- CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches
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Lamisil (terbinafine) is an effective, widely prescribed antifungal drug that causes rare idiosyncratic hepatotoxicity. The proposed toxic mechanism involves a reactive metabolite, 6,6-dimethyl-2-hepten-4-ynal (TBF-A), formed through three N-dealkylation pathways. We were the first to characterize them using in vitro studies with human liver microsomes and modeling approaches, yet knowledge of the individual enzymes catalyzing reactions remained unknown. Herein, we employed experimental and computational tools to assess terbinafine metabolism by specific cytochrome P450 isozymes. In vitro inhibitor phenotyping studies revealed six isozymes were involved in one or more N-dealkylation pathways. CYP2C19 and 3A4 contributed to all pathways, and so, we targeted them for steady-state analyses with recombinant isozymes. N-Dealkylation yielding TBF-A directly was catalyzed by CYP2C19 and 3A4 similarly. Nevertheless, CYP2C19 was more efficient than CYP3A4 at N-demethylation and other steps leading to TBF-A. Unlike microsomal reactions, N-denaphthylation was surprisingly efficient for CYP2C19 and 3A4, which was validated by controls. CYP2C19 was the most efficient among all reactions. Nonetheless, CYP3A4 was more selective at steps leading to TBF-A, making it more effective in terbinafine bioactivation based on metabolic split ratios for competing pathways. Model predictions did not extrapolate to quantitative kinetic constants, yet some results for CYP3A4 and CYP2C19 agreed qualitatively with preferred reaction steps and pathways. Clinical data on drug interactions support the CYP3A4 role in terbinafine metabolism, while CYP2C19 remains understudied. Taken together, knowledge of P450s responsible for terbinafine metabolism and TBF-A formation provides a foundation for investigating and mitigating the impact of P450 variations in toxic risks posed to patients.
- Davis, Mary A.,Barnette, Dustyn A.,Flynn, Noah R.,Pidugu, Anirudh S.,Swamidass, S. Joshua,Boysen, Gunnar,Miller, Grover P.
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- Conformational Effects in Fluorescent Excited Charge-transfer Complex Formation
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From a study if the variation in fluorescence quantum yield and lifetime with change in solvent polarity for some ω-(1-naphthyl)-N-alkylpyrroles it is concluded that the conformation of the excited complex has little effect upon the wavelength of fluorescence but does have an effect upon the relative efficiencies of the radiative and non-radiative decay processes.
- Luo, Xiu-Jin,Beddard, Godfrey S.,Porter, George,Davidson, R. Stephen,Whelan, Terence D.
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- Exploring reversible reactions between CO2 and amines
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The 'old' chemistry between CO2 and primary alkylamines has been revisited. Amines 1 and 2, with appended aromatic fluorophores, reversibly reacted with CO2 in polar aprotic solvent (e.g. DMSO, DMF) with the formation of carbamic acids 3 and 4. As a result, strong fluorescence occurred, thus directly reporting on the CO2 entrapment. Carbamic acids were studied by 1H and 13C NMR spectroscopy in DMSO-d 6. The carbamate bond, despite being covalent, is reversible and can be broken upon heating or simply flashing solutions with inert gases. Synthesis and evaluation of a CO2-sensing amino acid-α-naphthylglycine 7 is also reported for potential CO2 monitoring under biorelevant conditions in aqueous solutions.
- Hampe, Erin M.,Rudkevich, Dmitry M.
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- Synthesis of primary amines via nucleophilic addition of organometallic reagents to aldimines on solid support
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Resin-immobilized aldimines 5, derived from the condensation of amine-functionalized Rink polystyrene resin with aldehydes, react with Grignard reagents, lithium reagents or LiBH4 to afford a wide variety of primary amines in good to excellent yields upon trifluoroacetic acid cleavage. In this amine synthesis, Rink resin functions both as a solid support and as a NH protecting group.
- Katritzky, Alan R.,Xie, Linghong,Zhang, Guifen,Griffith, Michael,Watson, Karen,Kiely, John S.
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- Detoxification of the cruciferous phytoalexin brassinin in Sclerotinia sclerotiorum requires an inducible glucosyltransferase
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The phytoalexins, brassinin, 1-methoxybrassinin and cyclobrassinin, were metabolized by the stem rot fungus Sclerotinia sclerotiorum into their corresponding glucosyl derivatives displaying no detectable antifungal activity. Importantly, co-incubation of S. sclerotiorum with camalexins, various phytoalexin analogs, and brassinin indicated that a synthetic camalexin derivative could slow down substantially the rate of brassinin detoxification. Furthermore, inducible brassinin glucosyltransferase (BGT) activity was detected in crude cell-free extracts of S. sclerotiorum. BGT activity was induced by the phytoalexin camalexin, and the brassinin analogs methyl tryptamine dithiocarbamate and methyl 1-methyltryptamine dithiocarbamate. The overall results suggest that the fungus S. sclerotiorum in its continuous adaptation and co-evolution with brassinin producing plants, has acquired efficient glucosyltransferase(s) that can disarm some of the most active plant chemical defenses.
