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Author: Lucas William Erickson Publisher: ISBN: 9780355307122 Category : Languages : en Pages : 321
Book Description
In recent years, the Jarvo lab has developed the field of stereospecific nickel-catalyzed cross-coupling reactions of benzylic electrophiles. This chemistry allows for straightforward synthesis of asymmetric C--C bonds. The focus of this dissertation is on the study of the mechanism of these transformations, and the development of reductive cross-electrophile coupling reactions.First, the mechanism of the nickel-catalyzed Kumada cross-coupling reaction was studied via a 13C kinetic isotope effect experiment. This experiment indicated that oxidative addition of the nickel catalyst into the C--O sigma bond was the rate limiting step. Combining this data with a rate law allowed us to propose a catalytic cycle for this reaction. Additionally, the nickel-catalyzed deoxygenation of benzylic ethers was optimized for the formation of diaryl methanes. Deoxygenation performed best with a proton-rich Grignard reagent. We demonstrated that these Grignard reagents act as the hydride source for the reduction reaction.Next, an intramolecular nickel-catalyzed reductive cross-electrophile coupling reaction of benzylic ethers and alkyl chlorides was developed. This reaction proceeds with a variety of extended aromatic and heteroaromatic groups to produce cyclopropane rings in great yields and diastereoselectivity. This is the first example of a stereospecific reductive cross-electrophile coupling reaction, as well as the first to employ alkyl ethers and alkyl halides as the electrophiles.Finally, the work on nickel-catalyzed reductive cross-electrophile coupling reactions was expanded to synthesize vinylcyclopropanes from allylic ethers and alkyl halides. This reaction occurs with both alkyl fluorides and alkyl chlorides. To the best of our knowledge, this is the first reported cross-electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds with high stereospecificity, providing selective synthesis of either diastereomer of di- and tri-substituted cyclopropanes. The utility of this methodology is demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl cyclopropanes.
Author: Lucas William Erickson Publisher: ISBN: 9780355307122 Category : Languages : en Pages : 321
Book Description
In recent years, the Jarvo lab has developed the field of stereospecific nickel-catalyzed cross-coupling reactions of benzylic electrophiles. This chemistry allows for straightforward synthesis of asymmetric C--C bonds. The focus of this dissertation is on the study of the mechanism of these transformations, and the development of reductive cross-electrophile coupling reactions.First, the mechanism of the nickel-catalyzed Kumada cross-coupling reaction was studied via a 13C kinetic isotope effect experiment. This experiment indicated that oxidative addition of the nickel catalyst into the C--O sigma bond was the rate limiting step. Combining this data with a rate law allowed us to propose a catalytic cycle for this reaction. Additionally, the nickel-catalyzed deoxygenation of benzylic ethers was optimized for the formation of diaryl methanes. Deoxygenation performed best with a proton-rich Grignard reagent. We demonstrated that these Grignard reagents act as the hydride source for the reduction reaction.Next, an intramolecular nickel-catalyzed reductive cross-electrophile coupling reaction of benzylic ethers and alkyl chlorides was developed. This reaction proceeds with a variety of extended aromatic and heteroaromatic groups to produce cyclopropane rings in great yields and diastereoselectivity. This is the first example of a stereospecific reductive cross-electrophile coupling reaction, as well as the first to employ alkyl ethers and alkyl halides as the electrophiles.Finally, the work on nickel-catalyzed reductive cross-electrophile coupling reactions was expanded to synthesize vinylcyclopropanes from allylic ethers and alkyl halides. This reaction occurs with both alkyl fluorides and alkyl chlorides. To the best of our knowledge, this is the first reported cross-electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds with high stereospecificity, providing selective synthesis of either diastereomer of di- and tri-substituted cyclopropanes. The utility of this methodology is demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl cyclopropanes.
Author: Mikhail Olegovich Konev Publisher: ISBN: 9780355308976 Category : Languages : en Pages : 503
Book Description
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.
Author: Luke Edward Hanna Publisher: ISBN: 9781369667578 Category : Languages : en Pages : 333
Book Description
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.
