Grignard Coupling Research Articles

4,5‐Disubstituted N‐Methylimidazoles as Versatile Building Blocks for Defined Side‐Chain Introduction

Fungerin is a 1,4,5‐trisubstituted imidazole natural product characterised by a broad spectrum of antifungal activities. We planned to develop flexible strategies to access to such compounds. Imidazoles bearing suitable anchor groups at C‐4 and C‐5 allow the introduction of various substituted side‐chains, generating libraries of fungerin derivatives for biological tests. Starting from commercially available reactants, two N‐methyl 4,5‐substituted imidazole core units were synthesised. Derivatives of type 1 contained two orthogonally protected C‐1 anchors. Selective side‐chain introduction was achieved through a sequence of Grignard coupling at C‐5 to replace a tosylate and a Horner olefination through an aldehyde attached to C‐4. Two target fungerin derivatives were synthesised. Since the organometallic substitution of the C‐5‐CH2‐positioned leaving group proved to suffer from limitations concerning potential competing side‐reactions, a type 2 imidazole core was built up. These structures had a halogen centre at C‐4 and a hydroxyethyl anchor at C‐5. Now, selective side‐chain introduction allowed us to use Julia olefination to form the allyl side‐chain at C‐5 and Heck reactions to introduce the C‐4 acryl substituents. Eight derivatives, including fungerin, were synthesised by this latter strategy, without producing any regioisomers. The second approach had the advantage that various side‐chains could be coupled at C‐4 and C‐5 in two final steps. Thus, this strategy represents a versatile way to build up libraries of fungerin derivatives for biological testing.

Dinuclear Systems in the Efficient Nickel-Catalyzed Kumada–Tamao–Corriu Cross-Coupling of Aryl Halides

Highly active dinuclear nickel(I) complexes bearing bulky N-heterocyclic carbene ligands have been shown to be involved in the catalytic cycle of the Kumada–Tamao–Corriu cross-coupling reaction of aryl halides. The results of several stoichiometric reactions and kinetics experiments have revealed that monovalent and divalent dinickel species are the active species in the highly efficient, nickel-catalyzed, Kumada coupling reactions of aryl halides.

Synthesis of ceramides NS and NP with perdeuterated and specifically ω deuterated N-acyl residues.

The synthesis of 12 deuterated ceramides with either a deuteration at the last carbon atom of the amide bound fatty acid or a perdeuterated fatty acid chain is described. The ceramides were prepared starting from sphingosine or phytosphingosine and ω deuterated or perdeuterated fatty acids with PyBOP® as activating agent in high yields. For the synthesis of the specifically deuterated fatty acids, dicarboxylic acids were transformed into ω deuterated alkyl bromide, which was chain elongated with blocked ω bromo alcohols by copper catalyzed Grignard coupling. Oxidation of regenerated alcohol function yields the ω deuterated fatty acids.

Synthesis, Structures and Conformational Studies of 1,2‐Dimethyl[2.10]metacyclophan‐1‐enes

AbstractA series of 1,2‐dimethyl[2.10]metacyclophan‐1‐enes (MCP‐1‐enes) containing different substituent groups has been synthesized to illustrate their conformational behavior. 4,22‐dimethoxy‐1,2‐dimethyl[2.10]MCP‐1‐ene 3 was synthesized by a Grignard coupling reaction, Friedel‐Crafts acylation reactions and McMurry coupling reaction from 1,10‐dibromodecane. The formation of 4,22‐dihydroxy‐1,2‐dimethyl[2.10]MCP‐1‐ene 4 was carried out by demethylation of compound 3 with boron tribromide at room temperature. The syn type conformation of 4 was characterized by X‐ray diffraction and was found to form both intramolecular and intermolecular hydrogen bonds between the two hydroxyl groups. From this reaction an interesting compound [10]tetrahydrobenzofuranophane 5 was afforded on prolonging the reaction time. 5,21‐diformyl‐4,22‐dihydroxy‐1,2‐dimethyl[2.10]MCP‐1‐ene 6 has been prepared from 4,22‐dihydroxy‐1,2‐dimethyl[2.10]MCP‐1‐ene 4 by using the Duff method in the presence of hexamethylenetetramine. Structural analysis by 1H NMR spectroscopy and X‐ray diffraction confirmed that both the solution and the crystalline state of compound 6 adopts an anti‐conformation which forms an intramolecular hydrogen bond between the formyl group and the hydroxyl group, which is an interesting finding for long carbon chain MCP compounds.

