- Diazadispiroalkane derivatives are new viral entry inhibitors
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Herpesviruses are widespread and can cause serious illness. Many currently available antiviral drugs have limited effects, result in rapid development of resistance, and often exhibit dose-dependent toxicity. Especially for human cytomegalovirus (HCMV), new well-tolerated compounds with novel mechanisms of action are urgently needed. In this study, we characterized the antiviral activity of two new diazadispiroalkane derivatives, 11826091 and 11826236. These two small molecules exhibited strong activity against low-passage-number HCMV. Pretreatment of cellfree virus with these compounds greatly reduced infection. Time-of-addition assays where 11826091 or 11826236 was added to cells before infection, before and during infection, or during or after infection demonstrated an inhibitory effect on early steps of infection. Interestingly, 11826236 had an effect by addition to cells after infection. Results from entry assays showed the major effect to be on attachment. Only 11826236 had a minimal effect on penetration comparable to heparin. Further, no effect on virus infection was found for cell lines with a defect in heparan sulfate expression or lacking all surface glycosaminoglycans, indicating that these small molecules bind to heparan sulfate on the cell surface. To test this further, we extended our analyses to pseudorabies virus (PrV), a member of the Alphaherpesvirinae, which is known to use cell surface heparan sulfate for initial attachment via nonessential glycoprotein C (gC). While infection with PrV wild type was strongly impaired by 11826091 or 11826236, as with heparin, a mutant lacking gC was unaffected by either treatment, demonstrating that primary attachment to heparan sulfate via gC is targeted by these small molecules.
- Adfeldt, Rebekka,Schmitz, Janna,Kropff, Barbara,Thomas, Marco,Monakhova, Natalia,H?lper, Julia E.,Klupp, Barbara G.,Mettenleiter, Thomas C.,Makarov, Vadim,Bogner, Elke
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supporting information
(2021/03/29)
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- Methyl-Selective α-Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN-AZADO or 1-Me-AZADO)
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Methyl-selective α-oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α-oxygenation at the N-methyl positions using molecular oxygen (O2) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl-selective α-oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5-dimethyl-9-azanoradamantane N-oxyl (DMN-AZADO) and 1-methyl-2-azaadamanane N-oxyl (1-Me-AZADO), was very important to promote the oxygenation effectively mainly because these N-oxyls have longer life-times than less hindered N-oxyls. Various types of tertiary N-methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine-N-oxyl interactions.
- Nakai, Satoru,Yatabe, Takafumi,Suzuki, Kosuke,Sasano, Yusuke,Iwabuchi, Yoshiharu,Hasegawa, Jun-ya,Mizuno, Noritaka,Yamaguchi, Kazuya
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p. 16651 - 16659
(2019/11/11)
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- Novel clamp metal complex and application thereof
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The invention discloses a method for preparing a novel clamp-shaped complex and application of the novel clamp-shaped complex in the reaction of catalytic hydrogenation of carboxylic acid ester compounds to produce corresponding alcohols and reaction of carbon dioxide catalytic hydrogenation to form formamide compounds. Carboxylic acid esters and hydrogen as raw materials or carbon dioxide, hydrogen and amine compounds as raw materials are reacted in an organic solvent condition or a solvent-free condition in the presence of a transition metal complex as a catalyst to respectively form the corresponding alcohol compounds and/or corresponding formamide compounds. The method has the advantages of being high in reaction efficiency, good in selectivity, mild in conditions, economical, environmentally-friendly, and simple in operation, and has good promotion and application prospects.
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Paragraph 0240; 0241; 0242; 0341-0345
(2019/04/26)
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- Diverse catalytic reactivity of a dearomatized PN3P?-nickel hydride pincer complex towards CO2 reduction
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A dearomatized PN3P?-nickel hydride complex has been prepared using an oxidative addition process. The first nickel-catalyzed hydrosilylation of CO2 to methanol has been achieved, with unprecedented turnover numbers. Selective methylation and formylation of amines with CO2 were demonstrated by such a PN3P?-nickel hydride complex, highlighting its versatile functions in CO2 reduction.
