Development of Palladium-catalyzed Allylation Reactions of Alkylidene Malononitriles and Stereospecific Nickel-catalyzed Cross-coupling Reactions of Alkyl Electrophiles

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ISBN 13 : 9781303328121
Total Pages : 337 pages
Book Rating : 4.3/5 (281 download)

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Book Synopsis Development of Palladium-catalyzed Allylation Reactions of Alkylidene Malononitriles and Stereospecific Nickel-catalyzed Cross-coupling Reactions of Alkyl Electrophiles by : Elizabeth Claire Swift

Download or read book Development of Palladium-catalyzed Allylation Reactions of Alkylidene Malononitriles and Stereospecific Nickel-catalyzed Cross-coupling Reactions of Alkyl Electrophiles written by Elizabeth Claire Swift and published by . This book was released on 2013 with total page 337 pages. Available in PDF, EPUB and Kindle. Book excerpt: Transition-metal catalysis has enabled the development of an unprecedented number of mild and selective C-C bond-forming reactions. We sought to access the reactivity of palladium and nickel catalysts for two types of transformations: conjugate allylations and sp3-sp3 cross-coupling reactions. Conjugate allylation of malononitriles was evaluated with N-heterocyclic carbene-ligated palladium complexes. The allylation was found to yield a variety of mono-allylated products. These results are in contrast to the bis-allylation of malononitriles using other palladium-based catalysts. Additionally, conjugate addition of [alpha], [beta]-unsaturated N-acylpyrroles was found to be accelerated in the presence of sulfoxide substitution on the pyrrole ring. These substrates are lead compounds for the development of an enantioselective allylation reaction. Transition metal-catalyzed cross-coupling reactions have become standard practice in organic synthesis. Recent advances in alkyl-alkyl couplings have been transformative in the way organic chemists approach the construction of target molecules. This dissertation focuses on the development of stereospecific sp3-sp3 cross-coupling reactions. We discovered that in the presence of nickel catalysts, secondary benzylic ethers were found to undergo stereospecific substitution reactions with Grignard reagents. Reactions proceeded with inversion of configuration and high stereochemical fidelity. This reaction allows for facile enantioselective synthesis of biologically active diarylethanes from readily available optically enriched carbinols. Subsequently, this reaction was expanded to dialkylzinc reagents and the first stereospecific Negishi cross-coupling reaction of secondary benzylic esters was developed. A series of traceless directing groups were evaluated for their ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially-available 2-(methylthio)acetic acid were found to be the most effective. The products were formed in high yield and with excellent stereospecificity. A variety of functional groups were tolerated in the reaction including alkenes, alkynes, esters, amines, imides, and O-, S-, and N-heterocycles. The utility of this transformation was highlighted in the enantioselective synthesis of a retinoic acid receptor (RAR) agonist.

Development of Nickel-Catalyzed Coupling Reactions

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ISBN 13 : 9780355308976
Total Pages : 503 pages
Book Rating : 4.3/5 (89 download)

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Book Synopsis Development of Nickel-Catalyzed Coupling Reactions by : Mikhail Olegovich Konev

Download or read book Development of Nickel-Catalyzed Coupling Reactions written by Mikhail Olegovich Konev and published by . This book was released on 2017 with total page 503 pages. Available in PDF, EPUB and Kindle. Book excerpt: Transition metal catalyzed reactions are ubiquitous in the realm of synthetic chemistry, allowing for the strategic construction of complex molecular frameworks of pharmaceuticals, natural products, and synthetic materials. Palladium-catalyzed cross-coupling reactions are part of the foundation of these transformations, insofar as they were recognized with the 2010 Nobel Prize in chemistry. Traditionally, these reactions have relied on aryl and vinyl electrophiles, whereas the alkyl counterparts have only recently begun to emerge in the literature. Nickel has been on the forefront of enantioconvergent alkyl cross--coupling reactions due to its propensity to undergo single electron chemistry. However, under special conditions, it has a unique ability to break strong carbon--oxygen bonds in a stereospecific manner, making research into its reactivity a valuable endeavor to the field of organometallic chemistry.Chapter 1 describes the development of a stereospecific intramolecular alkyl-Heck cyclization of benzylic ethers. The reaction proceeds with inversion at the electrophilic carbon, for the synthesis of methylenecyclopentanes of both extended pi-electron and simple aromatic systems. The enantioenriched products can be effectively derivatized to cyclic alpha-aryl ketones in good yields with good transfer of chirality. Avenues to expand the utility of this reaction have been identified and further studies are ongoing.Chapter 2 discusses the development of nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides. An intermolecular reaction proceeds in high yields for primary benzylic esters for the synthesis of pharmacologically relevant diarylmethanes. The corresponding intramolecular cyclization proceeds under mild conditions, demonstrating the first example of a stereospecific cross-electrophile coupling of secondary benzylic esters. A variety of heterocyclic and functionalized substrates are tolerated under the reaction conditions.Chapter 3 examines the development a regio- and stereoselective nickel-catalyzed hydroarylation of alkynes with arylboronic acids. The reaction is facilitated by propargyl carbamates as directing groups. The reaction is tolerant of a range of functional groups and heterocycles. Mechanistic studies reveal that the acidic protons of the arylboronic acid coupling partner serve as the origin of hydrogen. Furthermore, the synthesis of tamoxifen can be completed in two steps from a simple hydroarylation product.

