- Facile synthesis of 3,6-diaminopyridazine
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An efficient two-step synthesis of 3,6-diaminopyridazine from 3,6-dichloropyridazine is reported. In this synthetic procedure, 4-methoxybenzylamine was used as a nitrogen source to substitute the chloro groups of 3,6-dichloropyridazine to form N,N'-bis-(4-methoxybenzyl)-pyridazine- 3,6-diamine. The 4-methoxybenzyl groups were then removed by treatment with hydrochloric acid to provide the target 3,6-diaminopyridazine with an overall yield of 78%. Copyright Taylor & Francis Group, LLC.
- Xing, Liyan,Petitjean, Anne,Schmidt, Rolf,Cuccia, Louis
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- Triphosgene/triphenylphosphine: A mild reagent for the conversion of alcohols to chlorides
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A mixture of triphosgene/triphenylphosphine in methylene chloride converts primary and secondary alcohols to chlorides at room temperature.
- Rivero,Somanathan,Hellberg
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Read Online
- Two approaches to the chemical development and large-scale preparation of a pyrimidyl tetrazole intermediate
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Two new routes to a pyrimidyl tetrazole intermediate are described. The first-generation route featured an ironcatalyzed cross-coupling between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. A subsequent intramolecular Heck cyclization afforded the desired bicyclic core, which was subsequently converted to the corresponding carboxylic acid via hydroboration and oxidation. This route was rapidly defined and used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate, which supported early toxicology and clinical studies of a drug candidate. A second-generation, eight-step route to the pyrimidyl tetrazole intermediate was defined and demonstrated on multikilogram scale in a 21% overall yield. The key transformation in this sequence was a copper(I) mediated cyclization of an iodopyrimidine, affording the bicyclic core of the target in quantitative yield. Due to the larger scale involved for the secondgeneration approach, significant process safety evaluation was undertaken for a number of steps in this route, and the highlights of these studies are presented.
- Mullens, Peter,Cleator, Ed,McLaughlin, Mark,Bishop, Brian,Edwards, John,Goodyear, Adrian,Andreani, Teresa,Jin, Yan,Kong, Jongrock,Li, Hongmei,Williams, Michael,Zacuto, Michael
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- Mechanism of solvolysis of substituted benzyl chlorides in aqueous ethanol
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The mechanism of solvolyses of activated ortho-, meta- and para-substituted benzyl chlorides in aqueous ethanol has been studied by using the Hammett-Brown and Yukawa-Tsuno treatments as well as by correlating logarithms of solvolysis rate constants with relative stabilities of corresponding benzyl carbocations in water calculated at the IEFPCM-M06–2X/6-311+G(3df,3pd) level of theory. Benzyl chlorides containing strong conjugative electron-donors in the para-position solvolyze by the SN1 mechanism, whereas other activated benzyl chlorides solvolyze by the SN2 mechanism via loose transition states.
- Denegri, Bernard,Mati?, Mirela,Va?ko, Monika
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supporting information
(2021/11/22)
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- Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense
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Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25–70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.
- Cullen, Danica R.,Gallagher, Ashlee,Duncan, Caitlin L.,Pengon, Jutharat,Rattanajak, Roonglawan,Chaplin, Jason,Gunosewoyo, Hendra,Kamchonwongpaisan, Sumalee,Payne, Alan,Mocerino, Mauro
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- COMPOUNDS AND METHODS FOR TREATING OXALATE-RELATED DISEASES
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Disclosed herein are compounds and compositions for modulating glycolate oxidase, useful for treating oxalate-related diseases, such as hyperoxaluria, where modulating glycolate oxidase is expected to be therapeutic to a patent in need thereof. Methods of modulating glycolate oxidase activity in a human or animal subject are also provided.
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Paragraph 0506
(2021/02/26)
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- Copper-catalyzed sp3-sp3 cross-coupling of turbo grignards with benzyl halides
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The aromatic ring in benzyl halides and sulfonates imparts unique reactivity at the benzylic carbon atom. Photoredox sp3-sp3 cross-coupling proved ineffective for coupling p-methoxybenzyl chloride (PMBCl), leading to a new strategy for the sp3-sp3 cross-coupling of benzyl halides and sulfonates. This strategy involved LiCl-accelerated synthesis of a Grignard reagent followed by a copper-catalyzed cross-coupling. The conditions worked well for PMBCl due to its exceptional reactivity but other benzyl bromides or sulfonates reacted poorly.
- Elahi-Mohassel, Synah,Girgis, Michael,Paige, Mikell,Petruncio, Greg
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supporting information
(2021/11/17)
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- Methods of synthesizing ionic liquids from primary alcohol-containing lignin compounds
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Methods and compositions are provided for synthesizing ionic liquids from lignin. Methods and compositions are also provided for treating lignin with ionic liquids.
