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Keith Fagnou - One of the best experts on this subject based on the ideXlab platform.
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palladium catalyzed direct Arylation of azine and azole n oxides reaction development scope and applications in synthesis
Journal of the American Chemical Society, 2009Co-Authors: Louischarles Campeau, David R Stuart, Jeanphilippe Leclerc, Megan Bertrandlaperle, Elisia Villemure, Sandrine Lasserre, Nicolas Guimond, Melanie Lecavallier, Keith FagnouAbstract:Palladium-catalyzed direct Arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for Arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by Arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.
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site selective sp2 and benzylic sp3 palladium catalyzed direct Arylation
Journal of the American Chemical Society, 2008Co-Authors: Louischarles Campeau, Derek J Schipper, Keith FagnouAbstract:Palladium-catalyzed site selective Arylation reactions of both sp2 and benzylic sp3 sites on azine and diazine N-oxide substrates are described that occur in good to excellent yield and with complete selectivity for reaction at the desired position. These studies have uncovered the need to properly control the metal to ligand ratio in sp2 Arylation and necessitated a complete reinvestigation of all reaction parameters for sp3 Arylation. From these studies, the choice of base emerged as a pivotal component for site selectivity, pointing to its intimate involvement in the mechanism of direct Arylation. These site selective reactions have been validated in both divergent and sequential derivatizations of heterocyclic compounds represent an attractive alternative to other routes to this class of molecule.
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palladium catalyzed benzene Arylation incorporation of catalytic pivalic acid as a proton shuttle and a key element in catalyst design
Journal of the American Chemical Society, 2006Co-Authors: Marc Lafrance, Keith FagnouAbstract:A palladium−pivalic acid cocatalyst system has been developed that exhibits unprecedented reactivity in direct Arylation. This reactivity is illustrated with the first examples of high yielding direct metalation−Arylation reactions of a completely unactivated arene, benzene. Experimental and computational evidence indicates that the pivalate anion is a key component in the palladation/C−H bond breaking event, that it lowers the energy of C−H bond cleavage and acts as a catalytic proton shuttle from benzene to the stoichiometric carbonate base. Eight examples of substituted aryl bromides are included which undergo direct Arylation with benzene in 55−85% yield.
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palladium catalyzed direct Arylation of simple arenes in synthesis of biaryl molecules
Chemical Communications, 2006Co-Authors: Louischarles Campeau, Keith FagnouAbstract:Significant progress has been made in the direct Arylation of simple arenes. A number of catalyst systems have been developed which enable the intramolecular direct Arylation of aryl chlorides, bromides and iodides in high yield as well as conditions capable of achieving intermolecular direct Arylation with simple arenes. This account describes recent progress by our group and others in the development of these reactions.
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catalytic direct Arylation with aryl chlorides bromides and iodides intramolecular studies leading to new intermolecular reactions
Journal of the American Chemical Society, 2006Co-Authors: Louischarles Campeau, Mathieu Parisien, Annie Jean, Keith FagnouAbstract:A catalyst for the intramolecular direct Arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct Arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C−H bond cleavage in palladium-catalyzed direct Arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular ...
Louischarles Campeau - One of the best experts on this subject based on the ideXlab platform.
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palladium catalyzed direct Arylation of azine and azole n oxides reaction development scope and applications in synthesis
Journal of the American Chemical Society, 2009Co-Authors: Louischarles Campeau, David R Stuart, Jeanphilippe Leclerc, Megan Bertrandlaperle, Elisia Villemure, Sandrine Lasserre, Nicolas Guimond, Melanie Lecavallier, Keith FagnouAbstract:Palladium-catalyzed direct Arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for Arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by Arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.
