- Carbon-13 and Proton NMR Spectra of 1(2H)-Isoquinolinone, 1(2H)-Phthalazinone, 4(3H)-Quinazolinone and their Substituted Derivatives
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The 13C NMR chemical shifts, one-bond and some long-range 13C-1H coupling constants and the 1H NMR chemical shifts for isoquinolinone, phthalazinone, quinazolinone and their derivatives containing CH3, COOH, COOCH3 and CH2COOH substituents in the hetero-ring are reported.The NMR data are in agreement with the lactam structure for all compounds studied; no evidence for the detectable presence of other tautomers was obtained.
- Spassov, S. L.,Atanassova, I. A.,Haimova, M. A.
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- Ruthenium(II)-Catalyzed C?H Activation/Annulation of Aromatic Hydroxamic Acid Esters with Enamides Leading to Aminal Motifs
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Hydroxamic acid ester directed C(sp2)?H activation/annulation strategy has been reported employing electron-rich enamides under Ru(II)-catalysis to access aminal frameworks. Both N-vinyl acetamide and N-vinyl formamide delivered aminals bearing
- Dana, Suman,Sureshbabu, Popuri,Giri, Chandan Kumar,Baidya, Mahiuddin
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supporting information
p. 1385 - 1389
(2021/02/26)
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- Efficient visible light mediated synthesis of quinolin-2(1H)-ones from quinolineN-oxides
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Quinolin-2(1H)-ones are one of the important classes of compounds due to their prevalence in natural products and in pharmacologically useful compounds. Here we present an unconventional and hitherto unknown photocatalytic approach to their synthesis from easily available quinoline-N-oxides. This reagent free highly atom economical photocatalytic method, with low catalyst loading, high yield and no undesirable by-product, provides an efficient greener alternative to all conventional synthesis reported to date. The robustness of the methodology has been successfully demonstrated with easy scaling up to the gram scale.
- Bhuyan, Samuzal,Chhetri, Karan,Hossain, Jagir,Jana, Saibal,Mandal, Susanta,Roy, Biswajit Gopal
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p. 5049 - 5055
(2021/07/29)
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- Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization
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A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.
- Jaime-Figueroa, Saul,Bond, Michael J.,Vergara, J. Ignacio,Swartzel, Jake C.,Crews, Craig M.
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p. 8479 - 8488
(2021/06/28)
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- Site-Selective Acceptorless Dehydrogenation of Aliphatics Enabled by Organophotoredox/Cobalt Dual Catalysis
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The value of catalytic dehydrogenation of aliphatics (CDA) in organic synthesis has remained largely underexplored. Known homogeneous CDA systems often require the use of sacrificial hydrogen acceptors (or oxidants), precious metal catalysts, and harsh reaction conditions, thus limiting most existing methods to dehydrogenation of non- or low-functionalized alkanes. Here we describe a visible-light-driven, dual-catalyst system consisting of inexpensive organophotoredox and base-metal catalysts for room-temperature, acceptorless-CDA (Al-CDA). Initiated by photoexited 2-chloroanthraquinone, the process involves H atom transfer (HAT) of aliphatics to form alkyl radicals, which then react with cobaloxime to produce olefins and H2. This operationally simple method enables direct dehydrogenation of readily available chemical feedstocks to diversely functionalized olefins. For example, we demonstrate, for the first time, the oxidant-free desaturation of thioethers and amides to alkenyl sulfides and enamides, respectively. Moreover, the system's exceptional site selectivity and functional group tolerance are illustrated by late-stage dehydrogenation and synthesis of 14 biologically relevant molecules and pharmaceutical ingredients. Mechanistic studies have revealed a dual HAT process and provided insights into the origin of reactivity and site selectivity.
- Zhou, Min-Jie,Zhang, Lei,Liu, Guixia,Xu, Chen,Huang, Zheng
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supporting information
p. 16470 - 16485
(2021/10/20)
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- Synthesis of Overloaded Cyclopentadienyl Rhodium(III) Complexes via Cyclotetramerization of tert-Butylacetylene
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Herein we describe the synthesis and reactivity of rhodium catalysts with the very bulky cyclopentadienyl ligand C8H3tBu4 (designated as tBu4Cp). The reaction of [Rh(cod)Cl]2 with tert-butylacetylene in the presence of Et3N gives the complex (tBu4Cp)Rh(cod) (60-65% yield), in which the cyclopentadienyl ligand tBu4Cp is assembled from four alkyne molecules. The oxidation of (tBu4Cp)Rh(cod) with chlorine or bromine gives the corresponding halide complexes (tBu4Cp)RhX2 (X = Cl (85%), Br (95%)), which have unusual 16-electron monomeric structures due to the steric shielding provided by tBu groups. A similar reaction with iodine gives the ionic dinuclear complex [(tBu4Cp)RhI3Rh(tBu4Cp)]I (99%) with halide bridges. The bromide complex (tBu4Cp)RhBr2 reacts with phosphorus ligands such as P(OMe)3, P(OPh)3, PMe2Ph, and PMePh2 to give the 18-electron adducts (tBu4Cp)RhBr2(PR3), but no reaction occurs with larger phosphines such as PPh3. The racemic chloride (tBu4Cp)RhCl2 can be separated into enantiomers by preparative TLC of its diastereomeric adducts with (R)-phenylglycinol. The complex (tBu4Cp)RhBr2 catalyzes C-H activation and annulation of O-pivaloyl-hydroxamate as well as insertion of phenyldiazoacetate into E-H bonds, although the reaction rates and the substrate scope are limited by the bulky tBu4Cp ligand.
