- Design, synthesis, biological activity evaluation of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives as potent JAK 2/3 and aurora A/B kinases multi-targeted inhibitors
-
In this study, a series of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives were designed, synthesized, and evaluated for their biological activities. Upon performing kinase assays, most of the compounds exhibited potent inhibition against JAK2/3 and Aurora A/B with the IC50 values ranging from 0.008 to 2.52 μM. Among these derivatives, compound 10e expressed the most moderate inhibiting activities against all the four kinases with the IC50 values of 0.166 μM (JAK2), 0.057 μM (JAK3), 0.939 μM (Aurora A), and 0.583 μM (Aurora B), respectively. Moreover, most of the derived compounds exhibited potent cytotoxicity against human chronic myeloid leukemia cells K562 and human colon cancer cells HCT116, while compound 10e expressed antiproliferative activities against K562 (IC50=6.726 μM). According to western blot analysis, compound 10e down-regulated the phosphorylation of STAT3, STAT5, Aurora A, and Aurora B in a dose-dependent manner in K562 and HCT116 cells. Cell cycle analysis revealed that compound 10e inhibited the proliferation of cells by inducing cell cycle arrest in the G2 phase. The molecular modeling suggested that compound 10e could maintain a binding mode similar to the binding mode of AT9832, a common JAK 2/3 and Aurora A/B kinases multi-target kinase inhibitor. Therefore, compound 10e might be a potential agent for cancer therapy deserving further research.
- Zheng, You-Guang,Wang, Jin-An,Meng, Long,Pei, Xin,Zhang, Ling,An, Lin,Li, Cheng-Lin,Miao, Ying-Long
-
-
- Photocatalytic continuous bromination method
-
The invention provides a photocatalytic continuous bromination method. The method comprises the following steps: carrying out a first-stage photocatalytic continuous bromination reaction on a materialcontaining an aromatic substrate with a structural general formula I and a bromination reagent in a first continuous illumination reactor to form a first continuous system; overflowing the obtained first continuous system into a second continuous illumination reactor for a second-stage photocatalytic continuous bromination reaction to form a second continuous system; and purifying the second continuous system, wherein the structural general formula I is shown in the specification, R is selected from any one of carboxyl, ester group, NO2, CN, C1 to C8 alkyl and alkoxy, and R1 is C1 to C8 alkyl; n is 1 or 2; X is N or C, and the bromination reagent is Nbromo succinimide or dibromohydantoin. According to the bromination reagent, the selectivity of a product is improved, so the yield of the product is improved; the photocatalytic continuous bromination reaction of the two stages effectively relieves the reaction heat accumulation, and enhances the yield of the target product.
- -
-
Paragraph 0068-0069
(2021/04/03)
-
- Non-natural amino acid and application thereof Recombinant protein and recombinant protein conjugate comprising same
-
The invention provides a non-natural amino acid. A compound represented by formula (I) or an enantiomer thereof. The invention also provides application of the non-natural amino acid. Further, the present invention also provides a protein conjugate comprising the recombinant protein and of the non-natural amino acid prepared from the recombinant protein. The non-natural amino acid provided by the invention is simple and convenient to prepare, good in safety, not prone to inactivation during protein insertion, high in conjugate rate with a coupling part, and higher in stability of the obtained conjugate.
- -
-
Paragraph 0076; 0080-0082; 0100; 0104-0106; 0122; 0126-0128
(2021/11/03)
-
- Dual-Metal N-Heterocyclic Carbene Complex (M = Au and Pd)-Functionalized UiO-67 MOF for Alkyne Hydration-Suzuki Coupling Tandem Reaction
-
Metal N-heterocyclic carbene complexes (NHC-M) have been recognized as an important class of organometallic catalysts. Herein, we demonstrate that different NHC-M (M = Au and Pd) species can be simultaneously introduced into a single metal organic framework (MOF) by direct assembly of NHC-M-decorated ligands and metal ions under solvothermal conditions. The obtained UiO-67-Au/Pd-NHBC MOF with different organometallic NHC-M species can be a highly reusable dual catalyst to sequentially promote alkyne hydration-Suzuki coupling reaction. The potential utility of this strategy is highlighted by the preparation of many more new multicatalysts of this type for various organic transformations in a sequential way.
- Dong, Ying,Li, Wen-Han,Dong, Yu-Bin
-
p. 1818 - 1826
(2021/01/13)
-
- 3-(4-phenyl-1H-2-imidazolyl)-1H-pyrazole compound as well as preparation method and application thereof
-
The invention relates to a 3-(4-phenyl-1H-2-imidazolyl)-1H-pyrazole compound as well as a preparation method and application thereof, and belongs to the field of medicinal chemistry and pharmacotherapeutics. The invention provides application of a compound shown as a formula I or pharmaceutically acceptable salt thereof in preparation of drugs for treating tumor-related diseases, particularly an application in preparation of an Aurora A kinase specific inhibitor.
- -
-
Paragraph 0074-0076
(2020/04/22)
-
- HYDROXYISOXAZOLINES AND DERIVATIVES THEREOF
-
The present disclosure relates to the use of hydroxyisoxazolines and derivatives thereof as fungicide. It also relates to new hydroxyisoxazolines derivatives, their use as fungicide and compositions comprising thereof.
