Ethoxymethyl Group Research Articles

Synthesis and structures of EOM-protected 2,6-bis(diphenylphosphino)-4-methylphenol and its deprotected P-chalcogenides, 2,6-bis(Ph2P = E)-4-methylphenols (E = O, S, Se)

Ethoxymethyl (EOM) group was used to protect the phenol functionality on 2,6-dibromo-4-methylphenol. Subjecting the protected phenol to n-butyllithium followed by reaction with chlorodiphenylphosphine produced 2,6-bis(diphenylphosphino)-4-methyl-ethoxymethylphenol (1). Reactions of 1 with H2O2, S8 and Se (grey) followed by treatment with HCl led to isolation of 2,6-bis(diphenylphosphinyl)-4-methylphenol (3a), 2,6-bis(diphenylphosphinothioyl)-4-methylphenol (3b), and 2,6-bis(diphenylphosphinoselenoyl)-4-methylphenol (3c). Compounds 1 and 3a–b were fully characterized by multinuclear NMR and high-resolution mass spectrometry. In addition, compounds 1, 3a·(HOO)2C(CH3)2, 3b, and 3c were characterized by single crystal X-ray diffraction experiments.

Decarboxylative arylation of substituted pyrroles N-protected with 2-(trimethylsilyl)ethoxymethyl (SEM)

Palladium-catalyzed decarboxylative arylation is reported using pyrroles N-protected with the 2-(trimethylsilyl)ethoxymethyl (SEM) group and featuring 2-, 3-, and 4-substituents about the pyrrolic framework. In contrast to N-protected pyrroles previously used in decarboxylative arylation, the use of SEM allows deprotection under mild conditions.

Tale of Two Protecting Groups—Boc vs SEM—for Directed Lithiation and C–C Bond Formation on a Pyrrolopyridazinone Core

The importance of the “SEM” group, or the 2-(trimethylsilyl)ethoxymethyl group, as an N-protecting group for special class of pyrrolopyridazinones is reported. Our studies indicate that standard Boc protection on the nitrogen of a pyrrolopyridazinone results in significant decomposition during the incorporation of biaryl groups via Pd-catalyzed cross coupling reactions. However, on using the SEM group, the resulting cross coupling reaction gives excellent yields with no decomposition products, enabling the synthesis of a variety of compounds that were targeted for their antitumor activity.

The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores.

Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a (19)F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to (13)C{(19)F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.

Self-assembly of coil-rod-coil triblock copolymers depending on lateral methyl groups at the interface of rod and coil segments

Triblock coil-rod-coil compounds, consisting of four biphenyls and a p-terphenyl unit linked together with ether bonds as a rod segment, incorporating lateral methyl or ethoxymethyl groups at 2 and 5 positions of the benzene ring of p-terphenyl and poly(ethylene oxide) (PEO) with a degree of polymerization of 7, 12, 17, incorporating lateral methyl groups between the rod and coil segment as the coil segments, were synthesized. The compound structures were characterized with 1H NMR and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectroscopy. The self-assembling behavior of the compounds is investigated by means of differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS), and optical polarized micrograph (POM) in the bulk state. These compounds spontaneously self-assemble into lamellar, hexagonal perforated lamellar, rectangular columnar, and oblique columnar structures in the crystalline phase, and hexagonal perforated lamellar, bicontinuous cubic, and oblique columnar structures in the liquid crystalline phase, respectively. The results revealed that the lateral methyl groups attached to the interface of rod and coil segments strongly induce the compounds to self-assemble into various supramolecular nanostructures in the crystalline phase and the liquid crystalline mesophase.

Design, synthesis, and biological evaluation of 2-benzylpyrroles and 2-benzoylpyrroles based on structures of insecticidal chlorfenapyr and natural pyrrolomycins

Based on structures of insecticidal chlorfenapyr and antibiotic natural pyrrolomycins, a series of new 2-benzylpyrroles and 2-benzoylpyrroles (with or without ethoxymethyl group on the nitrogen of pyrrole) were designed and synthesized. These compounds or their parent compounds possess weak acidity and high lipophilicity, the two characteristic properties for uncouplers of oxidative phosphorylation; therefore, they are expected to have insecticidal and acaricidal activity. The bioassay result verified that both 2-benzylpyrroles 17 and 2-benzoylpyrroles 19 had varied degrees of insecticidal activity against oriental armyworm depending on the substituents on the benzene ring, but they did not give any acaricidal activity. Conversely, most N-alkylated compounds 18 and 20 exhibited both insecticidal activity and acaricidal activity, of which compound 18i [4-bromo-2-(2,4-dichlorobenzyl)-1-(ethoxymethyl) -5-(trifluoromethyl) -1H-pyrrole-3-carbonitrile] has IC50 as low as 10-20 mg L(-1) on both activities.