- Pedras, M. Soledade C.,Ahiahonu, Pearson W.K.,Hossain, Mohammad
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- Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles
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Bromodomain and extra-terminal domain (BET) inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. XDM-CBP is a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. Along with X-ray crystal-structure analysis and thermodynamic profiling, XDM-CBP was used in screenings of several cancer cell lines in vitro to study its inhibitory potential on cancer cell proliferation. XDM-CBP is demonstrated to be a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia.
- Hügle, Martin,Lucas, Xavier,Ostrovskyi, Dmytro,Regenass, Pierre,Gerhardt, Stefan,Einsle, Oliver,Hau, Mirjam,Jung, Manfred,Breit, Bernhard,Günther, Stefan,Wohlwend, Daniel
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- Polymer bound iminodicarbonate: A new ammonia equivalent for solid-phase synthesis of primary amines
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A polymer bound iminodicarbonate has been designed and its use in solid-phase synthesis of primary amines is reported. (C) Elsevier Science Ltd.
- Subramanyam
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- Improved synthesis of (R)-glycine-d-15N
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Previously, we have synthesized the title glycine to permit assignment of the prochiral α-protons of glycine residues in the NMR study of the protein FKBP. A key, and low yielding step in this synthesis occurs in the ruthenium tetraoxide mediated degradation of N-t-Boc-p-methoxybenzyl amine to N-t-Boc-glycine. Efforts to improve this key step by exploring different substrates and N-protecting groups were successful to render this synthesis amenable for the large scale production of (R)-glycine-d-15N.
- Walker, Joel R,Curley Jr., Robert W
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- Recreating the natural evolutionary trend in key microdomains provides an effective strategy for engineering of a thermomicrobial N-demethylase
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N-demethylases have been reported to remove the methyl groups on primary or secondary amines, which could further affect the properties and functions of biomacromolecules or chemical compounds; however, the substrate scope and the robustness of N-demethylases have not been systematically investigated. Here we report the recreation of natural evolution in key microdomains of the Thermomicrobium roseum sarcosine oxidase (TrSOX), an N-demethylase with marked stability (melting temperature over 100 C) and enantioselectivity, for enhanced substrate scope and catalytic efficiency on -C-N-bonds. We obtained the structure of TrSOX by crystallization and X-ray diffraction (XRD) for the initial framework. The natural evolution in the nonconserved residues of key microdomains—including the catalytic loop, coenzyme pocket, substrate pocket, and entrance site—was then identified using ancestral sequence reconstruction (ASR), and the substitutions that accrued during natural evolution were recreated by site-directed mutagenesis. The single and double substitution variants catalyzed the N-demethylation of N-methyl-L-amino acids up to 1800- and 6000-fold faster than the wild type, respectively. Additionally, these single substitution variants catalyzed the terminal N-demethylation of non-amino-acid compounds and the oxidation of the main chain -C-N- bond to a -C=N- bond in the nitrogen-containing heterocycle. Notably, these variants retained the enantioselectivity and stability of the initial framework. We conclude that the variants of TrSOX are of great potential use in N-methyl enantiomer resolution, main-chain Schiff base synthesis, and alkaloid modification or degradation.
- Gu, Zhenghua,Guo, Zitao,Shao, Jun,Shen, Chen,Shi, Yi,Tang, Mengwei,Xin, Yu,Zhang, Liang
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- Hydroalkylation of Styrenes with Benzylamines by Potassium Hydride
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A method for the synthesis of 1,3-diarylpropylamines through hydroalkylation of styrenes with benzylamines by potassium hydride has been developed. The protocol is initiated by solvothermal treatment of benzylamines with KH at 100 °C to generate deprotonated anionic species, which undergo selective C-alkylation with arylalkenes at 0 °C to ambient temperature to afford 1,3-diarylpropylamines as the major product.
- Chiba, Shunsuke,Pang, Jia Hao,Takita, Ryo,Wang, Bin,Watanabe, Kohei
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- Nitrile Synthesis by Aerobic Oxidation of Primary Amines and in situ Generated Imines from Aldehydes and Ammonium Salt with Grubbs Catalyst
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Herein, a Grubbs-catalyzed route for the synthesis of nitriles via the aerobic oxidation of primary amines is reported. This reaction accommodates a variety of substrates, including simple primary amines, sterically hindered β,β-disubstituted amines, allylamine, benzylamines, and α-amino esters. Reaction compatibility with various functionalities is also noted, particularly with alkenes, alkynes, halogens, esters, silyl ethers, and free hydroxyl groups. The nitriles were also synthesized via the oxidation of imines generated from aldehydes and NH4OAc in situ. (Figure presented.).
- Utsumi, Tatsuki,Noda, Kenta,Kawauchi, Daichi,Ueda, Hirofumi,Tokuyama, Hidetoshi
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p. 3583 - 3588
(2020/08/05)
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- Ultra-small cobalt nanoparticles from molecularly-defined Co-salen complexes for catalytic synthesis of amines
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We report the synthesis of in situ generated cobalt nanoparticles from molecularly defined complexes as efficient and selective catalysts for reductive amination reactions. In the presence of ammonia and hydrogen, cobalt-salen complexes such as cobalt(ii)-N,N′-bis(salicylidene)-1,2-phenylenediamine produce ultra-small (2-4 nm) cobalt-nanoparticles embedded in a carbon-nitrogen framework. The resulting materials constitute stable, reusable and magnetically separable catalysts, which enable the synthesis of linear and branched benzylic, heterocyclic and aliphatic primary amines from carbonyl compounds and ammonia. The isolated nanoparticles also represent excellent catalysts for the synthesis of primary, secondary as well as tertiary amines including biologically relevant N-methyl amines.
