Copper-mediated Cross-coupling Reaction Research Articles

Design, synthesis and anticancer activity of N-aryl indolylsulfoximines: Identification of potent and selective anticancer agents

A facile and efficient approach utilizing copper-mediated cross-coupling reaction of N-boc-3-indolylsulfoximines with aryl iodides was developed to synthesize a diverse range of N-arylated indolylsulfoximines 11a-m in excellent yields (up to 91%). The key precursors, free NH sulfoximines 9 were readily prepared by the treatment of N-boc-3-methylthioindoles 8 with a combination of IBD and ammonium carbamate. Under similar conditions NH-free indolylsulfoximine 9a was successfully prepared in gram-scale quantities. The reaction is highly chemoselective and tolerant of a wide range of functional groups. The process is environmentally friendly and is amenable to scale-up. Among the prepared N-arylated indolylsulfoximines 11a-m, compounds 11i-j (2.68–2.76 μM), 11f-g (1.9–3.7 μM) and 11k (1.28 μM) showed potent and selective cytotoxicity against 22Rv1, C4-2 and MCF7 cells, respectively. Indolylsulfoximine derivative 11l displayed a broad spectrum of activity (1.7–8.2 μM) against the tested cancer cell lines. These compounds were found to be non-cytotoxic to normal HEK293 cells, indicating their potential selectivity for cancer cells. We analysed the impact of 11l on various cellular assays to uncover its mechanism of action. Cellular assay shows that 11l increases the endogenous level of ROS, leading to the increased level of p-53 and c-jun inducing apoptosis. 11l also induced mitochondrial dysfunction, further promoting apoptotic pathways. Besides, 11l also restricts cell invasiveness, indicating that it could serve as an effective anti-metastatic agent. As oxidative stress severe F actin causing tubulin depolymerization, we examined the impact of 11l on tubulin dynamics. Accordingly, 11l treatment decreased the levels of polymerized tubulin in 22Rv1 and C4-2 cells. Although future studies are needed to determine their exact molecular target(s), our data shows that N-aryl indolylsulfoximines could serve as effective anti-cancer agents.

Copper-Mediated Cross-Coupling of Diazo Compounds with Sulfinates.

A copper-mediated cross-coupling reaction between a diazo compound and a sodium alkane(arene)sulfinate gives a sulfone as the product. This reaction proceeds under mild conditions and features excellent functional group compatibility. A wide range of sodium alkane(arene)sulfinates were successfully applied in this chemistry. Mechanistic studies revealed that the overall reaction efficiency of the sulfinates was in line with their nucleophilicity in this reaction.

ChemInform Abstract: First Synthesis of Both 1‐Aryl‐4‐[(E)‐alk‐1‐enyl]‐1H‐1,2,3‐triazoles and 1‐Aryl‐4‐[(Z)‐1‐(trimethylsilyl)alk‐1‐enyl]‐1H‐1,2,3‐triazoles: Assembly of π‐Extended 1,2,3‐Triazoles Using a Cross‐Coupling/Click Reaction Sequence.

ChemInformVolume 47, Issue 44 Heterocyclic Compounds ChemInform Abstract: First Synthesis of Both 1-Aryl-4-[(E)-alk-1-enyl]-1H-1,2,3-triazoles and 1-Aryl-4-[(Z)-1-(trimethylsilyl)alk-1-enyl]-1H-1,2,3-triazoles: Assembly of π-Extended 1,2,3-Triazoles Using a Cross-Coupling/Click Reaction Sequence. Asuka Oikawa, Asuka Oikawa Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this authorGan Kindaichi, Gan Kindaichi Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this authorYasutaka Shimotori, Yasutaka Shimotori Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this authorMasayuki Hoshi, Masayuki Hoshi Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this author Asuka Oikawa, Asuka Oikawa Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this authorGan Kindaichi, Gan Kindaichi Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this authorYasutaka Shimotori, Yasutaka Shimotori Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this authorMasayuki Hoshi, Masayuki Hoshi Dep. Biotechnol. Environ. Chem., Kitami Inst. Technol., Hokkaido 090, JapanSearch for more papers by this author First published: 13 October 2016 https://doi.org/10.1002/chin.201644124Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue44October, 2016 RelatedInformation

First synthesis of both 1-aryl-4-[(E)-alk-1-enyl]-1H-1,2,3-triazoles and 1-aryl-4-[(Z)-1-(trimethylsilyl)alk-1-enyl]-1H-1,2,3-triazoles: assembly of π-extended 1,2,3-triazoles using a cross-coupling/click reaction sequence