Development of Stereospecific Nickel-Catalyzed Cross-Coupling Reactions

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ISBN 13 : 9781369226966
Total Pages : 575 pages
Book Rating : 4.2/5 (269 download)

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Book Synopsis Development of Stereospecific Nickel-Catalyzed Cross-Coupling Reactions by : Emily Jean Tollefson

Download or read book Development of Stereospecific Nickel-Catalyzed Cross-Coupling Reactions written by Emily Jean Tollefson and published by . This book was released on 2016 with total page 575 pages. Available in PDF, EPUB and Kindle. Book excerpt: The development of asymmetric transition-metal-catalyzed reactions has emerged as an important area of research in the past decade. Advances in the field are transforming the way chemists approach the construction of target compounds. This dissertation focuses on the expansion of stereospecific nickel-catalyzed reactions to synthesize small unnatural polyketide analogs, chiral long chain carboxylic acids, and highly substituted cyclopropanes. In the presence of an achiral nickel catalyst, a bidentate phosphine ligand, and a Grignard reagent, aryl-substituted tetrahydropyrans and tetrahydrofurans undergo a stereospecific ring-opening to afford acyclic polyketide analogs with complex stereoarrays and promising anti-cancer activity. Reactions proceed with inversion of stereochemistry at the benzylic position and are substrate controlled. Similarly, enantioenriched aryl-substituted lactones undergo a Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. The utility of this reaction was demonstrated in a two-step synthesis of an anti-dyslipidemia agent.The nickel catalyst system was employed to develop the first stereospecific reductive cross-coupling reaction. 2-Aryl-4-chlorotetrahydropyrans undergo an intramolecular ring contraction to afford highly substituted cyclopropanes. The reactions proceed with retention at the benzylic center and inversion at the alkyl halide position. Vinyl-substituted tetrahydropyrans are also amenable substrates for this transformation and afford vinylcyclopropane products with excellent control of stereochemistry. This is the first reported reductive coupling between alkyl ethers and alkyl halides and provides a new, mild synthetic route to both aryl- and vinyl-substituted cyclopropanes.

Advances in Palladium and Nickel Catalyzed Cross-Coupling Reactions

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ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (134 download)

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Book Synopsis Advances in Palladium and Nickel Catalyzed Cross-Coupling Reactions by : Ryan Sawatzky

Download or read book Advances in Palladium and Nickel Catalyzed Cross-Coupling Reactions written by Ryan Sawatzky and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Homogeneous organometallic complexes have become an indispensable tool as they are employed as catalysts for a large number of chemical transformations. Ancillary ligands, organic molecules that bind to the metal center, are critical for fine tuning the performance of these catalysts. The initial portion of this thesis describes a comparative survey of several state-of-the-art ligands for Pd catalyzed C-O cross-coupling reactions. As part of this survey two sets of conditions are employed: reactions carried out at 90 °C, using 1 mol % Pd, and room temperature reactions, using 7 mol % Pd. In these comparisons, it was found that Rockphos was the ligand of choice for reactions at room temperature, as well for electron rich electrophiles. The Josiphos variant, CyPF-tBu, was the optimal ligand for reactions at elevated temperatures, as well as for activated electrophiles. Many ligands that have found use in Pd chemistry have been repurposed for use in Ni catalysis. While this an effective strategy, it is not necessarily ideal. The bisphosphine PAd-Dalphos has been tailored for Ni catalyzed monoarylation of ammonia, and primary amines. Here, ammonium, methylamine, and ethylamine salts are successfully used as cross-coupling partners employing microwave heating. High yielding reactions, utilizing as little as 1 mol % Ni can be completed in as little as 5 minutes under these conditions. In an effort to establish trends of reactivity in Ni catalysis, the complex (DPEphos)Ni(mesityl)Br was developed for both C-N, C-C cross-coupling reactions. This complex was first established in the cross-coupling of secondary amines, and azoles with activated aryl chlorides. The observation of PhB(OH)2 required as a catalyst activator lead to the development of this complex as a catalyst for C-C cross-coupling using unstable 5-membered heterocyclic boronic acids for challenging biheteroaryl formation. Here reactions conducted at room temperature were found to be comparable to the previous state-of-the-art Ni catalysis. In addition, 3-pyridinyl-boronic acids were also successfully employed. While the scope of reactivity with such challenging substrates was modest, the work herein represents a step forward as only a small handful of examples exist for Ni catalyzed reactions.

