Development of Stereospecific Nickel-catalyzed Transformations of Benzylic Alcohol Derivatives
Development of Stereospecific Nickel-catalyzed Transformations of Benzylic Alcohol Derivatives

Author: Michael R. Harris

Publisher:

Published: 2015

Total Pages:

ISBN-13: 9781339125183

DOWNLOAD EBOOK

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.

Nickel Catalysis in Organic Synthesis
Nickel Catalysis in Organic Synthesis

Author: Sensuke Ogoshi

Publisher: John Wiley & Sons

Published: 2020-03-09

Total Pages: 348

ISBN-13: 3527344071

DOWNLOAD EBOOK

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.

Development of Nickel-catalyzed Stereospecific Cross-coupling Reactions
Development of Nickel-catalyzed Stereospecific Cross-coupling Reactions

Author: Buck L. H. Taylor

Publisher:

Published: 2012

Total Pages: 171

ISBN-13: 9781267652379

DOWNLOAD EBOOK

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.

Stereospecific, Nickel-catalyzed Cross-couplings of Amine and Alcohol Derived Substrates
Stereospecific, Nickel-catalyzed Cross-couplings of Amine and Alcohol Derived Substrates

Author: Kelsey M. Cobb

Publisher:

Published: 2017

Total Pages: 615

ISBN-13: 9780355252088

DOWNLOAD EBOOK

This dissertation focuses on nickel-catalyzed cross-couplings of amine and alcohol derivatives to set stereogenic centers. Chapter 1 focuses on the cross-coupling of benzylic ammonium triflates with aryl, heteroaryl, and vinyl boronic acids. This method expands the scope of previous methods from our group, utilizing Ni(cod)2 without any additional phosphine or N-heterocyclic carbene (NHC) ligands. This reaction allows for cross-coupling of both naphthyl and phenyl substituted ammonium salts. The mild conditions of this reaction displays excellent functional group tolerance. ☐ Chapter 2 focuses on the cross-coupling of benzylic ammonium triflates with bis(pinacolato)diboron to afford secondary benzylic boronates with excellent chirality transfer, This reaction utilizes Ni(cod)2 as a catalyst with either phosphine or NHC ligands. The reaction proceeds with mild reaction conditions and excellent functional group tolerance. It allows for the cross-coupling of both naphthyl and phenyl substituted ammonium salts. This is the first example of a Miyaura borylation of a non-allylic electrophile to deliver products in highly enantioenriched form. ☐ Chapter 3 describes the development of the cross-coupling of tertiary benzylic acetates to form all-carbon quaternary stereocenters. This reaction prioritizes the use of an air-stable nickel(II) catalyst and environmentally friendly 2-Me-THF. The mild reaction conditions allow for excellent functional group tolerance. The reaction provides an efficient route to both di-aryl and tri-aryl quaternary stereocenters in high stereochemical fidelity. This method shows an expansion in transition metal catalysis to go beyond electrophiles adjacent to functional groups such as carbonyls and alkenes, and displays the possibility for tertiary benzylic electrophiles to under go transition metal catalysis. ☐ Chapter 4 focuses on the cross-coupling of enantioenriched allylic pivalates with aryl and heteroaryl borxines to form allylic, all-carbon quaternary stereocenters. This utilizes an air-stable nickel (II) catalyst, and functional group tolerant boroxine coupling partners to afford these quaternary stereocenters with high stereochemical fidelity. This reaction provides a powerful way to readily access allylic quaternary stereocenters with substituted internal alkenes and a variety of functional groups and heteroatoms in high yield and enantioenrichment

Development of Stereospecific Nickel-Catalyzed Cross-Coupling Reactions
Development of Stereospecific Nickel-Catalyzed Cross-Coupling Reactions

Author: Emily Jean Tollefson

Publisher:

Published: 2016

Total Pages: 575

ISBN-13: 9781369226966

DOWNLOAD EBOOK

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.

Development of Nickel-Catalyzed Coupling Reactions
Development of Nickel-Catalyzed Coupling Reactions

Author: Mikhail Olegovich Konev

Publisher:

Published: 2017

Total Pages: 503

ISBN-13: 9780355308976

DOWNLOAD EBOOK

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.

Modern Organonickel Chemistry
Modern Organonickel Chemistry

Author: Yoshinao Tamaru

Publisher: John Wiley & Sons

Published: 2006-03-06

Total Pages: 346

ISBN-13: 3527604235

DOWNLOAD EBOOK

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.

