- Synthesis, characterization, antimicrobial, antioxidant and computational evaluation of N-acyl-morpholine-4-carbothioamides
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Abstract: The present research paper reports the convenient synthesis, successful characterization, in vitro antibacterial, antifungal, antioxidant potency and biocompatibility of N-acyl-morpholine-4-carbothioamides (5a–5j). The biocompatible derivatives were found to be highly active against the tested bacterial and fungal strains. Moreover, some of the screened N-acyl-morpholine-4-carbothioamides exhibited excellent antioxidant potential. Docking simulation provided additional information about possibilities of their inhibitory potential against RNA. It has been predicted by in silico investigation of the binding pattern that compounds 5a and 5j can serve as the potential surrogate for design of novel and potent antibacterial agents. The results for the in vitro bioassays were promising with the identification of compounds 5a and 5j as the lead and selective candidate for RNA inhibition. Results of the docking computations further ascertained the inhibitory potential of compound 5a. Based on the in silico studies, it can be suggested that compounds 5a and 5j can serve as a structural model for the design of antibacterial agents with better inhibitory potential. Graphic abstract: Binding mode of compound 5j inside the active site of RNA in 3D space. 5j displayed highest antibacterial potential than the reference drug ampicillin with ZOI 10.50?mm against Staphylococcus aureus. 5j also displayed highest antifungal potential than the reference drug amphotericin B with ZOI 18.20?mm against Fusarium solani.[Figure not available: see fulltext.].
- Aziz, Hamid,Saeed, Aamer,Khan, Muhammad Aslam,Afridi, Shakeeb,Jabeen, Farukh
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p. 763 - 776
(2020/03/04)
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- Rhodium(III)-catalyzed chemodivergent annulations between phenyloxazoles and diazos via C–H activation
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Acid-controlled, chemodivergent and redox-neutral annulations for the synthesis of isocoumarins and isoquinolinones have been realized via Rh(III)-catalyzed C[sbnd]H activation. Diazo compounds act as a carbene precursor, and coupling occurs in one-pot process, where adipic acid and trimethylacetic acid promote chemodivergent cyclizations.
- Zhang, Xueguo,Wang, Peigen,Zhu, Liangwei,Chen, Baohua
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supporting information
p. 695 - 699
(2020/06/28)
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- One-step Conversion of Amides and Esters to Acid Chlorides with PCl3
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A general and efficient iodine-promoted chlorination of amides and esters with phosphorus trichloride is described. For the first time. Various inactivated amides including secondary and tertiary amides were directly converted to the corresponding acid chlorides in one-step. The substrate scope of methyl esters including aromatic and aliphatic esters was also explored under this system. This method is simple, scalable and wide in scope, which provides an approach to preparation of these acid chlorides.
- Li, Fangshao,Wu, Xiaofang,Guo, Fengzhe,Tang, Zi-Long,Xiao, Jing
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supporting information
p. 4314 - 4317
(2021/07/16)
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- Decarboxylative Borylation of mCPBA-Activated Aliphatic Acids
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A decarboxylative borylation of aliphatic acids for the synthesis of a variety of alkylboronates has been developed by mixing m-chloroperoxybenzoic acid (mCPBA)-activated fatty acids with bis(catecholato)diboron in N,N-dimethylformamide (DMF) at room temperature. A radical chain process is involved in the reaction which initiates from the B-B bond homolysis followed by the radical transfer from the boron atom to the carbon atom with subsequent decarboxylation and borylation.
- Wei, Dian,Liu, Tu-Ming,Zhou, Bo,Han, Bing
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supporting information
p. 234 - 238
(2020/01/02)
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- Nickel-Catalyzed Cross-Coupling of Alkyl Carboxylic Acid Derivatives with Pyridinium Salts via C-N Bond Cleavage
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The electrophile-electrophile cross-coupling of carboxylic acid derivatives and alkylpyridinium salts via C-N bond cleavage is developed. The method is distinguished by its simplicity and steers us through a variety of functionalized ketones in good to excellent yields. Besides acid chlorides, carboxylic acids were also employed as acylating agents, which enabled us to incorporate acid-sensitive functional groups such as MOM, BOC, and acetal. Control experiments with TEMPO revealed a radical pathway.
- Pulikottil, Feba Thomas,Pilli, Ramadevi,Suku, Rohith Valavil,Rasappan, Ramesh
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supporting information
p. 2902 - 2907
(2020/04/09)
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- Palladium-catalyzed cascade decarboxylative amination/6- endo-dig benzannulation of o-alkynylarylketones with n-hydroxyamides to access diverse 1-naphthylamine derivatives
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An efficient and practical one-pot strategy to produce highly substituted 1-naphthylamines via sequential palladium-catalyzed decarboxylative amination/intramolecular 6-endo-dig benzannulation reactions has been described. In this reaction, a broad range of electron-rich, electron-neutral, and electron-deficient o-alkynylarylketones react well with N-hydroxyl aryl/alkylamides to give a diversity of 1-naphthylamines in good to excellent yields under mild reaction conditions. The gram-scale synthesis, with benefits such as undiminished product yield and easy transformation, illustrated the practicality of this method.
