Heterocyclic Phenols Research Articles

A General, Multimetallic Cross-Ullmann Biheteroaryl Synthesis from Heteroaryl Halides and Heteroaryl Triflates.

Despite their importance to medicine and materials science, the synthesis of biheteroaryls by cross-coupling remains challenging. We describe here a new, general approach to biheteroaryls: the Ni- and Pd-catalyzed multimetallic cross-Ullmann coupling of heteroaryl halides with triflates. An array of 5-membered, 6-membered, and fused heteroaryl bromides and chlorides, as well as aryl triflates derived from heterocyclic phenols, proved to be viable substrates in this reaction (62 examples, 63 ± 17% average yield). The generality of this approach to biheteroaryls was further demonstrated in 96-well plate format at 10 μmol scale. An array of 96 possible products provided >90% hit rate under a single set of conditions. Further, low-yielding combinations could be rapidly optimized with a single "Toolbox Plate" of ligands, additives, and reductants.

Visible Light‐ and Heat‐Promoted C−O Coupling Reaction of Phenols and Aryl Halides

AbstractA visible light‐ and heat‐promoted C‐O coupling reaction of phenols and aryl halides has been described. Compared to the traditional C‐O coupling reactions promoted by visible light, this strategy avoids the use of transition metals, photocatalysts and ligands. Moreover, the reaction has good substrate universality, suitable for substituted phenol, naphthol and heterocyclic phenol derivatives.

Determination of the food azo dye carmoisine vs chlorpheniramine maleate ion associate structure

Recently different excipients, including colouring agents, are often used to give a marketable appearance and improve the consumer characteristics of drugs. Usually they are applied in the composition of medicines for internal use (tablets, capsules, syrups, troches, lozenges, etc). Synthetic azo dyes – a group of compounds obtained by the coupling reaction of sulfonaftilamines and diazotised sulfoanilines with aromatic or heterocyclic phenols are the most widely used in the pharmaceutical practice. Compounds of this group give bright, easily reproducible colours, they are resistant to the light, oxidants, reducing agents, pH changes and less sensitive to different types of technological impact. Synthetic azo dyes are poorly absorbed from the intestines after intake, but they can form ion associates with salts of organic bases, including with drugs, and it may alter their bioavailability. The aim of our work was to determine the partition coefficient of the ion associate of a synthetic food azo dye carmoisine with the medicinal substance chlorpheniramine maleate in the water-chloroform system and to study the stoichiometric ratio of the components in this ion associate. The partition coefficient in the water-chloroform system has been determined spectrophotometrically. It is 3.44, indicating that the ion associate is more soluble in water than in chloroform. The stoichiometric ratio of carmoisine and chlorpheniramine maleate in the resulting ion associate has been determined by HPLC, and it is 1:2.

Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues

Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intra-molecular electron transfer that generates the Tyr385 radical required for abstraction of a hydrogen from arachidonic acid to initiate prostaglandin synthesis. Unrelated to this pharmacological action, metabolism of ApAP by CYPs yields an iminoquinone electrophile that is responsible for the hepatotoxicity, which results from high doses of the drug. We synthesized novel heterocyclic phenols predicted to be electron donors. Two of these inhibited the oxygenation of arachidonic acid by PGHS-1 and myoglobin and also were shown to be more metabolically stable and exhibited less direct cytotoxicity than acetaminophen. They are leading candidates for studies to determine whether they are free of the metabolism-based hepatotoxicity produced by acetaminophen.

ChemInform Abstract: General and Efficient Protocol for the Formylation of Aromatic and Heterocyclic Phenols.

AbstractThe formylation process is carried out by condensation with hexamethylene tetramine (I) followed by acidic hydrolysis.

General and Efficient Protocol for Formylation of Aromatic and Heterocyclic Phenols

A convenient, general procedure for formylation of diverse range of phenols with the Duff protocol has been developed. The procedure gives dialdehydes when possible.