Nickel(II) complexes of amine functionalized N-heterocyclic carbenes (NHCs), synthesis and catalysis in Kumada coupling of aryl chlorides

A new amine functionalized double chelate NHC nickel complex 2 was synthesized and characterized. Complexes 4a and 4b were generated through an improved synthetic method. Catalytic ability of the three nickel complexes were tested in Kumada coupling reaction. Complex 2 showed the best catalytic activity among them. With only 0.5 mol% of complex 2, the coupling of aryl chlorides with Grignard reagents received good yields.

An N-heterocyclic carbene-based nickel catalyst for the Kumada–Tamao–Corriu coupling of aryl bromides and tertiary alkyl Grignard reagents

In this study, nickel-catalyzed coupling reactions between arylhalides and tert-alkyl Grignard reagents were developed. Our original bicyclic NHC ligands reduced the formation of isomerized products, and we found that NMP as a co-solvent suppressed the reduction process. Under the optimal conditions we developed, the catalyst loading was lowered to 0.5mol%, and catalyst loading using ortho-substituted aryl bromides was also applicable at the level of 2.0mol%.

Toward Leiodermatolide: Synthesis of the Core Structure.

The macrocyclic core (35) of the marine natural product leiodermatolide (1) was synthesized from two key fragments, vinyl iodide 23 (C1-C11 part) and vinyl stannane 31 (C12-C18 part). A Stille coupling led to conjugated Z,Z-diene 32. The derived seco acid 34 was cyclized using a Yamaguchi macrolactonization. Key steps in the assembly of vinyl iodide 23 were a Paterson aldol reaction, and a Kumada coupling on a triflate derivative to create the C4-C5 trisubstituted double bond. The two stereocenters in fragment 31 were established by a Marshall-Tamaru reaction. The longest linear sequence comprises 20 steps.

Robert Corriu (1934–2016)

Robert Corriu, professor emeritus at the Université de Montpellier, passed away at the age of 82 on February 13, 2016. Corriu made many important contributions in the area of silicon chemistry, including hypervalent silicon and transition-metal–silane complexes. He also extended his research to silicon-based (nano)materials such as hybrid organic/inorganic materials and mesoporous silicas. Robert Corriu, professor emeritus at the Université de Montpellier, passed away at the age of 82 on February 13, 2016. Corriu was an enthusiastic researcher, passionate about science, and, demanding but also both warm and straightforward in his relationships. He enjoyed most the daily discussions with his group members, as evidenced by his blackboard always crammed with chemical structures and equations. Corriu was born in Port-Vendres, close to the French–Spanish border, on June 8, 1934. After obtaining excellent grades in his studies at the Faculty of Sciences of the Université de Montpellier, he obtained his Doctorat ès Sciences in 1961 with a thesis entitled “Structure de l'acide acétique et de ses dérivés en solution dans l'acide sulfurique. Mécanisme de la C-acétylation” (Structure of acetic acid and of its derivatives in sulfuric acid. Mechanism of C-acetylation) under the guidance of André Casadevall. Meanwhile, he became assistant at the Université de Montpellier in 1957 and maître-assistant in 1961. He was promoted to associate professor at the Université de Poitiers in 1964 and full professor in 1968. In Poitiers, he headed the Laboratory of Physical Organic Chemistry, where he started to take an interest in silicon chemistry. He developed elegant studies in stereochemistry and kinetics in order to understand the specificity of nucleophilic substitution reactions at silicon, and proved the presence of five- and six-coordinate intermediates, hence opening the field of hypervalent silicon. Corriu returned to Montpellier as a full professor in 1969 and subsequently took different leading positions, including Vice-President in charge of science from 1978–1981. He became leader of the Laboratoire de Chimie des Organométalliques (Laboratory of Organometallic Chemistry), which became the French school of silicon chemistry. His work on the dynamic stereochemistry and the chemistry of hypervalent compounds has had a great impact in the field. In addition, he pioneered the chemistry of transition-metal–silane complexes with an early example of η2-silane complexes and the catalytic activation of silanes. In 1972, at the same time as Makoto Kumada, he reported a new reaction now known as the Kumada–Corriu coupling, in which a carbon–carbon bond is formed between an alkyl or aryl Grignard reagent and an alkyl or aryl halide in presence of molecular nickel catalysts. This reaction was reported at the same time as, or before related coupling reactions that led to the award of the Nobel Prize to Heck, Negishi, and Suzuki. In the mid-1980s, Corriu's research took a new direction towards silicon-based materials. In collaboration with Rhône–Poulenc, he created a research unit devoted to the synthesis of silicon-based materials for the production of fibers towards, among others, aerospace applications. This research concerned polysilanes, polycarbosilanes, and polysilazanes for the production of silicon carbides and nitrides. The group used molecular chemistry as a framework for developing new materials, and Corriu followed this approach through the 1990s and up to the end of his career, by which time he was interested in the production of materials at the nanoscale. This area includes nanostructured materials, hybrid organic/inorganic materials, and a new family of mesoporous silicas, which led to many applications in the fields of catalysis, separation, and nanomedicine. The control of materials architecture at the nanoscale by using a molecular approach, and the development of various applications, is a strong and distinctive aspect of chemistry research in Montpellier, and a legacy of Robert Corriu. Corriu published over 700 research papers and received many awards, including the “Grands Prix” both in organic (1969) and inorganic (1985) chemistry of the Société Chimique de France, the CNRS Silver Medal, and a number of international awards. He was elected to the French Académie des Sciences in 1991, and was a founding member of the French Académie des Technologies. He was also elected to the Polish Academy of Sciences in 1997. He was Officer of the Légion d'Honneur and a member of the Ordre national du Mérite, as well as Commandeur de l'Ordre des Palmes Académiques. In addition, Corriu had an encyclopedic knowledge of wine that he loved to share. The name of Robert Corriu will always be associated with silicon chemistry. He was well-known worldwide, and was held in high esteem for his inspiring leadership and the warm relationships he established. He will be sorely missed by his family, friends, and colleagues.

