- Synthesis of Fluorenes and Dibenzo[ g,p]chrysenes through an Oxidative Cascade
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We have developed robust, operationally simple syntheses of fluorenes and of dibenzo[g,p]chrysenes through oxidative cascade processes. These structures that are commonly encountered in optoelectronic materials, dyes, and pharmaceutical products are acces
- Dickinson, Cody F.,Tius, Marcus A.,Yap, Glenn P. A.
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p. 1559 - 1563
(2022/02/07)
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- High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross-Coupling Reactions
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Traditional methods to discover optimal reaction conditions for small molecule synthesis is a time-consuming effort that requires large quantities of material and a significant expenditure of labor. High-throughput techniques are a potentially transformative approach for reaction condition screening, however, rapid validation of the reaction hotspots under continuous flow conditions remains necessary to build confidence in high throughput screening hits. Continuous flow technology offers the opportunity to upscale the screening hotspots and optimize their output of the target compounds due to the exceptional heat and mass transfer ability of flow reactions that are conducted in a smaller and safer reaction volume. We report a robotic high throughput technique to execute reactions in multi-well plates that were coupled with fast mass spectrometric analysis using an autosampler to accelerate the reaction screening process. Palladium-catalyzed Suzuki–Miyaura cross-coupling reactions were screened in this system and a heat map was generated to identify the best reaction conditions for downstream scale-up under continuous flow. Here, high throughput experimentation reactions in 96-well plates were performed for 1 h at 50 °C, 100 °C, 150 °C, and 200 °C before diluting them into 384-well plates for mass analysis. With the aid of high throughput tools, 648 unique experiments were conducted in duplicate. The cross-coupling reactions were evaluated as a function of stoichiometry, temperature, concentration, order of addition, and substrate type. The hotspots from high throughput experimentation were examined using a microfluidic Chemtrix system that confirmed the positive reaction leads as true positives. Negative outcomes identified by these experiments were found to be true negatives by microfluidic reaction evaluation. Quantitation of product yields was performed using high-performance liquid chromatography-mass spectrometry (HPLC/MS-MS).
- Jaman, Zinia,Mufti, Ahmed,Sah, Samyukta,Avramova, Larisa,Thompson, David H.
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supporting information
p. 9546 - 9554
(2018/07/14)
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- 3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations
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Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.
- Tang, Jing,Liu, Feng,Nagy, Eva,Miller, Lena,Kirby, Karen A.,Wilson, Daniel J.,Wu, Bulan,Sarafianos, Stefan G.,Parniak, Michael A.,Wang, Zhengqiang
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p. 2648 - 2659
(2016/04/10)
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- A divergent and selective synthesis of ortho- and para-quinones from phenols
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Abstract We describe a divergent synthesis of substituted ortho- and para-quinones by catalytic aerobic oxygenation of phenols. Substituted quinones are omnipresent in chemistry and biology, but their synthesis frequently suffers from low efficiency and poor scope. Our methodology employs a catalytic aerobic di-functionalization of phenols to aryloxy-ortho-quinones. Regioselective substitution with an alcohol provides the alkoxy substituted ortho- or para-quinone, while hydrolysis affords the para-hydroxyquinone. These are mild and selective conditions for the synthesis of diversely substituted quinones from readily available phenol starting materials.
- Huang, Zheng,Kwon, Ohhyeon,Esguerra, Kenneth Virgel N.,Lumb, Jean-Philip
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p. 5871 - 5885
(2015/08/04)
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- A short and efficient synthesis of honokiol via Claisen rearrangement
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A concise and efficient total synthesis of honokiol, a biphenyl-type neolignan is accomplished in six steps using readily available and cost-effective reagents. The synthetic route involves mainly the Grignard reaction, iodine mediated aromatization, and Claisen rearrangement as key steps. A predominant formation of honokiol (1a) was observed in the Claisen rearrangement under microwave irradiation whereas the isohonokiol (1b) was formed as a major product under conventional conditions.
- Subba Reddy,Nageshwar Rao,Siva Senkar Reddy,Somaiah,Yadav,Subramanyam, Ravi
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p. 1049 - 1051
(2014/02/14)
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- A short and efficient synthesis of honokiol via Claisen rearrangement
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A concise and efficient total synthesis of honokiol, a biphenyl-type neolignan is accomplished in six steps using readily available and cost-effective reagents. The synthetic route involves mainly the Grignard reaction, iodine mediated aromatization, and Claisen rearrangement as key steps. A predominant formation of honokiol (1a) was observed in the Claisen rearrangement under microwave irradiation whereas the isohonokiol (1b) was formed as a major product under conventional conditions.