- Zuo, Youpeng,He, Xinwei,Tang, Qiang,Hu, Wangcheng,Zhou, Tongtong,Shang, Yongjia
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supporting information
p. 3890 - 3894
(2020/05/18)
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- An α-Cyclopropanation of Carbonyl Derivatives by Oxidative Umpolung
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The reactivity of iodine(III) reagents towards nucleophiles is often associated with umpolung and cationic mechanisms. Herein, we report a general process converting a range of ketone derivatives into α-cyclopropanated ketones by oxidative umpolung. Mechanistic investigation and careful characterization of side products revealed that the reaction follows an unexpected pathway and suggests the intermediacy of non-classical carbocations.
- Bauer, Adriano,Di Mauro, Giovanni,Li, Jing,Maulide, Nuno
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supporting information
p. 18208 - 18212
(2020/08/21)
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- Acylated 1 H-1,2,4-Triazol-5-Amines Targeting Human Coagulation Factor XIIa and Thrombin: Conventional and Microscale Synthesis, Anticoagulant Properties, and Mechanism of Action
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We herein report the conventional and microscale parallel synthesis of selective inhibitors of human blood coagulation factor XIIa and thrombin exhibiting a 1,2,4-Triazol-5-Amine scaffold. Structural variations of this scaffold allowed identifying derivative 21i, a potent 29 nM inhibitor of FXIIa, with improved selectivity over other tested serine proteases and also finding compound 21m with 27 nM inhibitory activity toward thrombin. For the first time, acylated 1,2,4-Triazol-5-Amines were proved to have anticoagulant properties and the ability to affect thrombin-And cancer-cell-induced platelet aggregation. Performed mass spectrometric analysis and molecular modeling allowed us to discover previously unknown interactions between the synthesized inhibitors and the active site of FXIIa, which uncovered the mechanistic details of FXIIa inhibition. Synthesized compounds represent a promising starting point for the development of novel antithrombotic drugs or chemical tools for studying the role of FXIIa and thrombin in physiological and pathological processes.
- Korff, Marvin,Imberg, Lukas,Will, Jonas M.,Bückrei?, Nico,Kalinina, Svetlana A.,Wenzel, Benjamin M.,Kastner, Gregor A.,Daniliuc, Constantin G.,Barth, Maximilian,Ovsepyan, Ruzanna A.,Butov, Kirill R.,Humpf, Hans-Ulrich,Lehr, Matthias,Panteleev, Mikhail A.,Poso, Antti,Karst, Uwe,Steinmetzer, Torsten,Bendas, Gerd,Kalinin, Dmitrii V.
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p. 13159 - 13186
(2020/11/13)
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- Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X-Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone
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This study provides a structure-Activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.
- Andring, Jacob T.,Fouch, Mallorie,Akocak, Suleyman,Angeli, Andrea,Supuran, Claudiu T.,Ilies, Marc A.,McKenna, Robert
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p. 13064 - 13075
(2020/11/20)
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- Preparation method of 2,4,6-trimethylbenzoyl chloride and acyl chloride co-production technology
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The invention relates to the field of new materials of fine chemicals, in particular to 2,4,6-trimethylbenzoyl chloride (also known as trimesoyl chloride) and an environment-friendly and economical novel preparation process technology for co-producing series acyl chloride products.
- -
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Paragraph 0039-0041
(2020/11/25)
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- Preparation method of acid chloride
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The invention belongs to the technical field of compound preparation methods, and particularly discloses a preparation method of acid chloride. The problems that a chlorinating agent adopted in an existing preparation method of the acid chloride has high irritation, high toxicity and high corrosion are solved, carboxylic acid RCOOH is subjected to acylating chlorination by using triphenylphosphineand the chlorinating agent; and then a reaction is carried out at a room temperature, and violent stirring is performed in the reaction process. The preparation method has simple operation and a short reaction time for preparing the acid chloride, a high product recovery rate and high working efficiency, can be realized at the normal temperature, and reduces energy consumption, hydrogen chlorideis not escaped, a large amount of acid gas is not generated, fewer three wastes is generated, side reactions to acid-sensitive groups when acid-sensitive compounds are synthesized are avoided, and thepreparation method is more environmentally friendly and can be better realized.
