- Light-Promoted Dearomative Cross-Coupling of Heteroarenium Salts and Aryl Iodides via Nickel Catalysis
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Partially saturated nitrogen heterocycles are versatile building blocks for the preparation of other nitrogen heterocycles. For example, dihydropyridines can be converted to pyridines, tetrahydropyridines, and piperidines through oxidation, reduction, and functionalization reactions, respectively. Dearomatization of heteroarenes is an attractive approach for the synthesis of partially saturated heterocycles such as dihydropyridines due to the wide availability of heteroarenes. Significant research efforts have been dedicated to the addition of nucleophiles to various heteroarenium salts in this direction using organoboron or organometallic reagents. The availability of organoboron and organometallic coupling partners has been an important limitation to this chemistry. Direct coupling of electrophiles with heteroareniums could significantly improve the scope of these dearomatization reactions due to the wider availability of electrophiles compared to nucleophiles such as organoboron and organometallic reagents. Herein, we report the coupling of aryl iodides with pyridinium and related heteroarenium salts catalyzed by Ni/bpp and an Ir photocatalyst using Zn as a terminal reductant. This methodology tolerates a wide range of functional groups and allows the coupling of aryl and heteroaryl iodides, thus significantly expanding the scope of nitrogen heterocycle scaffolds that could be prepared through dearomatization of heteroarenes. The reaction products have been further functionalized to prepare various nitrogen heterocycles. Initial mechanistic studies indicate that the reaction described herein goes through a unique mechanism involving dimers of dihydroheteroarenes.
- Nallagonda, Rajender,Musaev, Djamaladdin G.,Karimov, Rashad R.
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p. 1818 - 1829
(2022/02/07)
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- Robust Packing of a Self-Assembling Iridium Complex via Endocytic Trafficking for Long-Term Lysosome Tracking
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Live cell imaging of lysosome positioning and motility is critical to studying lysosome status and function for pharmacological interventions. To create a super stable lysosomal probe for long-term live cell imaging, we have designed and synthesized an aromatic-peptide-conjugated cyclometalated iridium(III) complex that emits light via π–π stacking oriented self-assembly in water at extremely low concentration. Through endocytic trafficking, self-assemblies are transformed from nanoparticles into sturdily packed networks that are stabilized in lysosomal acidic environment. Upon short time/low dose treatment of the iridium complex at passage 0, live cell lysosomal tracking is applicable beyond the 14th passage of cells with high labelling rate and a mild decline in luminescence intensity. The illuminated lysosomes are trackable using super-resolution imaging to study their response to cellular processes.
- Jin, Chengzhi,Li, Guanying,Wu, Xia,Liu, Jiangping,Wu, Weijun,Chen, Yazhou,Sasaki, Toshio,Chao, Hui,Zhang, Ye
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supporting information
p. 7597 - 7601
(2021/03/06)
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- NEW HETEROARYL AMIDE DERIVATIVES AS SELECTIVE INHIBITORS OF HISTONE DEACETYLASES 1 AND/OR 2 (HDAC1-2)
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The present invention relates to novel heteroaryl amide derivatives of formula (1) as selective inhibitors of histone deacetylase 1 and 2 (hdac1-2) to processes for their preparation, to pharmaceutical compositions comprising said compounds and to the use of said compounds for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by inhibition the activity of histone deacetylase class I, particularly HDAC1 and HDAC2, such as cancer, neurodegenerative diseases, Infectious diseases, inflammatory diseases, heart failure and cardiac hypertrophy, diabetes, polycystic kidney disease, sickle cell disease and β-thalassemia disease and to methods for the treatment of the disesases mentioned above.
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Paragraph 0227
(2020/05/29)
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- Exhaustive Reduction of Esters Enabled by Nickel Catalysis
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We report a one-step procedure to directly reduce unactivated aryl esters into their corresponding tolyl derivatives. This is achieved by an organosilane-mediated ester hydrosilylation reaction and subsequent Ni/NHC-catalyzed hydrogenolysis. The resulting conditions provide a direct and efficient alternative to multi-step procedures for this transformation that often require the use of hazardous metal hydrides. Applications in the synthesis of -CD3-containing products, derivatization of bioactive molecules, and chemoselective reduction in the presence of other C-O bonds are demonstrated.
