- Hydrosilylative reduction of primary amides to primary amines catalyzed by a terminal [Ni-OH] complex
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A terminal [Ni-OH] complex1, supported by triflamide-functionalized NHC ligands, catalyzes the hydrosilylative reduction of a range of primary amides into primary amines in good to excellent yields under base-free conditions with key functional group tolerance. Catalyst1is also effective for the reduction of a variety of tertiary and secondary amides. In contrast to literature reports, the reactivity of1towards amide reduction follows an inverse trend,i.e., 1° amide > 3° amide > 2° amide. The reaction does not follow a usual dehydration pathway.
- Bera, Jitendra K.,Pandey, Pragati
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supporting information
p. 9204 - 9207
(2021/09/20)
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- Zirconium-hydride-catalyzed site-selective hydroboration of amides for the synthesis of amines: Mechanism, scope, and application
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Developing mild and efficient catalytic methods for the selective synthesis of amines is a longstanding research objective. In this respect, catalytic deoxygenative amide reduction has proven to be promising but challenging, as this approach necessitates selective C–O bond cleavage. Herein, we report the selective hydroboration of primary, secondary, and tertiary amides at room temperature catalyzed by an earth-abundant-metal catalyst, Zr-H, for accessing diverse amines. Various readily reducible functional groups, such as esters, alkynes, and alkenes, were well tolerated. Furthermore, the methodology was extended to the synthesis of bio- and drug-derived amines. Detailed mechanistic studies revealed a reaction pathway entailing aldehyde and amido complex formation via an unusual C–N bond cleavage-reformation process, followed by C–O bond cleavage.
- Han, Bo,Jiao, Haijun,Wu, Lipeng,Zhang, Jiong
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p. 2059 - 2067
(2021/09/02)
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- Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections
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The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds 41-50). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.
- Gaisina, Irina N.,Peet, Norton P.,Wong, Letitia,Schafer, Adam M.,Cheng, Han,Anantpadma, Manu,Davey, Robert A.,Thatcher, Gregory R. J.,Rong, Lijun
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p. 7211 - 7225
(2020/09/11)
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- Iron-Catalysed Reductive Amination of Carbonyl Derivatives with Ω-Amino Fatty Acids to Access Cyclic Amines
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An efficient method for the reductive amination of carbonyl derivatives with ω-amino fatty acids catalysed by an iron complex Fe(CO)4(IMes) [IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene] by means of hydrosilylation was developed. A variety of pyrrolidines, piperidines and azepanes were selectively synthesised in moderate-to-excellent yields (36 examples, 47–97 % isolated yield) with a good functional group tolerance.
- Wei, Duo,Netkaew, Chakkrit,Carré, Victor,Darcel, Christophe
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p. 3008 - 3012
(2019/05/15)
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- Photoredox-catalyzed Direct Reductive Amination of Aldehydes without an External Hydrogen/Hydride Source
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The direct reductive amination of aromatic aldehydes has been realized using a photocatalyst under visible light irradiation. The single electron oxidation of an in situ formed aminal species generates the putative α-amino radical that eventually delivers the reductive amination product. This method is operationally simple, highly selective, and functional group tolerant, which allows the direct synthesis of benzylic amines by a unique mechanistic pathway.
- Alam, Rauful,Molander, Gary A.
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p. 2680 - 2684
(2018/05/22)
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- BENZAMIDE DERIVATIVES FOR INHIBITING ENDOPLASMIC RETICULUM (ER) STRESS
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Novel 3-(N-piperidinyl)methyl benzamide derivatives are disclosed. The compounds can be used in treating diseases and conditions which are associated with abnormal cell function related to endoplasmic reticulum (ER) stress. For example, the compounds can
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Paragraph 0008; 0100; 0101
(2019/01/07)
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- HISTONE DEACETYLASE INHIBITORS
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Provided herein are compounds and methods for inhibiting histone deacetylase ("HDAC") enzymes (e.g., HDAC1, HDAC2, and HDAC3).
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Paragraph 00243; 00244
(2018/07/29)
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- Discovery of a Benzamide Derivative That Protects Pancreatic β-Cells against Endoplasmic Reticulum Stress
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Endoplasmic reticulum (ER) stress-mediated pancreatic insulin-producing β-cell dysfunction and death are critical elements in the onset and progression of both type 1 and type 2 diabetes. Here, through cell-based high throughput screening we identified be
- Duan, Hongliang,Li, Yu,Arora, Daleep,Xu, Depeng,Lim, Hui-Ying,Wang, Weidong
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p. 6191 - 6204
(2017/08/02)
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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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- Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents
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In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.