- Li, Huaifeng,Gon?alves, Théo P.,Zhao, Qianyi,Gong, Dirong,Lai, Zhiping,Wang, Zhixiang,Zheng, Junrong,Huang, Kuo-Wei
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supporting information
p. 11395 - 11398
(2018/10/20)
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- PYRIMIDYL-DI(DIAZASPIRO-ALKANES) WITH ANTIVIRAL ACTIVITY
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The invention relates to novel pyrimidyl-di(diazaspiro-alkane) derivatives of formula (I) or a pharmaceutically acceptable acid additive salt thereof. The compounds exhibit a wide spectrum of antiviral activity against herpes virus, human immunodeficiency
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Page/Page column 6
(2017/05/10)
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- Synthesis of formamides containing unsaturated groups by: N -formylation of amines using CO2 with H2
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Formamides have wide applications in the industry and have been synthesized using CO2 as a carbon source and H2 as a reducing agent. However, previous systems required a noble catalyst and high temperature to achieve high efficiency, and the substrate scope was mostly limited to saturated amines. The selective N-formylation of amines containing unsaturated groups using CO2 and H2 is challenging because the efficient catalysts for the N-formylation are usually very active for hydrogenation of the unsaturated groups. Herein, we achieved for the first time a selective and efficient N-formylation of amines containing unsaturated groups using CO2 and H2 with a Cu(OAc)2-4-dimethylaminopyridine (DMAP) catalytic system. The substrates were converted to the desired formamides, while the unsaturated groups, such as the carbonyl group, the CC bond, CN bond and the ester group remained. The main reason for the excellent selectivity of the Cu(OAc)2-DMAP catalytic system was that it was very active for the N-formylation reaction, but was not active for the hydrogenation of the unsaturated groups.
- Liu, Hangyu,Mei, Qingqing,Xu, Qingling,Song, Jinliang,Liu, Huizhen,Han, Buxing
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supporting information
p. 196 - 201
(2017/08/15)
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- Chelating Bis(1,2,3-triazol-5-ylidene) Rhodium Complexes: Versatile Catalysts for Hydrosilylation Reactions
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NHC-rhodium complexes (NHC=N-heterocyclic carbenes) have been widely used as efficient catalysts for hydrosilylation reactions. However, the substrates were mostly limited to reactive carbonyl compounds (aldehydes and ketones) or carbon-carbon multiple bonds. Here, we describe the application of newly-developed chelating bis(tzNHC)-rhodium complexes (tz=1,2,3-triazol-5-ylidene) for several reductive transformations. With these catalysts, the formal reductive methylation of amines using carbon dioxide, the hydrosilylation of amides and carboxylic acids, and the reductive alkylation of amines using carboxylic acids have been achieved under mild reaction conditions.
- Nguyen, Thanh V. Q.,Yoo, Woo-Jin,Kobayashi, Shu
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supporting information
p. 452 - 458
(2016/02/12)
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- Easy access to amides through aldehydic C-H bond functionalization catalyzed by heterogeneous Co-based catalysts
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A novel synthesis strategy for amides by oxidative amidation of aldehydes is developed using a heterogeneous Co-based catalyst. The Co composite was prepared by simple pyrolysis of a Co-containing MOF, to obtain well-dispersed Co nanoparticles enclosed by carbonized organic ligands. The catalysts were characterized by powder X-ray diffraction (PXRD), N2 physical adsorption, atomic absorption spectroscopy (AAS), transmission electron microscopy (TEM), scanning electronic microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The small Co nanoparticles embedded in the N-doped carbons were highly dispersed with an average size of ca. 7 nm. The Co@C-N materials exhibited significantly enhanced catalytic activity in the oxidative amidation of aldehydes in comparison to those of commercial sources. A series of amides can be easily obtained in good to excellent yields. It was found that the reaction proceeded via radicals under mild conditions, and the carbonyl group in the amide product was from the aldehyde. Moreover, the catalyst could be easily separated by using an external magnetic field and reused several times without significant loss in catalytic efficiency under the investigated conditions. (Chemical Equation Presented).
- Bai, Cuihua,Yao, Xianfang,Li, Yingwei
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p. 884 - 891
(2015/02/19)
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- Effective Formylation of Amines with Carbon Dioxide and Diphenylsilane Catalyzed by Chelating bis(tzNHC) Rhodium Complexes
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The reductive formylation of amines using CO2 and hydrosilanes is an attractive method for incorporating CO2 into valuable organic compounds. However, previous systems required either high catalyst loadings or high temperatures to achieve high efficiency, and the substrate scope was mostly limited to simple amines. To address these problems, a series of alkyl bridged chelating bis(NHC) rhodium complexes (NHC=N-heterocyclic carbene) have been synthesized and applied to the reductive formylation of amines using CO2 and Ph2SiH2. A rhodium-based bis(tzNHC) complex (tz=1,2,3-triazol-5-ylidene) was identified to be highly effective at a low catalyst loading and ambient temperature, and a wide substrate scope, including amines with reducible functional groups, were compatible. Beyond the norm: Rhodium complexes bearing a strong electron-donating bis(1,2,3-triazol-5-ylidene) ligand were found to be excellent catalysts for the reductive formylation of amines with CO2 and Ph2SiH2 at ambient temperature. The catalyst system possesses a broad substrate scope which tolerates a variety of reducible functional groups and is suitable for the synthesis of bioactive compounds. Tf=trifuoromethanesulfonyl.