- -
-
Page/Page column 63
(2019/07/13)
-
- Exploiting the chalcone scaffold to develop multifunctional agents for Alzheimer’s disease
-
Alzheimer’s disease still represents an untreated multifaceted pathology, and drugs able to stop or reverse its progression are urgently needed. In this paper, a series of naturally inspired chalcone-based derivatives were designed as structural simplification of our previously reported benzofuran lead compound, aiming at targeting both acetyl (AChE)- and butyryl (BuChE) cholinesterases that, despite having been studied for years, still deserve considerable attention. In addition, the new compounds could also modulate different pathways involved in disease progression, due to the peculiar trans-α,β-unsaturated ketone in the chalcone framework. All molecules presented in this study were evaluated for cholinesterase inhibition on the human enzymes and for antioxidant and neuroprotective activities on a SH-SY5Y cell line. The results proved that almost all the new compounds were low micromolar inhibitors, showing different selectivity depending on the appended substituent; some of them were also effective antioxidant and neuroprotective agents. In particular, compound 4, endowed with dual AChE/BuChE inhibitory activity, was able to decrease ROS formation and increase GSH levels, resulting in enhanced antioxidant endogenous defense. Moreover, this compound also proved to counteract the neurotoxicity elicited by Aβ1–42 oligomers, showing a promising neuroprotective potential.
- Rampa, Angela,Bartolini, Manuela,Pruccoli, Letizia,Naldi, Marina,Iriepa, Isabel,Moraleda, Ignacio,Belluti, Federica,Gobbi, Silvia,Tarozzi, Andrea,Bisi, Alessandra
-
-
- A Selective and Functional Group-Tolerant Ruthenium-Catalyzed Olefin Metathesis/Transfer Hydrogenation Tandem Sequence Using Formic Acid as Hydrogen Source
-
A ruthenium-catalyzed transfer hydrogenation of olefins utilizing formic acid as a hydrogen donor is described. The application of commercially available alkylidene ruthenium complexes opens access to attractive C(sp3)-C(sp3) bond formation in an olefin metathesis/transfer hydrogenation sequence under tandem catalysis conditions. High chemoselectivity of the developed methodology provides a remarkable synthetic tool for the reduction of various functionalized alkenes under mild reaction conditions. The developed methodology is applied for the formal synthesis of the drugs pentoxyverine and bencyclane.
- Zieliński, Grzegorz K.,Majtczak, Jaros?awa,Gutowski, Maciej,Grela, Karol
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p. 2542 - 2553
(2018/03/09)
-
- Carbonylative Coupling of Alkyl Zinc Reagents with Benzyl Bromides Catalyzed by a Nickel/NN2 Pincer Ligand Complex
-
An efficient catalytic protocol for the three-component assembly of benzyl bromides, carbon monoxide, and alkyl zinc reagents to give benzyl alkyl ketones is described, and represents the first nickel-catalyzed carbonylative coupling of two sp3-carbon fragments. The method, which relies on the application of nickel complexed with an NN2-type pincer ligand and a controlled release of CO gas from a solid precursor, works well with a range of benzylic bromides. Mechanistic studies suggest the intermediacy of carbon-centered radicals.
- Andersen, Thomas L.,Donslund, Aske S.,Neumann, Karoline T.,Skrydstrup, Troels
-
supporting information
p. 800 - 804
(2017/12/26)
-
- A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase to Counter Nonalcoholic Steatohepatitis
-
Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the disease's multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.
- Schmidt, Jurema,Rotter, Marco,Weiser, Tim,Wittmann, Sandra,Weizel, Lilia,Kaiser, Astrid,Heering, Jan,Goebel, Tamara,Angioni, Carlo,Wurglics, Mario,Paulke, Alexander,Geisslinger, Gerd,Kahnt, Astrid,Steinhilber, Dieter,Proschak, Ewgenij,Merk, Daniel
-
supporting information
p. 7703 - 7724
(2017/10/06)
-
- Method for preparing benzyl bromide
-
The invention provides a method for preparing benzyl bromide. The method comprises the following steps: by taking bromine released from a redox reaction between bromates and negative bromide ions in the presence of an acid as a bromine source in an organic solvent, carrying out a benzyl radical substitution reaction with a methylbenzene compound shown as a formula I under initiation of an initiator, thereby obtaining a corresponding benzyl bromide compound shown a formula II, wherein in the formula II, m represents the number of Br and is equal to 1 or 2; when m is equal to 1, the formula II shows a benzyl monobromo compound; and when m is equal to 2, the formula II shows a benzyl dibromo compound. The reaction is carried out in an organic solvent, the initiator is combined and used, the radical substitution reaction is high in selectivity and wide in substrate application range, the substituent group replacing methylbenzene may be an electron-withdrawing group or an electron-donating group and can give extremely high yield on strong electron-donating groups (such as methoxy group). Moreover, the method disclosed by the invention is also applicable to preparation of benzyl dibromo compounds, and the product yield is high.
- -
-
Paragraph 0058-0060
(2017/10/05)
-
- Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria
-
Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.