- Kolos, Andrey V.,Nelyubina, Yulia V.,Perekalin, Dmitry S.,Sundararaju, Basker
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supporting information
p. 3712 - 3719
(2021/09/18)
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- Cu(I)/sucrose-catalyzed hydroxylation of arenes in water: The dual role of sucrose
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A protocol for the hydroxylation of aryl halides catalyzed by copper(I) and sucrose in neat water has been developed. The dual role of sucrose, the reaction pathway, and the high selectivity for hydroxylation were investigated using a combination of experimental and theoretical techniques. This journal is
- Murata, Shigeo,Takagi, Mio,Takita, Ryo,Watanabe, Ayako,Watanabe, Kohei
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supporting information
p. 7827 - 7831
(2020/11/02)
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- Triflic acid mediated sequential cyclization of ortho-alkynylarylesters with ammonium acetate
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A triflic acid (TfOH) mediated sequential cyclization of ortho-alkynylarylesters and ammonium acetate (NH4OAc) was reported. The reaction took place via a Br?nsted acid-mediated intramolecular cyclization of ortho-alkynylarylesters followed by an ammonium acetate participated substitution reaction, forming isoquinolin-1-ones as the major products. Different from most of the known synthetic methods of isoquinolin-1-ones, no metal catalyst was required in the reported reaction. The regioisomers – isoindolin-1-ones were obtained together with isoquinolin-1-ones in a few cases. The intermediate compounds – isochromen-1-ones and isobenzofuran-1-ones were also isolated. The interconversion experiments showed that the regioisomers formed during the Br?nsted acid induced intramolecular cyclization of ortho-alkynylarylesters. A natural product – ruprechstyril was prepared in a moderate yield employing the new method.
- Domaradzki, Maciej E.,Liu, Xiaochen,Ong, Jiye,Yu, Gyeongah,Zhang, Gan,Simantov, Ariel,Perl, Eliyahu,Chen, Yu
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- Base-promoted aerobic oxidation of: N -alkyl iminium salts derived from isoquinolines and related heterocycles
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Potassium tert-butoxide-promoted aerobic oxidation of N-alkyl iminium salts is reported. The reaction is atom-economical and environmentally friendly. Iminium salts derived from isoquinoline, quinoline, phenanthridine, phenanthroline, and phthalazine were successfully transformed into their corresponding unsaturated lactams with up to 95% yield under mild conditions in the absence of photocatalysts and metallic or organic catalysts. Owing to the general substrate scope, low cost, feasibility of scale up, wide availability of reagents, and green reaction conditions, this method shows great potential for preparing isoquinolones and related compounds. The method was applied for atom- and step-economical total synthesis of natural products such as norketoyobyrine.
- Bai, Li-Gang,Zhou, Yue,Zhuang, Xin,Zhang, Liang,Xue, Jian,Lin, Xiao-Long,Cai, Tian,Luo, Qun-Li
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p. 197 - 203
(2020/01/13)
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- Aromatic compounds and preparation method and application thereof
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The invention discloses aromatic compounds and a preparation method and application thereof. The preparation method of the aromatic compounds includes the step of performing a cyclization reaction between an amide compound and a benzoic acid compound in the presence of a rhodium catalyst, a metal oxidant and base, wherein the aromatic compounds are isoquinolinone compounds or isocoumarin derivatives, and the amide compound is N-vinylformamide or N-vinylacetamide. Through the synergistic effect of the rhodium catalyst, the metal oxidant and the base, the isoquinolinone compounds or isocoumarinderivatives are obtained through the one-step reaction between the benzoic acid compound and the amide compound. The reaction has simple operation, the raw materials are cheap and easily available, reaction substrates can be selected flexibly according to the required isoquinolinone compounds and the isocoumarin derivatives, and the synthesized isoquinolinone compounds and the isocoumarin derivatives can be used as a backbone structure in multiple biologically active molecules and natural products, and have high practicality.
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Paragraph 0012; 0037-0039
(2020/02/19)
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- Divergent Synthesis of Isoquinolone and Isocoumarin Derivatives by the Annulation of Benzoic Acid with N-Vinyl Amide
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A simple and efficient method for the synthesis of isoquinolone and isocoumarin derivatives is reported. The method for the first time provides a one-step divergent synthesis of important isoquinolone and isocoumarin skeletons from benzoic acid by switching the coupling partners. In addition, a reliable mechanism has been proposed on the basis of experimental investigations, including kinetic isotope effect experiments, 13C labeling experiments, time-tracking experiments, and competitive experiments, as well as DFT calculation studies.
- Sun, Rui,Yang, Xiao,Li, Qianggen,Xu, Ke,Tang, Juan,Zheng, Xueli,Yuan, Maolin,Fu, Haiyan,Li, Ruixiang,Chen, Hua
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supporting information
p. 9425 - 9429
(2019/11/28)
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- Catalyst Pendent-Base Effects on Cyclization of Alkynyl Amines
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A family of [CpRu(PP)(MeCN)]PF6 complexes (2 a–e and 4) were prepared in which the bis-phosphine ligand contains a pendent tertiary amine in the second-coordination sphere. 2 a–e contain PPh2NR′2 ligands with two amine groups as the pendent base. Complex 4 has the PPh2NPh1 ligand with only one pendent amine. The catalytic performance of 2 a–e and 4 were assessed in the cyclization of 2-ethynyl aniline and 2-ethynylbenzyl alcohol. It was revealed that the positioning of the pendent amine near the metal active site is essential for high catalyst performance. A comparison of PPh2NR′2 catalysts (2 a–e) showed minimal difference in performance as a function of pendent amine basicity. Rather, only a threshold basicity – in which the pendent amine was more basic than the substrate – was required for high performance.
- Stubbs, James M.,Chapple, Devon E.,Boyle, Paul D.,Blacquiere, Johanna M.
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p. 3694 - 3702
(2018/08/06)
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- C(sp2)-H Trifluoromethylation of enamides using TMSCF3: Access to trifluoromethylated isoindolinones, isoquinolinones, 2-pyridinones and other heterocycles
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A method for the direct C(sp2)-H trifluoromethylation of enamides, including biologically relevant isoindolinones, isoquinolinones and 2-pyridinones using TMSCF3 under oxidative conditions is presented. The protocol is convenient, operationally simple and exhibits high tolerance across a multitude of relevant handles and functional groups.