- Cook, Adam,Prakash, Sekar,Zheng, Yan-Long,Newman, Stephen G.
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supporting information
p. 8109 - 8115
(2020/05/20)
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- Regio- and Stereoselective Synthesis of Functionalized Dihydropyridines, Pyridines, and 2H-Pyrans: Heck Coupling of Monocyclopropanated Heterocycles
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A palladium-catalyzed coupling between aryl halides and monocyclopropanated pyrroles or furans has been developed, leading to valuable six-membered N- and O-heterocycles. As the key step, a selective cleavage of the non-activated endocyclic C?C bond of the 2-heterobicyclo-[3.1.0]hexane framework is achieved. The developed method offers access to highly functionalized piperidines, pyridines, and pyrans that are challenging to access by traditional methods.
- Yedoyan, Julietta,Wurzer, Nikolai,Klimczak, Urszula,Ertl, Thomas,Reiser, Oliver
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supporting information
p. 3594 - 3598
(2019/02/13)
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- Transition-Metal-Free Decarboxylative Arylation of 2-Picolinic Acids with Arenes under Air Conditions
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A facile, transition-metal-free, and direct decarboxylative arylation of 2-picolinic acids with simple arenes is described. The oxidative decarboxylative arylation of 2-picolinic acids with arenes proceeds readily via N-chloro carbene intermediates to afford 2-arylpyridines in satisfactory to good yields under transition-metal-free conditions. This new type of decarboxylative arylation is operationally simple and scalable and exhibits high functional-group tolerance. Various synthetically useful functional groups, such as halogen atoms, methoxycarbonyl, and nitro, remain intact during the decarboxylative arylation of 2-picolinic acids.
- Zhang, Xitao,Feng, Xiujuan,Zhou, Chuancheng,Yu, Xiaoqiang,Yamamoto, Yoshinori,Bao, Ming
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supporting information
p. 7095 - 7099
(2018/11/23)
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- Cobalt-Catalyzed Cross-Coupling Reactions of Arylboronic Esters and Aryl Halides
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An efficient cobalt catalyst system for the Suzuki-Miyaura cross-coupling reaction of arylboronic esters and aryl halides has been identified. In the presence of cobalt(II)/terpyridine catalyst and potassium methoxide, a diverse array of (hetero)biaryls have been prepared in moderate to excellent yields.
- Duong, Hung A.,Wu, Wenqin,Teo, Yu-Yuan
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supporting information
p. 4363 - 4366
(2017/12/05)
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- Non-transition metal-catalyzed 2-phenylpyridine compound synthesis method
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The invention relates to a pharmaceutical and chemical intermediate preparation method, in particular to a non-transition metal-catalyzed 2-phenylpyridine compound synthesis method. A 2-phenylpyridine compound serves as an important component of a plurality of pharmacologically active molecules and bioactive molecules, has important application value in the fields of organic synthesis, pharmaceutical chemistry and the like, and is broad in market prospect. According to the non-transition metal-catalyzed 2-phenylpyridine compound synthesis method, namely a non-transition metal-catalyzed 2-phenylpyridine derivative synthesis method, pyridine-2-formic acid and benzene are adopted as raw materials; and under the presence of one or more alkalis and free radical initiators, the 2-phenylpyridine compound is synthesized in the mild condition. The non-transition metal-catalyzed 2-phenylpyridine compound synthesis method provided by the invention has the advantages that the steps are simple, the raw materials are easy to obtain, the reaction condition is mild, as well as the use value and the social and economic benefits are relatively great.
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Paragraph 0055; 0056; 0057
(2017/07/04)
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- Cobalt-Catalyzed Biaryl Couplings via C-F Bond Activation in the Absence of Phosphine or NHC Ligands
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A highly general and selective Co-catalyzed biaryl coupling through C-F cleavage under phosphine or NHC-free conditions was described. A broad range of aryl fluorides including unactivated fluorides as well as those with sensitive functionalities could couple with various Ti(OEt)4-mediated aryl Grignard reagents with high selectivity under the catalysis of CoCl2/DMPU. Importantly, selective C-F bond activation couplings between two types of fluorines (difluorinated aromatics and on two different coupling partners) and in the presence of C-Cl or C-Br bonds could also be achieved.