- Nguyen, Thanh V. Q.,Yoo, Woo-Jin,Kobayashi
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supporting information
p. 9209 - 9212
(2015/08/06)
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- Kinetic study on aminolysis of 4-pyridyl X-substituted benzoates: Effect of substituent X on reactivity and reaction mechanism
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A kinetic study is reported for nucleophilic substitution reactions of 4-pyridyl X-substituted benzoates 7a-e with a series of alicyclic secondary amines in H2O. The Bronsted-type plot for the reactions of 4-pyridyl benzoate 7c is linear with βnuc = 0.71. The corresponding reactions of 2-pyridyl benzoate 6, which is less reactive than 7c, resulted in also a linear Bronsted-type plot with βnuc = 0.77. The fact that the more reactive 7c results in a smaller βnuc value appears to be in accord with the reactivity- selectivity principle. The aminolysis of 7c has been suggested to proceed through a stepwise mechanism in which breakdown of the intermediate is the rate-determining step (RDS). The Hammett plot for the reactions of 7a-e with piperidine consists of two intersecting straight lines, i.e., ρX = 1.47 for substrates possessing an electron-donating group (EDG) and ρX = 0.91 for those possessing an electron-withdrawing group (EWG). In contrast, the corresponding Yukawa- Tsuno plot exhibits excellent linear correlation with ρX = 0.79 and r = 0.56. Thus, it has been concluded that the nonlinear Hammett plot is not due to a change in the RDS but is caused by stabilization of the ground state of the substrates possessing an EDG through resonance interaction between the EDG and the C=O bond of the substrates.
- Lee, Jong Pal,Bae, Ae Ri,Um, Ik-Hwan
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experimental part
p. 1907 - 1911
(2012/01/14)
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- A kinetic study on aminolysis of 2-pyridyl X-substituted benzoates: Effect of changing leaving group from 4-nitrophenolate to 2-pyridinolate on reactivity and mechanism
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Second-order rate constants (kN) have been measured spectrophotometrically for nucleophilic substitution reactions of 2-pyridyl X-substituted benzoates 8a-e with a series of alicyclic secondary amines in H2O at 25.0 ± 0.1 °C. The kN values for the reactions of 8a-e are slightly smaller than the corresponding reactions of 4-nitrophenyl X-substituted benzoates 1a-e (e.g., kN 1a-e/kN8a-e = 1.1 3.1), although 2-pyridinolate in 8a-e is ca. 4.5 pKa units more basic than 4-nitrophenolate in 1a-e. The Bronsted-type plot for the aminolysis of 8c (X = H) is linear with βnuc = 0.77 and R2 = 0.991 (Figure 1), which is typical for reactions reported previously to proceed through a stepwise mechanism with breakdown of a zwitterionic tetrahedral intermediate T± being the rate-determining step (RDS), e.g., aminolysis of 4-nitrophenyl benzoate 1c. The Hammett plot for the reactions of 8a-e with piperidine consists of two intersecting straight lines (Figure 2), i.e., ρ = 1.71 for substrates possessing an electron-donating group (EDG) while ρ = 0.86 for those bearing an electron-withdrawing group (EWG). Traditionally, such a nonlinear Hammett plot has been interpreted as a change in RDS upon changing substituent X in the benzoyl moiety. However, it has been proposed that the nonlinear Hammett is not due to a change in RDS since the corresponding Yukawa-Tsuno plot exhibits excellent linear correlation with ρ = 0.85 and r = 0.62 (R2 = 0.995, Figure 3). Stabilization of substrates 8a-e in the ground state has been concluded to be responsible for the nonlinear Hammett plot.
- Lee, Jong Pal,Bae, Ae Ri,Im, Li-Ra,Um, Ik-Hwan
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experimental part
p. 3588 - 3592
(2011/10/02)
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- Kinetics and mechanism of the reactions of S-2,4-dinitrophenyl 4-substituted thiobenzoates with secondary alicyclic amines
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The title reactions, in 44 wt % ethanol-water at 25.0 °C, exhibit slightly curved Bronsted-type plots (log kN versus pK a of amines) with slopes β1 = 0.1-0.44 (at high pKa) and β2 ca. 0.7 (at low pKa). The magnitude of some of these slopes, together with the fact that the curvature center (pKa0 = 9.5-10.8) does not change with the electronic effects of the benzoyl substituent, suggests that these reactions are not stepwise, but concerted.