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Page/Page column 19
(2021/06/09)
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- The Detosylation of Chiral 1,2-Bis(tosylamides)
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The deprotection of chiral 1,2-bis(tosylamides) to their corresponding 1,2-diamines is mostly unsuccessful under standard conditions. In a new methodology, the use of Mg/MeOH with sufficient steric additions allows the facile synthesis of 1,2-diamines in 78-98% yields. These results are rationalized using density functional theory and the examination of inner and outer-sphere reduction mechanisms.
- Butler, Nicholas M.,Clark, Timothy,Gaston, Jayden J.,Keller, Paul A.,Smyth, Jamie E.,Tague, Andrew J.,Van Eikema Hommes, Nico,Willis, Anthony C.,Yu, Haibo
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p. 9163 - 9180
(2021/07/19)
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- Turnover and Inactivation Mechanisms for (S)-3-Amino-4,4-difluorocyclopent-1-enecarboxylic Acid, a Selective Mechanism-Based Inactivator of Human Ornithine Aminotransferase
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The inhibition of human ornithine δ-aminotransferase (hOAT) is a potential therapeutic approach to treat hepatocellular carcinoma. In this work, (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, 6) was identified as a potent mechanism-based inactivator of hOAT while showing excellent selectivity over other related aminotransferases (e.g., GABA-AT). An integrated mechanistic study was performed to investigate the turnover and inactivation mechanisms of 6. A monofluorinated ketone (M10) was identified as the primary metabolite of 6 in hOAT. By soaking hOAT holoenzyme crystals with 6, a precursor to M10 was successfully captured. This gem-diamine intermediate, covalently bound to Lys292, observed for the first time in hOAT/ligand crystals, validates the turnover mechanism proposed for 6. Co-crystallization yielded hOAT in complex with 6 and revealed a novel noncovalent inactivation mechanism in hOAT. Native protein mass spectrometry was utilized for the first time in a study of an aminotransferase inactivator to validate the noncovalent interactions between the ligand and the enzyme; a covalently bonded complex was also identified as a minor form observed in the denaturing intact protein mass spectrum. Spectral and stopped-flow kinetic experiments supported a lysine-assisted E2 fluoride ion elimination, which has never been observed experimentally in other studies of related aminotransferase inactivators. This elimination generated the second external aldimine directly from the initial external aldimine, rather than the typical E1cB elimination mechanism, forming a quinonoid transient state between the two external aldimines. The use of native protein mass spectrometry, X-ray crystallography employing both soaking and co-crystallization methods, and stopped-flow kinetics allowed for the detailed elucidation of unusual turnover and inactivation pathways.
- Beaupre, Brett A.,Butrin, Arseniy,Doubleday, Peter F.,Ferreira, Glaucio M.,Kelleher, Neil L.,Liu, Dali,Melani, Rafael D.,Moran, Graham R.,Shen, Sida,Silverman, Richard B.,Tavares, Mauricio T.
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supporting information
p. 8689 - 8703
(2021/06/28)
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- Synthesis of ethylene bis [(2-hydroxy-5,1,3-phenylene) bis methylene] tetraphosphonic acid and their anticorrosive effect on carbon steel in 3%NaCl solution
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The inhibition performance of the newly synthesized Ethylene bis [(2-hydroxy-5,1,3-phenylene) bis methylene] tetraphosphonic acid (ETPA) toward carbon steel in 3% NaCl was investigated at different concentrations using potentiodynamic polarization (PDP) and impedance spectroscopy (EIS) methods. It was found that the inhibition capability was increased with increasing inhibitor dose and reach 92% at 10?3 mol/L. Also, Polarization curves showed that ETPA acts as a mixed type inhibitor with predominantly control of anodic reaction. The new inhibitor was investigated by different spectroscopic methods such as 1H, 13C and 31PNMR. The quantum parameters such as absolute electronegativity (χ), energy gap ΔE (EHOMO-ELUMO), global softness (σ), global hardness (η), electrophilicity index (ω) and the number of transfer electrons (ΔN) are calculated by density functional theory (DFT). The experimental also correlated with density functional theory results. The calculations show that ETPA has high density of negative charge located on the oxygen atoms of the phosphonate group facilitating the adsorption of ETPA on the surface of carbon steel. The inhibition efficiency of ETPA was discussed in terms of blocking of electrode surface by adsorption of ETPA molecules through active centers. The adsorption of ETPA on the surface of carbon steel obeyed the Langmuir isotherm paradigm.
- Sait,Aliouane,Toukal,Hammache,Al-Noaimi,Helesbeux,Duval
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- PROCESSES FOR PREPARING TRIAZOLE GLYCOLATE OXIDASE INHIBITORS
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The present disclosure provides processes for preparing 1,2,3-triazole-4-carboxylic acid related compounds of formulae (I) and (II) via a Suzuki coupling reaction. The Suzuki coupling reaction is achieved by coupling a compound of formula (IV), a boron-containing derivative of 1,2,3-triazole-4-carboxylate, with a cycloalkyl phenyl halide or sulfonate of formula (V).
