- Pd-Catalyzed C-H Annulation of Five-Membered Heteroaryl Halides with Norbornene Derivatives
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Complementary to Catellani-type reactions and 1:1 coupling of six-membered halo(hetero)arenes and norbornene (NBE) derivatives, Pd-catalyzed 1:2 coupling of five-membered haloheteroarenes with NBEs was achieved to afford rigid nonplanar heterocycles. Pyra
- Padhi, Birakishore,Kang, Geunhee,Kim, Eunmin,Ha, Jeongmin,Kim, Hyun Tae,Lim, Jeewoo,Joo, Jung Min
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- A general synthesis of diversely substituted indazoles and hetero-aromatic derivatives from o-halo-(het)arylaldehydes or -phenones
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A set of variously substituted indazoles and hetero-aromatic derivatives were synthesized from o-halo-(het)arylaldehydes using a palladium catalyzed amination followed by cyclization. Starting from phenones, this process was extended to give 3-substituted indazoles. Moreover, N-1-substituted-indazoles can be reached by this strategy using an optional selective N-1-alkylation step during the process. This methodology offers a general and easy route for the synthesis of regioselectively substituted indazoles.
- Dubost, Emmanuelle,Stiebing, Silvia,Ferrary, Thibault,Cailly, Thomas,Fabis, Frédéric,Collot, Valérie
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- Hetero-dicarbene complexes of palladium(II): Syntheses and catalytic activities
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A series of Pd(II) dibromido complexes 2-6 bearing cis-chelating hetero-dicarbenes, which contain two different types of NHCs linked by a propylene chain, have been synthesized. In most cases, the N-methylbenzimidazolin-2-ylidene moiety was kept as one NHC donor, while the other one varies with different heterocyclic backbones. As an exception, the hetero-diNHC in complex 8 is derived by combining 1,2,4-triazole and indazole precursors instead. Analogous complexes 9-17, carrying more labile CF3CO2- or CH3CN ligands, were synthesized by reacting the aforementioned bromido complexes with AgO2CCF3 or AgOTf in CH3CN. A systematic catalytic comparison of 9-17 in the direct arylation of pentafluorobenzene with 4-chlorobromobenzene was carried out, and complexes that contain bulkier and less electron-donating ligands were found to be more active. Complex 12, carrying the mesitylimidazolin-2-ylidene unit, proved to be the most efficient, and its activity was also tested in the direct arylation of tetrafluorobenzenes.
- Yuan, Dan,Huynh, Han Vinh
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- Novel synthesis of indazoles from (η6-arene)tricarbonylchromium complexes
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Indazole chromium complexes and some of its derivatives were synthesised by two strategies: (1) by cyclisation of [η 6-2-(2′-phenylhydrazine)-1,3-dioxolane]tricarbonylchromium (2) in acidic conditions which was converted into σ-complex (11); (2) by thermolysis of Cr(CO)6 with 1-bis(trimethylsilyl)methylindazole (3) and 2-bis(trimethylsilyl)methyl-3-trimethyl-silylindazole (4), using bulky protecting groups at N(1) or simultaneously at N(2) and C(3), to afford [η6-1-bis(trimethylsilyl)methylindazole]tricarbonylchromium (14) and [η 6-2-bis(trimethylsilyl)methyl-3-trimethylsilylindazole] tricarbonylchromium (15), respectively. The deprotonation of complex 14 followed by electrophilic quench occurs at the C(4) and C(7) positions in a ratio of 3:1 and with complex 15 the deprotonation was completely regioselective at the C(7) position. The position of this substitution was confirmed by n.O.e. difference spectroscopy and X-ray crystal structure determination of the [η 6-2-bis(trimethylsilyl)methyl-7-methyl-3-trimethylsilylindazole] tricarbonylchromium (5). These complexes were decomplexed to produce new substituted indazole derivatives in good yield.
- Da Costa, M. Rute G.,Curto, M. Jo?o M.,Davies, Stephen G.,Duarte, M. Teresa,Resende,Teixeira, Fátima C.