- Wei, Juan,Liu, Kun-Ming,Duan, Xin-Fang
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p. 1291 - 1300
(2017/02/10)
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- Direct ortho-Arylation of Pyridinecarboxylic Acids: Overcoming the Deactivating Effect of sp2-Nitrogen
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Direct arylations of pyridines are challenging transformations due to the high Lewis basicity of the sp2-nitrogen. The use of carboxylates as directing groups is reported, facilitating the Pd-catalyzed C-H arylation of this difficult class of substrates. This methodology allows regioselective C3/C4 arylation, without the need to use solvent quantities of the pyridine, and using low-cost chloro- and bromoarenes as coupling partners. Furthermore, carboxylates could be employed as traceless directing groups through a one-pot C-H arylation/Cu(I)-mediated decarboxylation sequence, thereby accessing directing-group-free pyridine biaryls.
- Johnston, Adam J. S.,Ling, Kenneth B.,Sale, David,Lebrasseur, Nathalie,Larrosa, Igor
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p. 6094 - 6097
(2016/12/09)
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- Aza-annulation of enynyl azides: A new approach to substituted pyridines
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Synthesis of substituted pyridines through a novel aza-annulation of 2-en-4-ynyl azides, derived from MBH-acetates of acetylenic aldehydes, is described. A variety of enynyl azides having aryl, heteroaryl, and alkyl groups on the alkyne functionality successfully participated in the Ag-mediated annulation reaction to provide the corresponding 3,6-disubstituted pyridines. I2-Mediated cyclization was found to be controlled by the substituent on the alkyne functionality, which offered the 5-iodo-3,6-disubstituted pyridines from enynyl azides having an electron-rich substituent on the alkyne functionality.
- Raji Reddy, Chada,Panda, Sujatarani A.,Reddy, Motatipally Damoder
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p. 896 - 899
(2015/04/13)
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- Upgrading malic acid to bio-based benzoates via a Diels-Alder-initiated sequence with the methyl coumalate platform
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The conversion of naturally-occurring malic acid to the 2-pyrone methyl coumalate was optimized using a variety of acid catalysts. Coupling methyl coumalate with electron-rich dienophiles in an inverse electron-demand Diels-Alder (IEDDA)/decarboxylation/elimination domino sequence resulted in an investigation of the scope and limitations of the methodology. The thermal, metal-free, and one-pot procedure allows regioselective access to diverse aromatic compounds including tricyclic, biphenyl, and pyridinyl systems for elaboration. A comparison with analogous pyrones demonstrates the striking efficacy of methyl coumalate as a versatile platform for the generation of biorenewable functionalized benzoates. This journal is
- Lee, Jennifer J.,Pollock Iii, Gerald R.,Mitchell, Donald,Kasuga, Lindsay,Kraus, George A.
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p. 45657 - 45664
(2015/02/19)
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- SELECTIVE CYP11B1 INHIBITORS FOR THE TREATMENT OF CORTISOL DEPENDENT DISEASES
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The present invention relates to compounds which selectively inhibit CYP11B1. Preferably, the compounds of the present invention do not substantially inhibit CYP11B2. Moreover, the compounds of the present invention do not substantially inhibit CYP17 and/or CYP19, either. Amongst other applications of the compounds of the present invention, they can be used for the treatment of Cushing's syndrome or metabolic disease.
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Page/Page column 69
(2012/05/05)
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- Phosphorescence imaging of living cells with amino acid-functionalized tris(2-phenylpyridine)iridium(III) complexes
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A series of nine luminescent cyclometalated octahedral iridium(III) tris(2-phenylpyridine) complexes has been synthesized, functionalized with three different amino acids (glycine, alanine, and lysine), on one, two, or all three of the phenylpyridine ligands. All starting complexes and final compounds have been fully analyzed by one-dimensional (1D) and twodimensional (2D) NMR spectroscopy, and photophysical data have been obtained for all the mono-, bis-, and tri- substituted iridium(III) complexes. Cellular uptake and localization have been studied with flow cytometry and confocal microscopy, respectively. Confocal experiments demonstrate that all nine substituted iridium(III) complexes show variable uptake in the tumor cells. The monosubstituted iridium(III) complexes give the highest cellular uptake, and the series substituted with lysines shows the highest toxicity. This systematic study of amino acid-functionalized Ir(ppy)3 complexes provides guidelines for further functionalization and possible implementation of luminescent iridium complexes, for example, in (automated) peptide synthesis or biomarker specific targeting.