- Krishnamurti, Vinayak,Munoz, Socrates B.,Ispizua-Rodriguez, Xanath,Vickerman, Jeffrey,Mathew, Thomas,Surya Prakash
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supporting information
p. 10574 - 10577
(2018/09/27)
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- Photoreductive Removal of O-Benzyl Groups from Oxyarene N-Heterocycles Assisted by O-Pyridine-pyridone Tautomerism
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Facile photoreductive protocols have been developed to remove benzyl O-protective groups from oxyarene N-heterocycles at positions capable for 2-/4-O-pyridine-2-/4-pyridone tautomerism. Blue light irradiation, a [Ru] or [Ir] photocatalyst, and ascorbic acid in a water-acetonitrile solution debenzylates a variety of aryl N-heterocycles cleanly and selectively. Ascorbic acid has two functions in the reaction. On the one hand, it protonates the N-heterocycles that reduces their reduction potentials notably and on the other hand it acts as a sacrificial reductant. Reduction potentials and free energy barriers calculated at the CPCM-B3LYP/6-31+G? level can predict the reactivities of the studied substrates.
- Todorov, Aleksandar R.,Wirtanen, Tom,Helaja, Juho
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p. 13756 - 13767
(2017/12/26)
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- A nitrogen oxide C2 - bit hydroxylated method (by machine translation)
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The present invention relates to nitrogen oxide C2 - bit hydroxylated method, in particular under reflux conditions in dichloroethane, three pyrrole alkyl bromide (PyBrop) [...] phosphate, sodium acetate, water and nitrogen oxides produced by the reaction of hydroxyl-substituted product. The process has simple operation, mild condition, high reaction selectivity, substrate wide applicability, high yield and the like. The application for the first time using this method to synthesize a series of 2 - hydroxyquinoline, 2 - hydroxy pyridine and 1 - hydroxy isoquinoline compound, in the establishment of the compounds of the library synthesis application have broad prospects. (by machine translation)
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Paragraph 0031; 0032; 0033; 0034; 0035; 0036-0038; 0087-0092
(2017/05/19)
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- Rhodium(III)-Catalyzed Annulation of N-Methoxybenzamides with Heterobicyclic Alkenes by C–H Functionalization: Synthesis of Benzo[b]phenanthridinones
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A protocol for the rhodium(III)-catalyzed annulation of N-methoxybenzamides with 7-oxa/azabenzonorbornadienes by C–H activation was developed. This method allowed the synthesis of polycyclic products containing an oxygen/nitrogen-bridged structure in excellent yields. The annulated products were successfully transformed into benzo[b]phenanthridinones by a ring-opening/aromatization sequence.
- Cheng, Ying,Parthasarathy, Kanniyappan,Bolm, Carsten
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supporting information
p. 1203 - 1206
(2017/03/11)
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- Direct Hydroxylation and Amination of Arenes via Deprotonative Cupration
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Deprotonative directed ortho cupration of aromatic/heteroaromatic C-H bond and subsequent oxidation with t-BuOOH furnished functionalized phenols in high yields with high regio- and chemoselectivity. DFT calculations revealed that this hydroxylation reaction proceeds via a copper (I → III → I) redox mechanism. Application of this reaction to aromatic C-H amination using BnONH2 efficiently afforded the corresponding primary anilines. These reactions show broad scope and good functional group compatibility. Catalytic versions of these transformations are also demonstrated.
- Tezuka, Noriyuki,Shimojo, Kohei,Hirano, Keiichi,Komagawa, Shinsuke,Yoshida, Kengo,Wang, Chao,Miyamoto, Kazunori,Saito, Tatsuo,Takita, Ryo,Uchiyama, Masanobu
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supporting information
p. 9166 - 9171
(2016/08/05)
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- Expeditious Synthesis of the Topoisomerase i Inhibitors Isoindolo[2,1- b ]isoquinolin-7(5 H)-one and the Alkaloid Rosettacin Based on Aryl Radical Cyclization of Enamide Generated by Using N -Acylaiminium Chemistry
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A short and effective approach to the synthesis of the topoisomerase I inhibitor isoindolo[2,1-b]isoquinolin-7(5H)-one and the alkaloid rosettacin belonging to the aromathecin family is presented. The key step of this sequence, which resulted in the formation of a five-membered ring, was the aryl radical cyclization of enamides generated using N-acyliminium chemistry.
- El Blidi, Lahssen,Namoune, Aurélie,Bridoux, Alexandre,Nimbarte, Vijaykumar D.,Lawson, Ata Martin,Comesse, Sébastien,Da?ch, Adam
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p. 3583 - 3592
(2015/11/18)
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- Enantioselective template-directed [2+2] photocycloadditions of isoquinolones: Scope, mechanism and synthetic applications
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A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron-deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio-, diastereo- and enantioselectivities (up to 990 ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4-biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications.
- Coote, Susannah C.,P?thig, Alexander,Bach, Thorsten
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supporting information
p. 6906 - 6912
(2015/04/27)
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- Rhodium(III)-catalyzed C-H activation/annulation with vinyl esters as an acetylene equivalent
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The behavior of electron-rich alkenes in rhodium-catalyzed C-H activation/annulation reactions is investigated. Vinyl acetate emerges as a convenient acetylene equivalent, facilitating the synthesis of sixteen 3,4-unsubstituted isoquinolones, as well as select heteroaryl-fused pyridones. The complementary regiochemical preferences of enol ethers versus enol esters/enamides is discussed.
- Webb, Nicola J.,Marsden, Stephen P.,Raw, Steven A.