- -
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Paragraph 0015-0020
(2019/03/28)
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- Isoalantolactone derivative, pharmaceutical composition and application thereof
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The invention relates to an isoalantolactone derivative, a pharmaceutical composition and application thereof, especially use of the isoalantolactone derivative shown as formula (I) or a salt pharmaceutical compound thereof in preparation of adjuvant drugs treating cancer, a pharmaceutical composition containing a therapeutically effective amount of isoalantolactone derivative (I) or its salt anda pharmaceutically acceptable carrier or a composition with other anticancer drugs.
- -
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Paragraph 0014
(2019/02/02)
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- Chiral Bifunctional Phosphine Ligand Enabling Gold-Catalyzed Asymmetric Isomerization of Alkyne to Allene and Asymmetric Synthesis of 2,5-Dihydrofuran
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The asymmetric isomerization of alkyne to allene is the most efficient and the completely atom-economic approach to this class of versatile axial chiral structure. However, the state-of-the-art is limited to tert-butyl alk-3-ynoate substrates that possess
- Cheng, Xinpeng,Wang, Zhixun,Quintanilla, Carlos D.,Zhang, Liming
-
supporting information
p. 3787 - 3791
(2019/03/07)
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- Electrochemical [4+2] Annulation-Rearrangement-Aromatization of Styrenes: Synthesis of Naphthalene Derivatives
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We report the first electrochemical strategy to synthesize functionalized naphthalene derivatives through [4+2] annulation—rearrangement–aromatization from styrenes under mild conditions. The electrolysis does not require metals, oxidants and high valence substrates, indicating the atom and step-economy ideals. The dehydrodimer produced through [4+2] cycloaddition of 4-methoxy α-methyl styrene is isolated and proved to be the key intermediate for the following oxydehydrogenation to form carbon cation, which undergoes rearrangement–aromatization to afford the final products. This reaction represents a powerful access to construct multi-substituted naphthalene blocks in a single step.
- Ma, Yueyue,Lv, Jufeng,Liu, Chengyu,Yao, Xiantong,Yan, Guoming,Yu, Wei,Ye, Jinxing
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supporting information
p. 6756 - 6760
(2019/04/17)
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- Nickel-Catalyzed Decarboxylative Alkenylation of Anhydrides with Vinyl Triflates or Halides
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Decarboxylative cross-coupling of aliphatic acid anhydrides with vinyl triflates or halides was accomplished via nickel catalysis. This methodology works well with a broad array of substrates and features abundant functional group tolerance. Notably, our approach addresses the issue of safe and environmental installation of methyl or ethyl group into molecular scaffolds. The method possesses high chemoselectivity toward alkyl groups when aliphatic/aromatic mixed anhydrides are involved. Furthermore, diverse ketones could be modified with our strategy.
- Chen, Hui,Sun, Shuhao,Liao, Xuebin
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supporting information
p. 3625 - 3630
(2019/05/24)
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- Nickel catalyzed decarboxylative alkylation of aryl triflates with anhydrides
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Aliphatic acid anhydrides are the versatile building blocks and the new method for the conversion of anhydrides is thus of great significance. Herein, we report the decarboxylative alkylation of aryl triflates with aliphatic acid anhydrides via nickel catalysis. This novel method provides a facile access to construct Csp2-Csp3 bond. In addition, this method is compatible with a broad array of functional groups and exhibits good substrates scope.
- Chen, Hui,Liao, Xuebin
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supporting information
p. 4186 - 4191
(2019/06/18)
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- Enantio- and Diastereoswitchable C?H Arylation of Methylene Groups in Cycloalkanes
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A complementary set of chiral N,N-ligands enables the Pd-catalyzed β-C?H arylation of unbiased internal methylene groups in good yield and with high levels of enantio- and diastereoinduction. Both the dia- and enantioselectivity can be reversed, thus allowing the selective arylation of any of the four β-C?H bonds in cycloalkanecarboxamides of various ring sizes. The method is applicable to a broad range of aryl iodides with electron-withdrawing and -donating substituents in the o-, m-, or p-position.
- Andr?, Michal S.,Schifferer, Lukas,Pollok, Corina H.,Merten, Christian,Goo?en, Lukas J.,Yu, Jin-Quan
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supporting information
p. 8503 - 8507
(2019/07/16)
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- 2-Amino-5,6-difluorophenyl-1 H-pyrazole-Directed PdII Catalysis: Arylation of Unactivated β-C(sp3)-H Bonds
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Palladium-catalyzed arylation of unactivated β-C(sp3)-H bonds in carboxylic acid derivatives with aryl iodides is described for the first time using 2-amino-5,6-difluorophenyl-1H-pyrazole as an efficient and readily removable directing group. Two fluoro groups are installed at the 5- and 6-position of the anilino moiety in 2-aminophenyl-1H-pyrazole, clearly enhancing the directing ability of the auxiliary. In addition, the protocol employs Cu(OAc)2/Ag3PO4 (1.2/0.3) as additives, evidently reducing the stoichiometric amount of expensive silver salts. Furthermore, this process exhibits high β-site selectivity, compatibility with diverse substrates containing α-hydrogen atoms, and excellent functional group tolerance.
