- Cys–Cys and Cys–Lys Stapling of Unprotected Peptides Enabled by Hypervalent Iodine Reagents
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Easy access to a wide range of structurally diverse stapled peptides is crucial for the development of inhibitors of protein-protein interactions. Herein, we report bis-functional hypervalent iodine reagents for two-component cysteine-cysteine and cysteine-lysine stapling yielding structurally diverse thioalkyne linkers. This stapling method works with unprotected natural amino acid residues and does not require pre-functionalization or metal catalysis. The products are stable to purification and isolation. Post-stapling modification can be accessed via amidation of an activated ester, or via cycloaddition onto the formed thioalkyne group. Increased helicity and binding affinity to MDM2 was obtained for a i,i+7 stapled peptide.
- Ceballos, Javier,Grinhagena, Elija,Sangouard, Gontran,Heinis, Christian,Waser, Jerome
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p. 9022 - 9031
(2021/03/16)
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- Au–Ag Bimetallic Catalysis: 3-Alkynyl Benzofurans from Phenols via Tandem C?H Alkynylation/Oxy-Alkynylation
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The development of new methodologies enabling a facile access to valuable heterocyclic frameworks still is an important subject of research. In this context, we describe a dual catalytic cycle merging C?H alkynylation of phenols and oxy-alkynylation of the newly introduced triple bond by using a unique redox property and the carbophilic π acidity of gold. Mechanistic studies support the participation of a bimetallic gold–silver species. The one-pot protocol offers a direct, simple, and regio-specific approach to 3-alkynyl benzofurans from readily available phenols. A broad range of substrates, including heterocycles, is transferred with excellent functional group tolerance. Thus, this methodology can be used for the late-stage incorporation of benzofurans.
- Hu, Long,Dietl, Martin C.,Han, Chunyu,Rudolph, Matthias,Rominger, Frank,Hashmi, A. Stephen K.
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p. 10637 - 10642
(2021/04/06)
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- Tetrasubstituted 1,3-Enynes by Gold-Catalyzed Direct C(sp2)-H Alkynylation of Acceptor-Substituted Enamines
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A gold-catalyzed synthesis of tetrasubstituted 1,3-enynes from hypervalent iodine(III) reagents and activated alkenes is reported. This reaction involves an in situ formed alkynyl Au(III) species and a subsequent direct C(sp2)-H functionalization of alkenes, offering 26 enynes in 62-92% yield with excellent functional group tolerance.
- Han, Chunyu,Tian, Xianhai,Zhang, Huili,Rominger, Frank,Hashmi, A. Stephen K.
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p. 4764 - 4768
(2021/06/30)
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- Dual Gold/Silver Catalysis: Indolizines from 2-Substituted Pyridine Derivatives via a Tandem C(sp3)–H Alkynylation/Iminoauration
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A dual gold/silver-catalyzed cascade C(sp3)–H alkynylation/iminoauration of 2-substituted pyridines with hypervalent iodine(III) reagents for the synthesis of indolizines is described. This novel reaction involves the formation of an alkynyl Au(III) species, a dual gold/silver-catalyzed C(sp3)–H functionalization, and a subsequent iminoauration process. A number of indolizines bearing diverse functionalities were prepared in good to excellent yield. Furthermore, a gram-scale reaction was efficiently conducted.
- Han, Chunyu,Liu, Yaowen,Tian, Xianhai,Rominger, Frank,Hashmi, A. Stephen K.
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p. 9480 - 9484
(2021/12/17)
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- Practical synthesis of α,β-Alkynyl ketones by oxidative alkynylation of aldehydes with hypervalent alkynyliodine reagents
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A practical, metal-free carbonyl C(sp2)H oxidative alkynylation of aldehydes with hypervalent alkynyliodine reagents without the use of any catalysts is described for the synthesis of various α,β-alkynyl ketones. Here, two different methods have been developed where limiting reagents or substrates can be switched, and adopted according to the valuableness of aldehyde substrates or hypervalent alkynyliodine reagents. These reactions proceed with a broad substrate scope and high functional-group compatibility.
- Tsuzuki, Saori,Sakamoto, Ryu,Maruoka, Keiji
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p. 633 - 636
(2020/10/08)
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- Metal-Free Electrophilic Alkynylation of Sulfenate Anions with Ethynylbenziodoxolone Reagents
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Alkynyl sulfoxides are important building blocks with a unique reactivity in organic chemistry, but only a few reliable methods have been reported to synthesize them. A novel route to access alkynyl sulfoxides is reported herein by using ethynyl benziodoxolone (EBX) reagents to trap sulfenate anions generated in situ, via a retro-Michael reaction. The reaction takes place under metal-free and mild conditions. It is compatible with aryl, heteroaryl, and alkyl sulfoxides with up to 90% yield. This practical access to alkynyl sulfoxides is expected to facilitate the application of these useful building blocks in organic synthesis.