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Paragraph 0019; 0220
(2021/07/17)
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- Synthesis and reactivity of α-sulfenyl-β-chloroenones, including oxidation and Stille cross-coupling to form chalcone derivatives
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The synthesis of a range of novel α-sulfenyl-β-chloroenones from the corresponding α-sulfenylketones, via a NCS mediated chlorination cascade, is described. The scope of the reaction has been investigated and compounds bearing alkyl- and arylthio substituents have been synthesised. In most instances, the Z α-sulfenyl-β-chloroenones were formed as the major products, while variation of the substituent at the β-carbon position led to an alteration in stereoselectivity. Stille cross-coupling with the Z α-sulfenyl-β-chloroenones led to selective formation of Z sulfenyl chalcones, while the E α-sulfenyl-β-chloroenones did not react under the same conditions. Oxidation of the Z α-sulfenyl-β-chloroenones was followed by isomerisation, leading to the E α-sulfinyl-β-chloroenones. Stille cross-coupling with the E α-sulfinyl-β-chloroenones produced the E sulfinyl chalcones. Either the E or Z sulfinyl chalcones can be obtained by altering the sequence of oxidation and Stille cross-coupling.
- Kearney, Aoife M.,Murphy, Linda,Murphy, Chloe C.,Eccles, Kevin S.,Lawrence, Simon E.,Collins, Stuart G.,Maguire, Anita R.
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supporting information
(2021/05/04)
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- Nickel catalyzed deoxygenative cross-coupling of benzyl alcohols with aryl-bromides
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A nickel-catalyzed cross-electrophile coupling of benzyl alcohols with aromatic bromides has been developed. This deoxygenative cross-coupling occurs under mild reaction conditions at ambient temperature affording diarylmethanes, or 1,3-diarylpropenes from benzyl allyl alcohols. The system demonstrated good chemoselectivity tolerating an assortment of reactive functional groups.
- Kumar Chenniappan, Vinoth,Peck, Devin,Rahaim, Ronald
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- Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase
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Aminotransferases are pyridoxal 5′-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and an α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident that γ-aminobutyric acid aminotransferase (GABA-AT), which balances the levels of inhibitory and excitatory neurotransmitters, has emerged as a promising therapeutic target for epilepsy and cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established an integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry to facilitate our design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue (6a), 25-times more efficient as an inactivator of GABA-AT compared to the parent compound (1R,3S,4S)-3-amino-4-fluorocyclopentane carboxylic acid (FCP, 4).
- Shen, Sida,Doubleday, Peter F.,Weerawarna, Pathum M.,Zhu, Wei,Kelleher, Neil L.,Silverman, Richard B.
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supporting information
p. 1949 - 1955
(2020/03/04)
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- Total synthesis of enhygrolide A and analogs
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The total synthesis of enhygrolide A, a γ-alkylidene butenolide natural product which exhibits antibacterial activities, is reported. The synthetic route features several key transformations, including a copper mediated Sonogashira/oxacyclization 5-exo-dig process to generate the alkylidene butenolide system and a Suzuki cross-coupling to introduce the benzylic unit. The methodology employed for this total synthesis represents a sufficiently flexible route to allow the synthesis of numerous analogs of these enhygrolides.
- Guilloteau, Vincent,Petrignet, Julien,Romdhani-Younes, Moufida,Sghairi, Douha,Thibonnet, Jér?me
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supporting information
(2020/03/10)
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- In vitro study and structure-activity relationship analysis of stilbenoid derivatives as powerful vasorelaxants: Discovery of new lead compound
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The development of vasorelaxant as the antihypertensive drug is important as it produces a rapid and direct relaxation effect on the blood vessel muscles. Resveratrol (RV), as the most widely studied stilbenoid and the lead compound, inducing the excellent vasorelaxation effect through the multiple signalling pathways. In this study, the in vitro vascular response of the synthesized trans-stilbenoid derivatives, SB 1-8e were primarily evaluated by employing the phenylephrine (PE)-precontracted endothelium-intact isolated aortic rings. Herein we report trans-3,4,4′-trihydroxystilbene (SB 8b) exhibited surprisingly more than 2-fold improvement to the maximal relaxation (Rmax) of RV. This article also highlights the characterization of the aromatic protons in terms of their unique splitting patterns in 1H NMR.
- Chan, Sock Ying,Loh, Yean Chun,Oo, Chuan Wei,Yam, Mun Fei
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- Photocatalytic Giese Addition of 1,4-Dihydroquinoxalin-2-ones to Electron-Poor Alkenes Using Visible Light
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The visible-light photoredox-catalyzed coupling of 1,4-dihydroquinoxalin-2-ones and Michael acceptors was achieved using Ru(bpy)3Cl2 as the photocatalyst and (PhO)2PO2H as an additive. The optimized reaction conditions provide a good yield for the radical conjugate addition products (44 examples) with a wide range of structurally different Michael acceptors. A gram scale reaction using sunlight irradiation is also described. Furthermore, several transformations were carried out with the Giese addition products.
