- Developing novel classes of protein kinase CK1δ inhibitors by fusing [1,2,4]triazole with different bicyclic heteroaromatic systems
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Protein kinase CK1δ expression and activity is involved in different pathological situations that include neuroinflammatory and neurodegenerative diseases. For this reason, protein kinase CK1δ has become a possible therapeutic target for these conditions. 5,6-fused bicyclic heteroaromatic systems that resemble adenine of ATP represent optimal scaffolds for the development of a new class of ATP competitive CK1δ inhibitors. In particular, a new series of [1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-a][1,3,5]triazines was developed. Some crucial interactors have been identified, such as the presence of a free amino group able to interact with the residues of the hinge region at the 5- and 7- positions of the [1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-a][1,3,5]triazine scaffolds, respectively; or the presence of a 3-hydroxyphenyl or 3,5-dihydroxyphenyl moiety at the 2- position of both nuclei. Molecular modeling studies identified the key interactions involved in the inhibitor-protein recognition process that appropriately fit with the outlined structure-activity relationship. Considering the fact that the CK1 protein kinase is involved in various pathologies in particular of the central nervous system, the interest in the development of new inhibitors permeable to the blood-brain barrier represents today an important goal in the pharmaceutical field. The best potent compound of the series is the 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol (compound 51, IC50 = 0.18 μM) that was predicted to have an intermediate ability to cross the membrane in our in vitro assay and represents an optimal starting point to both studies the therapeutic value of protein kinase CK1δ inhibition and to develop new more potent derivatives.
- Grieco, Ilenia,Bissaro, Maicol,Tiz, Davide Benedetto,Perez, Daniel I.,Perez, Conception,Martinez, Ana,Redenti, Sara,Mariotto, Elena,Bortolozzi, Roberta,Viola, Giampietro,Cozza, Giorgio,Spalluto, Giampiero,Moro, Stefano,Federico, Stephanie
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- Choline Hydroxide as a Versatile Medium for Catalyst-Free O-Functionalization of Phenols
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A versatile synthetic protocol for benzyl phenyl ether preparation via O-alkylation of phenolic oxygen with readily available benzyl derivatives was demonstrated. The newly designed procedure was carried out using an eco-friendly medium, room-temperature ionic liquid (choline hydroxide), under metal- and base-catalyst-free aerobic conditions. The reaction platform was also successfully applied to phenol protection strategy.
- Joo, Seong-Ryu,Kim, Seung-Hoi,Kwon, Gyu-Tae,Park, Soo-Youl
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p. 1200 - 1205
(2020/11/30)
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- An alternative route for boron phenoxide preparation from arylboronic acid and its application for C[sbnd]O bond formation
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An efficient synthetic route to benzyl phenyl ether preparation has been successfully developed via a one-pot synthetic protocol utilizing a combination of arylboronic acids, hydrogen peroxide (H2O2), and benzyl halides. The whole procedure consists of two consecutive reactions, formation of boron phenoxide from arylboronic acids and its nucleophilic attack. A simple operation under mild conditions such as room-temperature ionic liquid (choline hydroxide), aerobic environment, and absence of metal- and base-catalysts has been employed. Expansion to utilize benzyl surrogates was also successfully accomplished.
- Joo, Seong-Ryu,Kim, Seung-Hoi,Lim, In-Kyun
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- Nickel-catalyzed reductive amidation of aryl-triazine ethers
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The reaction of activated phenolic compounds, 2,4,6-triaryloxy-1,3,5-triazine (aryl-triazine ethers), with various isocyanates or carbodiimides in the presence of a nickel pre-catalyst resulted in the synthesis of aryl amides in good to excellent yields.