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site selective sp2 and benzylic sp3 palladium catalyzed direct Arylation
Journal of the American Chemical Society, 2008Co-Authors: Louischarles Campeau, Derek J Schipper, Keith FagnouAbstract:Palladium-catalyzed site selective Arylation reactions of both sp2 and benzylic sp3 sites on azine and diazine N-oxide substrates are described that occur in good to excellent yield and with complete selectivity for reaction at the desired position. These studies have uncovered the need to properly control the metal to ligand ratio in sp2 Arylation and necessitated a complete reinvestigation of all reaction parameters for sp3 Arylation. From these studies, the choice of base emerged as a pivotal component for site selectivity, pointing to its intimate involvement in the mechanism of direct Arylation. These site selective reactions have been validated in both divergent and sequential derivatizations of heterocyclic compounds represent an attractive alternative to other routes to this class of molecule.
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palladium catalyzed direct Arylation of simple arenes in synthesis of biaryl molecules
Chemical Communications, 2006Co-Authors: Louischarles Campeau, Keith FagnouAbstract:Significant progress has been made in the direct Arylation of simple arenes. A number of catalyst systems have been developed which enable the intramolecular direct Arylation of aryl chlorides, bromides and iodides in high yield as well as conditions capable of achieving intermolecular direct Arylation with simple arenes. This account describes recent progress by our group and others in the development of these reactions.
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catalytic direct Arylation with aryl chlorides bromides and iodides intramolecular studies leading to new intermolecular reactions
Journal of the American Chemical Society, 2006Co-Authors: Louischarles Campeau, Mathieu Parisien, Annie Jean, Keith FagnouAbstract:A catalyst for the intramolecular direct Arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct Arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C−H bond cleavage in palladium-catalyzed direct Arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular ...
Masahiro Miura - One of the best experts on this subject based on the ideXlab platform.
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transition metal catalyzedregioselective Arylation and vinylation of carboxylicacids
Synthesis, 2010Co-Authors: Tetsuya Satoh, Masahiro MiuraAbstract:Arene and heteroarene carboxylic acids undergo regioselectiveArylation and vinylation reactions at the positions ORTHO ( CINE)and IPSO to their carboxyl function undertransition-metal catalysis; these reactions are accompanied by carbon-hydrogenand carbon-carbon bond cleavages, respectively. Recentprogress in this area is summarized in this article. 1 Introduction 2 ORTHO- ( CINE-)Arylation 3 ORTHO- ( CINE-)Vinylation 4 IPSO-Arylation 5 IPSO-Vinylation 6 Conclusions
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Nickel-Catalyzed Direct Arylation of Azoles with Aryl Bromides
Organic Letters, 2009Co-Authors: Hitoshi Hachiya, Koji Hirano, Tetsuya Satoh, Masahiro MiuraAbstract:Nickel catalyst systems for the direct C2 Arylation of oxazoles and thiazoles have been developed. The catalyst systems are cost-efficient and allow the use of various aryl bromides in the C−H Arylation of azoles.
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rhodium catalyzed Arylation using arylboron compounds efficient coupling with aryl halides and unexpected multiple Arylation of benzonitrile
Organic Letters, 2005Co-Authors: Kenji Ueura, And Tetsuya Satoh, Masahiro MiuraAbstract:The Suzuki−Miyaura-type cross-coupling of arylboron compounds with aryl halides proceeds efficiently in the presence of a rhodium-based catalyst system to produce the corresponding biaryls. Furthermore, it has unexpectedly been observed that the treatment with benzonitrile under similar conditions brings about its multiple Arylation, in which nucleophilic Arylation on the cyano group and subsequent ortho Arylation via C−H bond cleavage are involved.
Antonio M Echavarren - One of the best experts on this subject based on the ideXlab platform.
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proton abstraction mechanism in the palladium catalyzed intramolecular Arylation substituent effects
Journal of the American Chemical Society, 2007Co-Authors: Domingo Garciacuadrado, Ataualpa A C Braga, Paula De Mendoza, Antonio M EchavarrenAbstract:The regioselectivity observed in the intramolecular palladium-catalyzed Arylation of substituted bromobenzyldiarylmethanes as well as theoretical results demonstrate that the Pd-catalyzed Arylation proceeds by a mechanism involving a proton abstraction by the carbonate, or a related basic ligand. The reaction is facilitated by electron-withdrawing substituents on the aromatic ring, which is inconsistent with an electrophilic aromatic-substitution mechanism. The more important directing effect is exerted by electron-withdrawing substituents ortho to the reacting site.