- Rostoll-Berenguer, Jaume,Blay, Gonzalo,Pedro, José R.,Vila, Carlos
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supporting information
p. 8012 - 8017
(2020/11/02)
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- AN EFFICIENT AND ENVIRONMENT FRIENDLY PROCESS FOR CHLOROMETHYLATION OF SUBSTITUTED BENZENES
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Disclosed herein is an efficient, environment friendly and commercially viable process for preparation of chloromethylated compound of formula I in substantially pure form and high yield, from the compound of formula II. The process includes contacting the compound of formula II with a chloromethylating agent generated in-situ by reaction of a formaldehyde precursor and hydrogen chloride, in a suitable solvent/contacting medium and in the presence of a catalytic amount of a short chain/low molecular weight carboxylic acid of formula III. I II III wherein, R1, R2, R3 and R4 are as defined in the description.
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Paragraph 0076; 0077; 0078; 0080
(2020/12/30)
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- Ionic-Liquid-Supported 1,3-Dimethylimidazolidin-2-one: Application as a Reusable Halogenation Reagent
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We describe the synthesis of ionic-liquid-supported 1,3-dimethylimidazolidin-2-one, together with the halogenation of alcohols in a reaction system in which this reagent is combined with oxalyl chloride. A new method was established that does not require additives such as bases, and which permits the ready isolation and purification of the product. Good conversions were obtained, and good reusability of the reagent was observed.
- Koguchi, Shinichi,Shibuya, Yuga,Igarashi, Yusuke,Takemura, Haruka
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supporting information
p. 943 - 946
(2019/05/10)
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- COMPOUNDS AND METHODS FOR TREATING OXALATE-RELATED DISEASES
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Disclosed herein are compounds and compositions for modulating glycolate oxidase, useful for treating oxalate-related diseases, such as hyperoxaluria, where modulating glycolate oxidase is expected to be therapeutic to a patent in need thereof. Methods of modulating glycolate oxidase activity in a human or animal subject is also provided.
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Paragraph 0248; 0273
(2019/09/12)
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- Preparation method of 4-p-hydroxyphenyl-2-butanone
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The invention discloses a preparation method of 4-p-hydroxyphenyl-2-butanone. The preparation method comprises the following steps of using anisaldehyde from a natural source as a raw material, preparing to obtain anisalcohol through a reduction reaction, preparing to obtain p-methoxybenzyl chloride through a chlorination reaction, next preparing to obtain 2-acetyl-3-(4-methoxyphenyl)ethyl propionate through a substitution reaction with ethyl acetoacetate from a biomass source, next preparing to obtain 4-(4-methoxyphenyl)-2-butanone through hydrolysis and decarboxylation reactions, and finallypreparing to obtain the 4-p-hydroxyphenyl-2-butanone through a demethylation reaction. The preparation method can be used for realizing the preparation of all-natural carbon-source raspberry ketone,and has the advantages of being simple and direct in route, easy to operate, environmentally friendly and high in yield and the like.
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Paragraph 0038-0039; 0041-0044
(2019/02/10)
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- On the Necessity of Nucleobase Protection for 2-Thiouracil for Fmoc-Based Pseudo-Complementary Peptide Nucleic Acid Oligomer Synthesis
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A selection of benzyl-based protecting groups for thiouracil (SU) for the synthesis of pseudo-complementary peptide nucleic acid (PNA) has been evaluated. The 4-methoxybenzyl-protecting group that has found use for SU during Boc-based oligomerization is also suitable for Fmoc-based oligomerization. Furthermore, it is demonstrated that SU protection is unnecessary for the successful synthesis of thiouracil-containing PNA. The new 2-thiothymine (ST) PNA monomer has also been prepared and incorporated into an oligomer and its binding to complementary PNA evaluated.
- Hudson, Robert H.E.,Heidari, Ali,Martin-Chan, Timothy,Park, Gyeongsu,Wisner, James A.
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p. 13252 - 13261
(2019/11/16)
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- α-Diimine-Niobium Complex-Catalyzed Deoxychlorination of Benzyl Ethers with Silicon Tetrachloride
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α-Diimine niobium complexes serve as catalysts for deoxygenation of benzyl ethers by silicon tetrachloride (SiCl4) to cleanly give two equivalents of the corresponding benzyl chlorides, where SiCl4 has the dual function of oxygen scavenger and chloride source with the formation of a silyl ether or silica as the only byproduct. The reaction mechanism has two successive trans-etherification steps that are mediated by the niobium catalyst, first forming one equivalent of benzyl chloride along with the corresponding silyl ether intermediate that undergoes the same reaction pathway to give the second equivalent of benzyl chloride and silyl ether.
- Parker, Bernard F.,Hosoya, Hiromu,Arnold, John,Tsurugi, Hayato,Mashima, Kazushi
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supporting information
p. 12825 - 12831
(2019/10/19)
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- NMP-mediated chlorination of aliphatic alcohols with aryl sulfonyl chloride for the synthesis of alkyl chlorides
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NMP-mediated chlorination of aliphatic alcohols has been developed for the synthesis of alkyl chlorides. This facile, efficient and practical approach used simple and readily available aryl sulfonyl chlorides as the chlorination reagent for the construction of C–Cl bond in good to excellent yields with mild conditions and broad substrate scope.