Self‐Assembled Multilayer‐Stabilized Nickel Nanoparticle Catalyst for Ligand‐Free Cross‐Coupling Reactions: in situ Metal Nanoparticle and Nanospace Simultaneous Organization

AbstractWe have developed a conceptually and methodologically novel self‐assembled multilayer nickel nanoparticle (NP) catalyst – sulfur‐modified gold‐supported Ni NPs (SANi) – for organic synthesis. The SANi catalyst was easily prepared through a three‐step procedure involving simultaneous in situ metal NP and nanospace organization. This unique method does not require any conventional preformed template for immobilizing and stabilizing NPs. SANi catalyzes carbon‐carbon bond‐forming cross‐coupling, Kumada coupling, and Negishi coupling reactions under ligand‐free conditions and can be used repeatedly for these reactions. Physical analysis of SANi showed that the active species in these reactions are self‐assembled multilayer zerovalent Ni NPs with a size of ∼3 nm.magnified image

Secondary Alkyl Groups in Palladium-Catalyzed Cross-Coupling Reactions

Important classes of cross-coupling reactions are those leading to the incorporation of secondary alkyl groups. While early work in cross-coupling focused mainly on primary alkyl groups, the past decade has seen significant advances in introducing secondary and tertiary groups. This review will focus on the advances made in recent years referencing landmark publications where necessary. Expansion of scope, ease of reaction setup, and mechanistic considerations will be stressed. Applications of methodologies towards complex scaffolds and natural products will be also be evaluated. 1 Introduction 2.1 Suzuki Coupling 2.2 Mizoroki–Heck Coupling 2.3 Stille Coupling 2.4 Sonagashira Coupling 2.5 Kumada Coupling 2.6 Negishi Coupling 2.7 Hiyama Coupling 2.8 Lithium Coupling 2.9 Titanium Coupling 2.10 C–H Activation 3 Conclusion

Efficient Modular Synthesis of Isomeric Mono‐ and Bispyridyl[2.2]paracyclophanes by Palladium‐Catalyzed Cross‐ Coupling Reactions

AbstractPyridyl‐substituted [2.2]paracyclophanes build a multifunctional structural motif that is useful in material chemistry, catalysis and for luminescent structures. Nonetheless, there is still a lack of general methods for the synthesis of these structures tolerating easily accessible bromides as well as different isomeric pyridyl groups. Hence the coupling of functionalized [2.2]paracyclophanes with various substituted and functionalized pyridyl derivatives was achieved using Stille, Suzuki and Kumada coupling conditions. Hereby the Stille coupling of a [2.2]paracyclophane is presented as a versatile reaction for the formation of heteromeric [2.2]paracyclophane‐containing biaryl structures.magnified image

Nickel‐catalysed Kumada polycondensation of di‐functionalized Grignard reagent with aryl fluoride