Self-assembly of rod-coil molecules into lateral chain-length-dependent supramolecular organization

In this article, we report synthesis and characterization of the self-assembly behavior of coil- rod-coil molecules, consisting of four biphenyls and a p-terphenyl unit linked together with ether bonds as a rod segment. These molecules contain lateral methyl or ethoxymethyl groups at 2 and 5 positions of the middle benzene ring of p-terphenyl. The self-assembling behavior of these materials was investigated by means of DSC, POM, and SAXS in the bulk state. The results reveal that self-assembling behavior of these molecules is dramatically influenced by a lateral methyl or ethoxymethyl groups in the middle of rod segment. In addition, molecule with PEO (DP = 17) coil chains of identical coil volume fraction to the corresponding molecule connected by PPO (DP = 12) coil chains, shows diverse self-organizing behavior that may result from the parameters of cross-sectional area of coil segment and the steric hindrance at the rod/coil interface. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Synthesis of 1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyluracils as Potent Nonnucleoside HIV‐1 RT Inhibitors

1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyl uracils (1) and (2) are analogs of MKC‐442, which is a very potent inhibitor of HIV‐1 reverse transcriptase. The target compound 1 was synthesized by the first approach, from the corresponding 1,3‐dibenzyl‐5‐(dimethylamino)‐6‐phenethylpyrimidine‐2,4(1H,3H)‐dione (7), which was synthesized in four steps from 6‐methyluracil (3) by nitration, benzylation, reduction, and methylation of the amino group. Compound 7 was then debenzylated to give the complete deprotected compound 8 with very low yield. To improve the yield, another pathway was developed for introducing the ethoxymethyl group at N‐1 of the uracil ring first. The result of adjusting reaction sequences increased the overall yield dramatically. All synthesized compounds were tested for their inhibition of HIV‐1 reverse transcriptase, and moderate activity was found for target compound 1.

High-quality oligo-RNA synthesis using the new 2′-O-TEM protecting group by selectively quenching the addition of p-tolyl vinyl sulphone to exocyclic amino functions

During the F–-promoted deprotection of the oligo–RNA, synthesized using our 2′-O-(4-tolylsulfonyl)ethoxymethyl (2′-O-TEM) group [Org. Biomol. Chem. 5, 333 (2007)], p-tolyl vinyl sulphone (TVS) is formed as a by-product. The TVS formed has been shown to react with the exocyclic amino functions of adenosine (A), guanosine (G), and cytidine (C) of the fully deprotected oligo–RNA to give undesirable adducts, which are then purified by HPLC and unambiguously characterized by 1H, 13C Heteronuclear Multiple Bond Correlation (HMBC) NMR and mass spectroscopic analysis. The relative nucleophilic reactivities of the nucleobases toward TVS have been found to be the following: N6–A > N4–C > N2–G > > N3–U. This reactivity of TVS toward RNA nucleobases to give various Michael adducts could, however, be suppressed by using various amines as scavengers. Among all these amines, morpholine and piperidine are the most efficient scavenger for TVS, which gave highly pure oligo–RNA even in the crude form and can be used directly in RNA chemical biology studies.Key words: RNA synthesis, RNA alkylation, p-tolyl vinyl sulphone, Michael addition.

Masked Imidazolyl—Dipyrromethanes in the Synthesis of Imidazole‐Substituted Porphyrins.

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Masked Imidazolyl−Dipyrromethanes in the Synthesis of Imidazole-Substituted Porphyrins

Imidazole-substituted metalloporphyrins are valuable for studies of self-assembly and for applications where water solubility is required. Rational syntheses of porphyrins bearing one or two imidazol-2-yl or imidazol-4-yl groups at the meso positions have been developed. The syntheses employ dipyrromethanes, 1-acyldipyrromethanes, and 1,9-diacyldipyrromethanes bearing an imidazole group at the 5-position. The polar, reactive imidazole unit was successfully masked by use of (1) the 2-(trimethylsilyl)ethoxymethyl (SEM) group at the imidazole pyrrolic nitrogen, and (2) a dialkylboron motif bound to the pyrrole of the dipyrromethane and coordinated to the imidazole imino nitrogen. The nonpolar nature of such doubly masked imidazolyl-dipyrromethanes facilitated handling. Selected masked dipyrromethanes were characterized by 11B and 15N NMR spectroscopy. Five distinct methods were examined to obtain trans-A2B2-, trans-AB2C-, and trans-AB-porphyrins. Each porphyrin contained one or two SEM-protected imidazole units. The SEM group could be removed with TBAF or HCl. Two zinc(II) porphyrins and a palladium(II) porphyrin bearing a single imidazole moiety were prepared and subjected to alkylation (with ethyl iodide, 1,3-propane sultone, or 1,4-butane sultone) to give water-soluble imidazolium- porphyrins. This work establishes the foundation for the rational synthesis of a variety of porphyrins containing imidazole units.