- Heravi, Majid M.,Panahi, Farhad,Iranpoor, Nasser
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supporting information
p. 1992 - 1995
(2020/02/22)
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- Nickel-Catalyzed Synthesis of N-(Hetero)aryl Carbamates from Cyanate Salts and Phenols Activated with Cyanuric Chloride
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A simple and efficient domino reaction has been designed and employed for the one-pot synthesis of N-(hetero)aryl carbamates through the reaction between alcohols and in-situ produced (hetero)aryl isocyanates in the presence of a nickel catalyst. The phenolic C?O bond was activated via the reaction of phenol with cyanuric chloride (2,4,6-trichloro-1,3,5-triazine (TCT)) as an inexpensive and readily available reagent. This strategy provides practical access to N-(hetero)aryl carbamates in good yields with high functional groups compatibility.
- Dindarloo Inaloo, Iman,Esmaeilpour, Mohsen,Majnooni, Sahar,Reza Oveisi, Ali
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p. 5486 - 5491
(2020/09/04)
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- A Triazolotriazine-Based Dual GSK-3β/CK-1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition
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Glycogen synthase kinase 3β (GSK-3β) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC50(GSK-3β)=0.17 μm; IC50(CK-1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.
- Redenti, Sara,Marcovich, Irene,De Vita, Teresa,Pérez, Concepción,De Zorzi, Rita,Demitri, Nicola,Perez, Daniel I.,Bottegoni, Giovanni,Bisignano, Paola,Bissaro, Maicol,Moro, Stefano,Martinez, Ana,Storici, Paola,Spalluto, Giampiero,Cavalli, Andrea,Federico, Stephanie
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supporting information
p. 310 - 314
(2019/01/24)
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- Nickel-catalysed C–O bond reduction of 2,4,6-triaryloxy-1,3,5-triazines in 2-methyltetrahydrofuran
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A nickel-catalysed reduction of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine (TCT) in ecofriendly 2-methyltetrahydrofuran (2-MeTHF) is described. The phenol-TCT derivatives were readily prepared using grinding method in short time without further purification. This catalytic system allowed the facile C–O cleavage of phenol-TCT derivatives under mild reaction conditions with high efficiency and good functional group tolerance. Gram-scale reaction was also achieved. Particularly, sequential functionalization of phenol-TCT derivatives followed by C–O bond reduction could also be realized, affording the high value-added products in moderate to good yields.
- Wang, Yaoyao,Shen, Jun,Chen, Qun,Wang, Liang,He, Mingyang
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p. 409 - 412
(2018/10/02)
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- Attempt to Synthesize Hindered 2,4,6-Tri-Aryloxy-s-Triazines: Bis(2,4-di-tert-Butylphenyl) Carbonate – Crystal Structure
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Some less hindered 2,4,6-tri-aryloxy-s-triazines were synthesized through the reaction of the corresponding phenols as a starting materials with cyanogen bromide (BrCN) to obtain the corresponding arylcyanates and then trimerized. Unexpectedly, 2,4-di-tert-butyl-1-cyanatobenzene derived from 2,4-di-tert-butylphenol did not trimerize but, indeed, yielded bis(2,4-di-tert-butylphenyl) carbonate. The structures of 2,4,6-tri-aryloxy-s-triazines and bis(2,4-di-tert-butylphenyl) carbonate were characterized by means of IR, 1H, and 13C NMR spectroscopies. Also the structure of the latter compound was studied by X-ray crystallography.