AbstractA nickel catalyst promoted the polymerization between various Grignard reagents with 2‐phenyl‐4,6‐bi(4‐fluorophenyl)‐1,3,5‐triazine. The reaction scope was thoroughly investigated and fully characterized. The Sp2‐C − F bond was successfully activated by the triazine group in Kumada coupling reactions. Also, di‐Grignard reagents showed higher activity than mono‐Grignard reagents. The reaction scope results reveal that a Grignard reagent with strong nucleophilicity and aryl fluoride with strong electrophilicity are necessary to lead to Kumada polycondensation of oligothiophenes with aryl fluoride. In this work, polymerization between di‐functionalized oligothiophene Grignard reagents with aryl fluoride was first conducted. The weight‐average molecular weight is high, up to 14.8 kDa. The π‐conjugated polymers obtained exhibit emission colours of blue, green and yellow with efficient photoluminescence. © 2016 Society of Chemical Industry

Synthesis and Reactivity of N-Heterocyclic PSiP Pincer Iron and Cobalt Complexes and Catalytic Application of Cobalt Hydride in Kumada Coupling Reactions

The new N-heterocyclic σ-silyl pincer ligand HSiMe(NCH2PPh2)2C6H4 (1) was designed. A series of tridentate silyl pincer Fe and Co complexes were prepared. Most of them were formed by chelate-assisted Si–H activation. The typical iron hydrido complex FeH(PMe3)2(SiMe(NCH2PPh2)2C6H4) (2) was obtained by Si–H activation of compound 1 with Fe(PMe3)4. The combination of compound 1 with CoMe(PMe3)4 afforded the Co(I) complex Co(PMe3)2(SiMe(NCH2PPh2)2C6H4) (3). The Co(III) complex CoHCl(PMe3)(SiMe(NCH2PPh2)2C6H4) (5) was generated by the reaction of complex 1 with CoCl(PMe3)3 or the combination of complex 3 with HCl. However, when complex 3 was treated with MeI, the Co(II) complex CoI(PMe3)(SiMe(NCH2PPh2)2C6H4) (4), rather than the Co(III) complex, was isolated. The catalytic performance of complex 5 for Kumada coupling reactions was explored. With a catalyst loading of 5 mol %, complex 5 displayed efficient catalytic activity for Kumada cross-coupling reactions of aryl chlorides and aryl bromides with Grignard r...

Half-sandwich nickel complexes with ring-expanded NHC ligands - synthesis, structure and catalytic activity in Kumada-Tamao-Corriu coupling.

The general synthesis of [Ni(Cp)(X)(NHC)] complexes from a nickel halide, CpLi, and a carbene solution is reported. This procedure yields unprecedented complexes with ring-expanded NHC ligands (RE-NHC) of six- (1a, 1b), seven- (1c), and eight-membered (1d) heterocycles. The NMR spectra of 1a-1d are consistent with the hindered rotation of Ni-Ccarbene and N-CMes bonds, while X-ray analyses of 1b, 1c, and 1d reveal a pronounced trans influence of the RE-NHC ligands. Complexes 1a-1e are efficient pre-catalysts in Kumada-Tamao-Corriu coupling with the maximum efficiency observed for complexes bearing the six-membered NHC.

ChemInform Abstract: A Historic Overview of the Metal‐Catalyzed Cross‐Coupling Reactions.

The main focus of this publication is the innovation of new synthetic reactions that can form various carbon–carbon bonds with high selectivity. The use of transition-metal-catalyzed cross-coupling reactions of organic electrophiles with organometallic nucleophiles started with the discovery of Kumada–Tamao–Corriu coupling in 1972—the reaction of organic halides and organomagnesium compounds under nickel catalysis. Combining fragments with a series of carbon centers into one segment, the transition-metal-catalyzed cross-coupling reactions have long been industrially utilized toward the synthesis of functional materials such as agricultural chemicals, pharmaceuticals, and polymers.

Ohmic Heating and Ionic Liquids in Combination for the Indium‐Promoted Synthesis of 1‐Halo Alkenyl Compounds: Applications to Pd‐Catalysed Cross‐Coupling Reactions

AbstractWe have explored the combination of ohmic heating (ΩH) with ionic liquids for indium‐promoted reactions and report herein the indium‐promoted dehalogenation of gem‐dibromo alkenes and the indium‐mediated reductive elimination of chlorohydrins for the synthesis of 1‐halo alkenyl derivatives. Heck, Stille, Suzuki, Kumada and Sonogashira couplings of the resulting 1‐halo‐1‐alkenes with appropriate reagents were carried out to give alkenes, dienes and enynes.

Asymmetric Catalysis with Ethylene. Synthesis of Functionalized Chiral Enolates.