- Zheng, Dagui,Mao, Liu-Liang,Zhu, Xian-Hong,Zhou, An-Xi
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supporting information
p. 2793 - 2800
(2018/11/06)
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- A General Catalytic Method for Highly Cost- and Atom-Efficient Nucleophilic Substitutions
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A general formamide-catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT-mediated dihydroxychlorination of an OH-containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E-factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional-group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one-pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN2 inversion, which demonstrates the high practical value of the presented method.
- Huy, Peter H.,Filbrich, Isabel
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supporting information
p. 7410 - 7416
(2018/04/30)
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- Visible-Light-Mediated Iminyl Radical Generation from Benzyl Oxime Ether: Synthesis of Pyrroline via Hydroimination Cyclization
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The treatment of an O-(4-methoxybenzyl) oxime ether bearing an olefin substituent and 1-chloroanthraquinone (1-Cl-AQN) catalyst in 2-butanone under visible-light irradiation affords pyrroline via an iminyl radical intramolecular hydroimination. Mechanistic studies indicate that iminyl radical generation mainly proceeds by hydrogen abstraction of the photocatalyst from the benzyl position of the oxime. Moreover, the hydrogen atom was identified in circulation from the benzylic position of the substrates between AQN and 2-butanone to quench the carbon radical without requiring any additional reagents.
- Usami, Kaoru,Yamaguchi, Eiji,Tada, Norihiro,Itoh, Akichika
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supporting information
p. 5714 - 5717
(2018/09/21)
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- Nucleophilic Substitutions of Alcohols in High Levels of Catalytic Efficiency
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A practical method for the nucleophilic substitution (SN) of alcohols furnishing alkyl chlorides, bromides, and iodides under stereochemical inversion in high catalytic efficacy is introduced. The fusion of diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride as a reagent allows notable turnover numbers up to 100. Moreover, the use of plain acetyl chloride as a stoichiometric promotor in an invertive SN-type transformation is demonstrated for the first time. The operationally straightforward protocol exhibits high levels of stereoselectivity and scalability and tolerates a variety of functional groups.
- Stach, Tanja,Dr?ger, Julia,Huy, Peter H.
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supporting information
p. 2980 - 2983
(2018/05/28)
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- Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic Substitutions of Alcohols
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Herein, a method for the nucleophilic substitution (SN) of benzyl alcohols yielding chloro alkanes is introduced that relies on aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol-%) and benzoyl chloride (BzCl) as reagent. A systematic screening of various sulfoxides and other sulfinyl containing Lewis bases afforded (2-methoxyphenyl)methyl sulfoxide as optimal catalyst. In contrast to reported formamide catalysts, sulfoxides also enable the application of plain acetyl chloride (AcCl) as reagent. In addition, it was demonstrated that weakly electrophilic carboxylic acid chlorides like BzCl promote Pummerer rearrangement of sulfoxides already at room temperature. This side-reaction also provided the explanation, why sulfoxide catalyzed SN-reactions of alcohols do not allow the effective production of aliphatic and electron deficient chloro alkanes. Comparison experiments provided further insight into the reaction mechanism.
- Motsch, Sebastian,Schütz, Christian,Huy, Peter H.
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supporting information
p. 4541 - 4547
(2018/09/13)
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- Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents
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A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.
- Semenova, Marina N.,Demchuk, Dmitry V.,Tsyganov, Dmitry V.,Chernysheva, Natalia B.,Samet, Alexander V.,Silyanova, Eugenia A.,Kislyi, Victor P.,Maksimenko, Anna S.,Varakutin, Alexander E.,Konyushkin, Leonid D.,Raihstat, Mikhail M.,Kiselyov, Alex S.,Semenov, Victor V.
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p. 700 - 721
(2019/01/03)
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- Electrochemical Deprotection of para-Methoxybenzyl Ethers in a Flow Electrolysis Cell
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Electrochemical deprotection of p-methoxybenzyl (PMB) ethers was performed in an undivided electrochemical flow reactor in MeOH solution, leading to the unmasked alcohol and p-methoxybenzaldehyde dimethyl acetal as a byproduct. The electrochemical method removes the need for chemical oxidants, and added electrolyte (BF4NEt4) can be recovered and reused. The method was applied to 17 substrates with high conversions in a single pass, yields up to 92%, and up to 7.5 g h-1 productivity. The PMB protecting group was also selectively removed in the presence of some other common alcohol protecting groups.
- Green, Robert A.,Jolley, Katherine E.,Al-Hadedi, Azzam A. M.,Pletcher, Derek,Harrowven, David C.,De Frutos, Oscar,Mateos, Carlos,Klauber, David J.,Rincón, Juan A.,Brown, Richard C. D.