- Noroozi Pesyan, Nader,Kashani, Elmira,Ghorbanzadeh, Kamaleh,Notash, Behrouz
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p. 554 - 560
(2018/01/01)
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- Synthesis, Spectra, and Theoretical Investigations of 1,3,5-Triazines Compounds as Ultraviolet Rays Absorber Based on Time-Dependent Density Functional Calculations and three-Dimensional Quantitative Structure-Property Relationship
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A series of 1,3,5-triazines were synthesized and their UV absorption properties were tested. The computational chemistry methods were used to construct quantitative structure-property relationship (QSPR), which was used to computer aided design of new 1,3,5-triazines ultraviolet rays absorber compounds. The experimental UV absorption data are in good agreement with those predicted data using the Time-dependent density functional theory (TD-DFT) [B3LYP/6–311 + G(d,p)]. A suitable forecasting model (R > 0.8, P 0.0001) was revealed. Predictive three-dimensional quantitative structure-property relationship (3D-QSPR) model was established using multifit molecular alignment rule of Sybyl program, which conclusion is consistent with the TD-DFT calculation. The exceptional photostability mechanism of such ultraviolet rays absorber compounds was studied and confirmed as principally banked upon their ability to undergo excited-state deactivation via an ultrafast excited-state proton transfer (ESIPT). The intramolecular hydrogen bond (IMHB) of 1,3,5-triazines compounds is the basis for the excited state proton transfer, which was explored by IR spectroscopy, UV spectra, structural and energetic aspects of different conformers and frontier molecular orbitals analysis.
- Wang, Xueding,Xu, Yilian,Yang, Lu,Lu, Xiang,Zou, Hao,Yang, Weiqing,Zhang, Yuanyuan,Li, Zicheng,Ma, Menglin
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p. 707 - 723
(2018/05/05)
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- Nickel-catalyzed cyanation of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine
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A nickel-catalyzed cyanation of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine (TCT) using aminoacetonitrile as the cyanating agent is described. This catalytic system delivered the desired products in moderate to good yields with good substrate compatibility. The readily available starting materials, cost-effective nickel catalyst and metal-free cyanating agent are the major features of the present method.
- Wang, Liang,Wang, Yaoyao,Shen, Jun,Chen, Qun,He, Ming-Yang
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supporting information
p. 4816 - 4820
(2018/07/13)
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- Chitosan-Supported Ni particles: An Efficient Nanocatalyst for Direct Amination of Phenols
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A practical method for the direct amination of phenols using 2,4,6-trichloro-1,3,5-triazine (TCT) as an efficient promotor for the activation of phenols in the presence of an efficient and recyclable heterogeneous catalyst prepared by immobilization of nickel particles on triazole modified chitosan is described. This heterogeneous catalyst has demonstrated a promising activity for the conversion of phenolic compounds to their corresponding amine under mild conditions. Moreover, the obtained catalyst can be reused in five consecutive runs with consistent catalytic activity.
- Hajipour, Abdol R.,Abolfathi, Parisa
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- Efficient Ni-catalyzed conversion of phenols protected with 2,4,6-trichloro-1,3,5-triazine (TCT) to olefins
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An efficient Ni(COD)2/dppf catalyzed olefination of Ar-O-TCT as synthetic equivalents of aryl halides is described. Activation of C-O bonds in phenols as readily available compounds was achieved with 2,4,6-trichloro-1,3,5-triazine (TCT). This method provides practical access to 1,2-disubstituted olefins in high yields and high functional group compatibility.
- Etemadi-Davan,Iranpoor
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supporting information
p. 12794 - 12797
(2017/12/06)
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- A Mild and Selective Method for the Catalytic Hydrodeoxygenation of Cyanurate Activated Phenols in Multiphasic Continuous Flow
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A low-energy, high-selectivity approach to the catalytic hydrodeoxygenation of phenols is reported using batch or continuous flow methods to react 3 equiv of phenol with cyanuric chloride then hydrogenolyzing the triarylcyanurate intermediate to give 3 equiv of deoxo aromatic. The use of cyanuric chloride compares favorably with existing activation methods, showing improved scalability, atom efficiency, and economics. The scope of both the activation and hydrogenolysis stages are explored using lignin-related phenols. Initial development has identified that continuous stir tank reactors (CSTRs) enable a multiphasic process for converting guaiacol to anisole and at steady state overcome the catalyst deactivation issues observed in batch, seemingly caused by the cyanurate byproduct. Green chemistry aspects and the potential for industrial adoption are discussed.