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supporting information
p. 4718 - 4721
(2015/04/27)
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- ALPHA-AMINO BORONIC ACID DERIVATIVES, SELECTIVE IMMUNOPROTEASOME INHIBITORS
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The present invention provides compounds of Formula (I) as inhibitors of LMP7 for the treatment of autoimmune and inflammatory diseases. In formula (I), Rb and Rc are independently selected from one another from H or C1-C6-alkyl; whereby Rb and Rc may be linked to form a 5 or 6 membered-ring containing the oxygen atoms to which they are linked; Q denotes Ar, Het or cycloalkyl; R1 R2 independently from each other denotes H, ORa, Hal, C1-C6-alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; Y denotes CR 3R4, preferably CH2 or C(CH3)2; R 3, R4 independently of one another denote H or C1-C6-alkyl; L denotes L1 or L2 or alkyl; n is an integer selected from 0 to 3; L 1 is Q1-CO-M- wherein Q 1 is Ar or Het, preferably, phenyl, naphthyl or pyridine, optionally substituted with 1 to 5 groups independently selected from ORa, Hal, phenyl, and C1-C6-alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; L2 is Q2-M- wherein Q 2 is a fused bicyclic system containing 1 nitrogen atom and 1 to 3 additional groups independently selected from O, S, N, or CO, and wherein at least one of the rings is aromatic whereby the fused bicyclic system is optionally substituted with 1 to 5 groups independently selected from ORa, Hal, phenyl, and C1-C6-alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; or Q 2 is unsaturated or aromatic 5 membered-ring system containing 1 to 3 heteroatoms selected from N, O, S and CO, and optionally substituted with a phenyl ring or pyridine ring whereby phenyl ring and pyridine ring are optionally substituted with 1 to 4 groups independently selected from ORa, Hal, phenyl, and C1-C6-alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; M is a linear or branched alkylene having 1 to 5 carbon atoms wherein 1 or 2 H atoms may be replaced by OR a or a phenyl ring optionally substituted with 1 to 5 groups independently selected from Hal, ORa, and C1-C6-alkyl optionally substituted with 1 to 5 groups independently selected from OH, and Hal; or M denotes a cycloalkylene having 3 to 7 carbon atoms; or M denotes a thiazolidinyl group; R a is H or C1-C6-alkyl wherein 1 to 5 H atom may be independently replaced by OH or Hal; Ar denotes a 6 membered-aromatic carbocyclic ring optionally fused with another carbocyclic saturated, unsaturated or aromatic ring having 5 to 8 carbon atoms; Het denotes a 5- or 6-membered saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from N, N+O-, O, S, SO, and SO 2, and optionally fused with another saturated, unsaturated or aromatic ring having 5 to 8 atoms and optionally containing 1 to 3 heteroatoms selected from N, O, and S; Hal denotes CI, Br, I of F; preferably CI or F.
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- Formation of indoles, dihydroisoquinolines, and dihydroquinolines by ruthenium-catalyzed heterocyclizations
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Indoles, dihydroisoquinolines, and dihydroquinolines were efficiently prepared by ruthenium-catalyzed heterocyclizations of aromatic homo- and bis-homopropargyl amines/amides in the presence of an amine/ammonium base-acid pair. These regioselective 5-endo and 6-endo cyclizations most probably occur by nucleophilic trapping of key ruthenium-vinylidene intermediates. Georg Thieme Verlag Stuttgart · New York.
- Varela-Fernández, Alejandro,Varela, Jesús A.,Saá, Carlos
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p. 3285 - 3295
(2013/01/15)
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- New synthetic methodology for construction of the 3,4-dihydroisoquinolinone skeleton: A key structure for isoquinoline alkaloids
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We hereby report a new method for preparation of 3,4-dihydroisoquinolin- 1(2H)-one as well as isoquinolin-1(2H)-one skeleton starting from the methyl 2-(3-methoxy-3-oxopropyl)benzoate. The ester functionality, adjacent to the methylene, was regiospecifically converted to the desired acyl azide. The isocyanate was transformed into the monoisocyanate by Curtius rearrangement followed by trapping with aniline. The formed urea derivative was cyclized with NaH to give a 3,4-dihydroisoquinolin-1(2H)-one derivative. Incorporation of a double bond into the six-membered ring followed by removal of the substituent resulted in the formation of isoquinolin-1(2H)-one skeleton.
- Muejde, Berk,Oezcan, Sevil,Balci, Metin
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p. 407 - 410
(2012/04/10)
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- Ruthenium-catalyzed cycloisomerization of aromatic homo- and bis-homopropargylic amines/amides: Formation of indoles, dihydroisoquinolines and dihydroquinolines
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Ruthenium-catalyzed cycloisomerizations of aromatic homo- and bis-homopropargylic amines/amides efficiently afford indoles, dihydroisoquinolines and dihydroquinolines. These processes were regioselective (5- and 6-endo cyclizations) on using key Ru vinylidene intermediates. The presence of an amine/ammonium base-acid pair increased the rate of cyclization and facilitated the catalytic turnover. Copyright
- Varela-Fernandez, Alejandro,Varela, Jesus A.,Saa, Carlos
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p. 1933 - 1937
(2011/10/08)
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- Rhodium(III)-catalyzed heterocycle synthesis using an internal oxidant: Improved reactivity and mechanistic studies
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Directing groups that can act as internal oxidants have recently been shown to be beneficial in metal-catalyzed heterocycle syntheses that undergo C-H functionalization. Pursuant to the rhodium(III)-catalyzed redox-neutral isoquinolone synthesis that we recently reported, we present in this article the development of a more reactive internal oxidant/directing group that can promote the formation of a wide variety of isoquinolones at room temperature while employing low catalyst loadings (0.5 mol %). In contrast to previously reported oxidative rhodium(III)-catalyzed heterocycle syntheses, the new conditions allow for the first time the use of terminal alkynes. Also, it is shown that the use of alkenes, including ethylene, instead of alkynes leads to the room temperature formation of 3,4-dihydroisoquinolones. Mechanistic investigations of this new system point to a change in the turnover limiting step of the catalytic cycle relative to the previously reported conditions. Concerted metalation-deprotonation (CMD) is now proposed to be the turnover limiting step. In addition, DFT calculations conducted on this system agree with a stepwise C-N bond reductive elimination/N-O bond oxidative addition mechanism to afford the desired heterocycle. Concepts highlighted by the calculations were found to be consistent with experimental results.