- Yang, Yiqing,Yu, You,Li, Xiaolu,Li, Jing,Wu, Yue,Yu, Jie,Ge, Jingpeng,Huang, Zhenghui,Jiang, Lubin,Rao, Yu,Yang, Maojun
-
supporting information
p. 1994 - 2005
(2017/03/17)
-
- Direct Carboxylation of the Diazo Group ipso-C(sp2)-H bond with Carbon Dioxide: Access to Unsymmetrical Diazomalonates and Derivatives
-
The direct carboxylation of the ipso-C(sp2)-H bond of a diazo compound with carbon dioxide under mild reaction conditions is described. This method is transition-metal-free, uses a weak base, and proceeds at ambient temperature under atmospheric pressure in carbon dioxide. The carboxylation exhibits high reactivity and is amenable to subsequent diversification. A series of unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with moderate to excellent yields (up to 99%) with good functional group compatibility.
- Liu, Qianyi,Li, Man,Xiong, Rui,Mo, Fanyang
-
supporting information
p. 6756 - 6759
(2017/12/26)
-
- COMPOSITE PREPARATION, CONTAINING NOVEL 3-(4-(BENZYLOXY)PHENYL)HEX-4-INOIC ACID DERIVATIVE AND ANOTHER ACTIVE INGREDIENT, FOR PREVENTING OR TREATING METABOLIC DISEASES
-
The present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, in which a novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative and at least another active ingredient, which is selected from the group consisting of dipeptidyl peptidase-4 (DPPIV) inhibitor-based, sulfonylurea-based, thiazolidinedione (TZD)-based, biguanide-based, and sodium/glucose cotransporter 2 (SGLT2) inhibitor-based drugs, may be administered in combination or in the form of a composite preparation. The use of the composition of the present invention can provide a remarkably excellent blood sugar reducing effect in various animal diabetic disease models, and the composition of the present invention can be favorably used as a pharmaceutical composition for preventing or treating metabolic diseases, such as obesity, diabetes type I, diabetes type II, glucose intolerance symptoms, insulin resistance symptoms, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X.
- -
-
Paragraph 0189-0191
(2017/09/04)
-
- A compound thereof in the preparation of anti-parasitic drug application
-
The invention discloses a compound and application of the compound in preparation of drugs for resisting parasitic diseases. The compound has the chemical formula (VII), in the chemical formula (VII), L is O or CH2, one of R1 and R2 is a halogen element, and the other is H. The compound provided by the invention belongs to a quinolones compound; through research, an inventor finds that the compound can inhibit activity of NDH-2 protein of plasmodium, and therefore, the compound can be used for slowing down the clinical symptoms at asexual reproduction stage and also can be used for stopping diseases spreading at the sexual reproduction stage of life cycle of plasmodium. The compound has great significances for treating the plasmodium diseases. The chemical formula (VII) is as shown in the specification.
- -
-
Paragraph 0115-0117
(2017/02/09)
-
- COMPOUNDS WITH NEURAL PROTECTIVE EFFECT, AND PREPARATION AND USE THEREOF
-
The invention generally relates to compounds of formula (I) with neural protective effect, and preparation and uses thereof. The compounds have multiple mechanisms or functions, for example, inhibition of monoamine oxidase and cholinesterase, scavenging of free radicals, and protection of cells such as nerve cells. The compounds can be used for manufacture of medicaments of cell protection, for prevention and/or treatment of monoamine oxidase, cholinesterase and free radicals related diseases, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, and free-radical related diseases such as heart disease, myocardial ischemia, diabetes and other cardiovascular and cerebrovascular diseases.
- -
-
Paragraph 0147
(2016/11/28)
-
- Palladium-catalyzed silylation reaction between benzylic halides and silylboronate
-
An efficient Pd-catalyzed silylation reaction of benzylic halides with silylboronate is reported. In this reaction, primary and secondary benzylic halides could react well with silylboronates to afford benzylic silanes. This reaction accommodates a broad substrate scope and proceeds smoothly under very mild reaction conditions. The corresponding products could be obtained in moderate to high yields and with stereospecificity.
- Huang, Zhi-Dao,Ding, Ran,Wang, Peng,Xu, Yun-He,Loh, Teck-Peng
-
supporting information
p. 5609 - 5612
(2016/05/09)
-
- NOVEL 3-(4(BENZYLOXY)PHENYL)HEX-4-INOIC ACID DERIVATIVE, METHOD OF PREPARING SAME AND PHARMACEUTICAL COMPOSITION FOR PREVENTING AND TREATING METABOLIC DISEASE INCLUDING SAME AS EFFECTIVE INGREDIENT
-
The present invention relates to a novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient for the prevention and treatment of metabolic disease. The novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention has excellent activities of activating GPR40 protein and promoting insulin secretion accordingly but has no toxicity when co-administered with other drugs. That is, the novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention can be co-administered with other drugs and can promote the activation of GPR40 protein significantly, so that the composition comprising the same as an active ingredient can be efficiently used as a pharmaceutical composition for the prevention and treatment of metabolic disease such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.