Regioselective Protection at N-2 and Derivatization at C-3 of Indazoles

Indazoles are regioselectively protected at N-2 by a 2-(trimethylsilyl)ethoxymethyl (SEM) group using novel conditions. The SEM group can efficiently direct regioselective C-3 lithiation, and the resulting nucleophile can react with a wide range of electrophiles to generate novel indazole derivatives. The SEM group can be removed by treatment with TBAF in THF or aqueous HCl in EtOH.

Heterocycles by PtCl2-Catalyzed Intramolecular Carboalkoxylation or Carboamination of Alkynes

PtCl2 constitutes a convenient catalyst for intramolecular hydroalkoxylation, carboalkoxylation, hydroamination, and carboamination reactions of alkynes, effecting the formation of substituted benzo[b]furan, indole-, and isochromene-1-one derivatives, respectively. This procedure allows for the transfer of (substituted) allyl, methoxymethyl (MOM), benzyloxymethyl (BOM), and (trimethylsilyl)ethoxymethyl (SEM) groups from oxygen to carbon and is compatible with functional groups that are susceptible to oxidative insertion of low valent metal species previously used for similar purposes. Although some of the reactions can even be carried out in air, the rates are significantly increased when conducted under an atmosphere of CO. A mechanistic rationale is proposed, implying activation of the alkyne by the carbophilic Pt(2+) template as the primary step of the catalytic cycle.

Preparation of a chemically amplified photosensitive polyimide based on norbornene‐end‐capped poly(amic acid ethoxymethylester)

AbstractA positive‐working chemically amplified photosensitive polyimide (PSPI) developable with basic aqueous solutions was obtained from poly(amic acid ethoxymethylester) (PAAE) as a polyimide precursor and diphenyliodonium 5‐hydroxynaphthalene‐1‐sulfonate (DINS) as a photoacid generator. The norbornene‐end‐capped PAAE based on 4,4′‐oxydiphthalic anhydride and 4,4′‐oxydianiline exhibited high transparency at 365 nm. The protection ratio of the ethoxymethyl groups was optimized to maximize the difference between the dissolution rates of the exposed and unexposed areas. The acid generated from DINS in the UV‐exposed region effectively deprotected the ethoxymethyl groups of PAAE by a chemical amplification mechanism. A 10‐μm‐thick film of the PSPI precursor system containing 16 wt % DINS exhibited a sensitivity (Do) of 1100 mJ cm−2 when developed with a 2.38 wt % aqueous tetramethyl ammonium hydroxide solution at room temperature. A fine, positive, 5‐μm line‐and‐space pattern was fabricated in a 15‐μm‐thick film with 1500 mJ cm−2 of UV exposure. This resolution is excellent in comparison with those previously reported for chemically amplified PSPIs, and such a film can thus be used as a buffer coating in semiconductor packaging. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5520–5528, 2005

Patternable block copolymers with high transparency at 157 nm: Fluorocarbinol functionalized poly(isoprene-b-cyclohexane)

A three-step polymer modification reaction was developed to prepare polydiene-based patternable block copolymers with high transparency at 157 nm wavelength. In the first step, the ene reaction of poly(isoprene-b-cyclohexadiene) with hexafluoroacetone was carried out to incorporate a pendent hexafluoro-2-hydroxy-2-propyl functional group in the polyisoprene block. Subsequently, the hexafluorocarbinol functionalized block copolymer was hydrogenated to enhance transparency at 157 nm and finally the fluorocarbinol was protected with an ethoxymethyl group to induce a solubility switch after exposure. The final block copolymer exhibited an absorption coefficient of 3.30 μm-1 at 157 nm. Exposure was carried out on a 248 nm stepper and feature sizes down to 0.5 μm were resolved prior to optimization of exposure and formulation conditions.

The Dissolution Behavior of Tetrafluoroethylene-based Fluoropolymers for 157-nm Resist Materials

Main-chain-fluorinated base-resins, using the copolymer of tetrafluoroethylene and functional (hexafluoroisopropanol (HFA) group) norbornene, were synthesized. Partial protection of the hydroxyl group as an ethoxymethyl group was achieved by two methods: by copolymerization (Method A) or by polymer reaction (Method B). The partial protection by copolymerization was conducted by copolymerizing TFE with a mixture of protected and unprotected monomers (Method A, copolymerization). Partial protection was also carried out by reacting the hydroxyl group of the polymer, which is composed of TFE and unprotected monomers with ethoxymethyl chloride in the presence of an amine (Method B). In the polymer reaction, only the exo position of the norbornene unit was protected. Their fundamental properties, such as transparency at 157 nm and solubility in a standard alkaline developer, were characterized and studied. High transparency, i.e., absorbance better than 0.4 μm-1, was achieved with both methods. However, the polymer prepared by the polymer reaction (Method B) was deprotected more quickly; it also had a higher dissolution rate and stronger development contrast than the polymer prepared by copolymerization (Method A). Positive-working resists based on these fluororesins were developed and 55 nm dense lines could be delineated by exposure at 157 nm wavelength with alternating phase shift mask on a 0.9 NA 157 nm exposure tool.