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- Amine-functionalized indazolin-3-ylidene complexes of palladium(II) by postmodification of a single precursor
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A series of five trans-[PdBr2(amine)(indy)] complexes (amine = diethylamine, dipropylamine, dibutylamine, diisobutylamine, morpholine; indy = indazolin-3-ylidene) with pendant teriary amine functionalities in the side chain of the NHC ligand has been prepared by postcoordinative modification of a single bromoalkyl-functionalized precursor complex. This approach allows for a synthesis of functionalized N-heterocyclic carbene complexes more efficient than the metalation of prefunctionalized azolium salts. All complexes have been fully characterized, and the molecular structures of three complexes are reported. A correlation exists between the 13C NMR shift of C carbene and the pKb values of the coordinated amines. Furthermore, all complexes were found to be active catalysts for the direct arylation of 1-methylpyrrole with good to excellent yields.
- Bernhammer, Jan C.,Singh, Harvenjit,Huynh, Han Vinh
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- “On Water” Palladium Catalyzed Direct Arylation of 1H‐Indazole and 1H‐7‐Azaindazole
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The C3 direct arylation of 1H-indazole and 1H-7-azaindazole has been a significant challenge due to the lack of the reactivity at this position. In this paper, we describe a mild and an efficient synthesis of new series of C3-aryled 1H-indazoles and C3-aryled 1H-7-azaindazoles via a C3 direct arylation using water as solvent. On water, PPh3 was effective as a ligand along with a lower charge of the catalyst Pd(OAc)2 (5 mol%) at 100 oC, leading to C3-aryled 1H-indazoles or C3-aryled 1H-7-azaindazoles in moderate to good yields.
- Abbouchi, Abdelmoula El,Akssira, Mohamed,Bousmina, Mostapha,El Kazzouli, Sa?d,Gambouz, Khadija,Guillaumet, Gérald,Nassiri, Sarah,Suzenet, Franck
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- Palladium-Catalyzed Oxidative Arylation of 1H-Indazoles with Arenes
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A simple method for the direct Pd(OAc)2-catalyzed oxidative arylation of inactivated 1H-indazole derivatives with simple arenes is reported. This method exhibits good reaction efficiency and good functional-group tolerance. Using the developed method, 28 arylated products were prepared in yields up to 80 %.
- Gambouz, Khadija,Abbouchi, Abdelmoula El,Nassiri, Sarah,Suzenet, Franck,Bousmina, Mostapha,Akssira, Mohamed,Guillaumet, Gérald,El Kazzouli, Sa?d
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supporting information
p. 7435 - 7439
(2020/11/30)
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- An Effective Method for the Synthesis of 1,3-Dihydro-2H-indazoles via N-N Bond Formation
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The [4+1] cycloaddition reaction of bifunctional amino reagents has been achieved with in situ formed aza-ortho-quinone methides. Specifically, N-(tosyloxy)carbamates were used as an N1 synthon and bifunctional amino reagents for this transformation, which provides a metal-free, catalyst-free, and oxidant-free strategy to form nitrogen-nitrogen bonds. (Figure presented.).
- Zhang, Xiaoke,Pan, Yang,Liang, Peng,Ma, Xiaofeng,Jiao, Wei,Shao, Huawu
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supporting information
p. 5552 - 5557
(2019/11/22)
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- Alkylation method for nitrogen-hydrogen containing compounds and application thereof
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The invention discloses an alkylation method for nitrogen-hydrogen containing compounds and an application thereof, belonging to the technical field of synthesis of organic compounds. The invention provides a series of methods for a nitrogen alkylation reaction of N-H containing heterocyclic compounds (II) with N,N-dimethylformamide dialkyl acetal as an alkyl source under the condition of no participation of metals, and a product with a hydrogen atom on a nitrogen atom substituted by R1 is obtained. The method provided by the invention has the advantages of highly-efficient reaction, high yield, simple treatment after the reaction, simple and convenient operation, mild reaction conditions, no participation of the metals, high tolerance of functional groups of a reaction substrate, wide range and easy preparation of the substrate, high reaction efficiency after amplification of the reaction, and applicability to large-scale industrial production.