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supporting information
p. 2050 - 2053
(2017/04/27)
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- Unusual C-I?O halogen bonding in triazole derivatives: Gelation solvents at two extremes of polarity and formation of superorganogels
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To investigate the influence of halogen bond (XB) on the gelation of a one-component organogel system, a new family of 5-iodo-1H-1,2,3-triazole and 1H-1,2,3-triazole gelators was designed and synthesized. The iodo gelators (1I, 3I) gelled various solvents at low concentrations and formed many superorganogels, whereas the hydrogenous gelators (1H, 3H) showed much poorer gelling performance. An X-ray analysis of the single crystals of two reference compounds (16I, 16H) reveals that the unusual C-I?O XB interaction is responsible for this difference. The results of spectroscopic examinations (XRD, SEM, 1H NMR, and UV) are well consistent with those of single-crystal analyses. Under the guidance of the XB interaction and the weak π-π interaction, 1I and 3I self-assemble to hexagonal columnar aggregations in the gel state, whereas 1H and 3H, driven by CH-π interactions, feature the formation of gels with a lamellar structure. The mechanical property of iodo gels is much better than that of hydrogenous gels under the same concentration. Gels from 1I respond to the stimuli of Hg2+, Cu2+, Zn2+, and Mg2+ as perchlorate salts, and gels from 1H are selectively responsive to Hg2+ solely.
- Huang, Yaodong,Li, Huimin,Li, Ziyan,Zhang, Yan,Cao, Wenwen,Wang, Luyuan,Liu, Shuxue
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p. 311 - 321
(2017/03/29)
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- Preparation of 7-phenylacetamide-3-chloromethyl-cephalosporanic acid p-methoxybenzyl ester
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The invention belongs to the field of synthesis of cephalosporin drug intermediates and disclosesa preparation method of 7-phenylacetamide-3-chloromethyl-cephalosporanic acid p-methoxybenzyl ester (short for GCLE). According to the method, penicillin G potassium salt taken as an initial raw material reacts with 4-methoxybenzylchloride firstly, penicillin sulfoxide ester is prepared through oxidation with peracetic acid and reacts with 2-mercaptobenzothiazole firstly, then a product reacts with benzene sulfinic acid, a ring opening product is obtained and reacts with chlorine, sodium methoxide is used for ring closing under the action of a methanol solvent, and 7-phenylacetamide-3-chloromethyl-cephalosporanic acid p-methoxybenzyl ester is obtained. The solvent is simple and easy to recover, reaction conditions are mild, operation is simple and convenient, and industrial production is easy.
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Paragraph 0024
(2017/09/02)
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- METHOD FOR PREPARATION OF MANNOSIDE DERIVATIVES
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A method for preparation of a compound of formula (I) wherein R is H or p-methoxybenzyl (PMB).
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Page/Page column 14; 15
(2018/01/17)
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- Direct halogenation of alcohols with halosilanes under catalyst- and organic solvent-free reaction conditions
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A chemoselective method for the direct halogenation of different types of alcohols with halosilanes under catalyst- and solvent-free reaction conditions (SFRC) is reported. Various primary, secondary and tertiary benzyl alcohols and tertiary alkyl alcohols were directly transformed to the corresponding benzyl and alkyl halides, respectively, using chlorotrimethylsilane (TMSCl) and bromotrimethylsilane (TMSBr).
- Ajvazi, Njomza,Stavber, Stojan
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supporting information
p. 2430 - 2433
(2016/05/19)
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- Direct synthesis of anilines and nitrosobenzenes from phenols
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A one-pot synthesis of anilines and nitrosobenzenes from phenols has been developed using an ipso-oxidative aromatic substitution (iSOAr) process. The products are obtained in good yields under mild and metal-free conditions. The leaving group effect on reactions that proceed through mixed quionone monoketals has also been investigated and a predictive model has been established.
- St Amant,Frazier,Newmeyer,Fruehauf,Read De Alaniz
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supporting information
p. 5520 - 5524
(2016/07/06)
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- Formamides as Lewis Base Catalysts in SNReactions—Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers
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A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.
- Huy, Peter H.,Motsch, Sebastian,Kappler, Sarah M.
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supporting information
p. 10145 - 10149
(2016/08/16)
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- Iodobenzene Dichloride in the Esterification and Amidation of Carboxylic Acids: In-Situ Synthesis of Ph3PCl2
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A novel, in-situ synthesis of dichlorotriphenylphosphorane (Ph3PCl2) is accomplished upon combining PPh3and the easily prepared hypervalent iodine reagent iodobenzene dichloride (PhICl2). The phosphorane is selectively generated in the presence of carboxylic acid or alcohol residues to rapidly produce acyl chlorides and alkyl chlorides in high yields. Addition of EtOH, PhOH, BnOH, Et2NH or CH2N2results in the direct synthesis of esters, amides and diazo ketones from carboxylic acids.
- Carle, Myriam S.,Shimokura, Grace K.,Murphy, Graham K.