- Guimond, Nicolas,Gorelsky, Serge I.,Fagnou, Keith
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p. 6449 - 6457
(2011/06/16)
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- PYRAZOLE-ISOQUINOLINE UREA DERIVATIVES AS P38 KINASE INHIBITORS
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The present invention provides kinase inhibitors of Formula (I) wherein R1, R2, and X are as described herein, or a pharmaceutically acceptable salt thereof.
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Page/Page column 20
(2008/06/13)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula (I) wherein A, R2, R3, R', B and Y are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 111
(2010/02/11)
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- 1H NMR studies on the reductively triggered release of heterocyclic and steroid drugs from 4,7-dioxoindole-3-methyl prodrugs
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Hypoxia is a feature of several disease states, including cancer and rheumatoid arthritis. Prodrug systems which, after bioreduction, selectively release active drugs in these tissues may be important in therapy. An improved preparation of 1,2-dimethyl-3-hydroxymethyl-5-methoxyindole-4,7-dione was developed. Mitsunobu coupling with (5-substituted) isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) gave 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and N-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethyl)isoquinolin-1-ones. Similar coupling with the anticancer drug pentamethylmelamine gave its potential prodrug 1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N- methylaminomethyl)-5-methoxyindole-4,7-dione. Treatment of sodium prednisolone hemisuccinate with 3-chloromethyl-1,2-dimethyl-5-methoxyindole-4,7-dione gave an analogous candidate prodrug of the anti-inflammatory drug prednisolone. In a chemical model system for bioreduction, SnCl2 in CDCl3/CD3OD triggered rapid stoichiometric release of isoquinolin-1-ones from the O-linked prodrugs but not from the N-linked analogues. Use of this system allowed the release process to be monitored in situ by 1H NMR spectroscopy. Diethyl hydrazine-1,2-dicarboxylate was found to reduce SnIV to SnII, making the overall reductive release catalytic in tin. The reduced (hydroquinone) prodrug may have a short lifetime under these reductive conditions, meaning that only good leaving groups are expelled. Thus 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and analogues may be useful as reductively triggered prodrugs.
- Ferrer, Sandra,Naughton, Declan P.,Threadgill, Michael D.
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p. 3445 - 3454
(2007/10/03)
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- Studies on the reductively triggered release of heterocyclic and steroid drugs from 5-nitrothien-2-ylmethyl prodrugs
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Hypoxia (inadequate concentrations of dioxygen in tissues) is present in several disease states, including cancer and rheumatoid arthritis. Prodrug systems, which after bioreduction, selectively release active drugs in these tissues may be important in therapy. The 5-nitrothien-2-ylmethyl ester of aspirin was synthesised by treatment of 5-nitrothiophene-2-methanol with 2-acetoxybenzoyl chloride, whereas that of prednisolone hemisuccinate was prepared by reaction of prednisolone with 5-nitrothien-2-ylmethyl pentafluorophenyl butanedioate. In chemical model systems, both of these ester-linked potential prodrugs suffered hydrolysis, rather than reductively triggered release of the corresponding drug. 1-(5-Nitrothien-2-ylmethoxy)isoquinolines released the corresponding isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) rapidly upon reduction of the nitro group with sodium borohydride/palladium, showing that these may be useful as reductively triggered prodrugs. In approaches to N-linked potential prodrugs, isoquinolin-1-one and nifedipine (a 1,4-dihydropyridine Ca2+ channel antagonist) were alkylated at nitrogen by 2-chloromethylthiophene but the corresponding 5-nitrothien-2-ylmethyl derivatives were synthetically inaccessible.
- Ferrer, Sandra,Naughton, Declan P.,Threadgill, Michael D.
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p. 3437 - 3444
(2007/10/03)
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- Methods, compounds and compositions for treating gout
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This invention relates to methods of preventing, treating or lessening verity of gout by administration of PARP inhibitors.
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- Superacidic activation of 1- and 3-isoquinolinols and their electrophilic reactions
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Isomeric 1- and 3-isoquinolinols (11 and 12) when activated in CF3SO3H-SbF5 acid system undergo selective ionic hydrogenation with cyclohexane to give 5,6,7,8-tetrahydro-1(2H)- and 5,6,7,8-tetrahydro-3(2H)-isoquinolinones (22 and 27). Under the influence of aluminum chloride similar products were also obtained along with 3,4-dihydro-1(2H)- and 1,4-dihydro-3(2H)-isoquinolinones (23 and 28), respectively. Compounds 11 and 12 also condense with benzene in the presence of aluminum halides, under mild conditions, to give 3,4-dihydro-3-phenyl-1(2H)- and 1,4-dihydro-1-phenyl-3(2H)-isoquinolinones (24 and 29), respectively. Prolonged reaction time or catalysis under strongly acidic HBr-AlBr3 provides an alternative reaction pathway to yield 5,6-dihydro-6,8-diphenyl-1(2H)- and 5,6,7,8-tetrahydro-6,8-diphenyl-3(2H)-isoquinolinones (25 and 30), respectively. Products 24 and 29 were also found to revert back to 11 and 12 in the presence of aluminum halides in o-dichlorobenzene. The mechanism of these intriguing reactions, which involves superelectrophilic dicationic intermediates, is discussed.
- Koltunov, Konstantin Yu.,Prakash, G. K. Surya,Rasul, Golam,Olah, George A.
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p. 8943 - 8951
(2007/10/03)
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- Substituent effect on anionic cycloaromatization of 2-(2-substituted ethynyl)benzonitriles and related molecules
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Methanolysis of 2-(2-substituted ethynyl)benzonitriles based on the nature of substituents gave 5-exo product, isoindolones and 6-endo product, isoquinolones, respectively. When a bulky substituent, such as tert-butyl group, was employed in this cyclization reaction, a 5-exo adduct was obtained. Phenyl and thienyl groups which can stabilize the α-anion affect the cyclization reaction to produce the 5-exo adducts. Pyridinyl and pyrazinyl groups can also stabilize the α-anion, but the formation of a more stable intermediate by coordination of sodium with nitrogen atom leads to the 6-endo products.