Development of an Updated Phytoestrogen Database for Use With the SWAN Food Frequency Questionnaire: Intakes and Food Sources in a Community-Based, Multiethnic Cohort Study

Phytoestrogens, heterocyclic phenols found in plants, may benefit several health outcomes. However, epidemiologic studies of the health effects of dietary phytoestrogens have yielded mixed results, in part due to challenges inherent in estimating dietary intakes. The goal of this study was to improve the estimates of dietary phytoestrogen consumption using a modified Block Food Frequency Questionnaire (FFQ), a 137-item FFQ created for the Study of Women's Health Across the Nation (SWAN) in 1994. To expand the database of sources from which phytonutrient intakes were computed, we conducted a comprehensive PubMed/Medline search covering January 1994 through September 2008. The expanded database included 4 isoflavones, coumestrol, and 4 lignans. The new database estimated isoflavone content of 105 food items (76.6%) vs. 14 (10.2%) in the 1994 version and computed coumestrol content of 52 food items (38.0%), compared to 1 (0.7%) in the original version. Newly added were lignans; values for 104 FFQ food items (75.9%) were calculated. In addition, we report here the phytonutrient intakes for each racial and language group in the SWAN sample and present major food sources from which the phytonutrients came. This enhanced ascertainment of phytoestrogens will permit improved studies of their health effects.

ChemInform Abstract: Synthesis of New Heterocyclic Phenols: 9-Hydroxypyrido(1,2-a)pyrimidin- 4-one and Derivatives.

9-Hydroxypyrido[1,2-a]pyrimidin-4-one (5) was prepared by condensation of 2-amino-3-hydroxypyridine with isopropylidene aminomethylenemalonate. The reaction first led to an enaminoester intermediate which underwent cyclization by heating at 250° affording the new heterocyclic phenol 5. A similar condensation performed on 2-amino-3-benzyloxypyridine yielded the corresponding benzylic ether which can be easily debenzylated to 5 by hydrogenolysis. Furthermore 2-amino-3-benzyloxypyridine condensed with diethyl ethoxymethylenemalonate gave 9-benzyloxy-3-ethoxycarbonylpyrido[1,2-a]pyrimidin-4-one which was also debenzylated to the corresponding free phenol.

Content and Profile of Isoflavones in Soy-Based Foods as a Function of the Production Process

Soy has been traditionally incorporated in diet as processed foods, such as soymilk, tofu, miso, tempeh, etc., and the consumption is commonly associated with a reduction of the development of chronic diseases due to their antioxidant, anti-inflammatory, and anti-allergic properties, among others. Many of the health benefits of soy have been attributed to isoflavones. They comprise a group of naturally occurring flavonoids consisting of heterocyclic phenols. Soy contains three types of isoflavones in four chemical forms: the aglycones daidzein, genistein, and glycitein; the β-glucosides daidzin, genistin, and glycitin; their 6″-O-malonyl-β-glucosides (6OMalGlc); and their 6″-O-acetyl-β-glucosides (6OAcGlc) conjugates. Industrial processing methods of soy-based food products commonly lead to the loss of isoflavones through removal of undesirable fractions. On the other hand, isoflavones can be transformed into different conjugates, which may have significant effects on the food texture and on the bioavailability and pharmacokinetics of the isoflavones. This article reviews the effect of a number of soybean processing treatments on the isoflavone content and profile. The preparation and manufacturing of different soy-based food and food ingredients, fermented and non-fermented, has been analyzed in terms of content and distribution of the three major isoflavone derivatives, daidzein, genistein, and glycitein, and their respective conjugates.

Soy Isoflavones as Safe Functional Ingredients

In recent years, isoflavones have increased in popularity as an alternative to estrogen therapy, particularly after the Women's Health Initiative demonstrated an increased risk of breast cancer, stroke, and heart attacks in response to estrogen and progesterone intervention. Isoflavones are heterocyclic phenols with structural similarity to estradiol-17beta and selective estrogen receptor modulators. Actions at the cellular level depend on the target tissue, receptor status of the tissue, and the level of endogenous estrogen. Clinical studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. Epidemiological studies suggest a protective effect of soy protein on breast tissue as evidenced by the lower rates of breast cancer in East Asian countries where soy is a predominant part of the diet. Soy products also alleviate menopausal symptoms by reducing hot flashes. However, whether these biological effects of soy products originated from isoflavones is not clear. Furthermore, data available from human studies on the effect of isoflavones on osteoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. To date, no adverse effects of short- or long-term use of soy proteins are known in humans, and the only adverse effects known are those reported in animals. In conclusion, isoflavones are biologically active compounds, and current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Large, long-term intervention studies examining adverse effects and disease outcomes are needed before definitive conclusion can be drawn.