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supporting information
p. 3930 - 3933
(2016/08/24)
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- Novel preparation method of anisyl propanal
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The invention relates to a novel preparation method of anisyl propanal. The method comprises the following steps: adding haloid acid into anisyl alcohol, and stirring at 5-20 DEG C to react for 1-3 hours, thereby obtaining the corresponding anisyl halide; and adding a solvent, a solid weak alkali and propenyl methyl ether into a reactor, slowly adding the halide into the reactor, and reacting at 15-25 DEG C for 4-6 hours, thereby obtaining the product. By using the commercially available anisyl alcohol as the raw material, the anisyl alcohol firstly reacts with the haloid acid to obtain the p-methoxy benzyl halogen, and the obtained p-methoxy benzyl halogen reacts with the propenyl methyl ether by using the solid weak alkali as the alkali and an acetonitrile-water mixed solvent as the solvent to obtain the product anisyl propanal. The method is economical and environment-friendly, does not need any high-pressure reactor or noble metal catalyst, is simple to operate, and has the advantages of low cost and mild reaction conditions.
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Paragraph 0019; 0020; 0021
(2016/12/01)
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- METHOD OF CONVERTING ALCOHOL TO HALIDE
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The present invention relates to a method of converting an alcohol into a corresponding halide. This method comprises reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom. The present invention also relates to a method of converting an alcohol into a corresponding substitution product. The second method comprises: (a) performing the method of the invention of converting an alcohol into the corresponding halide; and (b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.
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Page/Page column 93; 94; 95; 96
(2017/01/02)
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- A method for preparing finocchio yl-propionaldehyde
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The invention discloses a preparation method of anisyl propionaldehyde. The preparation method comprises that haloid acid is added into anisyl alcohol, the mixture is stirred and undergoes a reaction at a temperature of 5-20 DEG C for 1-3h, a solvent, alkali powder and a phase-transfer catalyst are added into a reactor, a halide and propionaldehyde are slowly added into the reactor, and the materials in the reactor undergo a reaction at a temperature of 60-110 DEG C for 12-16h to produce a product. The anisyl alcohol sold on the market is used as a raw material and reacts with haloid acid to produce p-methoxybenzyl halide, and the p-methoxybenzyl halide, propionaldehyde, sodium hydroxide powder as a base and toluene as a solvent undergo a reaction in the presence of the phase-transfer catalyst to produce anisyl propionaldehyde. The preparation method is economic and environmentally friendly, is free of high pressure reaction equipment and a noble metal catalyst, has a low cost and simple processes, and allows simple reaction conditions.
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Paragraph 0032-0033
(2019/02/02)
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- Method of manufacturing imidoyl diazidosulfochloride compd. various compd. and manufacturing method of using the same
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PROBLEM TO BE SOLVED: To provide a new production method for synthesizing an imidoyl chloride compound dispensing with chlorination agents having poor handleability, to provide a method for producing various compounds in high yield and purity by using the imidoyl chloride compound, and to provide a method for isolating the imidoyl chloride compound in high efficiency and purity from a mixture of the imidoyl chloride compound and a phthalic anhydride compound.SOLUTION: The method for producing the imidoyl chloride compound comprises reaction of a specific amide compound with a specific phthaloyl chloride compound to produce a specific imidoyl chloride compound.
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Paragraph 0052
(2016/12/16)
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- Trichloroisocynuric acid/DMF as efficient reagent for chlorodehydration of alcohols under conventional and ultrasonic conditions
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A new and efficient method for the chlorodehydration of alcohols utilizing TCCA/DMF is described. Various alcohols can be converted smoothly into their corresponding alkyl chlorides in high yields under mild conditions with short reaction times. Taylor & Francis Group, LLC.
- Venkana, Purugula,Kumar, Mukka Satish,Rajanna, Kamatala Chinna,Ali, Mir Moazzam
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- Discovery of phenoxybutanoic acid derivatives as potent endothelin antagonists with antihypertensive activity
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A series of phenoxybutanoic acid derivatives were synthesized and tested for their antagonistic activity on the contraction of the rat thoracic aortic ring induced by endothelin-1. Preliminary screening results showed that 6e and 6g with benzoheterocycles demonstrated significant antagonistic activities when compared to the reference compound BQ123. The results from additional assays for the binding affinity and selectivity for endothelin receptors showed that 6e was a selective ETA antagonist with a nanomolar IC50. Moreover, 6e was effective in relieving hypoxia-induced pulmonary arterial hypertension and right ventricular weight ratio. Therefore, 6e may have potential for further development as a therapeutic agent for the treatment of cardiovascular diseases.
- Cai, Jin,Liu, Ligang,Hong, Kwon Ho,Wang, Peng,Li, Lushen,Cao, Meng,Sun, Chunlong,Wu, Xiaoqing,Zong, Xi,Chen, Junqing,Ji, Min
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p. 657 - 667
(2015/02/19)
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- Aromatic cation activation: Nucleophilic substitution of alcohols and carboxylic acids
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A new method for the nucleophilic substitution of alcohols and carboxylic acids using aromatic tropylium cation activation has been developed. This article reports the use of chloro tropylium chloride for the rapid generation of alkyl halides and acyl chlorides under very mild reaction conditions. It demonstrates, for the first time, the synthetic potential of tropylium cations in promoting chemical transformations.