- Beller, Matthias,Chandrashekhar, Vishwas G.,Gawande, Manoj B.,Jagadeesh, Rajenahally V.,Kalevaru, Narayana V.,Kamer, Paul C. J.,Senthamarai, Thirusangumurugan,Zbo?il, Radek
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p. 2973 - 2981
(2020/03/27)
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- Dehydrogenation of Primary Alkyl Azides to Nitriles Catalyzed by Pincer Iridium/Ruthenium Complexes
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Pincer metal complexes exhibit superior catalytic activity in the dehydrogenation of plain alkanes, but find limited application in the dehydrogenation of functionalized organic molecules. Starting from easily accessible primary alkyl azides, here we report an efficient dehydrogenation of azides to nitriles using pincer iridium or ruthenium complexes as the catalysts. This method offers a route to cyanide-free preparation of nitriles without carbon chain elongation and without the use of strong oxidants. Both benzyl and linear aliphatic azides can be dehydrogenated with tert-butylethylene as the hydrogen acceptor to afford nitriles in moderate to high yields. Various functional groups can be tolerated, and the H?C?C?H bond dehydrogenation does not occur for linear alkyl azide substrates. Furthermore, the pincer Ir catalytic system was found to catalyze the direct azide dehydrogenation without the use of a sacrificial hydrogen acceptor.
- Gan, Lan,Jia, Xiangqing,Fang, Huaquan,Liu, Guixia,Huang, Zheng
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p. 3661 - 3665
(2020/06/02)
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- Method for preparing primary amines through hydrogen transfer selective nitrile reduction
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The invention discloses a method for preparing primary amines through hydrogen transfer selective nitrile reduction. The method includes the step of adding low-price copper, iron and other metal saltsor low-price easy-to-obtain iodine elementary substances as additives with a nitrile compound as the raw material and oxazole borane as the hydrogen transfer agent under the mild conditions, therebypromoting the hydrogen transfer reaction and selectively synthesizing a series of corresponding primary amines under different conditions respectively. The high yield and high selectivity are achievedin the reaction. The oxazole borane is obtained through reaction of alkamine and a tetrahydrofuran complex of borane. In addition, the method is mild in reaction condition, easy to operate, free of high-pressure devices, environmentally friendly and high in raw material general applicability, the agents required for the reaction are all low in price and easy to obtain, the reduction product is only primary amines, and selectivity and repeatability are high. Thus, an effective scheme is provided for the industrial production of other high-additional-value compounds of similar structures in future.
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Paragraph 0067-0071
(2019/05/02)
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- Mild palladium-catalysed highly efficient hydrogenation of CN, C-NO2, and CO bonds using H2 of 1 atm in H2O
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Here we present the first example of a mild and high-efficiency protocol enabling a process in water using 1 atm of H2 for the efficient and selective hydrogenation of nitriles, nitro compounds, ketones, and aldehydes to yield primary amines and alcohols with satisfactory yields of up to >99%. Several palladium-based nanoparticle catalysts were prepared from K2PdCl4 and ligands, and one of them was found to be the best and most suitable for the hydrogenation of CN, C-NO2, and CO bonds. In addition, the catalyst Pd-NPs can be easily recycled and reused without losing their activity and selectivity. A plausible mechanism for the hydrogenation of a CN bond was also proposed, representing the first example that possesses great potential for sustainable industrial purposes.
- Liu, Yaxu,He, Shaopo,Quan, Ziyi,Cai, Huizhuo,Zhao, Yang,Wang, Bo
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supporting information
p. 830 - 838
(2019/02/27)
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- Platinum-(phosphinito-phosphinous acid) complexes as bi-talented catalysts for oxidative fragmentation of piperidinols: An entry to primary amines
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Platinum-(phosphinito-phosphinous acid) complex catalyzes the oxidative fragmentation of hindered piperidinols according to a hydrogen transfer induced methodology. This catalyst acts successively as both a hydrogen carrier and soft Lewis acid in a one pot-two steps process. This method can be applied to the synthesis of a wide variety of primary amines in a pure form by a simple acid-base extraction without further purification.
- Membrat, Romain,Vasseur, Alexandre,Moraleda, Delphine,Michaud-Chevallier, Sabine,Martinez, Alexandre,Giordano, Laurent,Nuel, Didier
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p. 37825 - 37829
(2019/12/03)
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- Nano-Fe3O4@SiO2-SO3H: A magnetic, reusable solid-acid catalyst for solvent-free reduction of oximes to amines with the NaBH3CN/ZrCl4 system
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In this study, the immobilization of sulfonic acid on silica-layered magnetite was carried out by the reaction of ClSO3H with silica-layered magnetite. The prepared magnetic nanoparticles of Fe3O4@SiO2-SO3H were then characterized using scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, vibrating sample magnetometry, and transmission electron microscopy. The sulfonated nanocomposite exhibited excellent catalytic activity and reusability in the reduction of various aldoximes and ketoximes with NaBH3CN in the presence of ZrCl4. All reactions were carried out under solvent-free conditions (r.t. or 75–80°C) within 3–70 min to afford amines in high to excellent yields.