- Amos, Stephanie G. E.,Nicolai, Stefano,Gagnebin, Alec,Le Vaillant, Franck,Waser, Jerome
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p. 3687 - 3701
(2019/03/07)
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- Gold-Catalyzed Stereoselective Domino Cyclization/Alkynylation of N-Propargylcarboxamides with Benziodoxole Reagents for the Synthesis of Alkynyloxazolines
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A concise and highly stereoselective synthesis of alkynyloxazolines via a gold-catalyzed domino cyclization-alkynylation cascade of N-propargylcarboxamides with benziodoxole reagents is reported. This new protocol, which represents an attractive alternati
- Zhao, Ximei,Tian, Bing,Yang, Yangyang,Si, Xiaojia,Mulks, Florian F.,Rudolph, Matthias,Rominger, Frank,Hashmi, A. Stephen K.
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p. 3155 - 3162
(2019/05/10)
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- “Doubly Orthogonal” Labeling of Peptides and Proteins
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Herein, we report a cysteine bioconjugation methodology for the introduction of hypervalent iodine compounds onto biomolecules. Ethynylbenziodoxolones (EBXs) engage thiols in small organic molecules and cysteine-containing peptides and proteins in a fast and selective addition onto the alkynyl triple bond, resulting in stable vinylbenziodoxolone hypervalent iodine conjugates. The conjugation occurs at room temperature in an open flask under physiological conditions. The use of an azide-bearing EBX reagent enables a “doubly orthogonal” functionalization of the bioconjugate via strain-release-driven cycloaddition and Suzuki-Miyaura cross-coupling of the vinyl hypervalent iodine bond. We successfully applied the methodology on relevant and complex biomolecules, such as histone proteins. Through single-molecule experiments, we illustrated the potential of this doubly reactive bioconjugate by introducing a triplet-state quencher close to a fluorophore, which extended its lifetime by suppressing photobleaching. This work is therefore expected to find broad applications for peptide and protein functionalization. Understanding the molecular basis of life is essential in the search for new medicines. Chemical biology develops molecular tools for studying biological processes, setting the basis for new diagnostics and therapeutics, and relies heavily on the ability to selectively modify biomolecules. Two approaches have been especially fruitful: (1) selective modification of natural biomolecules and (2) selective reaction between non-natural functionalities in the presence of biomolecules (the so-called orthogonal bioconjugation). In our work, we contribute to both by transferring highly reactive hypervalent iodine reagents to cysteine residues in proteins and peptides. The obtained bioconjugates retain the reactive hypervalent bonds, which can be selectively functionalized via a metal-mediated reaction. Combined with a traditional azide tag, our approach allows a doubly orthogonal functionalization of biomolecules and is hence expected to be highly useful in chemical biology. Chemical biology develops molecular tools for studying biological processes, setting the basis for new diagnostics and therapeutics, and relies heavily on the ability to modify selectively biomolecules. In our work, we introduce hypervalent iodine bonds into peptides and proteins, via functionalization of cysteine, by using unique cyclic reagents developed in our group. The hypervalent bond can then be selectively modified in the presence of both natural and synthetic functional groups, opening new opportunities for applications in chemical biology.
- Tessier, Romain,Ceballos, Javier,Guidotti, Nora,Simonet-Davin, Raphael,Fierz, Beat,Waser, Jerome
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p. 2243 - 2263
(2019/08/08)
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- Synthesis of cis-β-Amidevinyl Benziodoxolones from the Ethynyl Benziodoxolone-Chloroform Complex and Sulfonamides
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The synthesis of cis-β-amidevinyl benziodoxolones from the ethynyl benziodoxolone-chloroform complex and sulfonamides is reported. Evidence indicates that highly reactive unsubstituted ethynyl benziodoxolone undergoes Michael addition of sulfonamides, including sterically demanding acyclic amino acid derivatives. The synthesis of selectively deuterated cis-β-amidevinyl benziodoxolones and investigation of ethynyl-λ3-iodane reactivity are also described.