Trialkylsilyl enol ethers are versatile intermediates often used as enolate surrogates for the synthesis of carbonyl compounds. Yet there are no reports of broadly applicable, catalytic methods for the synthesis of chiral silyl enol ethers carrying latent functionalities useful for synthetic operations beyond the many possible reactions of the silyl enol ether moiety itself. Here we report a general procedure for highly catalytic (substrate:catalyst ratio up to 1000:1) and enantioselective (92% to 98% major enantiomer) synthesis of such compounds bearing a vinyl group at a chiral carbon at the β-position. The reactions, run under ambient conditions, use trialkylsiloxy-1,3-dienes and ethylene (1 atm) as precursors and readily available (bis-phosphine)-cobalt(II) complexes as catalysts. The silyl enolates can be readily converted into novel enantiopure vinyl triflates, a class of highly versatile cross-coupling reagents, enabling the syntheses of other enantiomerically pure, stereodefined trisubstituted alkene intermediates not easily accessible by current methods. Examples of Kumada, Stille, and Suzuki coupling reactions are illustrated.

Newly-generated Al(OH)3-supported Pd nanoparticles-catalyzed Stille and Kumada coupling reactions of diazonium salts, (Het)aryl chlorides

A ligand-free Pd/Al(OH)3 nano-catalyst which is prepared by one-pot three-component method using Pd(PPh3)4, tetra (ethylene glycol), and aluminum tri-sec-butoxide exhibits excellent catalytic activity in Stille cross-couplings of (Het)aryl chlorides, arenediazonium tetrafluoroborate salts with phenyltributylstannane, respectively, and Kumada couplings of (Het)aryl chlorides with various Grignard reagents. More importantly, these two processes show excellent functional group compatibility with moderate to good yields and they are also versatile with respect to not only (Het)aryl chlorides, but also diazonium salts, and heteroaryl Grignard reagents. The nano-catalyst could also be recycled and reused 5 times without loss of activity and decrease of yield.

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers and esters.

ConspectusThis Account presents the development of a suite of stereospecific alkyl–alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal.The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination.Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details.Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent.

Preparation and synthetic value of π-bond-rich branched hydrocarbons.

The two simplest branched acyclic structures comprising only conjugated C═C units, namely, [3]dendralene (3-methylene-1,4-pentadiene) and [4]dendralene (3,4-dimethylene-1,5-hexadiene), were first reported in 1955 and 1962, respectively. No higher members of the series were described in the literature until 2000. This Account describes the modern phase of dendralene chemistry, driven to a large extent by research performed within the author's group. The first synthesis of the parent dendralene family allowed access to the hydrocarbons in batches of up to 5 mg. The synthetic approach took into account the prevailing dogma of the time, specifically that these compounds would be very reactive species and hence difficult to handle in the laboratory. As such, a route involving the cheleotropic elimination of SO2 from stable, and generally insoluble, 3-sulfolene-masked precursors was devised. Our second-generation approach was of significantly higher value in preparative terms, allowing the syntheses of the first six members of the unsubstituted [n]dendralenes (i.e., n = 3-8) directly, on scales of hundreds of milligrams to decagrams, using commercially available precursors and standard laboratory equipment and methods. This work demonstrated that the assumed high reactivity and instability this family of compounds was erroneous and ultimately led to the development of syntheses of structurally related cross-conjugated systems including substituted dendralenes, tetravinylethylene, 1,1-divinylallene, and furan-containing analogues of the dendralenes. Cross-coupling reactions feature strongly in the syntheses of these compounds, and methods involving single- to multifold Stille, Kumada, and Negishi couplings are mainstays of this work. The even parity [n]dendralenes were shown to exhibit enhanced stability over the odd parity congeners, a result that can be attributed to conformational effects. π-Bond-rich branched hydrocarbons are demonstrated to have significant value in the rapid generation of structural complexity. Pericyclic processes are particularly useful in this regard, with the dendralenes and their relatives serving as multidienes, participating in diene-transmissive cycloaddition sequences, sometimes in combination with electrocyclizations, to generate fused and bridged multicyclic systems containing many new covalent bonds. The outcomes of exploratory investigations into pericyclic sequences involving dendralenes are presented, along with methods developed to control chemoselectivity, regioselectivity, and stereoselectivity. Distinct from their use in diene-transmissive sequences, the dendralenes also serve as multialkenes, for the direct synthesis of polyols and oligo-cyclopropanes. Finally, the deployment of π-bond-rich branched hydrocarbons in the shortest total synthesis of a pseudopterosin natural product is summarized, as a prelude to future prospects in the areas of hydrocarbon chemistry and target synthesis.