- Sadighnia, Leila,Zeynizadeh, Behzad,Karami, Shiva,Abdollahi, Mohammad
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p. 535 - 542
(2019/01/04)
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- Cobalt complex, preparation method thereof, and application thereof in selective catalysis of transfer hydrogenation reaction of cyano group
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The invention discloses a cobalt complex, a preparation method thereof, and an application thereof in the selective catalysis of a transfer hydrogenation reaction of a cyano group. The structural formula of the cobalt complex is represented by formula I. The cobalt complex is prepared through a reaction of a cobalt salt and an NNP ligand or a PNP ligand under the protection of an inert atmosphere;and the chemical formula of the cobalt salt is CoX12, wherein X1 represents halogen, a sulfate radical, a perchlorate radical, a hexafluorophosphate radical, a hexafluoroantimonate radical, a tetrafluoroborate radical, a trifluoromethanesulfonate radical or a tetra(pentafluorophenyl)borate radical. The cobalt complex can be used in the selective catalysis of the transfer hydrogenation reaction ofthe cyano group to obtain a primary amine compound, a secondary amine compound and a tertiary amine compound, the primary amine compound, the secondary amine compound and the tertiary amine compoundare important intermediates in a series of subsequent functionalizing reactions, and the cobalt complex has a very high catalysis activity, and has great research values and a great application prospect.
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Paragraph 0157-0159; 0161
(2018/05/07)
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- Cobalt-based nanoparticles prepared from MOF-carbon templates as efficient hydrogenation catalysts
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The development of efficient and selective nanostructured catalysts for industrially relevant hydrogenation reactions continues to be an actual goal of chemical research. In particular, the hydrogenation of nitriles and nitroarenes is of importance for the production of primary amines, which constitute essential feedstocks and key intermediates for advanced chemicals, life science molecules and materials. Herein, we report the preparation of graphene shell encapsulated Co3O4- and Co-nanoparticles supported on carbon by the template synthesis of cobalt-terephthalic acid MOF on carbon and subsequent pyrolysis. The resulting nanoparticles create stable and reusable catalysts for selective hydrogenation of functionalized and structurally diverse aromatic, heterocyclic and aliphatic nitriles, and as well as nitro compounds to primary amines (>65 examples). The synthetic and practical utility of this novel non-noble metal-based hydrogenation protocol is demonstrated by upscaling several reactions to multigram-scale and recycling of the catalyst.
- Murugesan, Kathiravan,Senthamarai, Thirusangumurugan,Sohail, Manzar,Alshammari, Ahmad S.,Pohl, Marga-Martina,Beller, Matthias,Jagadeesh, Rajenahally V.
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p. 8553 - 8560
(2018/11/30)
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- Highly Stable COF-Supported Co/Co(OH)2 Nanoparticles Heterogeneous Catalyst for Reduction of Nitrile/Nitro Compounds under Mild Conditions
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Ordered nanoporosity in covalent organic framework (COF) offers excellent opportunity for property development. Loading nanoparticles (nPs) onto them is one approach to introducing tailor-made properties into a COF. Here, a COF–Co/Co(OH)2 composite containing about 16 wt% of 2 nPs is prepared on a N-rich COF support that catalyzes the release of theoretical equivalence of H2 from readily available, safe, and cheap NaBH4. Furthermore, the released H2 is utilized for the hydrogenation of nitrile and nitro compounds to amines under ambient conditions in a facile one-pot reaction. The COF “by choice” is built from “methoxy” functionalized dialdehydes which is crucial in enabling the complete retention of the COF structure under the conditions of the catalysis, where the regular Schiff bonds would have hydrolyzed. The N-rich binding pockets in the COF ensure strong nP–COF interactions, which provides stability and enables catalyst recycling. Modeling studies reveal the crucial role played by the COF in exposing the active facets and thereby in controlling the activation of the reducing agent. Additionally, via density functional theory, we provide a rational explanation for how these COFs can stabilize nanoparticles which grow beyond the limiting pore size of the COF and yet result in a truly stable heterogeneous catalyst – a ubiquitous observation. The study underscores the versatility of COF as a heterogeneous support for developing cheap and highly active nonnoble metal catalysts.
- Mullangi, Dinesh,Chakraborty, Debanjan,Pradeep, Anu,Koshti, Vijay,Vinod, Chathakudath P.,Panja, Soumendranath,Nair, Sunil,Vaidhyanathan, Ramanathan
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- Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources
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A Ru(ii) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using methanol as a methylating agent is reported. This methodology was successfully applied for a one-pot reaction of bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed by preparative scale reactions with different organic azides and synthesis of an anti-vertigo drug betahistine. Several kinetic experiments and DFT studies were carried out to understand the mechanism of this transformation.