Nickel-Catalyzed Cross-Coupling Reactions

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ISBN 13 : 9781369667578
Total Pages : 333 pages
Book Rating : 4.6/5 (675 download)

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Book Synopsis Nickel-Catalyzed Cross-Coupling Reactions by : Luke Edward Hanna

Download or read book Nickel-Catalyzed Cross-Coupling Reactions written by Luke Edward Hanna and published by . This book was released on 2016 with total page 333 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cross-coupling technology has become an indispensable tool for the rapid and efficient synthesis of complex molecules. Over the past few decades a foundational understanding of organometallic chemistry has been laid using palladium and other precious metals. Recent research on first row base metal catalysts such as nickel, cobalt and iron has uncovered new and complementary modes of reactivity compared to their more well-studied precious metal counterparts. While nickel sits one row above palladium on the periodic table, ongoing research has illustrated that nickel possesses a unique reactivity profile. Thus, while nickel is commonly thought of as a cheaper alternative to palladium, research in the field of nickel catalysis has demonstrated far more potential than this. The unique propensity of nickel to undergo single electron chemistry as well as its ability to break strong carbon oxygen bonds make research into nickel reactivity an immensely beneficial endeavor to the fields of inorganic, organometallic and synthetic organic chemistry.Chapter 1 describes the development of a stereospecific Suzuki coupling of benzylic carbamates and pivalates with aryl- and heteroarylboronic esters. The reaction proceeds with selective inversion or retention at the electrophilic carbon, depending on the identity of the ligand used. Tricyclohexylphosphine ligand provides products with retention of configuration at the electrophilic carbon, while an N-heterocyclic carbene ligand SIMes provides products with inversion.Chapter 2 discusses the development of a regio- and stereoselective nickel-catalyzed hydroarylation of alkynes using propargylic carbamates as directing groups. The reaction proceeds under mild reaction conditions using arylboronic acids in the absence of base. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the method is applied to the synthesis of tamoxifen.Chapter 3 details a nickel-catalyzed cross-electrophile coupling reaction of benzylic esters and aryl halides. Both inter- and intramolecular variants proceed under mild reaction conditions. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the first example of a stereospecific cross-electrophile coupling of a secondary benzylic ester is described.Chapter 4 presents secondary benzylzinc reagents generated from 2-pyridylcarbinols using a nickel catalyst and diethylzinc. Substrates are activated in situ using a chlorophosphate reagent. Quenching the organozinc reagents allows for facile deoxygenation of 2-pyridylcarbinols in a one-pot reaction with straightforward incorporation of a deuterium label from deuteromethanol. An intramolecular conjugate addition of a secondary benzylzinc reagent with an alpha,beta-unsaturated ester is also demonstrated.

Nickel- and Palladium-Catalyzed Cross Coupling Reactions

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ISBN 13 :
Total Pages : 183 pages
Book Rating : 4.:/5 (994 download)

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Book Synopsis Nickel- and Palladium-Catalyzed Cross Coupling Reactions by : Rebecca Green

Download or read book Nickel- and Palladium-Catalyzed Cross Coupling Reactions written by Rebecca Green and published by . This book was released on 2016 with total page 183 pages. Available in PDF, EPUB and Kindle. Book excerpt: The following dissertation discusses the development of a nickel catalyst for the synthesis of Csp2-Csp bonds in addition to the development and mechanistic studies of nickel and palladium catalysts for the synthesis of Csp2-N bonds. The first chapter is a review of the cross-coupling reactions discussed in this dissertation. Nickel and palladium will be compared with respect to physical properties and reactivity differences. The challenges associated with nickel-catalyzed cross coupling will be illustrated, while drawing analogies to analogous palladium-catalyzed reactions. The literature background for the synthesis of Csp2-Csp bonds, catalyzed by palladium and palladium/copper catalytic systems, will be reviewed, while highlighting the challenges and limitations of the field. The field of Csp2-N bond-forming reactions will be examined, as the differences in reactivity between nickel and palladium will be emphasized. Chapter 2 discusses our efforts towards the development of a nickel catalyst for the development of a Csp2-Csp bond forming reaction, performed in the absence of a copper co-catalyst. Chapter 3 describes the development of a single-component nickel complex that catalyzes the coupling of aryl chlorides with primary alkylamines. A series of mechanistic experiments, including synthesis of catalytic intermediates and kinetic experiments, were performed to elucidate the mechanism of the reaction. Chapter 4 discusses our report the palladium-catalyzed coupling of aryl halides withammonia and gaseous amines as their ammonium salts. A difference in selectivity between reactions of aryl chlorides and aryl bromides was discovered and investigated. Chapter 5 describes the development of a single-component nickel catalyst for the coupling of aryl chlorides with ammonia and ammonium sulfate to form the corresponding primary arylamines. The application of ammonium salts was extended to the coupling of gaseous amines, such as methylamine and ethylamine, which were subjected to the reaction conditions as their hydrochloride salt.

The Development of Palladium-catalyzed Cross-coupling Reactions of Allylic Silanolate Salts with Aromatic Bromides

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ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (774 download)

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Book Synopsis The Development of Palladium-catalyzed Cross-coupling Reactions of Allylic Silanolate Salts with Aromatic Bromides by : Nathan S. Werner