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Paragraph 0059; 0060
(2018/10/04)
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- Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4- d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds
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Alkylation of 4-methoxy-1H-pyrazolo[3,4-d]pyrimidine (1b) with iodomethane in THF using NaHMDS as base selectively provided N2-methyl product 4-methoxy-2-methyl-2H-pyrazolo[3,4-d]pyrimidine (3b) in an 8/1 ratio over N1-methyl product (2b). Interestingly, conducting the reaction in DMSO reversed selectivity to provide a 4/1 ratio of N1/N2 methylated products. Crystal structures of product 3b with N1 and N7 coordinated to sodium indicated a potential role for the latter reinforcing the N2-selectivity. Limits of selectivity were tested with 26 heterocycles which revealed that N7 was a controlling element directing alkylations to favor N2 for pyrazolo- and N3 for imidazo- and triazolo-fused ring heterocycles when conducted in THF. Use of 1H-detected pulsed field gradient-stimulated echo (PFG-STE) NMR defined the molecular weights of ionic reactive complexes. This data and DFT charge distribution calculations suggest close ion pairs (CIPs) or tight ion pairs (TIPs) control alkylation selectivity in THF and solvent-separated ion pairs (SIPs) are the reactive species in DMSO.
- Bookser, Brett C.,Weinhouse, Michael I.,Burns, Aaron C.,Valiere, Andrew N.,Valdez, Lino J.,Stanczak, Pawel,Na, Jim,Rheingold, Arnold L.,Moore, Curtis E.,Dyck, Brian
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p. 6334 - 6353
(2018/06/01)
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- Direct N-Alkylation and Kemp Elimination Reactions of 1-Sulfonyl-1H-Indazoles
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The reactions of 1-sulfonyl-1H-indazoles under basic conditions are discussed, and the direct N-alkylation and Kemp elimination reactions of these compounds are reported. A series of 2-(p-tosylamino)benzonitriles and N-alkyl indazoles were prepared in good yields. Moreover, the 2-(p-tosylamino)benzonitriles could be transformed into a diverse range of important derivatives in a one-pot reaction. This method was successfully applied to the total syntheses of quindolinone and cryptolepinone; quindolinone was prepared in a one-pot reaction from 1-sulfonyl-1H-indazole.
- Tang, Meng,Chu, Bingjie,Chang, Xiaowei
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p. 2109 - 2116
(2018/07/31)
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- Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: Synthesis of axitinib
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A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.
- Yu, Jingbo,Hong, Zikun,Yang, Xinjie,Jiang, Yu,Jiang, Zhijiang,Su, Weike
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supporting information
p. 786 - 795
(2018/04/16)
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- Direct C-H Cyanation of Arenes via Organic Photoredox Catalysis
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Methods for the direct C-H functionalization of aromatic compounds are in demand for a variety of applications, including the synthesis of agrochemicals, pharmaceuticals, and materials. Herein, we disclose the construction of aromatic nitriles via direct C-H functionalization using an acridinium photoredox catalyst and trimethylsilyl cyanide under an aerobic atmosphere. The reaction proceeds at room temperature under mild conditions and has proven to be compatible with a variety of electron-donating and -withdrawing groups, halogens, and nitrogen- and oxygen-containing heterocycles, as well as aromatic-containing pharmaceutical agents.
- McManus, Joshua B.,Nicewicz, David A.
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supporting information
p. 2880 - 2883
(2017/03/11)
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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supporting information
p. 8267 - 8276
(2017/06/27)
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- Direct C-H Alkenylation of Functionalized Pyrazoles
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We have developed inter- and intramolecular C-H alkenylation reactions of pyrazoles. The catalyst, derived from Pd(OAc)2 and pyridine, enabled the oxidative alkenylation of pyrazoles containing a variety of functional groups at the C4 position.