- Castro, Enrique A.,Aguayo, Raul,Bessolo, Jorge,Santos, Jose G.
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p. 7788 - 7791
(2007/10/03)
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- Kinetic investigation of the reactions of S-4-nitrophenyl 4-substituted thiobenzoates with secondary alicyclic amines in aqueous ethanol
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The reactions of S-4-nitrophenyl 4-X-substituted thiobenzoates (X = H, Cl, and NO2: 1, 2, and 3, respectively) with a series of secondary alicyclic amines (SAA) were subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 °C and an ionic strength of 0.2 M (KCl). The reactions were followed spectrophotometrically by monitoring the release of 4-nitrobenzenethiolate anion at 420-425 nm. Under excess amine, pseudo-first-order first-order rate constants (kobsd) are obtained for all reactions. The plots of kobsd vs [SAA] at constant pH are linear with the slope (kN) independent of pH. The statistically corrected Bronsted-type plots (log kN/q vs pKa + log p/q) for the reactions of 1 and 2 are nonlinear with slopes at high pK a, β1 = 0.27 and 0.10, respectively, and slopes at low pKa, β2 = 0.86 and 0.84, respectively. The Bronsted curvature is centered at pKa (pKa 0) 10.0 and 10.4, respectively. The reactions of SAA with 3 exhibit a linear Bronsted-type plot of slope 0.81. These results are consistent with a stepwise mechanism, through a zwitterionic tetrahedral intermediate (Ti±). For the reactions of 1 and 2, there is a change in rate-determining step with amine basicity, from T± breakdown to products at low pKa, to T± formation at high pKa. For the reactions of 3, breakdown to products of T ± is rate limiting for all the SAA series (pKa 0 > 11). The increasing pKa0 value as the substituent in the acyl group becomes more electron withdrawing is attributed to an increasing nucleofugality of SAA from T±. The greater pKa0 value for the reactions of SAA with 1, relative to that found in the pyridinolysis of 2,4-dinitrophenyl benzoate (pK a0 = 9.5), is explained by the greater nucleofugality from T± of the former amines, compared to isobasic pyridines, and the greater leaving ability from T± of 2,4-dinitrophenoxide relative to 4-nitrobenzenethiolate.
- Castro, Enrique A.,Bessolo, Jorge,Aguayo, Raul,Santos, Jose G.
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p. 8157 - 8161
(2007/10/03)
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- Effect of Acyl Substituents on the Reaction Mechanism for Aminolyses of 4-Nitrophenyl X-Substituted Benzoates
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Second-order rate constants (kN) have been measured spectrophotometrically for the reaction of 4-nitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in H2O containing 20 mol % dimethyl sulfoxide at 25.0°C.
- Um, Ik-Hwan,Min, Ji-Sook,Ahn, Jung-Ae,Hahn, Hyun-Joo
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p. 5659 - 5663
(2007/10/03)
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- Structure-reactivity correlations in the reaction of 2,4-dinitrophenyl X-substituted benzoates with alicyclic secondary amines
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Apparent second-order rate constants (kapp) have been measured spectrophotometrically for the reaction of 2,4-dinitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in H2O containing 20 mol% DMSO at 25°C. The microconstants involved in the reaction (k-1/k2, K1, and k1k2/k-1) have also been calculated. The magnitude of kapp, k1, and k1k2/k-1 values increases with increasing amine basicity and with increasing acid strengthening ability of the acyl substituent X. The k-1/k2 value decreases from ca. 6.5 to 0.3 with increasing the amine basicity, but remains almost constant upon changing the acyl substituent X for a given amine, indicating that the ratedetermining step is governed by the basicity of amine but not by the electronic nature of the acyl substituent X. The Bronsted-type plots for kapp show a break at pKa = 9.1, supporting the assumption that a change in the rate-determining step occurs from rate-limiting breakdown to formation of the addition intermediate as amine basicity increases. The corresponding Bronsted-type plots for k-1/k2, k1, and k1k2/k-1 are linear but their β values are different. σ+ constants show better correlation with log kapp, log kl and log k1k2/k-1 for the reaction with low basic amines (pKa a > 9.1). The magnitude of ρ1 is identical to that of ρapp and ρeq for a given amine.
- Um, Ik-Hwan,Min, Ji-Sook,Lee, Hye-Won
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p. 659 - 666
(2007/10/03)
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