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proton abstraction mechanism for the palladium catalyzed intramolecular Arylation
Journal of the American Chemical Society, 2006Co-Authors: Domingo Garciacuadrado, Ataualpa A C Braga, Antonio M EchavarrenAbstract:Under the usual conditions, the Pd-catalyzed Arylation does not involve an electrophilic aromatic substitution reaction. On the basis of DFT calculations, we propose a mechanism for the Pd-catalyzed Arylation that involves a proton abstraction by a carbonate or related ligand and that provides a satisfactory explanation for the experimental data.
Stephen L. Buchwald - One of the best experts on this subject based on the ideXlab platform.
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Development of a Method for the N -Arylation of Amino Acid Esters with Aryl Triflates
Organic Letters, 2016Co-Authors: Sandra M. King, Stephen L. BuchwaldAbstract:A general method for the N-Arylation of amino acid esters with aryl triflates is described. Both α-and β-amino acid esters, including methyl, tert-butyl, and benzyl esters, are viable substrates. Reaction optimization was carried out by design of experiment (DOE) analysis using JMP software. The mild reaction conditions, which use t-BuBrettPhos Pd G3 or G4 precatalyst, result in minimal racemization of the amino acid ester. This method is the first synthetic application of the t-BuBrettPhos Pd G4 precatalyst. Mechanistic studies show that the observed erosion in enantiomeric excess is due to racemization of the amino acid ester starting material and not of the product. T he functionalization of amino acids is of great importance for the pharmaceutical and agrochemical industries (Figure 1). 1 Derivatives of natural amino acids can be employed as inexpensive chiral building blocks in these and other fields. 2 Moreover, the incorporation of functionalized amino acids in peptides and proteins has been crucial for advances in chemical biology, as they allow the development of new methods to study protein structure and function. 3 Among the many variations of functionalized amino acids, N-arylated amino acids and their esters are desirable compounds in these contexts, and a general and straightforward synthesis of these compounds in enantioenriched form is of substantial synthetic utility. The N-Arylation of amino acids and esters through nucleophilic aromatic substitution 4 or hypervalent iodine chemistry 5 has been reported, along with other more indirect methods for the preparation of arylated amino acids. 6 Transition metal catalyzed N-Arylation of amino acids and esters using aryl (pseudo)halides constitutes another direct approach to these compounds. However, many reported methods for this transformation to date result in partial or complete racemization of the α stereocenter. In other instances, the stereochemical integrity of the product was not rigorously established. A general and robust protocol for the enantioretentive N-Arylation of amino acids and esters remains to be developed and would be a useful addition to the current methods for amino acid functionalization. Previous efforts toward the development of a method for the N-Arylation of amino acids have primarily focused on Cu-catalyzed Ullmann-type coupling reactions. Ma's seminal work constituted the first report in this field, and their conditions are generally applicable to the coupling of hydrophobic amino acids with aryl bromides. 7 More recently, methods with aryl iodides have been developed, but the stereochemical integrity of the product was only verified for a few substrates. 8 Other Cu-catalyzed methods employ harsh reaction conditions that likely result in racemization of the amino acid. 9 Comparatively little work has been done on the development of Pd-catalyzed N-Arylation methods. 4,10 The reported conditions suffer from limited substrate scope, and significant racemization is observed for a majority of amino acids examined as substrates. 11 Methods for the stereoretentive coupling of amino acid esters tend to be even narrower in scope due to their greater propensity to racemize compared to amino acids themselves. Thus, the development of a general method for the N-Arylation of these derivatives would be especially desirable. Over the past several years, our group has developed palladacycle precatalysts and demonstrated their advantages in challenging cross-coupling reactions. 12 In light of the mild conditions under which these precatalysts undergo activation, we believed that our third (G3) 13 and fourth (G4) 14 generation of precatalysts would be well suited for the N-Arylation of amino acid esters without concomitant racemization. Herein, we report the development of a general, enantioretentive method for the N-Arylation of amino acid esters. N-Arylation of phenylalanine tert-butyl ester (5a) with bromobenzene was chosen as a model system for reaction development. Table 1 summarizes initial studies for which t-BuBrettPhos Pd G3 (P1) was selected as the precatalyst. Additional optimization results are presented in the Supporting
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Catalyst-controlled chemoselective Arylation of 2-aminobenzimidazoles.