- Han, Su Jin,Kim, Hyun Tae,Joo, Jung Min
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p. 689 - 698
(2016/01/27)
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- Indazolium halides as efficient ligands for Pd-catalyzed Suzuki–Miyaura cross-coupling of aryl bromides with arylboronic acids
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The indazolium halides containing various N-substituents have been conveniently prepared and applied in the palladium-catalyzed Suzuki–Miyaura cross-coupling reactions of aryl bromides with arylboronic acids at mild reaction conditions. The cross-coupling reaction provides the desired products in good to high yields. The ease of synthesis and the modularity, and the broad range of aryl bromides and arylboronic acids make this type of ligand attractive and promising for transition metal catalysis.
- Chen, Qian,Mao, Zhuqing,Guo, Fang,Liu, Xiaoshuang
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supporting information
p. 3735 - 3738
(2016/07/26)
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- Palladium-catalyzed direct C7-arylation of substituted indazoles
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A novel direct C7-arylation of indazoles with iodoaryls is described using Pd(OAc)2 as catalyst, 1,10-phenanthroline as ligand, and K 2CO3 as base in refluxing DMA. Direct C7-arylation of 3-substituted 1H-indazole containing an EWG on the arene ring gave the expected products in good isolated yields. In addition, a one-pot Suzuki-Miyaura/ arylation procedure leading to C3,C7-diarylated indazoles has been developed.
- Naas, Mohammed,El Kazzouli, Sa?d,Essassi, El Mokhtar,Bousmina, Mosto,Guillaumet, Gérald
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p. 7286 - 7293
(2014/09/16)
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- NaBH4-TMEDA and a palladium catalyst as efficient regio- and chemoselective system for the hydrodehalogenation of halogenated heterocycles
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The pair NaBH4-TMEDA as hydride source and a palladium catalyst in THF prove to be an efficient system for the hydrodehalogenation of halogenated heterocycles with one or more heteroatoms. In general, Pd(OAc) 2-PPh3 rapidly hydrodehalogenates reactive halo-heterocycles such as bromo-pyridines, -quinolines, -thiophenes, -indoles, -imidazoles, etc., at room temperature in very good yields, whereas in most cases PdCl2(dppf) reduces less reactive halides such as chloro-pyridines, -quinolines, -pyrimidines and bromo-indoles, -benzofurans, etc. Moreover, PdCl2(tbpf) shows to be even more active removing the 2- and 5-chlorine from both thiophene and thiazole rings. The reaction conditions tolerate various functional groups, allowing highly chemoselective reactions in the presence of halide, ester, alkyne, alkene and nitrile substituents. Moreover, with a proper selection of the catalyst it is also possible to obtain a good control in the regioselective hydrodehalogenation of a variety of polyhalogenated substrates.
- Chelucci, Giorgio,Figus, Susanna
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p. 191 - 209
(2014/07/21)
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- Route design and development of a MET kinase inhibitor: A copper-catalyzed preparation of an N 1 - Methylindazole
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The synthesis of a MET kinase inhibitor in an overall yield of 22% was achieved over eight steps starting with 3-hydroxybenzaldehyde, an improvement from the initial 12-step process with a 5.4% yield. Highlights of the process chemistry design and development are a Cu-catalyzed cyclization to form an important N1-methylindazole ring, a selective nitro reduction in the presence of an aryl bromide, a late-stage Suzuki cross-coupling, and a base-promoted Boc deprotection to form the desired drug candidate.
- Kallman, Neil J.,Liu, Chin,Yates, Matthew H.,Linder, Ryan J.,Ruble, J. Craig,Kogut, Eugene F.,Patterson, Lawrence E.,Laird, Dana L. T.,Hansen, Marvin M.