- -
-
Paragraph 0295-0297
(2016/02/18)
-
- INHIBITORS OF HEPATITIS C VIRUS POLYMERASE
-
The present invention provides, among other things, compounds represented by the general Formula I: (I) and pharmaceutically acceptable salts thereof, wherein L and A (and further substituents) are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
- -
-
Paragraph 233
(2016/10/11)
-
- COMPOUNDS WITH NEURAL PROTECTIVE EFFECT, AND PREPARATION AND USE THEREOF
-
The invention generally relates to compounds of formula (I) with neural protective effect, and preparation and uses thereof. The compounds have multiple mechanisms or functions, for example, inhibition of monoamine oxidase and cholinesterase, scavenging of free radicals, and protection of cells such as nerve cells. The compounds can be used for manufacture of medicaments of cell protection, for prevention and/or treatment of monoamine oxidase, cholinesterase and free radicals related diseases, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, and free-radical related diseases such as heart disease, myocardial ischemia, diabetes and other cardiovascular and cerebrovascular diseases.
- -
-
Paragraph 29
(2015/08/06)
-
- Diphenylpyrazoles as replication protein A inhibitors
-
Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA-protein interactions. We evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein-protein interactions.
- Waterson, Alex G.,Kennedy, J. Phillip,Patrone, James D.,Pelz, Nicholas F.,Feldkamp, Michael D.,Frank, Andreas O.,Vangamudi, Bhavatarini,Souza-Fagundes, Elaine M.,Rossanese, Olivia W.,Chazin, Walter J.,Fesik, Stephen W.
-
supporting information
p. 140 - 145
(2015/03/04)
-
- P(NMe2)3-Mediated Umpolung Alkylation and Nonylidic Olefination of α-Keto Esters
-
A commercial phosphorus-based reagent (P(NMe2)3) mediates umpolung alkylation of methyl aroylformates with benzylic and allylic bromides, leading to either Barbier-type addition or ylide-free olefination products upon workup. The reaction sequence is initiated by a two-electron redox addition of the tricoordinate phosphorus reagent with an α-keto ester compound (Kukhtin-Ramirez addition). A mechanistic rationale is offered for the chemoselectivity upon which the success of this nonmetal mediated C-C bond forming strategy is based.
- Wang, Sunewang Rixin,Radosevich, Alexander T.
-
supporting information
p. 3810 - 3813
(2015/08/18)
-
- The flocculated acryloyldimethyltauric molecule ligand
-
Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example: formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
- -
-
Paragraph 0893; 0894
(2016/10/08)
-
- Efficient and versatile transfer hydrogenation catalysts: Iridium (III) and ruthenium (II) complexes with 4-acetylbenzyl-N-heterocyclic carbenes
-
New 4-acetylbenzyl-N-heterocyclic carbene ligands (1-4) have been used to synthesize iridium complexes 6-9 and ruthenium complex 10. All complexes were characterized by FT-IR, 1H and 13C NMR spectroscopy, elemental analysis, and in the case of 6, by X-ray diffraction studies. The catalytic performance of these iridium and ruthenium complexes for transfer hydrogenation of ketones and imines and N-alkylation of amines with primary alcohols were tested in a range of substrates, and showed high catalytic activity with 1 mol% catalytic loading. The neutral complex 8 with two acetyl groups also showed good catalytic efficiency under lower catalyst loading (0.01 mol%), with the maximum TON of 8000, while on the other hand, the cationic complex 9 with PF6- as counteranion showed good to excellent catalytic activity toward the N-alkylation of amines in a wide scope of substrates. We also found out that the Ir complex 6′ was formed through the intramolecular CH activition of 6 under the transfer hydrogenation conditions.
- Zhu, Xiao-Han,Cai, Li-Hua,Wang, Chen-Xi,Wang, Ya-Nong,Guo, Xu-Qing,Hou, Xiu-Feng
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p. 134 - 141
(2014/07/21)
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- A scalable procedure for light-induced benzylic brominations in continuous flow
-
A continuous-flow protocol for the bromination of benzylic compounds with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates containing different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h-1), which is not easily possible in batch photochemical reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h -1 for the desired bromide was achieved.
- Cantillo, David,De Frutos, Oscar,Rincon, Juan A.,Mateos, Carlos,Oliver Kappe
-
supporting information
p. 223 - 229
(2014/01/17)
-
- SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF
-
Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.
- -
-
Page/Page column 385
(2014/09/29)
-
- SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF
-
Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.