- Steunenberg, Peter,Ruggi, Albert,Van Den Berg, Nynke S.,Buckle, Tessa,Kuil, Joeri,Van Leeuwen, Fijs W.B.,Velders, Aldrik H.
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experimental part
p. 2105 - 2114
(2012/04/17)
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- Negishi cross-coupling reactions catalyzed by an aminophosphine-based nickel system: A reliable and general applicable reaction protocol for the high-yielding synthesis of biaryls
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Treatment of NMP solutions of NiCl2 with 1,1′,1″- (phosphanetriyl)tripiperidine (≈2.05 equiv), dissolved in THF, in air at 25°C forms a highly active catalytic system for the cross-coupling of a large variety of electronically activated, non-activated, deactivated, and ortho-substituted, heterocyclic, and functionalized aryl bromides and aryl chlorides with diarylzinc reagents. Very high levels of conversion and yields were obtained within 2 h at 60°C in the presence of only 0.1 mol% of catalyst (based on nickel) and thus at catalyst loadings far lower than typically reported for nickel-catalyzed versions of the Negishi reaction. Various aryl halides-which may contain trifluoromethyl groups, fluorides, or other functional groups such as acetals, ketones, ethers, esters, lactones, amides, imines, anilines, alkenes, pyridines, quinolines, and pyrimidines-were successfully converted into the corresponding biaryls. Electronic and steric variations are tolerated in both reaction partners. Experimental observations indicate that a molecular (NiI/NiIII) mechanism is operative.
- Gerber, Roman,Frech, Christian M.
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experimental part
p. 11893 - 11904
(2011/11/29)
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- Inverse electron demand diels-alder reactions of 1,2,3-triazines: Pronounced substituent effects on reactivity and cycloaddition scope
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A systematic study of the inverse electron demand Diels-Alder reactions of 1,2,3-triazines is disclosed, including an examination of the impact of a C5 substituent. Such substituents were found to exhibit a remarkable impact on the cycloaddition reactivity of the 1,2,3-triazine without altering, and perhaps even enhancing, the intrinsic cycloaddition regioselectivity. The study revealed not only that the reactivity may be predictably modulated by a C5 substituent (R = CO2Me > Ph > H) but also that the impact is of a magnitude to convert 1,2,3-triazine (1) and its modest cycloaddition scope into a heterocyclic azadiene system with a reaction scope that portends extensive synthetic utility, expanding the range of participating dienophiles. Significantly, the studies define a now powerful additional heterocyclic azadiene, complementary to the isomeric 1,2,4-triazines and 1,3,5-triazines, capable of dependable participation in inverse electron demand Diels-Alder reactions, extending the number of complementary heterocyclic ring systems accessible with implementation of the methodology.
- Anderson, Erin D.,Boger, Dale L.
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p. 12285 - 12292
(2011/09/16)
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- Identification of piperazine-bisamide GHSR antagonists for the treatment of obesity
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Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure-activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies.
- Yu, Ming,Lizarzaburu, Mike,Beckmann, Holger,Connors, Richard,Dai, Kang,Haller, Katrin,Li, Cong,Liang, Lingming,Lindstrom, Michelle,Ma, Ji,Motani, Alykhan,Wanska, Malgorzata,Zhang, Alex,Li, Leping,Medina, Julio C.
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scheme or table
p. 1758 - 1762
(2010/07/05)
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- A convenient domino access to substituted alkyl 1,2-dihydropyridine- 3carboxylates from propargyl enol ethers and primary amines
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A convenient domino access to substituted alkyl 1,2-dihydropyridine-3- carboxylates from propargyl enol ethers and primary amines was reported. A solution of propargyl sinyl ether 1a and p-anisidine in toluene was placed in a microwave-special closed vial and the solution was irradiated for 30 minutes in a single-mode microwave oven. The reaction mixture was dried over anhydrous sodium sulfate and filtrated using dichloromethane as solvent. After removing the solvent at reduced pressure the products were purified by flash column chromatography. Accordingly, the microwave irradiation of an ethanolic mixture of propargyl enol ether 1 a and MeONH2.HCl in the presence of NaOAc yielded the methyl 2-phenyl-4-pyridinecarboxylate in a convenient 54% yield. These results seem to point out to a new reaction pathway involving different thermally-driven rearrangements of the 2,4-dienal 3 intermediate.
