile. Yield 5.75 g (89%), orange– red crystals, mp 252–254°C (from acetone). IR spectrum, ν, cm: 3034 br (NH), 1580 br (C=O). H NMR spectrum, δ, ppm: 6.29 s (2H, CH), 6.93–7.90 m (26H, Harom), 15.70 s (2H, NH). Found, %: C 81.74; H 4.60; N 8.67. C44H30N4O2. Calculated, %: C 81.71; H 4.68; N 8.66. 2,2′-[3,3′-Bis(4-methylphenyl)-1,1′,2,2′-tetrahydro-6,6′-biquinoxaline-2,2′-diylidene]bis[1-(4-methylphenyl)ethanone] (IIIb) was synthesized in a similar way. Yield 5.98 g (85%), orange–red crystals, mp 223–225°C (from acetone). IR spectrum, ν, cm: 3024 br (NH), 1586 br (C=O). H NMR spectrum, δ, ppm: 2.34 s (6H, Me), 2.50 s (6H, Me), 6.35 s (2H, CH), 6.90–7.92 m (22H, Harom), 15.76 s (2H, NH). Found, %: C 82.09; H 5.43; N 7.95. C48H38N4O2. Calculated, %: C 82.03; H 5.45; N 7.97. 4,4′-(3,3′-Diphenyl-6,6′-biquinoxaline-2,2′-diyl)bis(5-phenyl-2,3-dihydrofuran-2,3-dione) (IVa). Oxalyl chloride, 2.52 g (20 mmol), was added to a solution of 6.47 g (10 mmol) of compound IIIa in 40 ml of anhydrous chloroform. The mixture was heated for

ChemInform Abstract: New Tetracyclic Guanidine Derivatives with H1-Antihistaminic Properties. Chemistry of Epinastine.

A series of new tetracyclic guanidines were synthesized by various methods. Specific binding of the described compounds to histamine-1 and histamine-2 receptors was determined. The compound 3-amino-9,13b-dihydro-1H-dibenz[c,flimidazo[1,5-a]azepine (epinastine, WAL 801, compound IIIa) combines high selectivity with high affinity for the H1 receptor and was selected from the compounds studied for further pharmacological and clinical investigations. Experimentally determined physicochemical parameters (pka-value, partition coefficient) and the hydrogen-bonding ability of epinastine are indications that this compound will not easily cross the blood-brain barrier. This explains the absence of CNS side-effects of epinastine in pharmacological and clinical studies.

Reaction of salicylalkylenediimines with 2-chloro-4,5-diphenyl-1,3,2-dioxaphospholene

The structure of compounds IIIa–IIIc was proved by the IR, Н, and Р NMR spectroscopy, mass spectrometry, and composition, by the elemental analysis data. The IR spectra of the products IIIa–IIIc contain absorption bands at 1623–1627 (С=N) and 2590–2724 cm (broadened complex band, NH2). The chemical shift of the phosphorus atom at δP from –114 to –122 ppm is characteristic of the hexacoordinated phosphorus derivatives. Notice that the P NMR spectra of the reaction mixtures of IIIa–IIIc contain signals indicative of the formation of diastereoisomers mixture. As a result of fractional crystallization compound IIIa was obtained as the two diastereoisomers mixture in the ratio 1:1. Compounds IIIb and IIIc were isolated as individual diastereomers. Due to their salt structure the Н NMR spectra of compounds IIIa– IIIc contain poorly resolved signals, therefore only group analysis of the proton signals was performed on the basis of chemical shifts without considering the fine structure of the spectra. The transannular N→P bond (2.006–2.007 A) is realized in the compounds IIIa–IIIc. The intermolecular bonding of similar type was earlier observed in the series of pentacoordinated phosphorus derivatives [1–5]. On treating with triethylamine, the product IIIa undergoes dehydrochlorination to give phosphorate IVa of neutral structure (δР –105.87 ppm).

Synthesis and mesomorphic properties of oxadiazole esters derived from (R)‐2‐octanol, (S)‐2‐n‐octyloxypropanol and (2S,3S)‐2‐chloro‐3‐methylpentanol

A novel series of chiral liquid crystalline materials based on 1,3,4‐ and 1,2,4‐oxadiazole derivatives were synthesised. These compounds contain a chiral chain derived from (R)‐2‐octanol (Ia–Ic), (S)‐ethyl lactate (IIa–IIc) or (S)‐isoleucine (IIIa–IIIc). Their liquid crystalline properties were studied by polarizing optical microscopy and differential scanning calorimetry. With the exception of compounds IIa and IIb, all of the new compounds exhibit an enantiotropic chiral nematic (cholesteric) phase. A monotropic chiral smectic C phase (ferroelectric) was also found in compounds Ia, IIa and IIb, whereas in compound IIIa an enantiotropic chiral smectic C phase was observed. Compounds Ic, IIc, IIIb and IIIc are purely chiral nematic (cholesteric) in character. In addition, a monotropic blue phase was observed in compounds Ib and IIIa.