- Subba Reddy,Nageshwar Rao,Siva Senkar Reddy,Somaiah,Yadav,Subramanyam, Ravi
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p. 1049 - 1051
(2015/02/19)
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- A biomimetic catalytic aerobic functionalization of phenols
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The importance of aromatic C-O, C-N, and C-S bonds necessitates increasingly efficient strategies for their formation. Herein, we report a biomimetic approach that converts phenolic C-H bonds into C-O, C-N, and C-S bonds at the sole expense of reducing dioxygen (O2) to water (H 2O). Our method hinges on a regio- and chemoselective copper-catalyzed aerobic oxygenation to provide ortho-quinones. ortho-Quinones are versatile intermediates, whose direct catalytic aerobic synthesis from phenols enables a mild and efficient means of synthesizing polyfunctional aromatic rings. The direct approach: Polyfunctional aromatic rings have been generated by direct functionalization of C-H bonds to C-O, C-N, and C-S bonds at the sole expense of reducing O2 to H2O. The method hinges on a regio- and chemoselective, copper-catalyzed aerobic oxygenation of phenols to provide ortho-quinones (see scheme), thus mimicking the ubiquitous biosynthetic pathway of melanogenesis.
- Esguerra, Kenneth Virgel N.,Fall, Yacoub,Lumb, Jean-Philip
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supporting information
p. 5877 - 5881
(2014/06/10)
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- Suzuki-Miyaura coupling of halophenols and phenol boronic acids: Systematic investigation of positional isomer effects and conclusions for the synthesis of phytoalexins from pyrinae
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The Suzuki-Miyaura couplings of o-, m-, and p-halophenols with o-, m-, and p-phenol boronic acids were investigated for all combinations under standardized conditions, using Pd/C as a heterogeneous catalyst and water as a solvent. In the case of iodophenols, conventional heating was used, while for bromophenols significantly better results could be obtained using microwave irradiation. This systematic study revealed that 2,4′-biphenol is particularly difficult to access, irrespective of the starting materials used, but that these difficulties can be overcome by using different additives. The conclusions drawn from this investigation allowed us to identify conditions for the protecting group-free or minimized total synthesis of biaryl-type phytoalexins. These compounds possess antibacterial activity and are produced by fruit trees as a response to microbial infection.
- Schmidt, Bernd,Riemer, Martin
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p. 4104 - 4118
(2014/05/20)
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- A mild robust generic protocol for the Suzuki reaction using an air stable catalyst
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A mild but robust procedure has been developed as a first pass generic protocol for the Suzuki-Miyaura reaction. The protocol employs an air stable palladium pre-catalyst at low loading (1 mol %) in aqueous solvent mixtures at moderate temperature using potassium carbonate as base. Under these mild conditions, most aryl bromides will react with sterically and electronically demanding aryl boronic acids to give complete conversion to the product biphenyls in less than 1 h. Aryl chlorides are also fully converted in most cases either under identical conditions in 8-24 h, or in 2 h at elevated temperature. A further advantage of these mild conditions of moderate temperature, weak base and benign solvent is that sensitive functional groups and structural motifs are well tolerated. In addition, the lipophilic biphenyl products are readily isolated after a simple work-up procedure. These generic conditions are ideal for proof of transformation, and as the starting point for development and optimization of a specific process. The discovery and fine-tuning of this generic protocol will be presented, supported extensively by examples to illustrate its scope and utility.
- Moseley, Jonathan D.,Murray, Paul M.,Turp, Edward R.,Tyler, Simon N.G.,Burn, Ross T.
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experimental part
p. 6010 - 6017
(2012/09/21)
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- An alternative approach to para-C-H arylation of phenol: Palladium-catalyzed tandem γ-arylation/aromatization of 2-cyclohexen-1-one derivatives
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An efficient approach to prepare para-aryl phenols has been developed by using a Pd-catalyzed tandem γ-arylation/aromatization of 2-cyclohexen-1-one derivatives with aryl bromides. This approach provides various p-aryl phenols from the phenol surrogates, 2-cyclohexen-1-one derivatives, in a single reaction step on the basis of C-H arylation.
- Imahori, Tatsushi,Tokuda, Toru,Taguchi, Tatsuya,Takahata, Hiroki
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supporting information; experimental part
p. 1172 - 1175
(2012/04/04)
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- Fingerprints of singlet and triplet phenyl cations
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The photolyses of seven phenyl cation precursors in acetonitrile in the presence of anisole resulted in four distinct product patterns. These patterns are due to the chemoselective and regioselective chemistry of various phenyl cation isomers. This spin-selective chemistry provides a tool with which to fingerprint the singlet/triplet nature of any phenyl cation. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Slegt, Micha,Overkleeft, Hermen S.,Lodder, Gerrit
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p. 5364 - 5375
(2008/03/14)
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- PEG-supported dipyridyl ligand for palladium-catalyzed Suzuki and Suzuki-type reactions in PEG and aqueous media
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An air- and water-stable PEG-supported bidentate nitrogen ligand is prepared and its applications in the palladium-catalyzed Suzuki reaction of aryl halides with arylboronic acids in PEG and Suzuki-type reaction of aryl halides with sodium tetraphenylborate in aqueous media are reported. The homogeneous catalyst system is environmentally friendly and offers the advantages of high activity, reusability and easy separation. Georg Thieme Verlag Stuttgart.