- Shimbo, Daisuke,Shibata, Atsushi,Yudasaka, Masaharu,Maruyama, Toshifumi,Tada, Norihiro,Uno, Bunji,Itoh, Akichika
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p. 9769 - 9773
(2019/11/28)
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- Metal-Free Oxidative Cross Coupling of Indoles with Electron-Rich (Hetero)arenes
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A new method for the synthesis of bi-heteroaryls is reported, based on the umpolung of indoles with benziodoxol(on)e hypervalent iodine reagents (IndoleBX). The oxidative coupling of IndoleBX with an equimolar amount of electron-rich benzenes, indoles, pyrroles, and thiophenes proceeded under mild transition-metal-free conditions. Functionalized non-symmetrical bi-indolyl heterocycles were accessed efficiently. Introduction of a new type of C2-substituted indole benziodoxole reagents further allowed extending the scope of the reaction to NH unprotected and C3-alkylated indoles. The obtained bi-heterocycles are important building blocks in synthetic and medicinal chemistry, and could be easily transformed into more complex heterocyclic systems.
- Caramenti, Paola,Nandi, Raj Kumar,Waser, Jerome
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p. 10049 - 10053
(2018/07/29)
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- Gold-catalyzed domino cyclization-alkynylation reactions with EBX reagents: New insights into the reaction mechanism
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Gold-catalyzed domino processes constitute a useful alternative to C-H functionalization for the synthesis of functionalized (hetero)arenes. Herein, we report computational studies on the gold-catalyzed cyclization alkynylation of keto-allenes with ethyny
- Ghari, Hossein,Li, Yifan,Roohzadeh, Roohollah,Caramenti, Paola,Waser, Jerome,Ariafard, Alireza
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supporting information
p. 12257 - 12262
(2017/09/25)
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- Gold-Catalyzed Cadiot–Chodkiewicz-type Cross-Coupling of Terminal Alkynes with Alkynyl Hypervalent Iodine Reagents: Highly Selective Synthesis of Unsymmetrical 1,3-Diynes
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A new and efficient method for the synthesis of unsymmetrical 1,3-butadiynes by gold-catalyzed C(sp)–C(sp) cross-coupling of terminal alkynes with alkynyl hypervalent iodine(III) reagents has been developed. The reaction features high selectivity and efficiency, mild reaction conditions, wide substrate scope, and functional-group compatibility, and is a highly attractive complement to existing methods. Mechanistic studies reveal that formation of a phenanthrolinyl-ligated gold(I) complex is crucial for the efficiency and selectivity of the target transformation.
- Li, Xiangdong,Xie, Xin,Sun, Ning,Liu, Yuanhong
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p. 6994 - 6998
(2017/06/08)
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- Heterotetracenes: Flexible Synthesis and in Silico Assessment of the Hole-Transport Properties
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Thienoacenes and furoacenes are among the most frequent molecular units found in organic materials. The efficient synthesis of morphologically different heteroacenes and the rapid determination of their solid-state and electronic properties are still challenging tasks, which slow down progress in the development of new materials. Here, we report a flexible and efficient synthesis of unprecedented heterotetracenes based on a platinum- and gold-catalyzed cyclization–alkynylation domino process using EthynylBenziodoXole (EBX) hypervalent iodine reagents in the key step. The proof-of-principle in silico estimation of the synthesized tetracenes’ charge transport properties reveals their strong dependence on both the position and nature of the heteroatoms in the ring system. A broad range of mobility is predicted, with some compounds displaying performance potentially comparable to that of state-of-the-art electronic organic materials.
- Li, Yifan,Gryn'ova, Ganna,Saenz, Felipe,Jeanbourquin, Xavier,Sivula, Kevin,Corminboeuf, Clémence,Waser, Jér?me
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p. 8058 - 8065
(2017/06/19)
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- Platinum-catalyzed domino reaction with benziodoxole reagents for accessing benzene-alkynylated Indoles
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Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene-ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinum-catalyzed cyclization/alkynylation domino process to selectively obtain C5- or C6-functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.