- Chakrabarti, Kaushik,Mishra, Anju,Panja, Dibyajyoti,Paul, Bhaskar,Kundu, Sabuj
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supporting information
p. 3339 - 3345
(2018/07/29)
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- Low-Pressure Hydrogenation of Nitriles to Primary Amines Catalyzed by Ruthenium Pincer Complexes. Scope and mechanism
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The catalytic hydrogenation of nitriles to primary amines constitutes an environmentally benign and atom-economical methodology in synthetic organic chemistry. However, selective hydrogenation can be challenging, and usually elevated pressure and the use of various additives is required. Herein the hydrogenation of aromatic and aliphatic nitriles to form primary amines catalyzed by ruthenium pincer complexes is described. The reactions are conducted at low H2 pressure, low catalytic loadings and, in case of a variety of benzonitriles, under neutral conditions and without any additives. Mechanistic insight is provided.
- Mukherjee, Arup,Srimani, Dipankar,Ben-David, Yehoshoa,Milstein, David
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p. 559 - 563
(2017/02/26)
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- Selective Hydrogenation of Nitriles to Primary Amines by using a Cobalt Phosphine Catalyst
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A general procedure for the catalytic hydrogenation of nitriles to primary amines by using a non-noble metal-based system is presented. Co(acac)3 in combination with tris[2-(dicyclohexylphosphino)ethyl]phosphine efficiently catalyzes the selective hydrogenation of a wide range of (hetero)aromatic and aliphatic nitriles to give the corresponding amines.
- Adam, Rosa,Bheeter, Charles Beromeo,Cabrero-Antonino, Jose R.,Junge, Kathrin,Jackstell, Ralf,Beller, Matthias
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p. 842 - 846
(2017/03/17)
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- Cobalt-Catalyzed and Lewis Acid-Assisted Nitrile Hydrogenation to Primary Amines: A Combined Effort
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The selective hydrogenation of nitriles to primary amines using a bench-stable cobalt precatalyst under 4 atm of H2 is reported herein. The catalyst precursor was reduced in situ using NaHBEt3, and the resulting Lewis acid formed, BEt3, was found to be integral to the observed catalysis. Mechanistic insights gleaned from para-hydrogen induced polarization (PHIP) transfer NMR studies revealed that the pairwise hydrogenation of nitriles proceeded through a Co(I/III) redox process.
- Tokmic, Kenan,Jackson, Bailey J.,Salazar, Andrea,Woods, Toby J.,Fout, Alison R.
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supporting information
p. 13554 - 13561
(2017/10/05)
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- NNP-Type Pincer Imidazolylphosphine Ruthenium Complexes: Efficient Base-Free Hydrogenation of Aromatic and Aliphatic Nitriles under Mild Conditions
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A series of seven novel NImNHP-type pincer imidazolylphosphine ruthenium complexes has been synthesized and fully characterized. The use of hydrogenation of benzonitrile as a benchmark test identified [RuHCl(CO)(NImNHPtBu)] as the most active catalyst. With its stable Ru-BH4 analogue, in which chloride is replaced by BH4, a broad range of (hetero)aromatic and aliphatic nitriles, including industrially interesting adiponitrile, has been hydrogenated under mild and base-free conditions.
- Adam, Rosa,Alberico, Elisabetta,Baumann, Wolfgang,Drexler, Hans-Joachim,Jackstell, Ralf,Junge, Henrik,Beller, Matthias
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p. 4991 - 5002
(2016/04/05)
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- Mild and Selective Cobalt-Catalyzed Chemodivergent Transfer Hydrogenation of Nitriles
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Herein, we describe a selective cobalt-catalyzed chemodivergent transfer hydrogenation of nitriles to synthesize primary, secondary, and tertiary amines. The solvent effect plays a key role for the selectivity control. The general applicability of this procedure was highlighted by the synthesis of more than 70 amine products bearing various functional groups in high chemoselectivity. Moreover, this mild system achieved >2000 TONs (turnover numbers) for the transfer hydrogenation of nitriles.
- Shao, Zhihui,Fu, Shaomin,Wei, Mufeng,Zhou, Shaolin,Liu, Qiang
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supporting information
p. 14653 - 14657
(2016/11/23)
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- Preparation method of benzylamine compound
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The invention discloses a preparation method of a benzylamine compound. The method adopting an aryl methane compound as a raw material comprises the following steps: carrying out an NBS bromination reaction to synthesize a bromobenzyl compound, carrying out an N-hydrocarbylation reaction to synthesize a 1-benzylpyrrolidyl-2,5-dione compound, and carrying out a hydrolyzing reaction to obtain the benzylamine compound. The preparation method of the benzylamine compound has the advantages of wide source of the raw material, no need of separation of intermediates generated in above reactions, realization of an all-in-a-pot technology, simple operation, mild reaction conditions, high reaction yield, few three wastes, and convenience for industrial production.
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Paragraph 0044-0046
(2017/01/23)
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- Selective Hydrogenation of Nitriles to Primary Amines Catalyzed by a Cobalt Pincer Complex
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The catalytic hydrogenation of nitriles to primary amines represents an atom-efficient and environmentally benign reduction methodology in organic chemistry. This has been accomplished in recent years mainly with precious-metal-based catalysts, with a single exception. Here we report the first homogeneous Co-catalyzed hydrogenation of nitriles to primary amines. Several (hetero)aromatic, benzylic, and aliphatic nitriles undergo hydrogenation to the corresponding primary amines in good to excellent yields under the reaction conditions.