- -
-
Paragraph 0292; 0293
(2014/09/30)
-
- Variation of formal hydrogen-bonding networks within electronically delocalized π-conjugated oligopeptide nanostructures
-
This photophysical study characterizes the generality of intermolecular electronic interactions present within nanomaterials derived from self-assembling oligopeptides with embedded π-conjugated oligophenylenevinylene (OPV) subunits stilbene and distyrylbenzene that in principle present two distinct β-sheet motifs. Two different synthetic approaches led to oligopeptides that upon self-assembly are expected to self-assemble into multimeric aggregates stabilized by β-sheet-like secondary structures. The target molecules express either two C-termini linked to the central OPV core (symmetric peptides) or the more common N-termini to C-termini polarity typical of natural oligopeptides (nonsymmetric peptides). Both peptide secondary structures were shown to form extended 1-D peptide aggregates with intimate intermolecular π-electron interactions. Differences in length of the π-conjugated OPV segments resulted in differing extents of intermolecular interactions and the resulting photophysics. The peptides containing the shorter stilbene (OPV2) units showed little ground state interactions and resulted in excimeric emission, while the longer distyrylbenzene (OPV3) peptides had different ground state interactions between adjacent π-conjugated subunits resulting in either perturbed electronic properties arising from exciton coupling or excimer-like excited states. Molecular dynamics simulations of nascent aggregate formation predict peptide dimerization to be a spontaneous process, possessing thermodynamic driving potentials in the range 2-6 kcal/mol for the four molecules considered. Antiparallel stacking of the peptides containing an OPV3 subunit is thermodynamically favored over the parallel orientation, whereas both arrangements are equally favored for the peptides containing an OPV2 subunit. This study validates the generality of peptide-π-peptide self-assembly to provide electronically delocalized supramolecular structures and suggests flexibility in peptide sequence design as a way to tune the material properties of π-conjugated supramolecular polymers.
- Wall, Brian D.,Zhou, Yuecheng,Mei, Shao,Ardoa, Herdeline Ann M.,Ferguson, Andrew L.,Tovar, John D.
-
p. 11375 - 11385
(2015/01/08)
-
- Highly enantioselective synthesis of chiral tetrahydroquinolines and tetrahydroisoquinolines by ruthenium-catalyzed asymmetric hydrogenation in ionic liquid
-
Asymmetric hydrogenation reactions of quinolines and 3,4- dihydroisoquinolines using the chiral cationic ruthenium complex Ru(TsDPEN) [TsDPEN=N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] as catalyst in neat imidazolium ionic liquids have been investigated. The catalytic performance was influenced by the anion of the ionic liquids for both substrate classes. A range of 2-alkyl-substituted 1,2,3,4-tetrahydroquinolines and 1-alkyl-substituted 1,2,3,4-tetrahydroisoquinolines was obtained in high yields with up to >99% ee. Interestingly, the hydrogenation of quinoline derivatives bearing a carbonyl group was selective for the C-N (quinoline) over the C-O (ketone) bonds, while such a unique chemoselectivity was not observed in methanol. Furthermore, the ruthenium catalysts could be easily recycled at least 5 times in the asymmetric hydrogenation of 3,4-dihydroisoquinoline by solvent extraction. To further facilitate the recovery of catalyst and reduce the use of organic solvent, a thin film of ionic liquid containing Ru(TsDPEN) was supported on silica gels. This supported ionic liquid-phase catalyst was effective in the asymmetric hydrogenation of quinoline, and could be recycled at least 6 times by simple filtration. Copyright
- Ding, Zi-Yuan,Wang, Tianli,He, Yan-Mei,Chen, Fei,Zhou, Hai-Feng,Fan, Qing-Hua,Guo, Qingxiang,Chan, Albert S. C.
-
supporting information
p. 3727 - 3735
(2014/01/06)
-
- Diverse organo-peptide macrocycles via a fast and catalyst-free oxime/intein-mediated dual ligation
-
Macrocyclic Organo-Peptide Hybrids (MOrPHs) can be prepared from genetically encoded polypeptides via a chemoselective and catalyst-free reaction between a trifunctional oxyamino/amino-thiol synthetic precursor and an intein-fusion protein incorporating a bioorthogonal keto group.
- Satyanarayana, Maragani,Vitali, Francesca,Frost, John R.,Fasan, Rudi
-
supporting information; experimental part
p. 1461 - 1463
(2012/03/26)
-
- Synthesis and characterization of a symmetric bis(7-hydroxyflavylium) containing a methyl viologen bridge
-
A symmetric bis(flavylium) constituted by two 7-hydroxyflavylium moieties linked by a methylviologen bridge was synthesized. The thermodynamic and kinetics of the network of chemical reactions involving bis(flavylium) and the model compound 7-hydroxy-4′-methylflavylium was completely characterized by means of direct and reverse pH jumps (stopped flow) and flash photolysis. Both compounds follow the usual pH-dependent network of chemical reactions of flavylium derivatives. The equilibrium species of the model compound are the flavylium cation (acidic species) and the trans-chalcone (basic species) with an apparent pK′a=2.85. In the case of the bis(flavylium) it was possible to characterize by 1H NMR spectroscopy three species with different degrees of isomerization: all flavylium, flavylium-trans-chalcone, and all trans-chalcone. Representation of the time-dependent mole fraction distribution of these three forms after a pH jump from equilibrated solutions of all-flavylium cation (lower pH values) to higher pH values, shows that formation of trans-chalcone is not completely stochastic (two independent isomerizations), the isomerization of one flavylium showing a small influence on the isomerization of the other. The radical of the methyl viologen bridge is formed upon reduction of the bis(trans-chalcone) with dithionite. The system is reversible after addition of an oxidant in spite of the occurrence of some decomposition. Copyright
- Diniz, Ana M.,Pinheiro, Carlos,Petrov, Vesselin,Parola, A. Jorge,Pina, Fernando
-
experimental part
p. 6359 - 6368
(2011/08/05)
-
- Competition between azido cleavage and triplet nitrene formation in azidomethylacetophenones