- Zhao, Yuhan,King, Georgina,Kwan, Maria H.T.,Blacker, A. John
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supporting information
p. 2012 - 2018
(2017/02/10)
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- Nickel-catalyzed one-pot deoxygenation and reductive homocoupling of phenols via C-O activation using TCT reagent
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A new method for C-O bond activation of phenolic compounds has been achieved using 2,4,6-trichloro-1,3,5-triazine to utilize in one-pot Ni-catalyzed deoxygenation and reductive homocoupling reactions. With this simple method, phenolic compounds were converted to their corresponding arenes or biaryl compounds under mild conditions. The introduced methodology has a broad scope and demonstrates good functional group compatibility.
- Iranpoor, Nasser,Panahi, Farhad
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supporting information
p. 214 - 217
(2015/01/30)
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- Unexpected cyclotrimerization of phenyl cyanate; does Chapman rearrangement occurred in the mass spectrometric ionization of 2,4,6-triphenoxy-1,3,5-S- triazine?
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Unexpected novel cyclotrimerization of phenyl cyanate gave 2,4,6-triphenoxy-1,3,5-s-triazine 3 with excellent yield. No special catalyst is used in this reaction!. The mass spectra of 3 is investigated and it shows some fragments generated by McLafferty and Chapman rearrangements.
- Noroozi-Pesyan, Nader
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p. 329 - 336
(2007/10/03)
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- Microwave assisted synthesis of triaryl cyanurates
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Rapid synthesis of triaryl cyanurates(2,4,6-triaryloxy-1,3,5-triazine) was carried out by reacting cyanuric chloride with the sodium salt of hydroxyaryl compounds in water using focused microwaves. Environmentally friendly procedure and isolation of pure products in excellent yields are important features of this method.
- Sagar,Patil,Bandgar
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p. 1719 - 1723
(2007/10/03)
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- Mild and efficient synthesis of triaryl cyanurates by using effective combination of tetrabutyl ammonium bromide and dibenzo-(18)-crown-6
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2,4,6-Triaryloxy-1,3,5-triazines (triaryl cyanurates) have been synthesized in high yield under mild reaction conditions by reacting cyanuric chloride with the potassium salts of phenols in a two phase system consisting of chloroform, water and effective catalytic mixture of tetrabutyl ammonium bromide and dibenzo-(18)crown-6.
- Sharma,Salunkhe
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p. 482 - 483
(2007/10/03)
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- Crystal engineering of some 2,4,6-triaryloxy-1,3,5-triazines: Octupolar nonlinear materials
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The principles of crystal engineering have been used to design a family of structures with potential as octupolar nonlinear optical (NLO) materials. The major aim in such an exercise, a carry-over of molecular symmetry into the crystal, is possible with a retrosynthetic approach. An appropriate choice of precursor trigonal molecules leads from the concept of the dimeric Piedfort unit. The crystal structures and NLO properties of a series of 2,4,6-triaryloxy-1,3,5-triazines, 1-6, are reported. These compounds consistently form quasitrigonal or trigonal networks that are two-dimensionally noncentrosymmetric. Substitutional variations on the phenyl moieties that were expected to maintain or to perturb this trigonal network have been explored. Molecular nonlinearities have been measured by Harmonic Light Scattering (HLS) experiments. Among the compounds studied, 2,4,6-triphenoxy-1,3,5-triazine, 1 adopts a noncentrosymmetric crystal structure with a measurable SHG powder signal. All these crystal structures are stabilized by weak intermolecular interactions such as herringbone, π...π, C-H...O, and C-H...N hydrogen bonding. These octupolar molecules are more isotropic than the classical p-nitroaniline based dipolar NLO molecules, and this is advantageous from the viewpoint of potential electrooptic applications. The principles of crystal engineering have been used to design a family of structures with potential as octupolar nonlinear optical (NLO) materials. The major aim in such an exercise, a carry-over of molecular symmetry into the crystal, is possible with a retrosynthetic approach. An appropriate choice of precursor trigonal molecules leads from the concept of the dimeric Piedfort unit. The crystal structures and NLO properties of a series of 2,4,6-triaryloxy-1,3,5-triazines, 1-6, are reported. These compounds consistently form quasitrigonal or trigonal networks that are two- dimensionally noncentrosymmetric. Substitutional variations on the phenyl moieties that were expected to maintain or to perturb this trigonal network have been explored. Molecular nonlinearities have been measured by Harmonic Light Scattering (HLS) experiments. Among the compounds studied, 2,4,6- triphenoxy-1,3,5-triazine, 1 adopts a noncentrosymmetric crystal structure with a measurable SHG powder signal. All these crystal structures are stabilized by weak intermolecular interactions such as herringbone, π···π, C-H···O, and C-H···N hydrogen bonding. These octupolar molecules are more isotropic than the classical p-nitroaniline based dipolar NLO molecules, and this is advantageous from the viewpoint of potential electrooptic applications.