- Lu, Wen-Der,Lin, Chi-Fong,Wang, Chyi-Jia,Wang, Shih-Jen,Wu, Ming-Jung
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p. 7315 - 7319
(2007/10/03)
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- Reactions of isoquinolinium salts with hydroxylamine derivatives, 2nd communication N-(alkyl) and N-(aryl) substituted compounds
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The N-alkyl- and N-aryl-isoquinolinium salts 7, 15-17 reacted with free hydroxylamine in pyridine to give the isoquinoline-2-oxide (9) as final product. The intermediate dioximes 8 were isolated and characterized by derivatisation with acetic anhydride to the oxime ester nitrile 10. From the reaction of 8 with trifluoroacetic anhydride/triethylamine 3-amino-isoquinoline-2-oxide (12) resulted after hydrolysis. Due to the electronic influence the 5-nitroisoquinolinium salts 1-3 react faster than the 5-hydroxy derivative 20, but with the same course of conversion via dioximes to amine oxides. An optimized method for preparation of the amine oxides was developed.
- Moehrle,Niessen
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p. 532 - 540
(2007/10/03)
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- Investigations of reactions of selected azaarenes with radicals in water. 1. Hydroxyl and sulfate radicals
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The oxidative degradation of binuclear azaarenes is studied in a number of environmentally relevant radical reactions. The comparison between oxidation mechanisms of hydroxyl and sulfate radicals, as well as between dark and photoreactions, is done. Most of the products formed are identified. With the change from dark to photoreactions of quinoline and isoquinoline, a shift of the oxidation center from the benzene to the pyridine rings is observed. The reaction behavior of the benzodiazines can be derived from the reaction patterns of quinoline and isoquinoline. The rate constants of second order are determined for the reactions of the azaarenes with carbonate radicals. The rate constants and the differences in the products formed conformably prove the importance of the inclusion of excited states in the reaction mechanism. The application of the frontier orbital concept allows an easy interpretation. Electron transfer reactions resulting in radical oxygen species are shown to be product determining in direct photolysis, too.
- Beitz, Toralf,Bechmann, Wolfgang,Mitzner, Rolf
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p. 6760 - 6765
(2007/10/03)
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- A new synthetic route to isoquinolin-1(2H)-one derivatives from 3-hydroxyphthalides
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A new synthetic route for the conversion of substituted 3-hydroxyphthalides into the corresponding isoquinolin-1(2H)-one was established. This method can be applied to the preparation of isoquinolin-1(2H)-ones with electron-withdrawing groups that are relatively difficult to synthesize by conventional procedures.
- Sugimoto,Shinba-Tanaka,Ishikawa
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p. 431 - 434
(2007/10/02)
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- O-Methylarenehydroxamates as Ortho-Lithiation Directing Groups. Ti(III)-Mediated Conversion of O-Methyl Hydroxamates to Primary Amides
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Reaction of O-methyl benzohydroxamates 2a-c with sec-butyllithium in the presence of TMEDA at -40 deg C regiospecifically generates the highly reactive N,ortho-dilithiated species (e.g. 3).These dilithio species react avidly with a wide spectrum of electrophilic reagents, including alkyl halides, givind adducts which on reduction with TiCl3 are converted into ortho-substituted primary benzamides in excellent yields.Ortho lithiation of O-methyl benzohydroxamates is thus formally equivalent to ortho lithiation of primary benzamides themselves.The utility of these synthetic operations is enhanced by the well-known facility with wich the primary amide moiety can be transformed into other useful functional groups.The conversion of O-methyl hydroxamates to primary amides is shown to be general, as exemplified by transformation of 14a-f to 15a-f.O-Methyl-2-methylbenzohydroxamate (4a) undergoes regiospecific dilithiation on nitrogen and on the methyl group when treated with sec-butyllithium at -70 deg C.These dilithio species react with DMF or "Weinreb-type" amides to give condensation products wich cyclize to N-methoxyisoquinolin-1(2H)-ones under mildly acidic conditions.Removal of the N-methoxy moiety under conditions analogous to those used for O-methyl benzohydroxamate provides N-unsubstituted isoquinolin-1(2H)-ones with high overall efficiency.This process is exemplified by the synthesis of isoquinolin-1(2H)-one 9a, its 3-n-butyl congener 9b, and the tricyclic isoquinolin-1(2H)-ones 20a and 20b from O-methyl 2-methylbenzohydroxamate (4a).
- Fisher, Lawrence E.,Caroon, Joan M.,Jahangir,Stabler, S. Russell,Lundberg, Scott,Muchowski, Joseph M.
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p. 3643 - 3647
(2007/10/02)
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- Heteroaromatic N-oxide rearrangements. Reinvestigation of 1,3 tosyloxy migration in the reaction of isoquinoline N-oxide with tosyl chloride
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Isoquinoline N-oxide (2) reacts with 18O-enriched tosyl chloride to furnish 18O-labeled 4-tosyloxy-isoquinoline (4), which was assessed for oxygen isotopic enrichment by NMR and mass spectrometry. The 30-45% 18O incorporation at the bridging oxygen is inconsistent with a high level of the intramolecular tight-ion-pair ('sliding') mechanism. A combination of two intramolecular mechanisms is probably operative.