Smiles Rearrangements in Ugi‐ and Passerini‐Type Couplings: New Multicomponent Access to O‐ and N‐Arylamides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Smiles Rearrangements in Ugi- and Passerini-Type Couplings: New Multicomponent Access to O- and N-Arylamides

The use of Smiles rearrangement in Ugi- and Passerini-type couplings with electron-deficient phenols allows very straightforward multicomponent formation of O-aryl- and N-arylamides. Best yields were observed with the highly activated o- and p-nitrophenols, salicylic derivatives giving adducts in lower yields. The scope of these new reactions is further increased by the successful couplings of heterocyclic phenols such as hydroxypyridines and hydroxypyrimidines.

Final Amended Report on the Safety Assessment of Oxyquinoline and Oxyquinoline Sulfate as Used in Cosmetics1

Oxyquinoline is a heterocyclic phenol and Oxyquinoline Sulfate is its salt, both of which are described as cosmetic biocides for use in cosmetic formulations. In an earlier Cosmetic Ingredient Review (CIR) safety assessment, the available data were found insufficient to support safety. Currently, some uses are reported to the Food and Drug Administration (FDA) by industry, but industry reports to CIR indicate no use. In Europe, Oxyquinoline and Oxyquinoline Sulfate are accepted for use as stabilizers for hydrogen peroxide in rinse-off and leave-on hair care preparations, with concentration limitations. Oxyquinoline is metabolized and excreted in the urine as glucuronides. Oxyquinoline and Oxyquinoline Sulfate exhibit little acute or subchronic toxicity in animal studies. A 100-mg dose of Oxyquinoline was only slightly irritating to the eye. Oxyquinoline and Oxyquinoline Sulfate were genotoxic in certain Salmonella typhimirium strains with metabolic activation and in a mouse lymphoma assay. There was some evidence of increased chromosome aberrations in an in vitro study, and an increase in sister-chromatid exchanges (but not chromosome aberrations) in rats treated with Oxyquinoline, but no genotoxicity was found in a Drosophilia sex-linked recessive lethal test, mouse bone marrow micronucleus test, a rat bone marrow and hepatocyte micronucleus test, and unscheduled DNA synthesis in rat hepatocytes. Oxyquinoline did bind to DNA in the presence of liver enzymes. Although the International Agency for Research on Cancer concluded that the existing evidence is inadequate to determine carcinogenicity in animals, Oxyquinoline was noncarcinogenic in several rodent feeding studies, and newly available studies using genetically altered mice, in one case carrying the human c-Ha-ras gene, demonstrated that Oxyquinoline was not carcinogenic. In clinical tests, Oxyquinoline is neither an irritant nor a sensitizer when tested at 1% in petrolatum. The available data demonstrate that Oxyquinoline and Oxyquinoline Sulfate are safe as stabilizers for hydrogen peroxide in rinse-off hair care cosmetic products in the present practices of use. For leave-on cosmetic products, however, the absence of impurities and ultraviolet (UV) absorption data resulted in a finding that the available data are insufficient to support safety. The data needed in order to complete the safety assessment of Oxyquinoline and Oxyquinoline Sulfate in leave-on cosmetic products are (1) UV absorption data -- if significant absorption occurs, then photoirritation/photosensitization data will be needed; and (2) data on impurities.

Knotted in-tube and mini-column solid phase extraction of polycyclic aromatic compounds and nitroaromatics from aqueous samples for their determination by gas chromatography mass spectrometry

The selectivity of in-tube extraction by PTFE tubing vis-a-vis mini-column SPE has been evaluated for preconcentration and cleanup of PACs in their natural matrix, and has been found to effectively remove many polar analytes such as nitrogen containing aromatic heterocyclic compounds, anilines, phenols and certain organophosphorus pesticides. Knitting of tubings created a secondary flow pattern that promoted radial diffusion and this has resulted in augmented retention of PACs. A rectilinear calibration graph was obtained for 1–100 µg L-1 of PACs by in-tube SPE, and 0.1–40 µg L-1 PACs and nitroaromatics by mini-column SPE of, respectively, 100 ml and 60 ml of aqueous sample. The detection limits were between 60 ng L-1 and 214 ng L-1(TIC detection), and 9 ng L-1 and 60 ng L-1 (SIM detection), respectively, in GC-MS of extracts.

Dopamine D1/D5 Receptor Antagonists with Improved Pharmacokinetics: Design, Synthesis, and Biological Evaluation of Phenol Bioisosteric Analogues of Benzazepine D1/D5 Antagonists

Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.