A practical and general synthetic approach to a series of π-extended 1,2,3-triazoles with both aryl and alkenyl moieties on the triazole ring is described. Synthesis of 1-aryl-4-[(E)-alk-1-enyl]-1H-1,2,3-triazoles can be achieved by the click reaction between terminal conjugated (E)-enynes, prepared by copper-mediated cross-coupling reaction of (E)-alk-1-enyldisiamylboranes with (trimethylsilyl)ethynyl bromide, and aryl azides, prepared from arylboronic acids and sodium azide in another flask and employed for the following click reaction without any purification. 1-Aryl-4-[(Z)-1-(trimethylsilyl)alk-1-enyl]-1H-1,2,3-triazoles can be also synthesized by a sequential three-step reaction, which involves copper-mediated cross-coupling reaction of (Z)-1-(trimethylsilyl)alk-1-enyldicyclohexylboranes with (trimethylsilyl)ethynyl bromide to form (Z)-1,3-bis(trimethylsilyl)alk-3-en-1-ynes, deprotection of the trimethylsilyl group on the alkynyl carbon atom to generate (Z)-3-(trimethylsilyl)alk-3-en-1-ynes and click reaction with aryl azides prepared in the same manner as described above. Both synthetic routes are tolerant of a wide range of functional groups with moderate to good yields.

Synthesis of Terminal Allenes through Copper-Mediated Cross-Coupling of Ethyne with N-Tosylhydrazones or α-Diazoesters.

Ethyne is employed as coupling partner in copper-mediated cross-coupling reactions with N-tosylhydrazones and α-diazoacetate, leading to the development of a new synthetic method for terminal allenes. With this novel coupling method, the terminal allenes were obtained in good yields and with excellent functional group tolerance. Copper carbene migratory insertion is proposed as the key step in these transformations.

Copper-Mediated Cross-Coupling Reactions. Editors: Gwilherm Evano and Nicolas Blanchard

Copper-Mediated Cross-Coupling Reactions. Editors: Gwilherm Evano and Nicolas Blanchard

ChemInform Abstract: One‐Pot Synthesis of 1‐Arylmethyl‐4‐[(E)‐alk‐1‐enyl]‐1H‐1,2,3‐triazoles via a Cross‐Coupling/Click Reaction Sequence.

1-Arylmethyl-4-[(E)-alk-1-enyl]-1H-1,2,3-triazoles have been synthesized from terminal conjugated (E)-enynes, prepared by copper-mediated cross-coupling reaction of (E)-alk-1-enyldisiamylboranes with (trimethylsilyl)ethynyl bromide, benzyl bromides and sodium azide in a one-pot fashion. In this cross-coupling/click reaction sequence, the copper precursor Cu(acac)2 can serve as a tandem catalyst.

Copper-Mediated Cross-Coupling Reactions. Edited by Gwilherm Evano and Nicolas Blanchard.

Copper-Mediated Cross-Coupling Reactions. Edited by Gwilherm Evano and Nicolas Blanchard.

One-pot synthesis of 1-arylmethyl-4-[(E)-alk-1-enyl]-1H-1,2,3-triazoles via a cross-coupling/click reaction sequence

1-Arylmethyl-4-[(E)-alk-1-enyl]-1H-1,2,3-triazoles have been synthesized from terminal conjugated (E)-enynes, prepared by copper-mediated cross-coupling reaction of (E)-alk-1-enyldisiamylboranes with (trimethylsilyl)ethynyl bromide, benzyl bromides and sodium azide in a one-pot fashion.

Synthesis and anticancer activity of all known (-)-agelastatin alkaloids.

The full details of our enantioselective total syntheses of (-)-agelastatins A-F (1-6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (-)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (-)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure-activity relationship within the natural series. Significantly, (-)-agelastatin A (1) is highly potent against six blood cancer cell lines (20-190 nM) without affecting normal red blood cells (>333 μM). (-)-Agelastatin A (1) and (-)-agelastatin D (4), the two most potent members of this family, induce dose-dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy, we have determined that neither alkaloid affects tubulin dynamics within cells.

A Scalable and Expedient Route to 1-Aza[6]helicene Derivatives and Its Subsequent Application to a Chiral-Relay Asymmetric Strategy

A rapid route to diversely functionalized 1-aza[6]helicenes has been achieved via the development of a copper-mediated cross-coupling reaction, followed by PtCl4-catalyzed cycloisomerization. Not only does this method allow access to these functionally important molecules on gram scale, but this strategy is also suitable for relaying the axial chirality of a key intermediate to the helicity of the product.

Palladium-catalyzed and copper-mediated cross-coupling reaction of aryl- or alkenylboronic acids with acid chlorides under neutral conditions: efficient synthetic methods for diaryl ketones and chalcones at room temperature

Palladium-catalyzed cross-coupling reaction of aryl- or alkenylboronic acids with acid chlorides in the presence of copper(I) thiophene-2-carboxylate (CuTC) as an activator in diethyl ether at room temperature under strictly non-basic conditions affords the diaryl ketones or chalcones in moderate to excellent yields. A wide range of substrates bearing an electron-donating or an electron-withdrawing substituent on the aromatic ring are compatible.