- Mukherjee, Arup,Srimani, Dipankar,Chakraborty, Subrata,Ben-David, Yehoshoa,Milstein, David
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supporting information
p. 8888 - 8891
(2015/08/03)
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- Transfer hydrogenation of unsaturated bonds in the absence of base additives catalyzed by a cobalt-based heterogeneous catalyst
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A novel non-noble Co@C-N catalytic system has been developed for catalytic transfer hydrogenation reactions. Co@C-N was found to be highly active and selective in the hydrogenation of a variety of unsaturated bonds with isopropanol in the absence of base additives.
- Long, Jilan,Zhou, Ying,Li, Yingwei
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supporting information
p. 2331 - 2334
(2015/02/05)
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- The efficient solvent-free reduction of oximes to amines with NaBH3CN catalyzed by ZrCl4/nano Fe3O4 system
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Reduction of various aldoximes and ketoximes to the corresponding amines was carried out easily and efficiently with NaBH3CN in the presence of ZrCl4/nano Fe3O4 system. The reactions were carried out under solvent-free conditions at room temperature or 75-80°C to afford amines in high to excellent yields.
- Sadighnia, Leila,Zeynizadeh, Behzad
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p. 873 - 878
(2015/03/18)
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- CuI-catalyzed coupling of gem-dibromovinylanilides and sulfonamides: An efficient method for the synthesis of 2-amidoindoles and indolo[1,2-a] quinazolines
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A Cu(I)-catalyzed, intermolecular protocol for the synthesis of 2-amidoindoles and tetrahydroindolo[1,2-a]quinazolines in shorter time and high yields is reported. The key highlight of this disclosure is the formation of 2-amidoindole and tetrahydroindolo[1,2-a]quinazoline moieties directly from gem-dibromovinylanilides and sulfonamides in a one-pot fashion through the in situ formation of ynamides followed by a base-promoted intramolecular hydroamidation.
- Kiruthika, Selvarangam E.,Perumal, Paramasivan Thirumalai
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p. 484 - 487
(2014/04/03)
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- Synthesis of pyrrolo-/indolo[1,2-a ]quinolines and naphtho[2,1- b ]thiophenes from gem -dibromovinyls and sulphonamides
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A highly efficient and simple route for the synthesis of pyrrolo-/indolo[1,2-a]quinolines and naphtho[2,1-b]thiophenes from gem-dibromovinyls and sulphonamides is reported. The noteworthy feature of this report is that the methodology involves a two-step protocol to synthesize tri- and tetracyclic heterocycles in a one-pot fashion through the Cu(I)-catalyzed formation of ynamide followed by a Ag(I)-assisted intramolecular hydroarylation. The photophysical properties of representative examples of pyrrolo- and indolo[1,2-a]quinolines in solid and solution states have also been studied.
- Kiruthika, Selvarangam E.,Nandakumar, Avanashiappan,Perumal, Paramasivan Thirumalai
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p. 4424 - 4427
(2015/02/05)
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- Selective catalytic transfer hydrogenation of nitriles to primary amines using Pd/C
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The catalytic transfer hydrogenation of (hetero)aryl nitriles using ammonium formate has been investigated in detail. In the presence of commercially available Pd/C, a straightforward and selective reduction is achieved without any additives under mild conditions.
- Vilches-Herrera, Marcelo,Werkmeister, Svenja,Junge, Kathrin,Boerner, Armin,Beller, Matthias
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p. 629 - 632
(2014/03/21)
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- BIO-ORTHOGONAL DRUG ACTIVATION
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Disclosed is a kit for the administration and activation of a Prodrug. The kit comprises a Masking Moiety linked, directly or indirectly, to a Trigger moiety, which in turn is linked to a Drug, and an Activator for the Trigger moiety. The Trigger moiety comprises a dienophile and the Activator comprises a diene, whereby the dienophile is an eight-membered non- aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The Trigger and the Activator undergo a fast, bio-orthogonal reaction resulting in the release of the Masking Moiety, and activation of the drug.
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Page/Page column 89-91
(2014/06/11)
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- CHEMICALLY CLEAVABLE GROUP
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Disclosed is the use of the reactive components of the inverse electron-demand Diels Alder reaction for chemical masking and unmasking in vitro. This can be applied in complex chemical reactions and, particularly in the synthesis of biomolecules, e.g. on solid supports. The reactice components are a dienophile, particularly a trans-cyclooctene, and a diene, particularly a tetrazine.
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Page/Page column 98-102
(2014/06/11)
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- CHANNEL PROTEIN ACTIVATABLE LIPOSOMES
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Disclosed is a liposome, comprising a lipid bilayer enclosing a cavity, wherein the bilayer comprises a channel protein releasably linked to an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The liposomes are used in a kit comprising the liposome, the liposomal membrane of which comprises a channel protein linked to a Trigger, and an Activator for the Trigger, wherein the Trigger comprises the eight- membered non-aromatic cyclic alkenylene group, and the Activator comprises a diene.