Stereospecific Nickel-catalyzed Cross-coupling Reactions
Stereospecific Nickel-catalyzed Cross-coupling Reactions

Author: Aaron George Johnson

Publisher:

Published: 2015

Total Pages: 246

ISBN-13: 9781321846461

DOWNLOAD EBOOK

Transition metal catalyzed cross-coupling reactions have become a staple of organic synthesis and are frequently the most practical strategy for the preparation of medicinal agents and fine chemicals. Catalysts based on the precious metal palladium are commonly used in cross-coupling reactions. Replacing palladium catalysts with nickel catalysts is an active area of research as such advances present significant benefits including increasing the sustainability of transformations and new mechanisms for control of stereochemistry in the construction of Csp-Csp3 bonds. In Chapter 1, a stereospecific nickel-catalyzed cross-coupling reaction of secondary benzylic ethers with a variety of aliphatic and aryl Grignard reagents is presented. The method is highly stereospecific and proceeds with inversion at the benzylic carbon. Products prepared by this method were subject to biological testing, and a thiophene-containing product was shown to selectively inhibit the growth of MCF-7 breast cancer cells. In Chapter 2, mechanistic studies that provide insight into the mechanism of oxidative addition as well as the mechanisms of major side reactions, hydrogenolysis and Îø-hydride elimination, are presented. Experiments presented provide evidence that the mechanisms of cross-coupling, hydrogenolysis, and B-hydride elimination reactions all include a step of oxidative addition with inversion at the benzylic center. Hydrogenolysis was also shown to be stereospecific, proceeding with overall inversion at the stereogenic center. In Chapter 3, the application of nickel-catalyzed cross-coupling reactions to the synthesis of either enantiomer of a bioactive triaryl methane from a single enantiomer of a precursor alcohol is presented. In the key cross-coupling step a Kumada protocol allows for cross-coupling with inversion at the benzylic carbon, while a Suzuki reaction allows for cross-coupling with retention.

Development of Nickel-Catalyzed Cross-Coupling Reactions
Development of Nickel-Catalyzed Cross-Coupling Reactions

Author: Liana Hie

Publisher:

Published: 2016

Total Pages: 620

ISBN-13:

DOWNLOAD EBOOK

Transition metal-catalyzed cross-couplings provide a powerful means to assemble carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds. Although Pd catalysis is most commonly used in these transformations, Ni catalysis offers a valuable alternative due to the low cost and high reactivity of Ni. More importantly, Ni catalysis has proven effective for the activation of traditionally inert carbon-heteroatom bonds and therefore provides exciting opportunities with regard to chemical reactivity and synthetic applications. Chapter one, two, and three describe the development of practical cross-coupling methodologies. Chapter one explains the amination of aryl sulfamates and carbamates that relies on an air-stable Ni(II) precatalyst. Chapter two introduces the development of green cross-couplings of phenolic derivatives and aryl halides to form biaryls. Subsequently, the couplings of heterocycles, which are commonly encountered in natural product synthesis and in the pharmaceutical sector, are described. Chapter three describes the development of green cross-couplings of aryl sulfamates and chlorides to form aryl amines. Chapter four and seven concern the utility of amides as electrophilic cross-coupling partners. These traditionally unreactive moieties are activated by nickel and coupled to alcohols to form acyl C-O bonds. This study suggests that amides may serve as useful building blocks to construct carbon-carbon and carbon-heteroatom bonds. Chapter four describes the development of nickel-catalyzed activation of benzamides and chapter seven introduces the development of nickel-catalyzed activation of aliphatic amide derivatives. Chapter five describes the nickel-catalyzed activation of the acyl carbon-oxygen bonds of methyl esters through an oxidative addition process. The oxidative addition adducts, formed using nickel catalysis, undergo in situ trapping to provide anilide products. DFT calculations are used to support the proposed reaction mechanism, understand why decarbonylation does not occur competitively, and to elucidate the beneficial role of the substrate structure and Al(OtBu)3 additive on the kinetics and thermodynamics of the reaction. Chapter six focus on the nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in bioactive molecules.

Stereospecific Nickel-Catalyzed Kumada-Type Cross-Coupling Reactions
Stereospecific Nickel-Catalyzed Kumada-Type Cross-Coupling Reactions

Author: David D. Dawson

Publisher:

Published: 2017

Total Pages: 246

ISBN-13: 9780355413625

DOWNLOAD EBOOK

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.