- Nguyen, Thanh V.,Bekensir, Alp
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supporting information
p. 1720 - 1723
(2014/04/17)
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- Sulfite formation versus chlorination of benzyl alcohols with thionyl chloride
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Recently, we have reported the photolytic decay of a library of para-substituted dibenzylic sulfites in a Srinivasan-Griffin-Rayonet photochemical reactor. In an attempt to synthesize the complete library for that study we discovered that bis(p-methoxybenzyl) sulfite and bis(p-phenoxybenzyl) sulfite could not be formed and only their corresponding benzyl chlorides were synthesized. Thus, sulfite formation versus chlorination of a range of para-substituted benzyl alcohols with thionyl chloride was investigated. Sulfite formation was observed to be parabolically related to Swain and Lupton's Field ?-values while chloride formation was found to be linearly related to Swain and Lupton's Field ?-values.
- Rodriguez, Deana A.,Priefer, Ronny
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p. 3045 - 3048
(2014/05/20)
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- Total synthesis of acerogenins E, G and K, and centrolobol
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The first total synthesis of the diarylheptanoid acerogenins E and K, isolated from Acer nikoense MAXIM., is described. Formation of the 13-membered m,m-cyclophane skeleton was successfully achieved on the basis of a domino process involving a Miyaura arylborylation-intramolecular Suzuki reaction. The cyclization precursor was prepared via a Wittig reaction and Claisen-Schmidt condensation, which proceeded in moderate yields. The total synthesis of acerogenin G and centrolobol was also achieved from a common synthetic intermediate.
- Ogura, Tetsuhiro,Usuki, Toyonobu
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supporting information
p. 2807 - 2815
(2013/03/28)
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- DMSO-catalyzed chlorination of alcohols using N-phenylbenzimidoyl chloride
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N-phenylbenzimidoyl chloride has been demonstrated as an efficient chlorination reagent catalyzed by dimethyl sulfoxide (DMSO) in conversion of alcohols to corresponding chlorides. The reaction conditions were mild, and most of the substrates gave satisfactory yields. The configuration inversion of the chlorination was proved using optically active phenyl alcohols. The amount of DMSO can be as low as 0.001 eq without reducing the efficiency of the chlorination. A plausible mechanism for the reaction was proposed and proved by experiments. The reaction is stereoselective and potentially chemoselective among primary benzyl alcohols, secondary benzyl alcohols, and unactivated aliphatic alcohols.
- Wang, Qiang,Xu, Jian,Xu, Zhou-Qing,Yan, Ji-Dan
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p. 2071 - 2076
(2013/06/05)
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- Palladium-catalyzed carboxylative coupling of benzyl chlorides with allyltributylstannane: Remarkable effect of palladium nanoparticles
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Palladium-catalyzed carboxylative coupling of benzyl chlorides with allyltributylstannane was successfully conducted to produce benzyl but-3-enoates in satisfactory to good yields. The carboxylative coupling reaction occurred smoothly under mild conditions in the presence of palladium nanoparticles in tetrahydrofuran.
- Feng, Xiujuan,Sun, Anle,Zhang, Sheng,Yu, Xiaoqiang,Bao, Ming
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supporting information
p. 108 - 111
(2013/04/10)
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- Investigation of peptide thioester formation via N→Se acyl transfer
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Native chemical ligation is widely used for the convergent synthesis of proteins. The peptide thioesters required for this process can be challenging to produce, particularly when using Fmoc-based solid-phase peptide synthesis. We have previously reported a route to peptide thioesters, following Fmoc solid-phase peptide synthesis, via an N→S acyl shift that is initiated by the presence of a C-terminal cysteine residue, under mildly acidic conditions. Under typical reaction conditions, we occasionally observed significant thioester hydrolysis as a consequence of long reaction times (~48h) and sought to accelerate the reaction. Here, we present a faster route to peptide thioesters, by replacing the C-terminal cysteine residue with selenocysteine and initiating thioester formation via an N→Se acyl shift. This modification allows thioester formation to take place at lower temperatures and on shorter time scales. We also demonstrate how application of this strategy also accelerates peptide cyclization, when a linear precursor is furnished with an N-terminal cysteine and C-terminal selenocysteine.
- Adams, Anna L.,Macmillan, Derek
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- Regio- and chemoselective palladium-catalyzed benzylallylation of activated olefins: The remarkable effect of palladium nanoparticles
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The palladium-catalyzed three-component reactions of benzyl halides, activated olefins, and allyltributylstannane were successfully conducted to produce the corresponding benzylallylation products in satisfactory to high yields. The benzylallylation reaction proceeded smoothly under mild conditions in the presence of palladium nanoparticles in tetrahydrofuran. The Royal Society of Chemistry 2013.
- Zhang, Xuan,Feng, Xiujuan,Yu, Xiaoqiang,He, Ren,Bao, Ming
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p. 4016 - 4024
(2013/07/05)
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