- Li, Yifan,Waser, Jerome
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p. 5438 - 5442
(2015/04/27)
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- Room-Temperature Decarboxylative Alkynylation of Carboxylic Acids Using Photoredox Catalysis and EBX Reagents
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Alkynes are used as building blocks in synthetic and medicinal chemistry, chemical biology, and materials science. Therefore, efficient methods for their synthesis are the subject of intensive research. Herein, we report the direct synthesis of alkynes fr
- Le Vaillant, Franck,Courant, Thibaut,Waser, Jerome
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p. 11200 - 11204
(2016/07/06)
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- Ethynylbenziodoxolones (EBX) as reagents for the ethynylation of stabilized enolates
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Herein, we report a detailed study on the electrophilic alkynylation of cyclic keto esters and amides with ethynylbenziodoxolone (EBX) reagents. The structure and stability of this class of reagents is first described more in details. Differential scannin
- Fernandez Gonzalez, Davinia,Brand, Jonathan P.,Mondiere, Regis,Waser, Jerome
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p. 1631 - 1639
(2013/07/05)
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- Gold-catalyzed regioselective synthesis of 2- and 3-alkynyl furans
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Chemical Matching: C2- or C3-alkynylated furans were selectively synthesized by using gold catalysis. Direct C-H alkynylation of furans was achieved with C2 selectivity, and a domino cyclization/alkynylation process starting from allenes gave C3-alkynylat
- Li, Yifan,Brand, Jonathan P.,Waser, Jerome
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p. 6743 - 6747
(2013/07/26)
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- Ethynyl benziodoxolones for the direct alkynylation of heterocycles: Structural requirement, improved procedure for pyrroles, and insights into the mechanism
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This report describes a full study of the gold-catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3-and 6-position of triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2-pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a π activation or an oxidative mechanism are most probable for the alkynylation reaction.
- Brand, Jonathan P.,Chevalley, Clara,Scopelliti, Rosario,Waser, Jerome
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p. 5655 - 5666
(2012/06/01)
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- New hypervalent iodine reagents for electrophilic trifluoromethylation and their precursors: Synthesis, structure, and reactivity
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Several new five- and a six-membered heterocyclic monochloroiodanes, including two cationic species, were synthesized. Three of which were used for the preparation of corresponding trifluoromethylation reagents. These compounds were characterized by X-ray crystallography for a comparative structural study. A reactivity study on the trifluoromethylation of para-toluenesulfonic acid has been conducted in order to compare initial rates. Compounds having a longer I-O bond display a higher reactivity.
- Niedermann, Katrin,Welch, Jan M.,Koller, Raffael,Cvengro, Ján,Santschi, Nico,Battaglia, Philip,Togni, Antonio
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scheme or table
p. 5753 - 5761
(2010/09/18)
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- A concise synthesis of ortho-iodobenzyl alcohols via addition of ortho-Iodophenyl grignard reagent to aldehydes and ketones
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A wide range of both secondary and tertiary ortho-iodobenzyl alcohols was synthesized via addition of ortho-iodophenyl Grignard reagents to aldehydes and ketones. Significant improvements in terms of yields were observed with ketones upon addition of CeCl3. The potential application of the target compounds as precursors for novel electrophilic trifluoromethylating reagents based on hypervalent iodine derivatives was demonstrated. Georg Thieme Verlag Stuttgart.
- Cvengro, Alcohols Jan,Stolz, Daniel,Togni, Antonio
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experimental part
p. 2818 - 2824
(2010/01/21)
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- Preparation of 1,1′-oxy-bis(3,3-bis(trifluoromethyl)-3(1H)-1,2- benziodoxole) and 2-(N-(p-toluenesulfonyl)imino)iodobenzylmethyl ether
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Conditions for improved preparation of the crystalline iodine(III) reagents [1,2-C6H4(C(CF3)2OI)]2O and 1,2-C6H4(CH2OMe)(I=NTs) are presented together with their x-ray structures. The former is prepared by hydrolysis of 1,2-C6H4(C(CF3)2OICl (x-ray) and allows the preparation of cyclic sulfates from alkenes; the latter fashions sulfamidate under related conditions. Copyright Taylor & Francis Group, LLC.
- Blake, Alexander J.,Novak, Andrew,Davies, Madeline,Robinson, Richard I.,Woodward, Simon
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experimental part
p. 1065 - 1075
(2009/09/08)
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- Directed Dilithiation of Hexafluorocumyl Alcohol - Formation of a Reagent for the Facile Introduction of a Stabilizing Bidentate Ligand in Compounds of Hypervalent Sulfur (10-S-4), Phosphorus (10-P-5), Silicon (10-Si-5), and Iodine (10-I-3)
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The reaction of 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol (RFOH) with either sec-butyllithium or n-bulyllithium/N,N,N'N'-tetramethylethylenediamine (TMEDA) provides 3, a reagent for the facile introduction of a bidentate ligand which is partic
- Perozzi, Edmund F.,Michalak, Ronald S.,Figuli, Garret D.,Stevenson III, William H.,Dess, Daniel B.,et al.
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p. 1049 - 1053
(2007/10/02)
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