Download or read book The Development of Palladium-catalyzed Cross-coupling Reactions of Allylic Silanolate Salts with Aromatic Bromides written by Nathan S. Werner and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The palladium-catalyzed cross-coupling of allylic silanolate salts with a wide variety of aromatic bromides was developed. The coupling of sodium allyldimethylsilanolate and 2-butenyldimethylsilanolate required extensive optimization to deliver the expected products in high yields. The reaction of the allyldimethylsilanolate takes place at 85 °C under 0́ligand-less0́9 conditions in 1,2-dimethoxyethane with allylpalladium chloride dimer (2.5 mol %) to afford 730́395% yields of the allylation products. Both electron-rich and sterically hindered bromides reacted smoothly, whereas electron-poor bromides cross-coupled in poor yield because of a secondary isomerization to the 1-propeneyl isomer (or concommitant polymerization). A modified protocol that employs an electron-rich phosphine ligand (SPhos), a lower reaction temperature (40 °C), and a less polar solvent (toluene) delivers the expected products from electron-poor bromides without isomerization. The 2-butenyldimethylsilanolate (E/Z, 80:20) required additional optimization to maximize the formation of the branched (gamma-coupled) product and resulted in the development of two distinct protocols for gamma-selective coupling. The first protocol took advantage of a remarkable influence of added alkenes (dibenzylideneacetone and norbornadiene) and led to good selectivities for a large number of electron-rich and electron-poor bromides in 400́383% yields. However, bromides containing coordinating groups (particularly in the 2-position) gave lower, and in one case even reversed, site-selectivity. Electron-rich aromatic bromides reacted sluggishly under this protocol and led to lower product yields. The second protocol employed a sterically bulky phosphonium tetrafluoroborate salt (t-BuCy2PH+BF48́2) and resulted in 730́394% yields and excellent site-selectivity (gamma/alpha, 25:10́3>99:1) in the coupling of electron-rich, electron-poor, sterically hindered, and heteroaromatic bromides. The use of a configurationally homogeneous (Z)-silanolate and nontransferable diethyl groups were critical to achieving excellent results. A unified mechanistic picture involving initial gamma-transmetalation followed by direct reductive elimination or sigma0́3pi isomerization can rationalize all of the observed trends. The stereochemical course of palladium-catalyzed cross-coupling reactions of an enantioenriched, alpha-substituted, allylic silanolate salt with aromatic bromides was determined. The allylic silanolate salt was prepared in high geometrical (Z/E, 94:6) and high enantiomeric (94:6 er) purity by a copper-catalyzed SN20́9 reaction of a resolved carbamate. Eight different aromatic bromides underwent cross-coupling with excellent constitutional site-selectivity and excellent stereospecificity. Stereochemical correlation established that the transmetalation event proceeds through a syn SE0́9 mechanism with is interpreted in terms of an intramolecular delivery of the arylpalladium electrophile through a key intermediate that contains a discrete Si0́3O0́3Pd linkage. The catalytic, asymmetric palladium-catalyzed cross-coupling of sodium 2-butenylsilanolate with aromatic bromides was investigated. A wide range of chiral ligands including olefin, bidentate phosphine, monodentate phosphine, and cyclic and acyclic stereogenic at phosphorus ligands were evaluated. Commonly used chiral, bidentate phosphine ligands provided ineffective palladium-catalysts for the coupling of 2-butenyldimethylsilanolate with aromatic bromides. A catalyst derived from the monodentate phosphine ligand neomenthyldiphenylphosphine (20 mol %) and Pd(dba)2 (5 mol %) provided moderate enantioselectivity (75:25 er) and modest site-selectivity (5.7:1 gamma/alpha) in the coupling. Increased site-selectivity (up to>99:1) was obtained from reactions employing bulky di or trialkylphosphine ligands.

Palladium-Catalyzed Coupling Reactions

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Publisher : John Wiley & Sons
ISBN 13 : 3527648305
Total Pages : 531 pages
Book Rating : 4.5/5 (276 download)

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Book Synopsis Palladium-Catalyzed Coupling Reactions by : Árpád Molnár

Download or read book Palladium-Catalyzed Coupling Reactions written by Árpád Molnár and published by John Wiley & Sons. This book was released on 2013-02-14 with total page 531 pages. Available in PDF, EPUB and Kindle. Book excerpt: This handbook and ready reference brings together all significant issues of practical importance in selected topics discussing recent significant achievements for interested readers in one single volume. While covering homogeneous and heterogeneous catalysis, the text is unique in focusing on such important aspects as using different reaction media, microwave techniques or catalyst recycling. It also provides a comprehensive treatment of key issues of modern-day coupling reactions having emerged and matured in recent years and emphasizes those topics that show potential for future development, such as continuous flow systems, water as a reaction medium, and catalyst immobilization, among others. With its inclusion of large-scale applications in the pharmaceutical industry, this will equally be of great interest to industrial chemists. From the contents * Palladium-Catalyzed Cross-Coupling Reactions - A General Introduction * High-turnover Heterogeneous Palladium Catalysts in Coupling Reactions: the Case of Pd Loaded on Dealuminated Y Zeolites Palladium-Catalyzed Coupling Reactions with Magnetically Separable Nanocatalysts * The Use of Ordered Porous Solids as Support Materials in Palladium-Catalyzed Cross-Coupling Reactions * Coupling Reactions Induced by Polymer-Supported Catalysts * Coupling Reactions in Ionic Liquids * Cross-Coupling Reactions in Aqueous Media * Microwave-Assisted Synthesis in C-C and C-Heteroatom Coupling Reactions * Catalyst Recycling in Palladium-Catalyzed Carbon-Carbon Coupling Reactions * Nature of the True Catalytic Species in Carbon-Carbon Coupling Reactions with * Heterogeneous Palladium Precatalysts * Coupling Reactions in Continuous Flow Systems * Large-Scale Applications of Palladium-Catalyzed Couplings in the Pharmaceutical Industry

Palladium- and Nickel-catalyzed C-N Cross-coupling Reactions Featuring Soluble Organic Bases

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ISBN 13 :
Total Pages : 549 pages
Book Rating : 4.:/5 (12 download)

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Book Synopsis Palladium- and Nickel-catalyzed C-N Cross-coupling Reactions Featuring Soluble Organic Bases by : Joseph Michael Dennis (Jr.)