- Zuo, Sai-Jie,Zhang, Sai,Mao, Shuai,Xie, Xiao-Xiao,Xiao, Xue,Xin, Min-Hnag,Xuan, Wei,He, Yuan-Yuan,Cao, Yong-Xiao,Zhang, San-Qi
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p. 179 - 190
(2015/12/31)
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- 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3β Fragment Hits against Alzheimer's Disease
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One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3β dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 μM against BACE-1 and GSK-3β, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimer's disease models.
- Prati, Federica,De Simone, Angela,Armirotti, Andrea,Summa, Maria,Pizzirani, Daniela,Scarpelli, Rita,Bertozzi, Sine Mandrup,Perez, Daniel I.,Andrisano, Vincenza,Perez-Castillo, Ana,Monti, Barbara,Massenzio, Francesca,Polito, Letizia,Racchi, Marco,Sabatino, Piera,Bottegoni, Giovanni,Martinez, Ana,Cavalli, Andrea,Bolognesi, Maria L.
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p. 1665 - 1682
(2015/11/09)
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- Liquid ammonia as a dipolar aprotic solvent for aliphatic nucleophilic substitution reactions
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The rate constants for the reactions of a variety of nucleophiles reacting with substituted benzyl chlorides in liquid ammonia (LNH3) have been determined. To fully interpret the associated linear free-energy relationships, the ionization constants of phenols ions in liquid ammonia were obtained using UV spectra. These equilibrium constants are the product of those for ion-pair formation and dissociation to the free ions, which can be separated by evaluating the effect of added ammonium ions. There is a linear relationship between the pKa of phenols in liquid ammonia and those in water of slope 1.68. Aminium ions exist in their unprotonated free base form in liquid ammonia and their ionization constants could not be determined by NMR. The rates of solvolysis of substituted benzyl chlorides in liquid ammonia at 25 °C show a Hammett ρ of zero, having little or no dependence upon ring substituents, which is in stark contrast with the hydrolysis rates of substituted benzyl halides in water, which vary 107 fold. The rate of substitution of benzyl chloride by substituted phenoxide ions is first order in the concentration of the nucleophile indicative of a SN2 process, and the dependence of the rate constants on the pKa of the phenol in liquid ammonia generates a Bronsted βnuc = 0.40. Contrary to the solvolysis reaction, the reaction of phenoxide ion with 4-substituted benzyl chlorides gives a Hammett ρ = 1.1, excluding the 4-methoxy derivative, which shows the normal positive deviation. The second order rate constants for the substitution of benzyl chlorides by neutral and anionic amines show a single Bronsted βnuc = 0.21 (based on the aqueous pKa of amine), but their dependence on the substituent in substituted benzyl chlorides varies with a Hammett ρ of 0 for neutral amines, similar to that seen for solvolysis, whereas that for amine anions is 0.93, similar to that seen for phenoxide ion.(Figure Presented)
- Ji, Pengju,Atherton, John,Page, Michael I.
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supporting information; scheme or table
p. 1425 - 1435
(2011/04/23)
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- Zinc-catalyzed chemoselective reduction of tertiary and secondary amides to amines
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General and convenient procedures for the catalytic hydrosilylation of secondary and tertiary amides under mild conditions have been developed. In the presence of inexpensive zinc catalysts, tertiary amides are easily reduced by applying monosilanes. Key to success for the reduction of the secondary amides is the use of zinc triflate and disilanes with dual Si-H moieties. The presented hydrosilylations proceed with excellent chemoselectivity in the presence of sensitive ester, nitro, azo, nitrile, olefins, and other functional groups, thus making the method attractive for organic synthesis.