Synthesis and characterization of diorganotin(IV) complexes of Schiff bases with ONO‐type donors and crystal structure of [N‐(2‐hydroxy‐4‐nitrophenyl)‐3‐ethoxysalicylideneiminato]diphenyltin(IV)

AbstractA series of neutral complexes, namely, [N‐(2‐hydroxy‐4‐nitrophenyl)‐3‐hydroxysalicylideneiminato]‐ diphenyltin(IV) (Ia), [N‐(2‐hydroxy‐4‐nitrophenyl)‐3‐methoxysalicylideneiminato]diphenyltin(IV) (IIa) and [N‐(2‐hydroxy‐4‐nitrophenyl)‐3‐ethoxysalicylideneiminato]diphenyltin(IV) (IIIa) were prepared by the reaction of diphenyltin dichloride on the corresponding Schiff bases. The Schiff bases were the reaction products of 2‐hydroxy‐4‐nitroaniline and appropriate salicylaldehydes. All the compounds were characterized by elemental analysis, 1H‐NMR, 13C‐NMR, IR and mass spectroscopy. Compound IIIa was also characterized by single crystal X‐ray diffraction and shows a C2NO2 coordination geometry nearly half‐way between a trigonal bipyramidal and square pyramidal arrangement. In the solid state, π− π interactions exist between the aniline fragments of neighbouring molecules. Copyright © 2007 John Wiley & Sons, Ltd.

Synthesis and crystal structure determination of 6,7‐dihydro‐2‐methoxy‐4‐(substituted)‐5H ‐benzo[6,7]cyclohepta[1,2‐b ]pyridine‐3‐carbonitrile

AbstractThe compounds 6,7‐dihydro‐2‐methoxy‐4‐(4‐methylphenyl)‐5H ‐benzo[6.7]cyclohepta[1,2‐b ]pyridine‐3‐carbonitrile (compound IIIa) and 4‐(4‐chlorophenyl)‐6,7‐dihydro‐2‐methoxy‐5H ‐benzo[6,7]cyclohepta[1,2‐b ]pyridine‐3‐carbonitrile (compound IIIb) were synthesized and their structures have been determined from three dimensional X‐ray data using direct method and refined by full matrix least squares with anisotropic thermal parameters for non‐hydrogen atoms to conventional R(gt) of 0.036 and 0.038 for the two compounds respectively. For compound (IIIa) the crystals are monoclinic, space group Cc, with a=11.2909 (5) Å, b=17.7755(8) Å, c=9.1437(4) Å and β=95.428(3)°, while the crystals of the second compound (IIIb) are triclinic, space group P1, with a=8.7465(3)Å, b=10.3958(3)Å, c=10.9011(4)Å, α= 108.3870(10)°, β=101.3741(12)°, γ=97.9594(12)°. The molecular structure of the two compounds have nearly the same configuration, where the cyclohepta ring takes the boat shape and the methoxy and the carbonitrile groups are attached at the same position C2 and C8. The difference occurs only at the position C4, where the substituent is methylphenyl for compound (IIIa) and chlorophenyl for the other. The bond lengths, valency angles and the hydrogen bonding were calculated and fully discussed. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Synthesis of 2-substituted methylthieno [2,3-<i> d</i>]pyrimidin-4(3<i> h</i>)-ones and evaluation for antihyperlipidemic activity

A series of nicotinyl 4-oxathieno[2,3- d ]pyridine-2-ylmethyl esters, title compounds were synthesized. Compound IIIa was subjected to in vivo antihyperlipidemic activity in Wistar rats. The activity exhibited by synthesized compound was found to be less as compared to that produced by a standard, atorvastatin, administered in the form of suspension in 2% gum acacia. The activity was even lesser than that produced by the lead IIa.

Antimicrobial Evaluation of Some Mannich Bases of Acetophenones and Representative Quaternary Derivatives.