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p. 501 - 510
(2014/05/06)
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- A method for the regioselective synthesis of 1-alkyl-1H-indazoles
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A method for the regioselective synthesis of 3-unsubstituted 1-alkyl-1H-indazoles, starting with 2-halobenzonitriles and N-alkylhydrazines, is described. The two-step reaction pathway proceeds through the intermediacy of 1-alkyl-3-amino-1H-indazoles follo
- Liu, Han-Jun,Hung, Shiang-Fu,Chen, Chuan-Lin,Lin, Mei-Huey
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p. 3907 - 3912
(2013/06/27)
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- High-temperature reaction of SiO2 with methanol: Nucleophilic assistance of some N-unsubstituted benzazoles
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SiO2-containing materials (quartz, Pyrex glass, silica gel, and H-Y zeolite) react slowly with methanol at 350 C under both supercritical and gas-phase conditions. The amount of SiO2 reacted with supercritical methanol depends on the kind of the material and is varied from 0.05 wt% for quartz sand to 4.0 wt% for wide-porous silica gel for 5 h of the reaction. The main products of the reaction are methyl orthosilicates, mainly tetramethyl orthosilicate. N-Unsubstituted 1H-indole, 1H-benzimidazole, and 1H-indazole additives considerably increase the amount of reacted SiO2-containing material. Noteworthy, quartz sand solubility is increased ca 14-fold when indole is used at the same reaction conditions. These benzazoles provide a nucleophilic assistance to the reaction between SiO2 and methanol. During the assistance, the azole ring is methylated by methanol, and the participation of SiO2-surface or tetramethyl orthosilicate molecule facilitates the alkylation reaction of benzazole used.
- Chibiryaev, Andrey M.,Kozhevnikov, Ivan V.,Martyanov, Oleg N.
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p. 159 - 167
(2013/06/26)
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- Direct C-3-arylations of 1H-indazoles
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The first example of intermolecular C-H arylation of substituted 1H-indazoles is reported. Various 1-substituted indazoles were used as starting materials, and (hetero)aryl bromides and iodides were investigated as coupling partners. Different reaction co
- Ben-Yahia, Ali,Naas, Mohammed,El Kazzouli, Said,Essassi, El Mokhtar,Guillaumet, Gerald
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p. 7075 - 7081
(2013/02/22)
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- A general, one-step synthesis of substituted indazoles using a flow reactor
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Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues.
- Wheeler, Rob C.,Baxter, Emma,Campbell, Ian B.,MacDonald, Simon J. F.
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experimental part
p. 565 - 569
(2011/12/02)
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- Nucleophilic substitution at a four-coordinate sulfur atom. IV. Reactivity of anionic nitrogen-containing nucleopiles
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The second-order rate constants for reactions of anions derived from azoles, arenesulfonamides, and arenesulfonohydrazides with aryl toluenesulfonates and methyl iodide in 5% aqueous ethanol (μ 1.0) at 25°C were compared with corresponding rate constants for aliphatic and heterocyclic amines. The kinetic behavior of neutral and anionic nitrogen-containing bases in reactions involving acyl (4-nitrophenyl acetate and 4-nitrophenyl heptanoate) and toluenesulfonyl group transfer suggests that deviation from the Bronsted dependence is due to unfavorable solvation effects for nucleophiles with pKa ≥ 11.0 rather than to change in the transition state structure. In reactions with a soft substrate, methyl iodide, solvation effects scarcely play the determining role, and the reduced reactivity of the anionic nucleophiles relative to neutral species is most likely to result from structural differences in the transition states corresponding to methyl group transfer to neutral and anionic nitrogen-containing compounds. The α-effect with arenesulfonohydrazides was revealed for the first time. 1996 MAEe Cyrillic signΚ Hayκa/Interperiodica Publishing.
- Savelova,Karpichev,Simanenko,Prokop'eva,Lobachev,Belousova
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p. 530 - 539
(2007/10/03)
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- Reaction of N-vinylindazolium and N-vinylbenzotriazolium salts with nucleophiles
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Reaction of N-vinylindazolium tetrafluoroborates with aqueous potassium carbonate or sodium borohydride affords 2,3-dihydroquinazolines which evolve to 1,2,3,4-tetrahydroquinazolines by intra or intermolecular nucleophilic attack. The X-ray structure of o
- Elguero, Jose,Gutierrez-Puebla, Enrique,Monge, Angeles,Parco, Carmen,Ramos, Mar
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p. 11305 - 11320
(2007/10/02)
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