Angewandte Chemie, 2012Co-Authors: Satoshi Ueda, Stephen L. BuchwaldAbstract:The chemoselective and complementary Pd-and Cu-catalyzed N-Arylation of 2-aminobenzimidazoles is described. Selective N-Arylation of the amino-group was achieved with a Pd-catalyzed method, while selective N-Arylation of azole nitrogen was achieved with a Cu-catalyzed procedure. The utility of these complementary sets of conditions is demonstrated in several two-step, selective syntheses of di-arylated aminoazoles.
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N- versus O-Arylation of Aminoalcohols: Orthogonal Selectivity in Copper-Based Catalysts
Journal of the American Chemical Society, 2007Co-Authors: Alexandr Shafir, Phillip A. Lichtor, Stephen L. BuchwaldAbstract:Two complementary protocols for copper-catalyzed Arylation of aminoalcohols were developed. Selective N-Arylation was accomplished at room temperature using 2-isobutyrylcyclohexanone (a β-diketone) as supporting ligand, while selective O-Arylation required the use of 3,4,7,8-tetramethylphenanthroline at 80−110 °C. Systematic examination of the reaction scope revealed that high levels of selectivity are achieved for a variety of substrates, provided that nonchelating (or weakly chelating) aminoalcohols are used. The generality of the method was highlighted by the synthesis, in a pairwise fashion, of a number of functionalized N- and O-arylated aminoalcohols.
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An improved catalyst for the asymmetric Arylation of ketone enolates.
Journal of the American Chemical Society, 2002Co-Authors: Takayuki Hamada, Andre Chieffi, Jens Ahman, Stephen L. BuchwaldAbstract:A new catalyst system for the enantioselective α-Arylation of ketones is reported. This catalyst, prepared from Pd2(dba)3 and a bulky dialkylphosphino-binaphthyl ligand, is able to effect the asymmetric Arylation of ketone enolates with aryl bromides utilizing NaOtBu as base. These new catalysts enjoy much higher reactivity than previous systems; Arylation reactions could be effected at room temperature with only 2 mol % of the Pd catalyst. The coupling of α-alkyl-α‘-protected cyclopentanones proceeded in high yield, and the resulting quaternary stereogenic center was installed in up to 94% ee.
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Palladium-Catalyzed α-Arylation of Esters
Journal of the American Chemical Society, 2001Co-Authors: Wahed A. Moradi, Stephen L. BuchwaldAbstract:A new and simple one-pot procedure for the palladium-catalyzed intermolecular α-Arylation of esters is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)2 or Pd2(dba)3 and bulky electron-rich o-biphenyl phosphines 1−3. Under the reaction conditions, using LiHMDS as base, α-Arylation proceeds at room temperature or at 80 °C with very good yields and high selectivities for monoArylation. Important nonsteroidal antiinflammatory drug derivatives such as (±)-naproxen tert-butyl ester and (±)-flurbiprofen tert-butyl ester can be prepared in 79% and 86% yield, respectively. The catalyst system based on the di-tert-butylphosphine (2) is also active for the α-Arylation of esters using aryl chlorides. Furthermore, using (3) the α-Arylation of trisubstituted ester enolates can be accomplished to provide compounds that have quaternary centers.