1-Aryl-3-dimethylamino-1-propanone hydrochlorides Ia-f (series I) as mono-Mannich bases bis (β-aroylethyl) ethylamine hydrochlorides IIa, IIb, IId, IIe (series II) as bis-Mannich bases, 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (structural isomer of bis derivatives IIIa-e, series III), and some of their representative quaternary salts (Ig, IIIf, IIIg) were synthesized. Antimicrobial activities of the compounds were evaluated against some bacteria and fungi. Series I and III showed antimicrobial activity against gram positive bacteria. All series demonstrated activity against fungi, however, they generally did not affect gram negative bacteria at the concentration range tested (2–64 µg/ml). Quaternisation procedure improved the bioactivity in compound IIIa for antibacterial activity and in compounds IIIa and IIIb for antifungal activity against Trichophyton rubrum and Mycosporium canis. There was no relationship between Hammett values of the aryl substituents and bioactivities in series III. The mono-Mannich bases of series I had better antimicrobial activities than bis-Mannich bases of series II. Compounds Ia, If, IIId had equal and compounds If and IIIf had higher antibacterial activities compared to the reference drug, streptomycin (CAS 57-92-1), against various gram positive bacteria. On the other hand, compounds Ia, IIIa, IIIc, IIIe, IIIf, and IIIg had equal and If, IIId, IIIf, IIIg had higher antifungal activity compared to the reference drug, amphotericin-B (CAS 1397-89-3), against various fungi. To conclude, the compounds of series III, having both marked antifungal and antibacterial activities, may serve as candidate compounds for further studies. Especially compound IIIf may serve as a model compound to develop new agents against dermatophytes.

Palladium Coordination Compounds of σ3λ5-Phosphoranes: First Examples of Phosphonio−Methylene(imino)metallophosphorane [(R3P)(Me3Si)CP(MLn)NSiMe3] and Phosphonio−Methylene(oxo)phosphorane [(R3P)(Me3Si)CP(O)NSiMe3] Ligands

The oxidative addition reaction of Pd(PPh3)4 with Cl2CPN(SiMe3)2 forms the phosphavinyl phosphonium complex Cl(Ph3P)Pd[η2-C(Cl)(PPh3)PN(SiMe3)2] (IIIa), which results from PPh3 migration from Pd to carbon in the η1-phosphavinyl intermediate trans-Cl(Ph3P)2Pd[C(Cl)PN(SiMe3)2] (IIa). The reaction of Pd(dba)(dppe) with Cl2CPN(SiMe3)2 forms the η1-phosphavinyl complex cis-Cl(dppe)Pd[C(Cl)PN(SiMe3)2] (VI), which does not undergo phosphine migration. Compound IIIa undergoes substitution of the chloride ligand by PPh3 or MeCN in the presence of KPF6 to generate [(Ph3P)2Pd(η2-C(Cl)(PPh3)PN(SiMe3)2)](PF6) (IV) or [(Ph3P)(MeCN)Pd(η2-C(Cl)(PPh3)PN(SiMe3)2)](PF6) (V), respectively; the structure of V was determined by X-ray diffraction studies. The reaction of Pd(PEt3)4 with Cl2CPN(SiMe3)2 forms the η1-phosphavinyl complex trans-Cl(Et3P)2Pd[C(Cl)PN(SiMe3)2] (IIb), which does not undergo PEt3 migration. When 2 equiv of Pd(PEt3)4 are reacted with Cl2CPN(SiMe3)2 the phosphonio−methylene(imino)metallophosphorane complex ...

Preparation of Phosphonomethyl Ethers Derived from 2-Phenylethanol and Its Amino Derivatives

A series of compounds derived from the acyclic nucleoside antiviral 9-(2-phosphonomethoxyethyl)adenine (PMEA), in which the adenine ring is replaced by phenyl, 4-aminophenyl, 3-aminophenyl or 3,5-diaminophenyl group, has been prepared starting from the corresponding phenethyl alcohols. 2-(3-Aminophenyl)ethanol was prepared from 3-nitrobenzoyl chloride using the Arndt-Eistert reaction. The primarily formed diazoketone Ia was converted into ethyl 3-nitrophenylacetate (IIa) which on catalytic hydrogenation afforded ethyl 3-aminophenylacetate (IIIa). Compound IIIa was reduced with lithium aluminium hydride to give 2-(3-aminophenyl)ethanol (IVa). 2-(3,5-Diaminophenyl)ethanol (IVb) was prepared analogously from 3,5-dinitrobenzoyl chloride. After protection of the amino group with dimethylaminomethylene group, the alcohol IVa was converted to diisopropyl 2-(3-aminophenyl)ethoxymethylphosphonate (XII) by reaction with sodium hydride and diisopropyl p-toluenesulfonyloxymethanephosphonate, followed by deprotection of the amino group by treatment with ammonia. Reaction of diisopropyl ester XII with bromotrimethylsilane gave free 2-(3-aminophenyl)ethoxymethylphosphonic acid (XVII). The same procedure, applied to the corresponding aminophenethyl alcohols, afforded: 2-(4-aminophenyl)ethoxymethylphosphonic acid (XVI) and 2-(3,5-diamino phenyl)ethoxymethylphosphonic acid (XVIII). The synthesized compounds were tested in vitro on cell cultures for the cytostatic and antiviral activity (HSV-1, HSV-2, VSV, VZV, CMV). No antiviral activity has been found for any of the compounds.