Download or read book Palladium- and Nickel-catalyzed C-N Cross-coupling Reactions Featuring Soluble Organic Bases written by Joseph Michael Dennis (Jr.) and published by . This book was released on 2020 with total page 549 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chapter 1: Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling Due to the low intrinsic acidity of amines, palladium-catalyzed C-N cross-coupling plagued continuously by the necessity to employ strong, inorganic, or insoluble bases. To surmount the many Due to the low intrinsic acidity of amines, palladium-catalyzed C-N crosscoupling has been practical obstacles associated with these reagents, we utilized a commercially available dialkyl triarylmonophosphine-supported palladium catalyst that facilitates a broad range of C-N coupling reactions in the presence of weak, soluble bases. The mild and general reaction conditions show extraordinary tolerance for even highly base-sensitive functional groups. Additionally, insightful heteronuclear NMR studies using −15N-labeled amine complexes provide evidence for the key acidifying effect of the cationic palladium center. Chapter 2: Pd-Catalyzed C-N Coupling Reactions Facilitated by Organic Bases: Mechanistic Investigation Leads to Enhanced Reactivity in the Arylation of Weakly Binding Amines The ability to use soluble organic amine bases in Pd-catalyzed C-N cross-coupling reactions has provided a long-awaited solution to the many issues associated with employing traditional, heterogeneous reaction conditions. However, little is known about the precise function of these bases in the catalytic cycle or about the effect of variations in base structure on catalyst reactivity. We used 19F NMR to analyze the kinetic behavior of C-N coupling reactions facilitated by different organic bases. In the case of aniline coupling reactions employing DBU, the resting state was a DBU-bound oxidative addition complex, LPd(DBU)(Ar)X, and the reaction was found to be inhibited by base. Generally, however, depending on the binding properties of the chosen organic base, increasing the concentration of the base can have a positive or negative influence on the reaction rate. Furthermore, the electronic nature of the aryl triflate employed in the reaction directly affects the reaction rate. The fastest reaction rates were observed with electronically neutral aryl triflates, while the slowest were observed with highly electron-rich and electrondeficient substrates. We propose a model in which the turnover-limiting step of the catalytic cycle is dependent on the relative nucleophilicity of the base, compared to that of the amine. This hypothesis guided the discovery of new reaction conditions for the coupling of weakly binding amines, including secondary aryl amines, which were unreactive nucleophiles in our original protocol. Chapter 3: Use of a Droplet Platform to Optimize Pd-Catalyzed C-N Coupling Reactions Promoted by Organic Bases Recent advances in Pd-catalyzed carbon-nitrogen cross-coupling have enabled the use of soluble organic bases instead of insoluble or strong inorganic bases that are traditionally employed. The single-phase nature of these reaction conditions facilitates their implementation in continuous flow systems, high-throughput optimization platforms, and large-scale applications. In this work, we utilized an automated microfluidic optimization platform to determine optimal reaction conditions for the couplings of an aryl triflate with four types of commonly employed amine nucleophiles: anilines, amides, primary aliphatic amines, and secondary aliphatic amines. By analyzing trends in catalyst reactivity across different reaction temperatures, base strengths, and base concentrations, we have developed a set of general recommendations for Pd-catalyzed crosscoupling reactions involving organic bases. The optimization algorithm determined that the catalyst supported by the dialkyltriarylmonophosphine ligand AlPhos was the most active in the coupling of each amine nucleophile. Furthermore, our automated optimization revealed that the phosphazene base BTTP can be used to facilitate the coupling of secondary alkylamines and aryl triflates. Chapter 4: The Quest for the Ideal Base: Rational Design of a Nickel Precatalyst Enables Mild, Homogeneous C-N Cross-Coupling Palladium-catalyzed amination reactions using soluble organic bases have provided a solution to the many issues associated with heterogeneous reaction conditions. Still, homogeneous C-N crosscoupling approaches cannot yet employ bases as weak and economical as trialkylamines. Furthermore, organic base-mediated methods have not been developed for Ni(0/II) catalysis, despite some advantages of such systems over analogous Pd-based catalysts. We designed a new air-stable and easily prepared Ni(II) precatalyst bearing an electron-deficient bidentate phosphine ligand that enables the cross-coupling of aryl triflates with aryl amines using triethylamine (TEA) as base. The method is tolerant of sterically-congested coupling partners, as well as those bearing base- and nucleophile-sensitive functional groups. With the aid of density functional theory (DFT) calculations, we determined that the electron-deficient auxiliary ligands decrease both the pK[subscript a] of the Ni-bound amine and the barrier to reductive elimination from the resultant Ni(II)-amido complex. Moreover, we determined that precluding Lewis acid-base complexation between the Ni catalyst and the base, due to steric factors, is important for avoiding catalyst inhibition.