- Das, Shoubhik,Addis, Daniele,Junge, Kathrin,Beller, Matthias
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experimental part
p. 12186 - 12192
(2011/11/07)
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- Chelating carboxylic acid amides as robust relay protecting groups of carboxylic acids and their cleavage under mild conditions
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Free choice: Carboxamides of bispicolylamine are alternative protecting groups for carboxylic acids (see scheme). As a consequence of their straightforward applicability, their high chemical stability towards a broad range of conditions, and their selective cleavage under mild conditions to give either carboxylic acids or their methyl esters, this new protection method should find widespread application in the realm of organic synthesis. Copyright
- Broehmer, Manuel C.,Mundinger, Stephan,Braese, Stefan,Bannwarth, Willi
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p. 6175 - 6177
(2011/08/03)
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- Searching for the Multi-Target-Directed Ligands against Alzheimer's disease: Discovery of quinoxaline-based hybrid compounds with AChE, H 3R and BACE 1 inhibitory activities
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A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H3R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT
- Huang, Wenhai,Tang, Li,Shi, Ying,Huang, Shufang,Xu, Lei,Sheng, Rong,Wu, Peng,Li, Jia,Zhou, Naiming,Hu, Yongzhou
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scheme or table
p. 7158 - 7167
(2012/02/05)
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- A new robust and versatile tetradentate linker for amides to be cleaved under mild conditions by unusual complexation of the amide nitrogen to Cu ++
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The concept of weakening amide bonds by the rather unusual forced complexation of nitrogen to Cu++ is not limited to tridentate ligands and was extended in this work to tetradentate ligands as well. The use of cyclic tetradentate ligands was to no avail, but an open-chain and more-flexible tetradentate ligand allowed mild cleavage by methanolysis after complexation. The principle was applied to the development of a new linker for solid-phase chemistry, which was proven to be extremely robust, yet allowed mild cleavage after activation by Cu ++ complexation. Its stability and versatility was demonstrated by the successful application to a whole plethora of different types of reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.
- Kramer, Rolf A.,Broehmer, Manuel C.,Forkel, Nina V.,Bannwarth
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experimental part
p. 4273 - 4283
(2011/02/25)
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- Design, synthesis and AChE inhibitory activity of indanone and aurone derivatives
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A new series of indanone and aurone derivatives have been synthesized and tested for in vitro AChE inhibitory activity by modified Ellman method. Most of them exhibit AChE inhibitory activities superior to rivastigmine. Further, the most potent compound 1g was selected to evaluate the effect on the acquisition and memory impairment by mice step-down passive avoidance test.
- Sheng, Rong,Xu, Yu,Hu, Chunqi,Zhang, Jing,Lin, Xiao,Li, Jingya,Yang, Bo,He, Qiaojun,Hu, Yongzhou
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experimental part
p. 7 - 17
(2009/04/06)
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- Forced complexation of nitrogen leading to a weakening of amide bonds: Application to a new linker for solid-phase chemistry
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Cu2+ complexation of a bispicolylamide entity leads to a weakening of the N-C-amide bond, which subsequently can be cleaved under very mild conditions by methanolysis. On the basis of this principle we developed a versatile and robust linker for solid-phase chemistry. The stability of the linker was demonstrated under acidic and basic conditions, and it was evaluated for its utility in peptide synthesis as well as for reductive amination, Pd-mediated C-C-coupling, and metathesis reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Broehmer, Manuel C.,Bannwarth, Willi
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experimental part
p. 4412 - 4415
(2009/05/07)
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- Novel nonimidazole histamine H3 receptor antagonists: 1-(4-(phenoxymethyl)benzyl)piperidines and related compounds
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In an extension of very recently published studies on successful imidazole replacements in some series of histamine H3 receptor antagonists, we report on a new class of lipophilic nonimidazole antagonist having an aliphatic tertiary amino moiet
- Mikó, Tibor,Ligneau, Xavier,Pertz, Heinz H.,Ganellin, C. Robin,Arrang, Jean-Michel,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 1523 - 1530
(2007/10/03)
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- Antitumor Activity of 5-Aryl-2,3-dihydroimidazoisoquinolines
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A series of 5-aryl-2,3-dihydroimidazoisoquinolines previously reported to be platelet activating factor (PAF) receptor antagonist were evaluated for potential antitumor activity.Several compounds, such as the 5-(4'-tert-butylphenyl) (65), 5- (69), and 5-(4'-cyclohexylphenyl) (71) analogs showed very good cytotoxicity against several tumor cell lines. 5--2,3-dihydroimidazoisoquinoline (SDZ 62-434, 53) was more effective on a milligram per kilogram basis than the clinical cytostatic agent edelfosine (1) in increasing survivors and decreasing tumor volume in the oral mouse Meth A fibrosarcoma assay.It was selected for further development and is currently in phase I clinical trials in cancer patients.
- Houlihan, William J.,Munder, Paul G.,Handley, Dean A.,Cheon, Seung H.,Parrino, Vincent A.
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p. 234 - 240
(2007/10/02)
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