- Yang, Jinyue,Fu, Xiaopan,Tang, Shibiao,Deng, Kezuan,Zhang, Lili,Yang, Xianjin,Ji, Yafei
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p. 10221 - 10236
(2019/08/20)
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- Synthesis of 1,3-Diketones and β-Keto Thioesters via Soft Enolization
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Ketones and thioesters undergo soft enolization and acylation using crude acid chlorides on treatment with MgBr2·OEt2 and i-Pr2NEt to give 1,3-diketones and β-keto thioesters, respectively. The use of crude acid chlorides adds efficiency and cost reduction by avoiding the need to purify and/or purchase them. The process is conducted in a direct fashion that does not require prior enolate formation, further enhancing its efficiency and making it very easy to carry out. The method is suitable for large scale applications. ?
- Aderibigbe, Sabrina O.,Coltart, Don M.
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p. 9770 - 9777
(2019/08/27)
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- Visible light-induced transformation of aldehydes to esters, carboxylic anhydrides and amides
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A transition metal- and organophotocatalyst free synthesis of esters, carboxylic anhydrides and amides from aldehydes induced by visible-light has been reported. The proposed methodology can be carried out by the use of sunlight or artificial visible light as a blue LED source. The methodology has a very broad applicability and the desired products are obtained in very satisfactory yields.
- Gaspa, Silvia,Raposo, Inês,Pereira, Leonor,Mulas, Gabriele,Ricci, Pier Carlo,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 10711 - 10715
(2019/07/15)
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- Site-Selective Linear Alkylation of Anilides by Cooperative Nickel/Aluminum Catalysis
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We report meta- and para-selective linear alkylation reactions of anilides with alkenes by nickel/N-heterocyclic carbene (NHC) and aluminum catalysis. With a less bulky NHC, the alkylation reaction of N-methyl-N-phenylcyclohexanecarboxamides proceeded mainly at the meta position. In contrast, a bulky NHC ligand led to the para-selective alkylation of N-sec-alkyl anilides.
- Okumura, Shogo,Komine, Takuya,Shigeki, Erika,Semba, Kazuhiko,Nakao, Yoshiaki
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supporting information
p. 929 - 932
(2017/12/26)
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- Ferric(III) Chloride Catalyzed Halogenation Reaction of Alcohols and Carboxylic Acids Using α,α-Dichlorodiphenylmethane
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A new method for chlorination of alcohols and carboxylic acids, using α,α-dichlorodiphenylmethane as the chlorinating agent and FeCl3 as the catalyst, was developed. The method enables conversions of various alcohols and carboxylic acids to their corresponding alkyl and acyl chlorides in high yields under mild conditions. Particulary interesting is the observation that the respective alkyl bromides and iodides can be generated from alcohols when either LiBr or LiI are present in the reaction mixtures.
- Lee, Chang-Hee,Lee, Soo-Min,Min, Byul-Hana,Kim, Dong-Su,Jun, Chul-Ho
-
supporting information
p. 2468 - 2471
(2018/04/25)
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- Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles
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A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions.
- Sun, Alexandra C.,McClain, Edward J.,Beatty, Joel W.,Stephenson, Corey R. J.
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supporting information
p. 3487 - 3490
(2018/06/26)
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- Highly efficient synthesis of aryl ketones by PEPPSI-palladium catalyzed acylative Suzuki coupling of amides with diarylborinic acids
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An improved acylative cross-coupling of various N-methyl-N-tosyl amides with diarylborinic acids for synthesis of aryl ketones is developed. In most cases, aryl ketones could be obtained in excellent yields by using 1 mol% 2,6-diisopropylphenylimidazolylidene and 3-chloropyridine co-supported palladium chloride as catalyst in the presence of 3 equiv. K2CO3 as base in refluxing THF. The readily prepared and cost-effective substrates, N-methyl-N-tosylamides and diarylborinic acids, and the commercially available catalyst system promise a practical and efficient access to aryl ketones.
- Wang, Chen,Huang, Lingyun,Wang, Fengze,Zou, Gang
-
supporting information
p. 2299 - 2301
(2018/05/16)
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- NON-PEPTIDE OXYTOCIN RECEPTOR AGONISTS
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Disclosed herein are compounds according to Formula I; a pharmaceutical composition including, consisting essentially of, or consisting of: a pharmaceutically acceptable compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient; the use of compounds of Formula I in the preparation of a medicament; and a method including administering a pharmaceutical compositions comprising the compound of Formula I to a patient. The compounds, compositions, use, and methods are directed to the treatment of neurological, psychiatric disorders which are characterised by a fundamental disruption of social behaviour, and substance use disorders.