The Search for Promising Antioxidants and Thermostabilizers for Synthetic Fibres in a Number of Nitrogen-Containing Heterocycle Derivatives

The properties of a series of polynitrogen heterocyclic compounds of different structure were investigated as thermostabilizers for polypropylene and polycaproamide. It was found that polyheterocyclic compounds containing a condensed heterocyclic nucleus (1,2,4-triazole, thiazole, thiodiazole) and sterically-hindered phenol residue are the most promising compounds investigated.

Soy Isoflavones: Are They Useful in Menopause?

In October 1999, the US Food and Drug Administration authorized the use on food labels of health claims associated with soy protein and the reduced risk of coronary heart disease. Several studies have indicated that a total daily intake of 25 g of soy protein paired with a low-fat diet resulted in clinically important reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Soybeans are a rich source of isoflavones, a class of phytoestrogens found predominantly in legumes and beans. Soy isoflavones are heterocyclic phenols with structural similarity to estradiol-17beta and selective estrogen receptor modulators. Actions at the cellular level depend on the target tissue, receptor status of the tissue, and the level of endogenous estrogen. Studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, LDL cholesterol, and triglyceride levels. However, the soy isoflavones do not increase high-density lipoprotein cholesterol or triglyceride levels. The effects of soy protein on other target tissues reflect estrogenlike agonist and antagonist effects. Epidemiological studies suggest a protective effect of soy protein on breast tissue as evidenced by the lower rates of breast cancer in East Asian countries where soy is a predominant part of the diet. Data available from human studies on the effect of isoflavones on osteoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. Thus far, there is no evidence for a stimulatory effect of isoflavones on the endometrium. A few studies reveal a minimal effect of soy on hot flashes, with soy reducing hot flashes 45% and placebo causing a 30% reduction compared with an approximate 70% reduction in hot flashes with estrogen replacement therapy. Evidence from laboratory studies reveals neither a positive nor a negative effect of soy isoflavones on cognition. To date, no adverse effects of short- or long-term use of soy proteins are known in humans. The only adverse effects known are those reported in animals (infertility in sheep and quails grazing on phytoestrogen-rich pastures). In conclusion, soy isoflavones are biologically active compounds. Current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Although epidemiological and basic laboratory studies allude to the possible protective effects of soy isoflavones at specific target tissues, randomized, placebo-controlled clinical trials are necessary to address these important issues.

Determination of the lipophilicity of aroma compounds by RPHPLC

The lipophilicity of aroma compounds was measured by reversed-phase high pressure liquid chromatography (RP-HPLC). The lipophilicity index provided by this technique is the capacity factor, log k(w), obtained by extrapolating series of log k values measured at various proportions of methanol in the methanol-water mobile phase. This article lists the log k(w) capacity factors of 96 flavouring compounds belonging to various families (pyrazines, thiazoles, other heterocyclic compounds, alcohols and phenols, ketones, caters, aldehydes and sulphur compounds). (C) 1998 John Wiley & Sons, Ltd.

Furo-fused 2H-chromenes: synthesis and photochromic properties

New photochromic chromenes annulated with a furan ring have been synthesized. Thus, suitable heterocyclic phenols react with different propargylic alcohols in acidic medium to give the corresponding ethers, which cyclize into benzopyrans by thermal Claisen rearrangement. This synthetic approach was found to lead to a mixture of linear and angular chromenes that is strictly related to the nature of the phenol. However, regiospecificity could be obtained by reacting β-phenylcinnamaldehyde, in refluxing aprotic nonpolar solvents, with titanium(IV) salts of the former phenols. Electrocyclization of intermediately generated o-quinoid structures occurs on the α position towards the heterocyclic junction. All compounds exhibit photochromic behavior at room temperature. Furo-fused benzopyrans are particularly interesting with respect to naphthopyran parents in view of the bathochromically shifted and broadened absorption spectra of photoinduced forms. This trend is confirmed by the spectral data of several heterocyclospiro(7H-furo[3,2-f] chromenes). The achievable color depends significantly on the relative position of annulation on the chromenic moiety and substitution on the sp3 carbon atom. Key words: photochromism, heterocycle, regiospecificity, 2H-chromene, furan.

Pharmacological properties and specific psychotropic activity of new derivatives of heterocyclic phenols with a bridging nitrogen atom

Pharmacological properties and specific psychotropic activity of new derivatives of heterocyclic phenols with a bridging nitrogen atom