Synthesis and evaluation of new potential HIV-1 non-nucleoside reverse transcriptase inhibitors. New analogues of MKC-442 containing Michael acceptors in the C-6 position.

Analogues of MKC-442 capable of undergoing Michael addition reactions were synthesised in order to investigate the activity against the HIV-1 mutant (Y181C). An improved activity was postulated on the basis of a possible covalent binding to the mercapto group of Cys181. Lithiation of the C-6 position of 1-ethoxymethyl-5-ethyl-1H-pyrimidine-2,4-dione (5) was followed by reaction with alpha,beta-unsaturated aldehydes and oxidation of the alcohols formed to give the alkenoyl analogues 1a-3a. Analogues 1b-3b containing an allyloxymethyl group in the N-1 position instead of the ethoxymethyl group could not be synthesised due to isomerisation of the allylic group during the metallation reaction. The NMR data for compounds 1a-3a showed a hindered rotation, which was more pronounced for the 6-cyclohexenylcarbonyl derivative 3a than for the propenyl derivatives 1a and 2a. Moderate activity against wild type HIV-1 was observed for the alcohol 8 and the ketones 2a-3a. However, no activity was observed against the Y181C mutant.

Synthesis of Novel N-1 (Allyloxymethyl) Analogues of 6-Benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, Emivirine) with Improved Activity Against HIV-1 and Its Mutants

This paper reports the synthesis and the antiviral activities of a series of 6-arylmethyl-1-(allyloxymethyl)-5-alkyluracil derivatives, which can be viewed as analogues of the anti-HIV-1 drug emivirine (formerly MKC-442) from which they differ in the replacement of the ethoxymethyl group with variously allyloxymethyl moieties. The most active compounds N-1 allyloxymethyl- and N-1 3-methylbut-2-enyl substituted 5-ethyl-6-(3,5-dimethylbenzyl)uracils (12 and 13) showed activity against HIV-1 wild-type in the picomolar range with selective index of greater than 5 x 10(6) and activity in the submicromolar range against the clinically important Y181C and K103N mutant strains known to be resistant to emivirine. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the substitution pattern of the N-1 allyloxymethyl group.

An Enzyme-Linked Immunosorbent Assay (Elisa) for the Detection of Acetochlor

Competitive enzyme-linked immunosorbent assays (ELISAs) were developed in hapten-homologous and hapten-heterologous formats for the detection of the chloroacetanilide herbicide acetochlor. ELISA systems were devised using antibodies generated against acetochlor conjugated to carrier proteins through a thioether moiety replacing the chlorine atom in the parent structure, while haptens modified both on the chloroacetyl moiety and on the ethoxymethyl group of acetochlor have been used for coating antigens. The optimized ELISA systems allowed the detection of acetochlor 0.2-65 µg/L, and cross-reactivity studies revealed high specificity of the immunoassay: only four (propisochlor, butachlor, alachlor and metolachlor) among 18 structurally related acetanilide herbicides, fungicides and intermediates showed significant (> 1%) cross-reactivity, with even the highest value (propisochlor) being below 10%. Assay performance was not affected detrimentally by methanol up to 10% (v/v) and ethanol up to 5% (v/v). Assay performance was tested by measuring acetochlor concentration in water samples and compared favorably ( r 2 = 0.976) with those detected by gas chromatographic method coupled with mass spectrometry (GC-MS) using solid-phase microextraction (SPME) for sample preparation.

Fragmentation of substituted oxonium ions: the role of ion–neutral complexes

Disubstituted trialkyloxonium ions R 1OCH 2O +(R 1)CH 2OR 2 (R 1, R 2 = CH 3 or C 2H 5) have been prepared by chemical ionization of dimethoxy- and diethoxymethane individually or as a mixture, and their fragmentation has been studied by means of metastable ion and collision-induced dissociations. It is found that when a methoxymethyl group is attached to the charged oxygen atom, the oxonium ions can fragment by C–O bond cleavage to generate a methoxymethyl cation/dialkoxymethane ion–neutral complex, in which methyl cation transfer occurs to expel neutral formaldehyde. When an ethoxymethyl group is connected with the central oxygen atom, a reaction channel involving loss of C 2H 4O is observed and found to be insensitive to collisions. This process is proposed to involve isomerization prior to fragmentation leading to methylated dialkoxymethanes coordinated with neutral acetaldehyde in ion–neutral complexes; these ion–neutral complexes are estimated to be 35 kJ mol −1 more stable than the original oxonium ions.