Development of Iridium-catalyzed Allylation Reactions of Ketones and Imines and Nickel-catalyzed and Titanium-mediated Cross-coupling Reactions of N-chloroamines

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ISBN 13 : 9781124677385
Total Pages : 310 pages
Book Rating : 4.6/5 (773 download)

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Book Synopsis Development of Iridium-catalyzed Allylation Reactions of Ketones and Imines and Nickel-catalyzed and Titanium-mediated Cross-coupling Reactions of N-chloroamines by : Timothy James Barker

Download or read book Development of Iridium-catalyzed Allylation Reactions of Ketones and Imines and Nickel-catalyzed and Titanium-mediated Cross-coupling Reactions of N-chloroamines written by Timothy James Barker and published by . This book was released on 2011 with total page 310 pages. Available in PDF, EPUB and Kindle. Book excerpt: Transition metal catalysts have enabled many synthetically useful transformations to be developed under mild reaction conditions. Often the mild reaction conditions are a consequence of transition metals' ability to access reactive intermediates by lowering transition state energies, and in some situations the transition metal is able to reverse the polarity of a functional group. This latter type of reactivity may be referred to as umpolung reactivity. We sought to develop transition metal-catalyzed umpolung reactions to address two types of bond formations: allylation reactions of carbonyls and carbonyl derivatives and the synthesis of anilines. The allylation reaction of carbonyl and carbonyl derivatives is a synthetically useful transformation that has been studied by many research groups. Two limitations in allylation methodology that we wanted to address were that most allylation methods require the use of stoichiometric amounts of allylmetal reagents and that there is no general catalytic method for intramolecular allylation reactions. We were interested in addressing these limitations by using nucleophilic allylmetal species as catalytic reaction intermediates that could be generated in situ by oxidative addition of an allyl alcohol derivative. Nucleophilic NHC-ligated palladium complexes as catalysts were examined for the intramolecular allylation reaction of aldehydes. The palladium complexes did not promote the desired umpolung allylation reactions using allyl alcohol derivatives with reductants such as silanes and formates. Diene-ligated allyliridium catalysts were examined for the allylation of aldehydes, ketones, and aldimines. The iridium catalyst was found to be effective for the allylation of ketones and aldimines with allylboronic acid pinacol ester. Expansion of this methodology to include an iridium-catalyzed redox allylation reaction was examined. The formation of aryl-nitrogen bonds has been an active area of research due to the prevalence of anilines in pharmaceuticals, agrochemicals, and other industrial applications. We sought to develop an aniline synthesis using N-chloroamines as electrophiles, reversing the polarity of the nitrogen atom. Diarylzinc reagents were found to be competent nucleophiles for this reaction in the presence of a nickel catalyst. This reaction was found to be amenable to a one-pot reaction in which the N-chloroamine could be formed in situ. A titanium-mediated reaction between aryl Grignard reagents and N-chloroamines formed in situ was later realized that expanded the functional group tolerance and substrate scope of this transformation.

Development of Stereospecific Nickel-catalyzed Transformations of Benzylic Alcohol Derivatives

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ISBN 13 : 9781339125183
Total Pages : pages
Book Rating : 4.1/5 (251 download)

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Book Synopsis Development of Stereospecific Nickel-catalyzed Transformations of Benzylic Alcohol Derivatives by : Michael R. Harris

Download or read book Development of Stereospecific Nickel-catalyzed Transformations of Benzylic Alcohol Derivatives written by Michael R. Harris and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Transition metal catalyzed reactions are indispensable tools for the asymmetric construction of carbon–carbon bonds. Traditionally, cross-coupling reactions have relied on the use of aryl, vinyl or 1° alkyl electrophiles. Advances in asymmetric catalysis have permitted the use of 2° alkyl electrophiles in cross-coupling reactions allowing for the development of several stereoconvergent transformations. Herein, we report a complementary approach to asymmetric cross-coupling reactions by means of the development of stereospecific, nickel-catalyzed transformations of benzylic alcohol derivatives. Our initial efforts were directed toward expanding upon a Kumada cross-coupling reaction of secondary benzylic ethers with methylmagnesium iodide previously reported by the Jarvo laboratory. We extended the scope of this reaction by developing conditions to enable the use of aryl Grignard reagents for the construction of enantioenriched triarylmethanes by stereospecific nickel-catalyzed cross-coupling of diaryl methanol derivatives. The reaction proceeds in high enantiospecificity and overall inversion. This methodology is used to prepare a single enantiomer of an anti-breast-cancer agent. Further advances in our cross-coupling methodology are demonstrated in the development of a stereospecific Suzuki–Miyaura coupling of benzylic carbamates and pivolates with aryl- and heteroarylboronic esters. The reaction proceeds with selective inversion or retention at the electrophilic carbon depending on the nature of the ligand. Tricyclohexylphosphine ligand provides product with retention, while an NHC ligand provides product with inversion. The reaction proceeds in high enantiospecificity to afford either enantiomer of a variety of triarylmethanes.Taking advantage of our growing expertise in nickel catalyzed reactions of secondary alkyl electrophiles, we designed the first alkyl Heck reaction with control of stereochemistry at the electrophilic carbon. Enantioenriched methylenecyclopentanes are synthesized by stereospecific, nickel-catalyzed Heck cyclizations of secondary benzylic ethers. The reaction proceeds in high yield and enantiospecificity for benzylic ethers of both [pi]-extended and simple arenes. Ethers with pendant 1,2-disubstituted olefins form trisubstituted olefins with control of both absolute configuration and alkene geometry. The diastereoselective synthesis of a polycyclic furan is demonstrated. In the final chapter of this work, we demonstrate a nickel-catalyzed generation of secondary benzylzinc reagents from 2-pyridyl carbinols that are phosphorylated in situ. A variety of benzylzinc reagents are formed in high yield, allowing for facile hydrogenolysis of 2-pyridyl carbinols. The utility of this transformation is highlighted in a high-yielding intramolecular addition of a secondary benzylzinc reagent to an [alpha],[beta]-unsaturated ester.