- Tejedor, David,Mendez-Abt, Gabriela,Garcia-Tellado, Fernando
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supporting information; experimental part
p. 428 - 431
(2010/06/13)
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- INDANE DERIVATES AS MUSCARINIC RECEPTOR AGONISTS
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The present invention relates to compounds of Formula I: I which are agonists of the M-1 muscarinic receptor.
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- MUSCARINIC AGONISTS
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The present invention relates to compounds of Formula (I): which are agonists of the M-1 muscarinic receptor.
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- MUSCARINIC AGONISTS
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The present invention relates to compounds of Formula (I): which are agonists of the M-1 muscarinic receptor.
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- Benzoheterocyclic derivatives
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A benzoheterocyclic derivative of the following formula [1]: and pharmaceutically acceptable salts thereof, which show excellent anti-vasopressin activity, vasopressin agonistic activity and oxytocin antagonistic activity, and are useful as a vasopressin antagonist, vasopressin agonist or oxytocin antagonist.
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Page column 114
(2010/01/21)
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- Inhibitors of acyl-coA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N- (heteroaryl-substituted benzyl)-N'-arylureas
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A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3- yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (At3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0.44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.
- Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
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p. 2390 - 2410
(2007/10/03)
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- SYNTHESES OF 2-AZAFLUORENONES FROM 3-SUBSTITUTED 4-ARYLPYRIDINES
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3-substituted 4-arylpyridines (5a-i) were synthesized in good yields by reaction of mixed copper, zinc aryl organometallics (2a-e) with 1-ethoxycarbonylpyridinium chlorides (1a-d) followed by o-chloranil oxidation under reflux in toluene.The arylpyridines (5a-i) are obtained predominantly.Having compounds (5a-i) in hand, a convenient method was developed for the synthesis of 2-azafluorenones (7a-f) by using cyclization of 4-arylpyridines (5a-i) with phosphoric acid.
- Shiao, Min-Jen,Liu, Kang-Hsiuan,Lin, Pen-Yuan
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p. 507 - 518
(2007/10/02)
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- Regioselective Addition ofd Copper-Zinc Aryl Organometallic Reagents to 3-substituted Pyridinium Salts
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A number of 3-substituted pyridinium salts are subjected to nucleophilic addition by copper-zinc aryl organometallic reagents.The adducts are oxidized subsequently to form the corresponding 4-arylpyridines.In all the cases 1,4-addition products are obtained predominantly.The regioselectivity can be rationalized according to the hard-soft acid-base principle.Calculations on both charge distributions and FMO coefficients indicate that these reactions may be classified on the basis of the type of soft acid-soft base reactions.The observed γ-attack complies very well with the orientation of the FMO coefficients as estimated by a semiempirical method.
- Shiao, Min-Jen,Chia, Win-Long,Shing, Tai-Li,Chow, Tahsin J.
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p. 2101 - 2121
(2007/10/02)
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- Regioselective addition of Grignard reagents to the 1-phenoxycarbonyl salts of alkyl nikotinates
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The addition of Grignard reagents to the 1-phenoxycarbonyl salts of alkyl nicotinates affords substituted 1,2- and 1,4-dihydropyridines.The crude dihydropyridines were aromatized with o-chloranil or sulfur to give 6-and 4-substituted alkyl nicotinates.The regioselectivity of this two-step process, 6- vs. 4- substitution, was examined and found to be dependent upon the structure of the Grignard reagent.When a catalytic amount of cuprous iodide is present during the Grignard reaction, nearly exclusive 1,4- addition results.The crude 1,4-dihydropyridines were aromatized with sulfur to provide 4-substituted methyl nicotinates in moderate yield and high isomeric purity.
- Comins, Daniel L.,Stroud, Eric D.,Herric, James J.
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p. 151 - 157
(2007/10/02)
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