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-
Page/Page column 26; 52; 53
(2018/07/05)
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- BENZAMIDE DERIVATIVE
-
The present invention relates to a benzamide derivative of general formula I, a drug composition containing same and a use thereof as a drug, wherein the definitions of R1, Z and Q are as described in the description.
- -
-
Paragraph 0093
(2018/08/20)
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- A General Approach to Site-Specific, Intramolecular C?H Functionalization Using Dithiocarbamates
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Intramolecular hydrogen atom transfer is an established approach for the site-specific functionalization of unactivated, aliphatic C?H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C?H halogenations or intramolecular aminations. Herein, we report a site-specific C?H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N-dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.
- Na, Christina G.,Alexanian, Erik J.
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supporting information
p. 13106 - 13109
(2018/09/21)
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- Synthesis method of ciclopirox olamine
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The invention discloses a synthesis method of ciclopirox olamine. The synthesis method includes following steps: (1), preparing dimethyl methacrylate; (2), preparing cyclohexane formyl chloride; (3), preparing 5-oxo-3-methyl-5-cyclohexyl-3-methyl pentenoate; (4), preparing 1-hydroxy-4-methyl-6-cyclohexyl-2(1H)-pyridone; (5), preparing 1-hydroxy-4-methyl-6-cyclohexyl-2(1H)-pyridone-2-amino-ethylate ciclopirox olamine. The synthesis method has the advantages of high yield, high product quality, low running cost, automatic running of equipment, high stability and easiness in meeting industrial needs.
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-
Paragraph 0031; 0033; 0036; 0037
(2017/12/29)
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- Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation
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Pd(II)-catalyzed enantioselective borylation of C(sp3)-H bonds has been realized for the first time using chiral acetyl-protected aminomethyl oxazoline ligands. This reaction is compatible with carbocyclic amides containing α-tertiary as well as α-quaternary carbon centers. The chiral β-borylated amides are useful synthons for the synthesis of chiral β-hydroxylated, β-fluorinated, and β-arylated carboxylic acids.
- He, Jian,Shao, Qian,Wu, Qingfeng,Yu, Jin-Quan
-
supporting information
p. 3344 - 3347
(2017/03/15)
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- Structure-activity relationship study and optimisation of 2-aminopyrrole-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile as a broad spectrum metallo-β-lactamase inhibitor
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A SAR study on derivatives of 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile 5a revealed that the 3-carbonitrile group, vicinal 4,5-diphenyl and N-benzyl side chains of the pyrrole are important for the inhibitory potencies of these compounds against members representing the three main subclasses of metallo-β-lactamases (MBLs), i.e. IMP-1 (representing the B1 subgroup), CphA (B2) and AIM-1 (B3). Coupling of 5a with a series of acyl chlorides and anhydrides led to the discovery of two N-acylamide derivatives, 10 and 11, as the two most potent IMP-1 inhibitors in this series. However, these compounds are less effective towards CphA and AIM-1. The N-benzoyl derivative of 5a retained potent in vitro activity against each of MBLs tested (with inhibition constants in the low μM range). Importantly, this compound also significantly enhanced the sensitivity of IMP-1, CphA- or AIM-1-producing cell cultures towards meropenem. This compound presents a promising starting point for the development of a universal MBL inhibitor, targeting members of each of the major subgroups of this family of enzymes.
- McGeary, Ross P.,Tan, Daniel T.C.,Selleck, Christopher,Monteiro Pedroso, Marcelo,Sidjabat, Hanna E.,Schenk, Gerhard
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p. 351 - 364
(2017/06/19)
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- Novel inhibitors of tyrosinase produced by the 4-substitution of TCT (П)
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Novel Tyrosinase Inhibitors of 4-functionalized Thiophene-2-carbaldehyde thiosemicarbazone (TCT) derivatives (1–8) had been synthesized and Spectrofluorimetry, 1H and 13C NMR titration and Molecular docking had been used to investigate their inhibitory activities and mechanisms on tyrosinase. The results showed that the inter-molecular interactions or hydrogen bond formation by increasing length of carbon chain or introducing benzene ring to the 4-functionalized ester group promoted or stabilized formation of complexes between modifier and tyrosinase, and enhanced the inhibitory activity of modifiers. The inhibitory activity of 4-benzoy methoxy-TCT was much stronger than that of any other synthesized tested modifiers, which was well explained by molecular docking and further verified by spectrofluorimetry and NMR titration by assuming that there existed an inter-molecular interaction besides formation of hydrogen bonds between the amino acid residues ASN260, GLU256, HIS85 of enzyme and the modifier.We concluded that 4-benzoy methoxy substitution of TCT was a good route obtaining novel tyrosinase inhibitors and deserved further studies.