- Maryanoff,Zhang,Reitz,Leo,Jones
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p. 7247 - 7250
(2007/10/02)
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- Heteroatom-Directed Metalation. Lithiation of N-Propenylbenzamides and N-Propenyl-o-toluamides. Novel Routes to Ortho-Substituted Primary Benzamide Derivatives and N-Unsubstituted Isoquinolin-1(2H)-ones
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Reaction of N-propenylbenzamides 4 and 9, obtained by LDA-induced isomerization of the corresponding N-allylbenzamides, 1, 8, and 14, with 2 equiv of sec-butyllithium or tert-butyllithium at low temperature regiospecifically generates the highly reactive N,ortho-dilithiated species (e.g., 5 and 17).These dilithio species react avidly with a wide spectrum of electophilic reagents, including alky halides, giving adducts which on hydrolysis with warm 50percent aqueous acetic acid are converted into ortho-substituted primary benzamides in excellent yields.Ortho-lithiation of N-propenylbenzamides is thus formally equivalent to ortho-lithiation of primary benzamides themselves.The utility of this important, previously unknown, synthetic operation is enhanced by the well-known facility with which the primary amide moiety can be transformed into other useful functional groups, as exemplified by the synthesis of 2-methoxy-6-methylbenzoic acid (12) and 2-methoxy-6-methylbenzonitrile (13) from N-propenyl-2-methoxybenzamide (9).N-Propenyl-o-toluamide (7) undergoes regiospecific dilithiation on nitrogen and on the methyl group under conditions analogous to those used for the N-propenylbenzamides.These dilithio species react with DMF or "Weinreb type" amides to give condensation products which cyclize to N-propenylisoquinolin-1(2H)-ones under mildly acidic conditions.Removal of the N-propenyl moiety under more strongly acidic conditions provides N-unsubstituted isoquinolin-1(2H)-ones with high overall efficiency.This process is exemplified by the synthesis of isoquinolin-1(2H)-one (23) and its 3-n-butyl congener 26 from N-propenyl-2-methylbenzamide (7).
- Fisher, Lawrence E.,Muchowski, Joseph M.,Clark, Robin D.
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p. 2700 - 2705
(2007/10/02)
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- Palladium-catalyzed Synthesis of Isocoumarin and 1-Isoquinolinone Derivatives
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In the presence of copper(I) chloride, the palladium catalyzed oxidation of methyl 2-ethenylbenzoates and 2-ethenylbenzamides have been studied.This reaction was used to form isocoumarins and 1-isoquinolinones.
- Izumi, Taeko,Nishimoto, Yasuhiro,Kohei, Kunihiro,Kasahara, Akira
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p. 1419 - 1424
(2007/10/02)
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- The Chemistry of Phthalide-3-carboxylic Acid. VII Reaction with Isoquinoline Derivatives
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Phthalide-3-carboxylic acid has been decarboxylated in the presence of isoquinoline, 1-chloroisoqinoline and isoquinoline N-oxides to give low yields of compounds resulting from alkylation of the isoquinoline heterocycle at C1 with a phthalidyl group.Attempted Barton decarboxylation-alkylation in the presence of isoquinolinium salts was unsuccessful.
- Donati, Cosimo,Hung, Tran V.,Prager, Rolf H.
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p. 375 - 381
(2007/10/02)
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- ADDITION OF PYRIDINE AND ISOQUINOLINE TO BENZOYLCARBONITRILE OXIDE
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Addition of pyridine to benzoylcarbonitrile oxide affords a fragile zwitterionic adduct, which slowly reverts to the addends, leading ultimately to benzoyl isocyanate and products deriving from it.A moderately stable cycloadduct is obtained in the reaction with isoquinoline.
- Caramella, P.,Bandiera, T.,Albini, F. Marinone,Gamba, A.,Corsaro, A.,Perrini, G.
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p. 4917 - 4926
(2007/10/02)
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- Isoquinoline derivatives and their preparation
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Isoquinoline derivatives of the formula (I) STR1 in which R is a group selected from t-butyl and groups of the formula STR2 and R' is selected from methyl and ethyl, are useful in the preparation of 1(2H)-isoquinolone.
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-
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- CYCLOADDUCTS OF BENZONITRILE OXIDE TO PYRIDINE. A CASE OF A TWO-STEP CYCLOADDITION
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Pyridine adds benzonitrile oxide in apolar solvents, affording fair yields of bisadducts III and IV.Quinoline and isoquinoline afford isolable monocycloadducts VIII and IX.
- Corsaro, A.,Perrini, G.,Caramella, P.,Albini, F. Marinone,Bandiera, T.
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p. 1517 - 1520
(2007/10/02)
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- Photochemical Magnetic-Field Effects of Isoquinoline N-oxide in Various Alcohols
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A pronounced solvent dependence of the magnetic-field effect due to the HFI-J mechanism was found for the first time in the case of a photochemical isomerization of isoquinoline N-oxide into lactam (1-isoquinolone).The chemical yield of the lactam showed a minimum at a higher magnetic field as one changes the reaction medium from t-butyl alcohol to 2-propanol (or ethanol) and then to methanol, which was the same order as the pKa value (t-butyl alcohol>2-propanol ca. ethanol>methanol).Such a solvent dependence provides corroborating evidence that the photoisomerization proceeds via the S1-born singlet radical-ionpair intermediate, which is linked by a hydrogen bond between the N->O group in the cation radical of N-oxide and the OH group in the anion radical of alcohol.Another interesting finding was that, in the case of the photochemical isomerization in t-butyl alcohol, the chemical yield of the lactam showed distinct maxima at approximately 0.9T and 1.35T in addition to a minimum at about 0.72T.The anomalous magnetic-field effect in a high field region (>0.8T) could reasonably be explained in terms of an HFI-J mechanism by assuming the T1-born triplet hydrogen-bonded radical-ion pair to have an electron-exchange interaction larger than that in the S1-born singlet hydrogen-bonded radical-ion pair.