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Page/Page column 114; 115
(2014/06/11)
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- ACTIVATABLE LIPOSOMES
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Disclosed are reactive liposome, comprising a lipid bilayer enclosing a cavity, wherein the bilayer comprises a linkage to an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The liposomes are use in a kit comprising the liposome linked, directly or indirectly, to a Trigger, and an Activator for the Trigger, wherein the Trigger comprises an eight-membered non-aromatic cyclic alkenylene group, and the Activator comprises a diene.
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Page/Page column 131
(2014/06/11)
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- An unexpected formation of the novel 7-oxa-2-azabicyclo[2.2.1]hept-5-ene skeleton during the reaction of furfurylamine with maleimides and their bioprospection using a zebrafish embryo model
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An unexpected intramolecular cyclization during the reaction of furfurylamine with maleimides is reported as a novel strategy for the efficient green synthesis of the 7-oxa-2-azabicyclo[2.2.1]hept-5-ene skeleton. Under the same reaction conditions, 7-oxabicyclo[2.2.1]hept-5-enes were synthesized when furfurylamine was N-protected by the acetyl group. Both types of bicycloheptenes were screened using the zebrafish model system for genetics and developmental biology. The Royal Society of Chemistry 2013.
- Puerto Galvis, Carlos E.,Kouznetsov, Vladimir V.
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p. 407 - 411
(2013/02/25)
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- Selective ruthenium-catalyzed transfer hydrogenations of nitriles to amines with 2-butanol
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Transfer your hydrogen: Fast and general transfer hydrogenation of nitriles to form primary amines is possible with a homogeneous Ru/1,4- bis(diphenylphosphino)butane (DPPB) catalyst (see scheme). The use of 2-butanol as the hydrogen-transfer reagent is essential for the selective reduction of aromatic, heteroaromatic, and aliphatic nitriles with this system. Copyright
- Werkmeister, Svenja,Bornschein, Christoph,Junge, Kathrin,Beller, Matthias
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supporting information
p. 4437 - 4440
(2013/04/23)
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- Two iron catalysts are better than one: A general and convenient reduction of aromatic and aliphatic primary amides
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It takes two: For the reduction of amides to amines iron catalysts were developed. A combination of two different iron catalysts made possible the challenging reduction of primary amides (see picture). Copyright
- Das, Shoubhik,Wendt, Bianca,Moeller, Konstanze,Junge, Kathrin,Beller, Matthias
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supporting information; experimental part
p. 1662 - 1666
(2012/05/05)
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- Organophosphorus-catalysed Staudinger reduction
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The first Staudinger reduction that is catalytic in phosphine has been developed, showing excellent yields and functional group selectivity. To this end we utilised dibenzophosphole catalysts and mild in situ reduction of the intermediate iminophosphoranes. We could avoid the necessity of water during the reduction, obtained no phosphine oxides as waste and thus enabled facile purification of the product. A range of azides was converted into amines with good to excellent yields and high functional group tolerance. Copyright
- Van Kalkeren, Henri A.,Bruins, Jorick J.,Rutjes, Floris P. J. T.,Van Delft, Floris L.
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supporting information; experimental part
p. 1417 - 1421
(2012/07/03)
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- N-Alkylation of poor nucleophilic amines and derivatives with alcohols by a hydrogen autotransfer process catalyzed by copper(II) acetate: Scope and mechanistic considerations
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Copper(II) acetate is a versatile, cheap and simple catalyst for the selective N-monoalkylation of amino derivatives with poor nucleophilic character, such as aromatic and heteroaromatic amines as well as carboxamides, phosphinamides, sulfonamides, and phosphazenes, using in all cases primary alcohols as initial source of the electrophiles, through a hydrogen autotransfer process. In the case of sulfonamides, the monoalkylation process followed by a naphthalene-catalyzed reductive deprotection gives primary amines, which is an indirect alternative to the direct monoalkylation of ammonia. A study of the reaction using deuterium labelled reagents was performed, indicating that the dehydrogenation and hydrogenation steps do not take placed on the same copper-atom coordination sphere, with the condensation step occurring out of the dehydrogenating catalytic species.
- Martínez-Asencio, Ana,Ramón, Diego J.,Yus, Miguel
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experimental part
p. 3140 - 3149
(2011/05/06)
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- A new and convenient method for reduction of oximes to amines with NaBH3CN in the presence of MoCl5/NaHSO4? H2O system
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Various aldoximes and ketoximes were efficiently reduced to their corresponding amines with NaBH3CN in the presence of MoCl 5/NaHSO4?H2O system. Reduction reactions were carried out in refluxing EtOH or DMF within 0.3-3.8 h to afford the amines in high to excellent yields.
- Kouhkan, Mehri,Zeynizadeh, Behzad
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experimental part
p. 3323 - 3326
(2012/02/04)
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- A rapid and practical protocol for solvent-free reduction of oximes to amines with NaBH4/ZrCl4/Al2O3 system
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Solvent-free reduction of various aldoximes and ketoximes to the corresponding amines was performed easily and efficiently with NaBH4 in the presence of ZrCl4 supported on Al2O3. The reactions were carried out rapidly (within 2 min) at room temperature to afford the amines in high to excellent yields.