Copper-Mediated Radical Cross-Coupling Reaction of 2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) with Phenols or Thiophenols

A copper-mediated cross-coupling reaction between HCFC-123 and phenols or thiophenols has been achieved. It is found that diethyl amine, which serves as both the activator and ligand of copper, plays a key role in this reaction. Two possible radical involved processes are proposed for the reaction mechanism.

Copper-Mediated Fluoroalkylation of Aryl Iodides Enables Facile Access to Diverse Fluorinated Compounds: The Important Role of the (2-Pyridyl)sulfonyl Group

The (2-pyridyl)sulfonyl group was found to be a multifunctional group in the preparation of structurally diverse fluorinated products. It not only facilitates the copper-mediated (or catalyzed) cross-coupling reaction between α-fluoro sulfone 4a and aryl iodides, but also enables further transformations of the coupling products 2.

Homo- and Heterocoupling of Terminal Conjugated Enynes: One-Pot Synthesis of Alka-1,7-diene-3,5-diynes and Alk-1-ene-3,5-diynes via Two Types of Coupling Reaction

Conjugated dienediynes and enediynes with definite geometry­ have been prepared in a one-pot manner. This protocol involves two types of coupling reaction, a Suzuki-type coupling and either a Hay coupling or a Cadiot-Chodkiewicz coupling. Thus, the copper-mediated cross-coupling reaction of (E)-alk-1-enyldisiamylborane with (trimethylsilyl)ethynyl bromide is carried out in the presence of 1 M NaOMe to generate (E)-alk-3-en-1-yne, which is subjected to either palladium/copper-catalyzed homocoupling in the presence of DABCO or copper-catalyzed heterocoupling with 1-iodoalk-1-yne in the presence of TBD or pyrrolidine in a single reaction pot without isolating (E)-alk-3-en-1-yne. The homocoupling has realized the stereoselective construction of (1E,7E)-alka-1,7-diene-3,5-diynes, and the heterocoupling has achieved the formation of (E)-alk-1-ene-3,5-diynes. In addition, starting from (Z)-alk-1-enyldisiamylborane instead of the E-isomer, this series of reactions has led to the formation of (1Z,7Z)-alka-1,7-diene-3,5-diynes and (Z)-alk-1-ene-3,5-diynes, albeit limiting the scope of the substrate.

ChemInform Abstract: Copper‐Mediated Cross‐Coupling Reactions

AbstractReview: 493 refs.

Synthesis of a Polymerizable Fluorosurfactant for the Construction of Stable Nanostructured Proton-Conducting Membranes

The synthesis of the polymerizable fluorinated surfactant sodium 1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-(4-vinylphenyl)ethoxy)ethanesulfonate (1) and a number of related fluorocarbon compounds is described. Compound 1 is synthesized using a copper-mediated cross-coupling reaction of 4-bromobenzaldehyde and sodium 5-iodooctafluoro-3-oxapentanesulfonate. The resulting benzaldehyde is converted to a styrene unit using a Wittig reaction with methyltriphenylphosphonium bromide in acetonitrile, using DBU as a base. This strategy for converting an iodo-functionalized fluorosurfactant to a styrene-containing fluorosurfactant is highly efficient because both reactions are performed in polar solvents and are compatible with the sulfonate moiety. In addition, the copper-mediated cross-coupling reaction is most efficient with electron-poor aryl bromides like 4-bromobenzaldehyde. We wish to employ 1 for the construction of nanostructured membranes by polymerization of 1 in a microemulsion or in lyotropic liquid crystalline phases.

ChemInform Abstract: Diamine Ligands in Copper‐Catalyzed Reactions.

AbstractReview: 229 refs.

Diamine ligands in copper-catalyzed reactions

The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this review we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials.

Total Synthesis of Photoactivatable or Fluorescent Anandamide Probes: Novel Bioactive Compounds with Angiogenic Activity

Endocannabinoids are endogenous polyunsaturated fatty acids involved in a multitude of health and disease processes. Recently, several lines of evidence suggest the presence of a novel non-CB1/CB2 anandamide receptor in endothelial cells. Thus, we synthesized two types of photoaffinity probes that contain either an arylazide group or a diazirin moiety, together with a fluorescent analogue. The key steps rely on selective hydrogenation of skipped tetrayne backbones and on copper-mediated cross-coupling reactions between diynic precursors. Three synthetic routes were investigated. In biological functional assays, we found that both the arylazide and the fluorescent probes induced robust increases in matrix metalloprotease activity and produced positive angiogenic responses in in vitro endothelial cell tube formation assays. Irradiation of the arylazide probe nicely enhanced this effect in both HUVEC and CB1-KO HUVEC. These results suggest that the arylazide and the fluorescent probes can be used to identify "non-CB1/CB2 anandamide receptor" from endothelial cells.