- Hata, Norisuke
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p. 2723 - 2728
(2007/10/02)
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- The Mechanism of Thermal Eliminations. Part 21. Rate Data for Pyrolysis of 2-Ethoxyquinoline, 1-and 3-Ethoxyisoquinoline, and 1-Ethoxythiazole: Correlation of Reactivities with ?-Bond Order of the C=N Bond
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We have measured the rates of thermal elimination of ethylene from the title compounds between 587.3 and 722.9 K.The reactivities relative to 2-ethoxypyridine at 650 K are: 3-ethoxyisoquinoline (0.21), 2-ethoxyquinoline (3.13), 1-ethoxyisoquinoline (6.47), 2-ethoxythiazole (63.1).These reactivities parallel the ?-bond order of the C=N bond, though the exceptional reactivity of 2-ethoxythiazole is attributed to additional acceleration through +M electron release from sulphur to nitrogen.This emphasizes the greater relative importance of nucleophilic attack by the nitrogen upon the β-hydrogen atom as compared with the analogous mechanism for pyrolysis of esters.Because of semi-concentrated nature of the reaction, interruption of aromaticity is much less significant than in, for example, electrophilic aromatic substitution.Thus retention of the benzenoid character of the ring not involved in the elimination is not an important rate-determining feature, as shown by the lower reactivity of 3-ethoxyisoquinoline relative to 2- ethoxypyridine.The unimportance of the interruption of aromaticity of the benzenoid ring means that conjugative effects are better relayed to nitrogen in the β-naphthalene-like position (isoquinoline) than in the α-naphthalene-like position (quinoline).This is the reverse of the familiar pattern for reactions of naphthalene-like systems where full charges are involved, and may be an additional factor contributing to the higher reactivity of 1-ethoxyisoquinoline than of 2-ethoxyquinoline, as may also be the -I effect of the benzo substiutent.The conclusions are used to predict elimination rates for alkoxyheterocycles not yet studied.
- Al-Awadi, Nouria,Taylor, Roger
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p. 1589 - 1592
(2007/10/02)
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- Photochemical Cycloreversion Reactions of 1,2,2a,8b-Tetrahydrocyclobutaisoquinolin-4(3H)-ones
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Irradiation (350 nm) of 2-(3-butenyl)- and 2-(4-pentenyl)isoquinolin-1(2H)-ones (1a and 1b) afforded the intramolecular adducts (2a and 2b).The additions proceeded regioselectively to give only the parallel adducts.Though stable to irradiation at 350 nm, these adducts (2a and 2b) gave o-vinylbenzamide derivatives (3a and 3b) on irradiation at 300 nm.The intermolecular adducts (7d and 7e) obtained by irradiation (300 nm) of isoquinolin-1(2H)-one (6) in the presence of a large excess of alkenes were also found to be unstable and reverted to the original components on irradiation at 300 nm in the absence of the alkenes.Keywords - 2-(ο-alkenyl)isoquinolin-1(2H)-one; photochemical cycloaddition; photochemical cycloreversion; olefin metathesis; photo-photo olefin metathesis; o-vinylbenzamide derivative; wavelength dependency
- Kaneko, Chikara,Katagiri, Nobuya,Uchiyama, Keiji,Yamada, Toru
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p. 4160 - 4166
(2007/10/02)
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- Condensed Heteroaromatic Ring Systems. III. Synthesis of Naphthyridine Derivatives by Cyclization of Ethynylpyridinecarboxamides
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Four kinds of naphthyridinones, i.e. 1,6-naphthyridin-5-one, 1,7-naphthyridin-8-one, 2,6-naphthyridin-2-one, and 2,7-naphthyridin-1-one derivatives, were commonly synthesized by the intramolecular cyclization of pyridinecarboxamides having an ethynyl group or β,β-dimethoxyethyl group adjacent to the carbamoyl group.The syntheses of the starting pyridine derivatives were easily accomplished by cross-coupling of the corresponding halopyridines with acetylenes.Keywords-intramolecular cyclization; palladium catalyst; trimethylsilylacetylene; naphthyridinone; pyridineacetaldehyde; 1(2H)-isoquinolone
- Sakamoto, Takao,Kondo, Yoshinori,Yamanaka, Hiroshi
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p. 626 - 633
(2007/10/02)
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- The Photochemical Magnetic Field Effect of Isoquinoline N-Oxides
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The irradiation of isoquinoline N-oxide in ethanol resulted in the formation of lactam in a ca.67percent yield via the S1 state (Process I).When the photochemical isomerization was carried out in the presence of a magnetic field, the chemical yield of lactam was found to show a minimum at approximately 1T.In order to interpret this new phenomenon, Process I was assumed to be initiated by electron transfer from the excited singlet N-oxide to the hydrogen-bonded ethanol (the formation of a singlet hydrogen-bonded radical ion pair).Thus, the new type of magnetic-field effect was excellently explained in terms of an electron-nuclear hyperfine interaction mechanism including the electron-exchange interaction in the radical-ion pair (the magnetic-field effect due to HFI-J mechanism).This implies that the magnetic-field effect is unambiguous evidence that Process I (N-oxide - lactam) does not involve the oxaziridine intermediate, but proceeds via the singlet hydrogen-bonded radical-ion pair (radical-ion-pair mechanism of Process I).The irradiation of 1-cyanoisoquinoline N-oxide in ethanol resulted in the formation of 1,3-oxazepine in a ca. 66percent yield via the S1 state (Process II).The photochemical isomerization was not affected at all by an external magnetic field.This is consistent with the idea that Process II (N-oxide - oxazepine) does not involve a field-sensitive intermediate, but occurs with the intervention of oxaziridine (the oxaziridine mechanism of Process II).
- HATA, Norisuke
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p. 1088 - 1093
(2007/10/02)
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- Synthesis of Functionalised Heterocyclic Selenoamide Derivatives and Their Reactions
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Sodium pyridyl (8b)/isoquinolinyl (8c) selenates on treatment with ethyl chloroacetate give ethyl 2,2'-diselenobis(acetate) (9) and the corresponding carboxamides, but sodium quinazolinylselenate (8a) forms ethyl 2-(4-quinazolinylseleno)acetate (6a) and ethyl 2-acetate (12).With chloroacetonitrile, 8a-c form condensed mesoionic selenazoles, 3-aminoselenazolequinazolin-4-ium hydroxide inner salt (14a), 3-aminoselenazolepyridinium hydroxide inner salt (14b) and 3-aminoselenazoleisoquinolinium hydroxide inner salt (14c) respectively.
- Singh, Harjit,Malhotra, Nageshwar
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p. 328 - 330
(2007/10/02)
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