- Liu, Jing,Li, Mengrong,Yu, Yanying,Cao, Shuwen
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p. 1096 - 1106
(2017/06/07)
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- Aerobic oxidative homocoupling reaction of anilides using heterogeneous metal catalysts
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We have developed a heterogeneous catalytic oxidative homocoupling reaction of dimethoxyanilides under an oxygen atmosphere. The resulting homo-dimers are useful for the construction of heterocycles, demonstrating the potential of heterogeneous metal catalysts.
- Fujimoto, Shigenobu,Matsumoto, Kenji,Iwata, Takayuki,Shindo, Mitsuru
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supporting information
p. 973 - 976
(2017/02/15)
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- Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors
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Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.
- Taha, Taha Y.,Aboukhatwa, Shaimaa M.,Knopp, Rachel C.,Ikegaki, Naohiko,Abdelkarim, Hazem,Neerasa, Jayaprakash,Lu, Yunlong,Neelarapu, Raghupathi,Hanigan, Thomas W.,Thatcher, Gregory R. J.,Petukhov, Pavel A.
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supporting information
p. 824 - 829
(2017/08/16)
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- Design, synthesis and biological evaluation of Lenalidomide derivatives as tumor angiogenesis inhibitor
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Lenalidomide is a type of immunomodulatory agent with anti-tumor activity by mainly expressed in the anti-angiogenesis. In order to enhance the pharmacological activity of Lenalidomide, a series of Lenalidomide derivatives were designed as tumor angiogenesis inhibitors. The potential anti-angiogenesis targets of Lenalidomide derivatives were virtual screened on Auto-Dock 4.0 by using reverse docking method. The six target proteins, such as vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, BCR-ABL tyrosine kinase, p38 mitogen activated protein kinase and metal protein kinase, were chosen as the targets. The Lenalidomide derivatives were synthesized by alkylated, acylated or sulfonylated Lenalidomide and verified by the 1H NMR, 13C NMR and LC–MS. Their anti-cancer activities were detected by using CCK-8 in the esophageal carcinoma cell line EC9706. The results indicate that the inhibitory activities of Lenalidomide derivatives were higher than that of Lenalidomide.
- Hu, Shengquan,Yuan, Libin,Yan, Hong,Li, Zhigang
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supporting information
p. 4075 - 4081
(2017/08/23)
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- Optimized synthesis of new LE404-derived azecine-prodrugs
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Dibenzoazecines represent a class of high-affinity dopamine and serotonin receptor antagonists. The former synthesis of the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404) has been 5 steps with a total yield of 13%. The present work enabled the synthesis of LE404 with a much higher yield. Based on this research, further azecin derivatives were synthesized with the aim to improve pharmacokinetic parameters.
- Zergiebel, Stephanie,Arndt, Hans-Dieter,Seeling, Andreas
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supporting information
p. 3640 - 3642
(2017/08/23)
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- Photoinduced, Copper-Catalyzed Decarboxylative C-N Coupling to Generate Protected Amines: An Alternative to the Curtius Rearrangement
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The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C-N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical.
- Zhao, Wei,Wurz, Ryan P.,Peters, Jonas C.,Fu, Gregory C.
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supporting information
p. 12153 - 12156
(2017/09/12)
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- Anhydrides from aldehydes or alcohols via oxidative cross-coupling
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A novel type of metal-free oxidative cross-coupling for the synthesis of symmetrical and mixed anhydrides from aldehydes or benzylic alcohols has been developed. The aldehydes or alcohols were converted in situ into their corresponding acyl chlorides, which were then reacted with an array of carboxylic acids. The methodology has a general applicability, and was successfully employed to prepare either aromatic or aliphatic symmetrical anhydrides and mixed anhydrides, which are very unstable compounds.
- Gaspa, Silvia,Amura, Ida,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 931 - 939
(2017/02/10)
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- Metal-free oxidative self-coupling of aldehydes or alcohols to symmetric carboxylic anhydrides
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A metal-free synthesis of symmetrical anhydrides has been developed starting from aldehydes, both aliphatic and aromatic or primary benzylic alcohols. The reaction occurs at room temperature and makes use of trichloroisocyanuric acid (TCCA) as an oxidant providing the desired carboxylic anhydrides in satisfactory yields.
- Gaspa, Silvia,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 2533 - 2536
(2017/06/13)
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- Design and Synthesis of 2-Methyl-7-aminobenzoxazole as Auxiliary in the Palladium(II)-Catalyzed Arylation of a beta-Positioned C(sp3)-H Bond
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A palladium(II)-catalyzed direct arylation of methylene C(sp3)-H bonds by 2-methyl-7-aminobenzoxazole as an effective auxiliary is reported. This process exhibited high beta-site selectivity, broad substrate scope, and compatibility with different functional groups with moderate to high yields up to 89%.
- Luo, Feihua,Yang, Jun,Li, Zhengkai,Xiang, Haifeng,Zhou, Xiangge
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supporting information
p. 887 - 893
(2016/04/05)
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- A C-H Insertion Approach to Functionalized Cyclopentenones
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Cyclopentenones are synthetically versatile structures, and their straightforward construction from alkynone substrates by employing synthetically streamlining C-H insertion is conceptually appealing and of high synthetic potential. But, its implementation is very limited. Herein we report a Au-catalyzed version, which affords 2-bromocyclopent-2-en-1-ones with a broad scope and synthetically desirable diastereoselectivities. The proposed key intermediate capable of the observed insertion into unactivated C-H bonds is a fully functionalized gold vinylidene, which is generated via a novel intermolecular strategy. This flexible access of likely gold vinylidenes opens various opportunities to explore their versatile reactivities.
- Wang, Youliang,Zarca, Maxence,Gong, Liu-Zhu,Zhang, Liming
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supporting information
p. 7516 - 7519
(2016/07/06)
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- Synthesis of oxazolines from amides via palladium-catalyzed functionalization of unactivated C(sp3)-H bond
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A complementary method that enables the expeditious synthesis of oxazolines from amides via Pd-catalyzed C(sp3)-H functionalization has been described. Preliminary studies indicate that the reaction might go through a chlorination/nucleophilic cyclization sequence, and the high efficiency of this sequence is enhanced by the in situ cyclative capture of the chlorinated intermediate. The resulting oxazolines can be further converted into the corresponding β-amino alcohols without chromatography.
- Li, Bo,Wang, Si-Qing,Liu, Bin,Shi, Bing-Feng
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supporting information
p. 1200 - 1203
(2015/03/14)
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- Acylative Suzuki coupling of amides: Acyl-nitrogen activation via synergy of independently modifiable activating groups
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A highly efficient palladium-catalyzed acylative cross-coupling of carboxylic amides with arylboronic acids has been achieved via synergistic activation of the Cacyl-N bond by independently modifiable activating groups. Coupling of amides features not only good functional group tolerance but also modifiable reactivities to overcome steric hindrance. This journal is
- Li, Xijing,Zou, Gang
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supporting information
p. 5089 - 5092
(2015/03/30)
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- Metal-free n -arylation of secondary amides at room temperature
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The arylation of secondary acyclic amides has been achieved with diaryliodonium salts under mild and metal-free conditions. The methodology has a wide scope, allows synthesis of tertiary amides with highly congested aryl moieties, and avoids the regioselectivity problems observed in reactions with (diacetoxyiodo)benzene.
- Tinnis, Fredrik,Stridfeldt, Elin,Lundberg, Helena,Adolfsson, Hans,Olofsson, Berit
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supporting information
p. 2688 - 2691
(2015/06/16)
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- Palladium-catalyzed acylative cross-coupling of amides with diarylborinic acids and sodium tetraarylborates
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Abstract A general and efficient acylative Suzuki coupling of active amides with diarylborinic acids has been achieved by using 1 mol% Pd(PCy3)2Cl2/0.6 mol% PCy3 as catalyst system taking advantage of modifiable reactivities of acyl-nitrogen bonds of amides. Both electronic and steric influences from either aryl or acyl counterparts on the coupling proved to be negligible or small. A variety of aryl ketones including sterically hindered ones could be synthesized by the coupling of diarylborinic acids in good to excellent yields. Sodium tetraarylborates could also be used as high atom-economy aryl source in the palladium-catalyzed cross-coupling with active amides.
- Li, Xijing,Zou, Gang
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p. 136 - 145
(2015/07/27)
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- Readily Removable Directing Group Assisted Chemo- and Regioselective C(sp3)-H Activation by Palladium Catalysis
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Currently used directing groups for selective aliphatic β-functionalization of carbonyl compounds show excellent reactivity and selectivity with an amide as a linker. Described herein is 2-piconimide, used for the first time with commercially available 2-picolinamide/2-picolic acid as precursors, to direct C-H arylation/alkenylation by palladium catalysis. The directing group is essential for promoting the sequnetial primary and secondary C(sp3)-H arylation with different aryl iodides in one substrate. The directing group was easily removed under simple reaction conditions at room temperature.
- Zhang, Yun-Fei,Zhao, Hong-Wei,Wang, Hui,Wei, Jiang-Bo,Shi, Zhang-Jie
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supporting information
p. 13686 - 13690
(2015/11/16)
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- Unactivated C(sp3)-H hydroxylation through palladium catalysis with H2O as the oxygen source
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A novel palladium catalyzed hydroxylation of unactivated aliphatic C(sp3)-H bonds was successfully developed. Different from conventional methods, water serves as the hydroxyl group source in the reaction. This new reaction demonstrates good reactivity and broad functional group tolerance. The C-H hydroxylated products can be readily transformed into various highly valuable chemicals via known transformations. Based on experimental and theoretical studies, a mechanism involving the Pd(ii)/(iv) pathway is proposed for this hydroxylation reaction.
- Hu, Jiantao,Lan, Tianlong,Sun, Yihua,Chen, Hui,Yao, Jiannian,Rao, Yu
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supporting information
p. 14929 - 14932
(2015/10/06)
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- Pd(II)-catalyzed chelation-assisted cross dehydrogenative coupling between unactivated C(sp3)H bonds in aliphatic amides and benzylic CH bonds in toluene derivatives
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The chelation-assisted cross dehydrogenative coupling of C(sp3)H bonds is achieved by the Pd(II)-catalyzed reaction of aliphatic amides that contain a 5-chloro-8-aminoquinoline moiety as the directing group with toluene derivatives in the presence of heptafluoroisopropyl iodide. A variety of functional groups are tolerated.
- Kubo, Teruhiko,Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 1365 - 1367
(2015/11/24)
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- Novel ion-binding C3 symmetric tripodal triazoles: Synthesis and characterization
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Novel C3 symmetric tripodal molecules were synthesized from cyclohexane 1,3,5-tricarboxylic acid. Utilizing click and Sonogashira reactions, ion-binding triazole and pyridazin-3(2H)-one units were incorporated to form polydentate ligands for ion complexation. The structures of the novel C 3 symmetric derivatives were extensively characterized by 1H, 13C and 2D NMR techniques along with HRMS and IR. The copper(I)-binding potentials of these ligands were investigated by using them as additives in model copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) reactions. The copper(I) complexation ability of our compound was also proved by different spectroscopic methods, such as mass spectrometry, UV and NMR spectroscopy. Based on the mass spectrometric data all of the C3 symmetric ligands formed 1:1 complex with copper(I) ion. The specific role of C3 symmetric polydentate form in the complexation process was also discussed [Figure not available: see fulltext.]
- Neumajer, Gabor,Toth, Gergo,Beni, Szabolcs,Noszal, Bela
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p. 115 - 125
(2014/01/06)
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- Discovery of a series of thiazole derivatives as novel inhibitors of metastatic cancer cell migration and invasion
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Effective inhibitors of cancer cell migration and invasion can potentially lead to clinical applications as a therapy to block tumor metastasis, the primary cause of death in cancer patients. To this end, we have designed and synthesized a series of thiazole derivatives that showed potent efficacy against cell migration and invasion in metastatic cancer cells. The most effective compound, 5k, was found to have an IC50 value of 176 nM in the dose-dependent transwell migration assays in MDA-MB-231cells. At a dose of 10 μM, 5k also blocked about 80% of migration in HeLa and A549 cells and 60% of invasion of MDA-MB-231 cells. Importantly, the majority of the derivatives exhibited no apparent cytotoxicity in the clonogenic assays. The low to negligible inhibition of cell proliferation is a desirable property of these antimigration derivatives because they hold promise of low toxicity to healthy cells as potential therapeutic agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy demonstrate that compound 5k substantially reduced cellular f-actin and prevented localization of fascin to actin-rich membrane protrusions. These results suggest that the antimigration activity may result from impaired actin structures in protrusions that are necessary to drive migration.
- Zheng, Shilong,Zhong, Qiu,Jiang, Quan,Mottamal, Madhusoodanan,Zhang, Qiang,Zhu, Naijue,Burow, Matthew E.,Worthylake, Rebecca A.,Wang, Guangdi
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supporting information
p. 191 - 196
(2013/03/28)
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- Iridium(I)-catalyzed vinylic C-H borylation of 1-cycloalkenecarboxylates with bis(pinacolato)diboron
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Ir(i)-catalyzed C-H borylation of 1-cycloalkenecarboxylic derivatives with bis(pinacolato)diboron affords various alkenylboronates with functional groups in excellent yields. This reaction was also used in a one-pot borylation/Suzuki-Miyaura cross-coupling procedure.
- Sasaki, Ikuo,Doi, Hana,Hashimoto, Toshiya,Kikuchi, Takao,Ito, Hajime,Ishiyama, Tatsuo
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supporting information
p. 7546 - 7548
(2013/08/23)
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