- Mai, Wenpeng,Gao, Lianxun
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p. 2553 - 2558
(2008/09/16)
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- ERbeta ligands. Part 1: the discovery of ERbeta selective ligands which embrace the 4-hydroxy-biphenyl template.
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The synthesis and structure-activity relationships of a series of simple biphenyls is described. Optimization of the 4-hydroxy-biphenyl template led to compounds with ERbeta selectivity on the order of 20-70-fold.
- Edsall Jr., Richard J,Harris, Heather A,Manas, Eric S,Mewshaw, Richard E
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p. 3457 - 3474
(2007/10/03)
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- Pd/C as a reusable catalyst for the coupling reaction of halophenols and arylboronic acids in aqueous media
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Pd/C was found to catalyze the Suzuki-Miyaura coupling reaction of halophenols in aqueous media. When halophenols were treated with ArB(OH)2 and a catalytic amount of 10% Pd/C (0.3 mol % Pd) in aqueous K2CO3 solution, the corresponding hydroxybiaryls were obtained in a high yield or quantitatively. The palladium catalyst was easily recovered and reused.
- Sakurai, Hidehiro,Tsukuda, Tatsuya,Hirao, Toshikazu
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p. 2721 - 2722
(2007/10/03)
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- PHENOXENIUM IONS. IDENTICAL INTERMEDIATES IN THE ACID-CATALYZED SOLVOLYSIS OF N-TOSYL-O-ARYLHYDROXYLAMINES AND IN THE THERMOLYSIS OF N-ARYLOXYPYRIDINIUM SALTS
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The acid-catalyzed solvolysis of N-tosyl-O-arylhydroxylamines in aromatic solvents and the thermolysis of N-aryloxypyridinium salts involve common intermediates, phenoxenium ions, for the formation of hydroxybiphenyl derivatives.Diphenylethers are formed when the heterolysis of the N-O bonds is slow and the aromatic solvent has high nucleophilicity.
- Iijima, Hiroyuki,Endo, Yasuyuki,Shudo, Koichi,Okamoto, Toshihiko
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p. 4981 - 4986
(2007/10/02)
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- Acid-Catalyzed Solvolysis of N-Sulfonyl- and N-Acyl-O-arylhydroxylamines. Phenoxenium Ions
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The acid-catalyzed reaction of N-acyl- and N-sulfonyl-O-arylhydroxylamines with benzene proceeded quite smoothly to give 2- and 4-hydroxybiphenyls.The results of product analysis, the orientation of the reaction, and the effects of substituents on the nitrogen atom and on the phenyl ring suggested a mechanism that involves a phenoxenium ion.The phenoxenium ion was trapped by benzene and other various nucleophiles.
- Endo, Yasuyuki,Shudo, Koichi,Okamoto, Toshihiko
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p. 6393 - 6397
(2007/10/02)
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- Aryloxenium Ions. Generation from N-(Aryloxy)pyridinium Tetrafluoroborates and Reaction with Anisole and Benzonitrile
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N-(Aryloxy)pyridinium tetrafluoroborates (4) decompose thermally at 180-200 deg C in anisole and benzonitrile to form products of intermolecular C-O-C and C-C bond formation.With anisole, diphenyl ethers (5) and hydroxybiphenyls (6) are formed; with benzonitrile, the main product is benzoxazole (14).A homolytic process was ruled out by showing that none of these products were formed when perbenzoyl p-nitrophenyl carbonate (18) was decomposed in these solvents.The main products in this case were those of homolytic phenylation (and benzoyloxylation with anisole).A concerted SN2-type heterolytic process was ruled out by showing that the nature of the substituent in the pyridine ring had no effect on the isomer ratios of 5 and 6 in the thermolysis of 4 (X = p-NO2) in anisole.The results are explained in terms of a unimolecular heterolysis of 4 to give the pyridine and aryloxenium ion 2 which now attacks solvent molecules.When an electron-withdrawing substituent is present in 2, more C-O-C than C-C products are formed in anisole.When it is absent only products of C-C bond formation are found.PhO+ is apparently electrophilic enough to attack anisole and give the four possible hydroxymethoxybiphenyls (10-13).
- Abramovitch, Rudolph A.,Alvernhe, Gerard,Bartnik, Romuald,Dassanayake, Nissanke L.,Inbasekaran, Mutiah N.,Kato, Shiego
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p. 4558 - 4565
(2007/10/02)
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