Palladium and Nickel Catalyzed Transformations Forming Functionalized Heterocycles

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Publisher : Springer Nature
ISBN 13 : 3030540774
Total Pages : 236 pages
Book Rating : 4.0/5 (35 download)

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Book Synopsis Palladium and Nickel Catalyzed Transformations Forming Functionalized Heterocycles by : Hyung Yoon

Download or read book Palladium and Nickel Catalyzed Transformations Forming Functionalized Heterocycles written by Hyung Yoon and published by Springer Nature. This book was released on 2020-09-02 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents Pd- and Ni-catalyzed transformations generating functionalized heterocycles. Transition metal catalysis is at the forefront of synthetic organic chemistry since it offers new and powerful methods to forge carbon–carbon bonds in high atom- and step-economy. In Chapter 1, the author describes a Pd- and Ni-catalyzed cycloisomerization of aryl iodides to alkyl iodides, known as carboiodination. In the context of the Pd-catalyzed variant, the chapter explores the production of enantioenriched carboxamides through diastereoselective Pd-catalyzed carboiodination. It then discusses Ni-catalyzed reactions to generate oxindoles and an enantioselective variant employing a dual ligand system. Chapter 2 introduces readers to a Pd-catalyzed diastereoselective anion-capture cascade. It also examines diastereoselective Pd-catalyzed aryl cyanation to synthesize alkyl nitriles, a method that generates high yields of borylated chromans as a single diastereomer, and highlights its synthetic utility. Lastly, Chapter 3 presents a Pd-catalyzed domino process harnessing carbopalladation, C–H activation and π-system insertion (benzynes and alkynes) to generate spirocycles. It also describes the mechanistic studies performed on these reactions.

New Frontiers in Palladium-catalyzed Asymmetric Allylic Alkylations

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ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (814 download)

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Book Synopsis New Frontiers in Palladium-catalyzed Asymmetric Allylic Alkylations by : David Andrew Thaisrivongs

Download or read book New Frontiers in Palladium-catalyzed Asymmetric Allylic Alkylations written by David Andrew Thaisrivongs and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The research described in this dissertation defines two endeavors into the field of palladium-catalyzed allylic alkylation chemistry: the employment of unstabilized nitrogen-containing aromatic heterocycles as nucleophiles and the use of C--H activation to access [pi]-allyl-palladium electrophiles. With regard to the former program, we demonstrate that 2-methylpyridines, substrates whose corresponding anions are too unstabilized to react productively in palladium-catalyzed asymmetric allylic alkylation (AAA) reactions, form complexes when exposed to boron trifluoride diethyl etherate that can be deprotonated with lithium hexamethyldisilazide to afford competent nucleophiles for AAA processes. Investigations into the reaction mechanism establish that the configuration of the allylic stereocenter of the electrophile is retained, a finding that is consistent with the canonical outer sphere mechanism invoked for palladium-catalyzed allylic substitution processes of stabilized anions. We also show that under modified conditions, this protocol is applicable to the highly regio-, diastereo-, and enantioselective allylic alkylation of 2-substituted pyridines, reactions that form homoallylic stereocenters containing alkyl, aryl, heteroaryl, and nitrogen substituents. When the reaction is correspondingly performed with unsymmetric acyclic electrophiles, both linear and branched products may be obtained regio- and enantioselectively by choosing the appropriate regioisomeric starting material and ligand. We further report that this strategy extends to reactions of a variety of nitrogen-containing aromatic heterocycles, including pyrazines, pyrimidines, pyridazines, quinoxalines, benzoimidazoles, and tetrazoles. The mesityl ester, whose steric bulk prevents competitive deacylation of the electrophile from these nucleophiles, is introduced as a new leaving group in allylic alkylation chemistry. We describe the first general palladium-catalyzed allylic alkylation of 1,4-dienes that proceeds via C--H activation. A broad range of nucleophiles undergo reaction with variously substituted 1,4-dienes under relatively mild conditions, providing direct access to the corresponding 1,3-diene-containing products with high regio- and stereocontrol. This is the first catalytic allylic alkylation that proceeds via C--H activation in the absence of sulfoxide ligands, a discovery that provides for further developments in this chemistry enabled by phosphorus-based ligands. This finding is applied to a new assisted tandem catalytic process that effects sequential palladium(0)-catalyzed allylic alkylations via leaving group ionization and palladium(II)-catalyzed allylic alkylations via C--H activation. By employing an oxidative trigger to convert the initial palladium(0) species to a palladium(II) one, both transformations can be conducted in a single reaction vessel using the same precatalyst. This strategy allows for the introduction of otherwise indistinguishable allyl groups by exploiting complementary catalytic redox cycles. Finally, we detail the discovery and development of the first catalytic enantioselective palladium-catalyzed allylic C--H alkylations, an achievement made possible by a novel class of pyroglutamic-based phosphoramidite ligands. A wide array of sterically and electronically diverse allylarenes undergo allylic substitution by 2-acetyl-1-tetralones to form quaternary carbon stereocenters. Control experiments verify that this palladium-catalyzed process involves direct allylic alkylation, rather than initial allylic C--H acetoxylation. This conceptually and mechanistically distinct strategy averts many of the chemoselectivity issues inherent to traditional methods for the synthesis of enantioenriched allylic substitution products, providing the groundwork for the next generation of palladium-catalyzed allylic alkylation methods.