- Thalladi, Venkat R.,Brasselet, Sophie,Weiss, Hans-Christoph,Bl?ser, Dieter,Katz, Amy K.,Carrell,Boese, Roland,Zyss, Joseph,Nangia, Ashwini,Desiraju, Gautam R.
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p. 2563 - 2577
(2007/10/03)
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- SYNTHESIS OF TRIARYL CYANURATES CATALYSED BY POLYETHYLENE GLYCOL IN A TWO-PHASE SYSTEM : PHASE TRANSFER CATALYSIS
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The synthesis of triaryl cyanurates (2,4,6-triaryloxy-1,3,5-triazines) was accomplished at room temperature in high yields in a two-phase system using PEG-400 as a phase transfer catalyst.
- Kavitake, Bhanudas P.,Patil, Sucheta V.,Salunkhe, Manikrao M.,Wadgaonkar, Prakash P.
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p. 675 - 678
(2007/10/03)
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- Cycloaddition Reactions of Azide Ligands in Phosphane Complexes of Palladium(II), Platinum(II), and Iridium(I)
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Nitriles are added to the azide ligands of the planar compounds cis-(R3P)2Pt(N3)2 and trans-(Ph3P)2Ir(CO)N3 to give to 5-R-tetrazolato complexes 1 - 3.Kinetic studies show that the rate of the -cycloaddition increases with donor strength of the phosphane ligands and with electron-poor nitriles.The mechanism of the reactions is discussed.Using HCl or acyl chlorides, from 3 and (Ph3P)2Pd(5-R-tetrazolate)2 the free 5-R-tetrazoles or disubstituted tetrazoles are obtained under mild conditions. (Ph3P)2Pd(N3)2 reacts with MeO2CCCCO2Me to give the triazolato complexes 5, 6.Organic isothiocyanates and thiocyanates yield tetrazolinethionato (7) and 5-(methylthio)tetrazolato complexes (8).Using 1H NMR spectroscopy isomeric complexes with these ambidentate heterocyclic ligands can be detected.
- Kreutzer, Peter H.,Weis, Johann Ch.,Bock, Henning,Erbe, Juergen,Beck, Wolfgang
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p. 2691 - 2707
(2007/10/02)
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- Pressure-Induced Cyclotrimerization of Electron-Deficient Nitriles. Catalysis by Acidic Alcohols and Phenols
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Fluorodinitroacetonitrile (1) was pressurized at 1 GPa in the presence of a variety of ROH catalysts.Cyclotrimerization of 1 occurred in several cases, but the observed triazines contained RO groups in place of one or several CF(NO2)2 groups.Some mechanistic aspects of this reaction are explored by comparison with the results of the pressurization of preformed fluorodinitroacetimidates.
- Koppes, William M.,Adolph, Horst G.
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p. 406 - 412
(2007/10/02)
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