Author: Sensuke Ogoshi Publisher: John Wiley & Sons ISBN: 3527344071 Category : Science Languages : en Pages : 348
Book Description
A comprehensive reference to nickel chemistry for every scientist working with organometallic catalysts Written by one of the world?s leading reseachers in the field, Nickel Catalysis in Organic Synthesis presents a comprehensive review of the high potential of modern nickel catalysis and its application in synthesis. Structured in a clear and assessible manner, the book offers a collection of various reaction types, such as cross-coupling reactions, reactions for the activation of unreactive bonds, carbon dioxide fixation, and many more. Nickel has been recognized as one of the most interesting transition metals for homogeneous catalysis. This book offers an overview to the recently developed new ligands, new reaction conditions, and new apparatus to control the reactivity of nickel catalysts, allowing scientists to apply nickel catalysts to a variety of bond-forming reactions. A must-read for anyone working with organometallic compounds and their application in organic synthesis, this important guide: -Reviews the numerous applications of nickel catalysis in synthesis -Explores the use of nickel as a relatively cheap and earth-abundant metal -Examines the versatility of nickel catalysis in reactions like cross-coupling reactions and CH activations -Offers a resource for academics and industry professionals Written for catalytic chemists, organic chemists, inorganic chemists, structural chemists, and chemists in industry, Nickel Catalysis in Organic Synthesis provides a much-needed overview of the most recent developments in modern nickel catalysis and its application in synthesis.
Author: Emily Jean Tollefson Publisher: ISBN: 9781369226966 Category : Languages : en Pages : 575
Book Description
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.
Author: Yoshinao Tamaru Publisher: John Wiley & Sons ISBN: 3527604235 Category : Science Languages : en Pages : 346
Book Description
Organonickel chemistry plays an increasingly important role in organic chemistry, and interest in this topic is now just as keen as in organopalladium chemistry. While there are numerous, very successful books on the latter, a book specializing in organonickel chemistry is long overdue. Edited by one of the leading experts in the field, this volume covers the many discoveries made over the past 30 years, and previously scattered throughout the literature. Active researchers working at the forefront of organonickel chemistry provide a comprehensive review of the topic, including cross-coupling reactions, asymmetric synthesis and heterogeneous catalysis reaction types. A must-have for both organometallic chemists and synthetic organic chemists.
Author: Buck L. H. Taylor Publisher: ISBN: 9781267652379 Category : Languages : en Pages : 171
Book Description
Transition-metal catalyzed cross-coupling reactions are powerful methods for the synthesis of natural products and medicinal compounds. Cross-coupling reactions of secondary alkyl electrophiles are currently more challenging than those of aryl or vinyl halides, but these reactions enable the construction of tertiary stereogenic centers with control of configuration. Several methods have been reported for the stereoconvergent cross-coupling of alkyl halides using chiral nickel catalysts. Herein, we report the development of a stereospecific cross-coupling reaction of enantioenriched benzylic ethers using achiral nickel catalysts. We initially performed mechanistic studies to determine the stereochemical course of established nickel-catalyzed cross-coupling reactions. A deuterium-labeled alkylborane reagent was used to establish that transmetalation from boron to nickel occurs with retention of configuration. In addition, these studies establish that alkylnickel intermediates are stereochemically stable under these cross-coupling conditions. A stereospecific cross-coupling reaction of benzylic ethers with alkyl Grignard reagents has been developed. Enantioenriched benzylic ethers, derivatives of easily synthesized chiral secondary alcohols, undergo cross-coupling with high enantiospecificity using an achiral nickel catalyst. The method was applied to the asymmetric synthesis of a biologically active diarylethane, a common structural motif in medicinally relevant compounds. Initial mechanistic studies are consistent with a rate-limiting oxidative addition that is facilitated by a magnesium Lewis-acid. The cross-coupling method has been extended to include aryl Grignard reagents for the asymmetric synthesis of triarylmethanes. The reaction proceeds in high enantiospecificity and employs an ether leaving group capable of chelating to magnesium ions. The method was applied to the asymmetric synthesis of an anti-breast-cancer agent.
Author: Arkaitz Correa Publisher: Springer ISBN: 3319497847 Category : Science Languages : en Pages : 342
Book Description
The series Topics in Current Chemistry Collections presents critical reviews from the journal Topics in Current Chemistry organized in topical volumes. The scope of coverage is all areas of chemical science including the interfaces with related disciplines such as biology, medicine and materials science. The goal of each thematic volume is to give the non-specialist reader, whether in academia or industry, a comprehensive insight into an area where new research is emerging which is of interest to a larger scientific audience. Each review within the volume critically surveys one aspect of that topic and places it within the context of the volume as a whole. The most significant developments of the last 5 to 10 years are presented using selected examples to illustrate the principles discussed. The coverage is not intended to be an exhaustive summary of the field or include large quantities of data, but should rather be conceptual, concentrating on the methodological thinking that will allow the non-specialist reader to understand the information presented. Contributions also offer an outlook on potential future developments in the field.
Author: Yasushi Nishihara Publisher: Springer Science & Business Media ISBN: 3642323685 Category : Science Languages : en Pages : 247
Book Description
“Applied Cross-Coupling Reactions” provides students and teachers of advanced organic chemistry with an overview of the history, mechanisms and applications of cross-coupling reactions. Since the discovery of the transition-metal-catalyzed cross-coupling reactions in 1972, numerous synthetic uses and industrial applications have been developed. The mechanistic studies of the cross-coupling reactions have disclosed that three fundamental reactions: oxidative addition, transmetalation, and reductive elimination, are involved in a catalytic cycle. Cross-coupling reactions have allowed us to produce a variety of compounds for industrial purposes, such as natural products, pharmaceuticals, liquid crystals and conjugate polymers for use in electronic devices. Indeed, the Nobel Prize for Chemistry in 2010 was awarded for work on cross-coupling reactions. In this book, the recent trends in cross-coupling reactions are also introduced from the point of view of synthesis design and catalytic activities of transition-metal catalysts.
Author: Seoyoung Kim (Ph.D.) Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
Cross-coupling is one of the most commonly used reactions in synthetic chemistry. While palladium-catalyzed cross-coupling is well-developed and established, cross-electrophile coupling is significantly younger field of study. In this approach two carbon electrophiles are directly coupled under reductive conditions, avoiding the need to prepare organometallic reagents. This is an attractive strategy because these reactions proceed through mild conditions, have high functional group tolerance, and employ readily available coupling partners. Nickel-catalyzed cross-electrophile couplings have seen considerable success in the past decade, initially in the coupling of organic iodides and later organic bromides. Despite these advances, the cross-coupling with the more abundant and inexpensive organic chlorides remain elusive due to their low reactivity. Furthermore the nickel-catalyzed cross-coupling of aryl triflates presents analogous challenges due to their differential reactivity. This thesis presents our studies to address these limitations. Through a combination of: (1) new ligand application, (2) fine tuning of alkyl electrophile reactivity through in situ halide exchange, (3) detailed mechanistic investigation of elementary steps, we demonstrate the nickel-catalyzed cross-electrophile coupling of these traditionally inert organic coupling partner. This dissertation is presented as follows: Chapter 1 is an introduction to cross-coupling strategies. Common palladium-catalyzed cross-coupling methods are discussed and their origin of cross-selectivity is highlighted. This is contrasted to cross-electrophile approaches of which mechanism is less well-understood. Early reports on nickel-catalyzed cross-electrophile coupling are presented and how mechanistic studies have elucidated the origin of cross-selectivity in these processes. Finally, the challenges of applying aryl chlorides in these first generation approaches are briefly discussed. Chapter 2 describes the development of nickel-catalyzed cross-electrophile coupling of aryl chlorides with primary alkyl chlorides to form C(sp2)-C(sp3) bonds. Investigation of ligands on selectivity and in situ halide exchange on the activation of C(sp3)-Cl bonds are detailed. Chapter 3 discusses a strategy for nickel-catalyzed cross-electrophile coupling of aryl triflates with alkyl halides. The development of reaction conditions for differing aryl electronics and mechanistic insights are described in detail. Mechanistically driven optimization and the extent of halide exchange to modulate alkyl halide reactivity are also discussed.
Author: Lucas William Erickson
Author: Lucas William Erickson
Author: Mikhail Olegovich Konev
Author: Luke Edward Hanna
Author: Sensuke Ogoshi
Author: Emily Jean Tollefson
Author: Yoshinao Tamaru
Author: Buck L. H. Taylor
Author: Arkaitz Correa
Author: Yasushi Nishihara
Author: Seoyoung Kim (Ph.D.)