Stereospecific Nickel-Catalyzed Kumada-Type Cross-Coupling Reactions

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ISBN 13 : 9780355413625
Total Pages : 246 pages
Book Rating : 4.4/5 (136 download)

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Book Synopsis Stereospecific Nickel-Catalyzed Kumada-Type Cross-Coupling Reactions by : David D. Dawson

Download or read book Stereospecific Nickel-Catalyzed Kumada-Type Cross-Coupling Reactions written by David D. Dawson and published by . This book was released on 2017 with total page 246 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent years, the Jarvo lab has developed a range of stereospecific nickel-catalyzed Kumada-type cross-coupling reactions of benzylic electrophiles. This transformation allows for the facile synthesis of asymmetric Csp3 --Csp3 bonds. The focus of this dissertation is on the investigation of a new class of substrates, aryl-substituted cyclic ethers, and their reactivity in our reaction manifold. In addition, applications of this method to the pharmaceutical industry are discussed. Finally, this dissertation focuses on the determination of the active catalyst identity.First, investigations into a novel class of substrates, substituted aryltetrahydrofurans, are described. Substitution at each position of the aryltetrahydrofuran is tolerated by our reaction conditions. Aryl and alkyl Grignard reagents are successfully incorporated into our reaction manifold by use of a pre-formed nickel catalyst. Stereochemical proofs are performed on both substrates and products to confirm the stereochemical course of the reaction.Next, potential applications of our Kumada-type cross-coupling reaction to the pharmaceutical industry are described. An air-stable pre-formed nickel catalyst successfully effected a five gram scale cross-coupling reaction between an aryltetrahydropyran and methyl Grignard reagent. For the first time, isotopically-labeled Grignard reagents are tolerated by our reaction conditions, providing biologically relevant molecules containing isotopic tracers.Finally, an investigation of the active catalyst identity is discussed. Three pre-formed nickel catalysts were synthesized and characterized. These pre-formed catalysts were subjected to the reaction conditions and the product formation rate was monitored by GC assays. Spectroscopic analyses, including EPR and UV-Vis, were undertaken on both pure pre-formed catalysts and reaction mixtures. The data gathered shows an outsized effect of the cod ligand on catalyst stability, as well as the role of Grignard reagent as a reductant in solution. Ultimately, the data suggests the catalytic cycle follows a traditional Ni(0)/Ni(II) path.

Palladium-Catalyzed Mechanochemical Cross-Coupling Reactions

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Publisher : Springer Nature
ISBN 13 : 9819719917
Total Pages : 287 pages
Book Rating : 4.8/5 (197 download)

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Book Synopsis Palladium-Catalyzed Mechanochemical Cross-Coupling Reactions by : Tamae Seo

Download or read book Palladium-Catalyzed Mechanochemical Cross-Coupling Reactions written by Tamae Seo and published by Springer Nature. This book was released on with total page 287 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Stereospecific Palladium Catalyzed Cross-coupling Reactions

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ISBN 13 :
Total Pages : 322 pages
Book Rating : 4.:/5 (834 download)

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Book Synopsis Stereospecific Palladium Catalyzed Cross-coupling Reactions by : James H. Simpson

Download or read book Stereospecific Palladium Catalyzed Cross-coupling Reactions written by James H. Simpson and published by . This book was released on 1986 with total page 322 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Development and Application of Palladium-catalyzed Carbon-nitrogen Bond Forming Reactions

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ISBN 13 :
Total Pages : 280 pages
Book Rating : 4.:/5 (438 download)

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Book Synopsis Development and Application of Palladium-catalyzed Carbon-nitrogen Bond Forming Reactions by : Seble-Hiwot Teshome Wagaw

Download or read book Development and Application of Palladium-catalyzed Carbon-nitrogen Bond Forming Reactions written by Seble-Hiwot Teshome Wagaw and published by . This book was released on 1999 with total page 280 pages. Available in PDF, EPUB and Kindle. Book excerpt: