512171-81-2Relevant academic research and scientific papers
Discovery of 9,10-dihydrophenanthrene derivatives as SARS-CoV-2 3CLpro inhibitors for treating COVID-19
Zhang, Jian-Wei,Xiong, Yuan,Wang, Feng,Zhang, Fu-Mao,Yang, Xiaodi,Lin, Guo-Qiang,Tian, Ping,Ge, Guangbo,Gao, Dingding
, (2021/12/09)
The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CLpro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CLpro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CLpro inhibition activity, with IC50 values of 1.55 ± 0.21 μM and 1.81 ± 0.17 μM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CLpro via a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CLpro inhibitor.
Importance of Two-Electron Processes in Fe-Catalyzed Aryl-(hetero)aryl Cross-Couplings: Evidence of Fe0/FeIICouple Implication
Wowk, Vincent,Rousseau, Lidie,Lefèvre, Guillaume
supporting information, p. 3253 - 3266 (2021/10/12)
We demonstrate in this work that two drastically distinct mechanisms can be involved in aryl-(hetero)aryl Fe-mediated cross-couplings between Grignard reagents and organic halides, depending on the nature of the latter. (Hetero)aryl electrophiles, which easily undergo one-electron reduction, can be involved in a FeII/FeIII coupling sequence featuring an in situ generated organoiron(II) species, akin to their aliphatic analogues. On the other hand, less easily reduced substrates can be activated by transient Fe0 species formed by the reduction of the precatalyst. In this case, the coupling mechanism relies on two-electron elementary steps involving the Fe0/FeII redox couple and proceeds by an oxidative addition/reductive elimination sequence. Hammett analysis shows that both those elementary steps are faster for electrophiles substituted by electron-withdrawing groups. The two mechanisms discussed herein can be involved concomitantly for electrophiles displaying an average oxidative power. Attesting to the feasibility of the aforementioned bielectronic mechanism, high-spin organoiron(II) intermediates formed by two-electron oxidative addition onto (hetero)aryl halides in catalytically relevant conditions were also characterized for the first time. Those results are sustained by paramagnetic 1H NMR, kinetics monitoring, and density functional theory (DFT) calculations.
Orthogonal cross-coupling through intermolecular metathesis of unstrained C(aryl)–C(aryl) single bonds
Zhu, Jun,Zhang, Rui,Dong, Guangbin
, p. 836 - 842 (2021/08/09)
While metathesis reactions involving carbon–carbon double bonds, namely olefin metathesis, have been well established with broad utility in organic synthesis and materials science, direct metathesis of kinetically less accessible C–C single bonds is extremely rare. Here we report a ruthenium-catalysed reversible C–C single-bond metathesis reaction that allows redox- and pH-neutral biaryl synthesis. Assisted by directing groups, unstrained homo-biaryl compounds undergo aryl exchanges to generate cross-biaryl products, catalysed by a well-defined air-stable ruthenium(II) complex. Functional groups reactive under typical cross-coupling reactions, such as halogen, silyl and boronate moieties, are compatible under the metathesis conditions. Mechanistic studies disclose an intriguing ‘olefin-metathesis-like’ pathway that involves an unexpected heptacoordinated, 18-electron closed-shell intermediate. The distinct reaction mode discovered here is expected to inspire the development of more general C–C single-bond metathesis and orthogonal cross-coupling reactions. [Figure not available: see fulltext.].
COMPOUNDS AND COMPOSITIONS FOR USE IN TREATING SKIN DISORDERS
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Paragraph 1722-1724, (2021/08/06)
Provided herein is a compound of formula (XXXII) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer thereof or a physiologically functional derivative thereof, wherein R1, R2, R3, G, A, E, n, p, and q are defined herein. Also provided herein are compositions comprising a compound of formula (XXXII), and methods of using a compound of formula (XXXII), e.g., in the treatment or prevention of skin disorders.
Ruthenium-Catalyzed Reductive Cleavage of Unstrained Aryl-Aryl Bonds: Reaction Development and Mechanistic Study
Zhu, Jun,Chen, Peng-hao,Lu, Gang,Liu, Peng,Dong, Guangbin
supporting information, p. 18630 - 18640 (2019/11/21)
Cleavage of carbon-carbon bonds has been found in some important industrial processes, for example, petroleum cracking, and has inspired development of numerous synthetic methods. However, nonpolar unstrained C(aryl)-C(aryl) bonds remain one of the toughest bonds to be activated. As a detailed study of a fundamental reaction mode, here a full story is described about our development of a Ru-catalyzed reductive cleavage of unstrained C(aryl)-C(aryl) bonds. A wide range of biaryl compounds that contain directing groups (DGs) at 2,2′ positions can serve as effective substrates. Various heterocycles, such as pyridine, quinoline, pyrimidine, and pyrazole, can be employed as DGs. Besides hydrogen gas, other reagents, such as Hantzsch ester, silanes, and alcohols, can be employed as terminal reductants. The reaction is pH neutral and free of oxidants; thus a number of functional groups are tolerated. Notably, a one-pot C-C activation/C-C coupling has been realized. Computational and experimental mechanistic studies indicate that the reaction involves a ruthenium(II) monohydride-mediated C(aryl)-C(aryl) activation and the resting state of the catalyst is a η4-coordinated ruthenium(II) dichloride complex, which could inspire development of other transformations based on this reaction mode.
Effects of fluorine substituent on properties of cyclometalated iridium(III) complexes with a 2,2′-bipyridine ancillary ligand
Chen, Yan,Liu, Chun,Wang, Lei
supporting information, (2019/11/05)
Cationic cyclometalated Ir(III) complexes (Ir1-Ir5) with fluorine-substituted 2-phenylpyridine (ppy) derivatives as C^N cyclometalating ligands and 2,2′-bipyridine (bpy) as the ancillary ligand, have been synthesized and fully characterized. The influences of the number and the position of fluorine atoms at the cyclometalating ligands on the photophysical, electrochemical and oxygen sensing properties of the Ir(III) complexes have been investigated systematically. The introduction of fluorine on the C^N cyclometalating ligands of the complexes results in blue-shifts of the maximum emission wavelengths, and increases in the photoluminescence quantum yields (ΦPL), phosphorescence lifetimes and energy gaps, compared to the non-fluorinated [Ir(ppy)2(bpy)]+PF6? (Ir0). Among them, 2-(2,4-difluorophenyl)pyridine-derived Ir4 shows the maximum blue-shift (514 nm vs. 575 nm for Ir0) and the highest ΦPL (50.8% vs. 6.5% for Ir0). The complex Ir3 with 2-(4-fluorophenyl)-5-fluoropyridine as C^N ligand exhibits the highest oxygen sensitivity and excellent operational stability in 10 cycles within 4000 s.
C6-Selective Direct Arylation of 2-Phenylpyridine via an Activated N-methylpyridinium Salt: A Combined Experimental and Theoretical Study
Yin, Changzhen,Zhong, Kangbao,Li, Wenjing,Yang, Xiao,Sun, Rui,Zhang, Chunchun,Zheng, Xueli,Yuan, Maolin,Li, Ruixiang,Lan, Yu,Fu, Haiyan,Chen, Hua
supporting information, p. 3990 - 3998 (2018/09/12)
An elegant pre-activation strategy, based on the formation of N-methylpyridinium iodide salts for C6-selective direct arylation of 2-phenylpyridines using Pd/Cu cooperative catalysis, has been developed. By this methodology, a wide range of unsymmetrical 2, 6-diarylpyridines were synthesized with high reactivity and regioselectivity as well as good functional group tolerance. In particular, challenging substrates bearing electron donating groups (EDGs), such as OMe, NMe2, were also successfully employed in this reaction. Deuterium incorporation studies revealed that the C?H bond acidity is improved significantly in N-methylpyridinium salts compared with their N-Oxide and N-iminopyridinium ylide counterparts, thus solving the long-standing problem associated with previous strategies for the synthesis of diaryl pyridines. Finally, the control experiments and DFT calculations supported a Pd-catalyzed and Cu-mediated mechanism in which a carbenoid copper species that is formed in-situ from N-methylpyridinium salts, participates in a Pd-catalyzed arylation followed by an iodide-promoted N-demethylation process. (Figure presented.).
METHOD FOR AROMATIC FLUORINATION
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Paragraph 0047-0049, (2017/12/18)
Disclosed is a fluorination method comprising providing an aryl fluorosuifonate and a fluorinating reagent to a reaction mixture; and reacting the aryl fluorosuifonate and the fluorinating reagent to provide a fluorinated aryl species. Also disclosed is a fluorination method comprising providing, a salt comprising a cation and an aryloxyiate, and SO2F2 to a reaction mixture; reacting the SO2F2 and the ammonium salt to provide a fluorinated aryl species. Further disclosed a fluorination method comprising providing a compound having the structure Ar-OH to a reaction mixture; where A is an aryl or heteroaryl; providing SO2F2 to the reaction mixture; providing a fluorinating reagent to the reaction mixture; reacting the SO2F2, the fluorinating reagent and the compound having the structure Ar-OH to provide a fluorinated aryl species having the structure Ar-F.
Nucleophilic deoxyfluorination of phenols via aryl fluorosulfonate intermediates
Schimler, Sydonie D.,Cismesia, Megan A.,Hanley, Patrick S.,Froese, Robert D.J.,Jansma, Matthew J.,Bland, Douglas C.,Sanford, Melanie S.
, p. 1452 - 1455 (2017/02/10)
This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (NMe4F) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMe4F proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SO2F2 and NMe4F. Ab initio calculations suggest that carbon-fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate.
α-Halo carbonyls enable: Meta selective primary, secondary and tertiary C-H alkylations by ruthenium catalysis
Paterson, Andrew J.,Heron, Callum J.,McMullin, Claire L.,Mahon, Mary F.,Press, Neil J.,Frost, Christopher G.
supporting information, p. 5993 - 6000 (2017/07/25)
A catalytic meta selective C-H alkylation of arenes is described using a wide range of α-halo carbonyls as coupling partners. Previously unreported primary alkylations with high meta selectivity have been enabled by this methodology whereas using straight chain alkyl halides affords ortho substituted products. Mechanistic analysis reveals an activation pathway whereby cyclometalation with a ruthenium(ii) complex activates the substrate molecule and is responsible for the meta selectivity observed. A distinct second activation of the coupling partner allows site selective reaction between both components.