- Zeynizadeh, Behzad,Kouhkan, Mehri
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experimental part
p. 3448 - 3452
(2012/02/01)
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- Facile and efficient amination of organic halides catalyzed by copper sulfate in PEG1000-DIL/methylcyclohexane temperature-dependent biphasic system
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A simple, efficient, and environmentally friendly procedure for the amination of organic halides catalyzed by CuSO4·5H 2O in PEG1000-DIL/methylcyclohexane temperature-dependent biphasic system is described. The product can be easily isolated by a simple decantation, and the catalytic system can be recycled and reused without loss of catalytic activity.
- Hu, Yu-Lin,Wanga, Peng-Cheng,Chen, Tian,Lu, Ming
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experimental part
p. 604 - 611
(2011/04/19)
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- Ruthenium N-heterocyclic carbene catalysts for selective reduction of nitriles to primary amines
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Easily accessible in situ catalysts composed of [Ru(cod)(2-methylallyl)2] and N-heterocyclic carbene ligands have been developed for the environmentally benign hydrogenation of various nitriles to give primary amines. Applying optimized conditions in the presence of SIMesBF4 as ligand high catalyst activity of up to 392 h-1 is achieved in the hydrogenation of benzonitrile. The general applicability and functional group tolerance of this novel catalyst system are shown in the reduction of ten different nitriles.
- Addis, Daniele,Enthaler, Stephan,Junge, Kathrin,Wendt, Bianca,Beller, Matthias
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experimental part
p. 3654 - 3656
(2009/10/04)
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- A metal-free catalytic system for the oxidation of benzylic methylenes and primary amines under solvent-free conditions
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Iodine-pyridine-tert-butylhydroperoxide is developed as a green and efficient catalytic system for the oxidation of benzylic methylenes to ketones and primary amines to nitriles. The reaction conditions are quite mild and environmentally benign, no transition metals, organic solvents or hazard reagents being needed. The oxidation of benzylic methylenes gave the corresponding ketones in excellent yields with complete chemoselectivity, while the oxidation of primary amines was complete in several minutes, affording various nitriles in moderate to good yields.
- Zhang, Jintang,Wang, Zhentao,Wang, Ye,Wan, Changfeng,Zheng, Xiaoqi,Wang, Zhiyong
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supporting information; scheme or table
p. 1973 - 1978
(2010/06/15)
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- Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus
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The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
- Xie, Hui,Ng, Danny,Savinov, Sergey N.,Dey, Barna,Kwong, Peter D.,Wyatt, Richard,Smith III, Amos B.,Hendrickson, Wayne A.
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p. 4898 - 4908
(2008/03/11)
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- A novel naphthylmethyleneimino-type photocleavable protecting group for primary amines
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A novel naphthylmethyleneimino-type protecting group for aliphatic and aromatic primary amines including α-amino acids was devised and its introduction was accomplished in good to excellent yields. This type of protecting group was found to be cleanly removed photochemically to regenerate the primary amines in good to high yields, regardless of steric and electronic properties. Georg Thieme Verlag Stuttgart.
- Igarashi, Tetsutaro,Shimokawa, Masaru,Iwasaki, Miyuki,Nagata, Kensaku,Fujii, Masato,Sakurai, Tadamitsu
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p. 1436 - 1440
(2008/02/13)
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- First report for the efficient reduction of oximes to amines with zinc borohydride in the form of (Pyridine)(tetrahydroborato)zinc complex
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(Pyridine)(tetrahydroborato)zinc complex, (Py)Zn(BH4) 2, as a stable modification of zinc borohydride can easily reduce a variety of aromatic and aliphaticaldoximes or ketoximes to their corresponding amines in high to excellent yields in refluxing THF.
- Zeynizadeh, Behzad,Zahmatkesh, Karam
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p. 109 - 112
(2007/10/03)
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- Pharmaceutically active pyrrolidine derivatives as bax inhibitors
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The present invention is related to new substituted pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of neurodegenerative disorders, diseases associated with polygultamine tracts, epilepsy, ischemia, infertility, cardiovascular disorders renal hypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display a modulatory and most notably a down-regulating-up to an inhibitory-activity with respect to the cellular death agonist Bax and/or the activation pathways leading to Bax and allows therefore to block the release of cytochrome (c). The present invention is furthermore related to novel pharmaceutically activity substituted pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of O, S, CRR, NOR, NNRR; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2-, —SO2NH—; —CH2-; B is either a group —(C═O)—NRR or represents a heterocyclic residue having the formula (II) wherein Q is NR, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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- Pharmaceutically active pyrrolidine derivatives
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The present invention is related to pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of CR6R7, NOR6, NNR6R7; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO22—, —SO2NH—, —CH2—,B is either a group —(C═O)—NR8R9 or represents a heterocyclic residue having the formula (a) wherein Q is NR10, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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- 2-aminobenzoxazole derivatives and combinatorial libraries thereof
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The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula: wherein R1 to R4 and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.
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- Rapid reduction of nitriles to primary amines with nickel boride at ambient temperature
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Reduction of a variety of nitriles to their corresponding primary amines can be achieved with nickel boride generated in situ in dry ethanol at ambient temperature. The reductions are very rapid and chemoselective.
- Khurana, Jitender M.,Kukreja, Gagan
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p. 1265 - 1269
(2007/10/03)
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