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Photolysis of p- and m-azidomethylacetophenone (1a, 1b) in argon-saturated solutions yields predominantly imine 2a, 2b, whereas irradiation of 1a, 1b in oxygen-saturated solutions results in heterocycles 3a, 3b, aldehydes 4a, 4b and nitriles 5a, 5b. Density functional theory calculations place the energy of the first and second excited state of the triplet ketones (T1K and T 2K) in 1a, 1b in close proximity to each other. The triplet transition state for cleaving the CN bond in 1a, 1b to form azido and benzyl radicals 1aB, 1bB is located only 3 kcal mol-1 (1 kcal = 4.184 kJ) above T1K, indicating that azido cleavage is feasible. The calculations place the energy of the triplet azido group (TA) in 1a, 1b ~25 kcal mol-1 below T1K; thus, this process is also easily accessible via energy transfer. Further, the transition state barrier for TA to expel N2 and form triplet nitrenes is less than 1 kcal mol-1 above TA in 1a, 1b. Laser flash photolysis of 1a, 1b reveals the formation of the triplet excited ketones of 1a, 1b, which decay to form benzyl radicals 1aB, 1bB and triplet alkylnitrenes. The triplet ketones and the benzyl radicals are quenched with molecular oxygen at rates close to diffusion, whereas the triplet nitrenes react more slowly with oxygen (~5 × 105 M-1s-1). We conclude that the triplet alkylnitrenes intercept the benzyl radicals to form 2 in argon-saturated solution, whereas the benzyl radicals are trapped to form 4 in oxygen-saturated solution; thus, the triplet nitrenes react with oxygen to form 3. CSIRO 2010.
- Ranaweera, Ranaweera A. A. Upul,Zhao, Yu,Muthukrishnan, Sivaramakrishnan,Keller, Christopher,Gudmundsdottir, Anna D.
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experimental part
p. 1645 - 1655
(2011/09/14)
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- Preparation of multifunctional supported metallocene catalyst using organic multifunctional modifier for synthesizing polyethylene/clay nanocomposites via in situ intercalative polymerization
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A new type of multifunctional ammonium modifier with carbonyl group and vinyl group was synthesized to prepare multifunctional montmorillonites (F-MMTs), which were used as multifunctional catalyst supports for in situ ethylene polymerization. High loading of metallocene catalyst in the galleries of F-MMT had been achieved due to the presence of carbonyl group in the multifunctional modifier. XRD profiles and TEM images showed that polyethylene/montmorillonite (PE/F-MMT) nanocomposites with exfoliated structure could be synthesized using the intercalated catalyst described above, even when the content of MMT was very high (more than 15.1 wt%). The as-produced PE/F-MMTs nanocomposites were composed of flower-like particles with a diameter of about 5 μm. A thermal stable monoclinic phase was observed in PE/F-MMT nanocomposites. Comparatively, the resultant PE/F-MMT nanocomposites showed low gas permeability. Interfacial interaction between PE matrix and F-MMT was enhanced due to the chemical linking between the two components via copolymerization of ethylene with vinyl group of F-MMT. Thus the resultant PE/F-MMT nanocomposites showed good structural stability.
- Ren, Changyi,Du, Xiaohua,Ma, Li,Wang, Yanhui,Zheng, Jun,Tang, Tao
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experimental part
p. 3416 - 3424
(2011/12/02)
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- Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase
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Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.
- Wang, Zhengqiang,Tang, Jing,Salomon, Christine E.,Dreis, Christine D.,Vince, Robert
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experimental part
p. 4202 - 4211
(2010/09/12)
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- Poly(N,N′-dibromo-N-ethyl-benzene-1,3-disulfonamide), N,N,N′,N′-tetrabromobenzene-1,3-disulfonamide and novel poly(N,N′-dibromo-N-phenylbenzene-1,3-disulfonamide) as powerful reagents for benzylic bromination
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N,N,N′,N′-Tetrabromobenzene-1,3-disulfonamide [TBBDA], poly(N,N′-dibromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS], and novel poly(N,N′-dibromo-N-phenylbenzene-1,3-disulfonamide) [PBPS] can be used for bromination of benzylic positions in solvent.
- Ghorbani-Vaghei, Ramin,Chegini, Mohammad,Veisi, Hojat,Karimi-Tabar, Mehdi
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scheme or table
p. 1861 - 1865
(2009/07/19)
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- Environmentally benign electrophilic and radical bromination 'on water': H2O2-HBr system versus N-bromosuccinimide
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A H2O2-HBr system and N-bromosuccinimide in an aqueous medium were used as a 'green' approach to electrophilic and radical bromination. Several activated and less activated aromatic molecules, phenylsubstituted ketones and styrene were efficiently brominated 'on water' using both systems at ambient temperature and without an added metal or acid catalyst, whereas various non-activated toluenes were functionalized at the benzyl position in the presence of visible light as a radical activator. A comparison of reactivity and selectivity of both brominating systems reveals the H2O2-HBr system to be more reactive than NBS for benzyl bromination and for the bromination of ketones, while for electrophilic aromatic substitution of methoxy-substituted tetralone it was higher for NBS. Also, higher yields of brominated aromatics were observed when using H2O2-HBr 'on water'. Bromination of styrene reveals that not just the structure of the brominating reagent but the reaction conditions: amount of water, organic solvent, stirring rate and interface structure, play a key role in defining the outcome of bromination (dibromination vs bromohydroxylation). In addition, mild reaction conditions, a straightforward isolation procedure, inexpensive reagents and a lower environment impact make aqueous brominating methods a possible alternative to other reported brominating protocols.
- Podgor?ek, Ajda,Stavber, Stojan,Zupan, Marko,Iskra, Jernej
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experimental part
p. 4429 - 4439
(2009/10/09)
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- Substituted isoxazolines, pharmaceutical compositions containing the same, methods of preparing the same, and uses of the same
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The invention relates to substituted isoxazolines according to the general formula (I) : in which A, R1, R2, R3, R4, Z, X, m, n, and p, are given in the claims, and salts thereof, to pharmaceutical compositions comprising said substituted isoxazolines, to methods of preparing said substituted isoxazolines as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases known to be at least in part mediated by HDAC activity or whose symptoms are known to be alleviated by HDAC inhibitors.
- -
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Page/Page column 20
(2008/06/13)
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- PNA-based reagents for the direct and site-specific synthesis of thymine dimer lesions in genomic DNA
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An acetophenone containing PNA-based reagent was designed for the direct and site-specific synthesis of a cis-syn thymidine dimer lesion in genomic DNA. Copyright
- Pieck, J. Carsten,Kuch, David,Grolle, Friederike,Linne, Uwe,Haas, Clemens,Carell, Thomas
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p. 1404 - 1405
(2007/10/03)
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- NOVEL INHIBITORS OF HISTONE DEACETYLASE FOR THE TREATMENT OF DISEASE
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Disclosed herein are carbonyl compounds of Formula: (I) as described herein. Compounds as modulators of histone deacetylase (HDAC), pharmaceutical compositions comprising the same, and methods of treating disease using the same are disclosed.
- -
-
Page/Page column 34-35
(2010/11/08)
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- Visible light induced 'on water' benzylic bromination with N-bromosuccinimide
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Benzylic bromination of various 4-substituted toluenes (Me, tert-Bu, COOEt and COMe) was effectively conducted with NBS in pure water and with a 40 W incandescent light-bulb as an initiator of the radical chain process, while electron donating groups (OMe and NHAc) directed the reaction to electrophilic aromatic substitution.
- Podgor?ek, Ajda,Stavber, Stojan,Zupan, Marko,Iskra, Jernej
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p. 1097 - 1099
(2007/10/03)
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- Azido-containing aryl β-diketo acid HIV-1 integrase inhibitors
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Aryl β-diketo acids (ADK) comprise a general class of potent HIV-1 integrase (IN) inhibitors, which can exhibit selective inhibition of strand transfer reactions in extracellular recombinant IN assays and provide potent antiviral effects in HIV-infected cells. Recent studies have shown that polycyclic aryl or aryl rings bearing aryl-containing substituents are components of potent members of this class. Reported herein is the first use of azido functionality as an aryl replacement in β-diketo acid IN inhibitors. The ability of azido-containing inhibitors to exhibit potent inhibition of IN and antiviral protection in HIV-infected cells, renders the azide group of potential value in the further development of ADK-based IN inhibitors.
- Zhang, Xuechun,Pais, Godwin C.G.,Svarovskaia, Evguenia S.,Marchand, Christophe,Johnson, Allison A.,Karki, Rajeshri G.,Nicklaus, Marc C.,Pathak, Vinay K.,Pommier, Yves,Burke Jr., Terrence R.
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p. 1215 - 1219
(2007/10/03)
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- Synthesis of cored dendrimers with internal cross-links
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Hydrolytic removal of the core unit and cross-linking of their wedges enables dendrimers to be "cored" (see schematic representation). By internalizing the alkenes, the ring-closing metathesis reaction will "stitch" the dendritic wedges to gather intramolecularly, even at dendrimer concentrations of 10-3M. In contrast peripheral alkenes react intermolecularly at this concentration.
- Schultz, Laura G.,Zhao, Yan,Zimmerman, Steven C.
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p. 1962 - 1966
(2007/10/03)
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- Efficient photodecarboxylation of aroyl-substituted phenylacetic acids in aqueous solution: A general photochemical reaction
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Photolysis (254-350 nm) of a variety of aroyl-substituted phenylacetic acids and p-acetylphenylacetic acid in aqueous solution at pH > pK(a) resulted in efficient photodecarboxylation (Φ = 0.2-0.7), to give in most cases a single product arising via the corresponding arylmethyl carbanion, indicating that photodecarboxylation is an efficient and general reaction for these types of compounds.
- Xu,Wan
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p. 2147 - 2148
(2007/10/03)
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- Photo-Arbuzov rearrangements of dimethyl benzyl and dimethyl p-acetylbenzyl phosphite
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The direct ultraviolet irradiation of dimethyl benzyl phosphite (1) and dimethyl p-acetylbenzyl phosphite (8) was investigated in acetonitrile, cyclohexane, and benzene. Phosphite 1 gives predominantly the photo-Arbuzov product, dimethyl benzylphosphonate (2), in 67-81% accountability yields, based of phosphite consumed, along with minor amounts of bibenzyl (20) and dimethyl phosphite (10). The quantum yield for formation of 2 in cyclohexane, φp, is 0.43. By contrast, irradiation of phosphite 8 yields only 7-13% of photo-Arbuzov phosphonate (9) but relatively large amounts of radical diffusion products: dimethyl phosphite (10) the p-acetylbenzyl radical dimer (11); and p-acetyltoluene (12). Evidently 8, closely related to acetophenone, reacts predominantly via the triplet excited estate to generate long-lived, triplet, free-radical pairs (6 and 7a). In benzene, further products (15, 16, 17a and 17b) are identified that result from addition of the phosphinoyl radical (6) to benzene to give cyclohexadienyl radical 14, followed by combination and disproportionation reactions with radical 7a. (Total product quantum yields in benzene (Σφi) = 0.47.) In benzene, accountabilities of radical 6 from photolysis of 8 as high as 56% are encountered along with up to 92% accountabilities of p-acetylbenzyl (7a) radicals. Addition of radical scavengers PhSH, PhCH2Br, and TEMPO in the three solvents establishes the cage yield of 9 as 3-5%. The products of radical trapping provide further proof of the radical-pair nature of the photolysis of phosphite 8, including a 95% accountability of 6 with PhCH2Br in benzene. It is proposed that the CH2-O scission of triplet 8 must occur concertedly with partial phosphoryl (P=O) bond formation. The trapping of radicals 6 and 7b from irradiation of phosphite 1 as the benzene adducts 22 and 23, analogous structurally to those (16 and 17) from phosphite 8, supports the postulation that photoisomerization of 1 to 2 proceeds via short-lived, presumably singlet, free-radical pairs.
- Ganapathy, Srinivasan,Sekhar, B. B. V. Soma,Cairns, S. Matthew,Akutagawa,Bentrude, Wesley G.
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p. 2085 - 2096
(2007/10/03)
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- Acetyl substituted benzenes. Useful cores for the synthesis of dendrimeric polyketones
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Benzylation of acetyl substituted benzenes is an efficient route to dendrimeric polyketones. A benzyl bromide possessing a masked carbonyl group is the key reagent for the dendrimeric growth. π-Stacking in the crystals of the first generation from 1,4-diacetylbenzene is observed.
- Diez-Barra, Enrique,Gonzalez, Raquel,De La Hoz, Antonio,Rodriguez, Ana,Sanchez-Verdu, Prado
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p. 8557 - 8560
(2007/10/03)
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- SYNTHESE D'UN ANALOGUE DU FOSTEDIL: LE DIETHYL 4-(1,2,3-DIAZAPHOSPHOL-5-YL)BENZYLPHOSPHONATE. ETUDE DE SON ACTIVITE INHIBITRICE DU TRANSPORT CALCIQUE A TRAVERS LES MEMBRANES BIOLOGIQUES
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We describe a four step synthesis of dicoordinated phosphorus Fostedil analogues: the diethyl-4(1,2,3-diazaphosphol-5-yl)benzylphosphonates 6, in which the benzothiazole Fostedil group is replaced by a 1,2,3 diazaphosphole ring.Inhibitive activity of calcium transfert, through biological membranes, of compounds 6 is weak. Key words: 1,2,3-Diazaphospholes; Fostedil analogues, calcium antagonist.
- Rodi, Youssef Kandri,Lopez, Lucien,Bellan, Jacques,Barrans, Jean,Essassi, El Moktar
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p. 225 - 231
(2007/10/02)
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- Radical Cleavage and Competing Photoreactions of Phenacyl Sulfides
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The photochemistry of ketones with the stuctures PhCOCH2SR, PhCOCH2S(O)R, PhCOCH2SO2R, and p-X-PhCOCH2SPh has been studied.They all give primarily acetophenone as product when irradiated in the presence of benzenethiol, which traps free phenacyl radicals formed by excited state β-cleavage.The sulfur-centered radicals give coupling products.The maximum quantum yield for β-cleavage is 0.40; apparently 60percent of the initially formed radical pairs undergo in-cage reaction.When R = methyl or butyl, some acetophenone is formed by γ-hydrogen abstraction as well.Alkyl subtituents on the α-carbon enhance the disproportionation reactions of the phenacyl radicals.Measurements of quantum yields and triplet life times (by Stern-Volmer quenching of acetophenone formation) allowed determination of rate constants for β-cleavage as follows: PhS, 1E10-1E11; MeS(O), 6 * 1E9; BuS, 1.5 * 1E8; BuSO2, 1 * 1E7 s-1.Ring substituents increase triplet lifetimes.Absorption and phosphorescence spectra indicate that the n,?* and ?,?* transitions both involve some population of the C-S ?* orbital.This mixing, together with free spin density on the excited carbonyl carbon, appears to determine the rate constant for cleavage.Radical cleavage is also very fast and efficient for p-((phenylthio)methyl)acetophenone.
- Wagner, Peter J.,Lindstrom, Michael J.
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p. 3062 - 3067
(2007/10/02)
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