Grignard Reagents Research Articles

Chemoselective Preparation of Alkynes from Vicinal and Geminal Dibromoalkenes.

The reductive conversion of vicinal and geminal dibromoalkenes into the corresponding alkynes with iPrMgCl-LiCl (Turbo Grignard reagent) is described. This reaction proceeded in the presence of various functional groups such as ethers, esters, or carbamates under mild conditions in high yields. Due to the selective reactivity, the easily prepared vic-dibromoalkene is considered to be a protecting group of alkyne toward an electrophile. Although butyl lithium has been widely used for the conversion of gem-dibromoalkenes into alkynes in the Corey-Fuchs alkyne synthesis, we report here alternative mild and chemoselective reaction conditions for alkyne synthesis.

Co-Catalyzed Suzuki-Miyaura Coupling of Organoboronic Acids and Alkynyl Chlorides Using Potassium Bicarbonate as Base.

Organoboronic acids, some of the most common and widely used organoboron compounds, have not yet been used in the cobalt-catalyzed cross coupling reactions, despite cobalt demonstrating good reactivity with zinc reagents, Grignard reagents, and metal organoborates that are formed by n-butyl lithium or alkaline metal alkoxide salts and organoboron esters. Herein, a highly efficient and practical cobalt-catalyzed coupling reaction of aryl/alkenyl boronic acids and alkynyl chloride under mild reaction conditions is reported. The advantages of the organoboronic acids, along with a broad functional group compatibility and the reaction's tolerance to moisture and air, enable this reaction to be a synthetically useful protocol for the construction of a C(sp2)-C(sp) bond. Lastly, the synthesis of two natural products and a key intermediate of roxadustat was effectively accomplished using the methodology to construct the critical alkynyl-aryl bond.

New Method for the Synthesis of 1,3-Diallyl-1,1,3,3-tetramethyldisiloxane

A new method for the synthesis of 1,3-diallyl-1,1,3,3-tetramethyldisiloxane is proposed that includes several steps: the synthesis of dicellosolvoxy(dimethyl)silane by the transesterification reaction followed by obtaining allyl(cellosolvoxy)dimethylsilane from it under the action of the Grignard reagent and its condensation. The resulting product was characterized by 1H, 13C, and 29Si NMR spectroscopy as well as gas-liquid chromatography. The yield of the product was more than 90%, its purity was 99%.

Total Synthesis of (-) and (+)-Zingibergingerols A.

The first total synthesis of both of the enantiomers of Zingibergingerol A has been accomplished. The distinctive 3,7,9-trioxabicyclo[4.2.1]nonane skeleton is crafted through gold-catalyzed alkynol cycloisomerization. The synthesis comprises sequential C-C bond formations at both ends of epichlorohydrin: first opening the epoxide with eugenol-derived alkyne, followed by subsequent epoxide installation, and again opening with a Grignard reagent. The resulting alkynol with a fixed C5 stereochemistry was subjected to O-allylation, followed by dihydroxylation and alkynol cycloisomerization.

Reductive C(sp2)–Si Cross‐Couplings by Catalytic Sodium‐Bromine Exchange

The metal‐halogen exchange reaction constitutes one of the most important preparative routes towards polar organometallic reagents such as aryllithium or Grignard reagents. However, despite extensive developments over the past eight decades, this fundamental organometallic elementary step has only been exploited stoichiometrically. Against this background, we demonstrate that the sodium‐bromine exchange reaction can be implemented in a catalytic setting as a mean to activate C(sp2)–Br bonds in a transition metal‐free manner en route to the regioselective and general preparation of (hetero)aryl silanes. Simply treating structurally diverse (hetero)aryl bromides with N‐tert‐butyl‐N’‐silyldiazenes (tBu–N=N–Si) as silylating reagents and inexpensive sodium alkoxides as catalytic promoters yields a range of aromatic organosilicon compounds under ambient conditions. Mechanistic studies provide solid evidence for the involvement of tert‐butyl sodium as the C(sp2)–Br metalating agent.

Reductive C(sp2)–Si Cross‐Couplings by Catalytic Sodium‐Bromine Exchange

The metal‐halogen exchange reaction constitutes one of the most important preparative routes towards polar organometallic reagents such as aryllithium or Grignard reagents. However, despite extensive developments over the past eight decades, this fundamental organometallic elementary step has only been exploited stoichiometrically. Against this background, we demonstrate that the sodium‐bromine exchange reaction can be implemented in a catalytic setting as a mean to activate C(sp2)–Br bonds in a transition metal‐free manner en route to the regioselective and general preparation of (hetero)aryl silanes. Simply treating structurally diverse (hetero)aryl bromides with N‐tert‐butyl‐N’‐silyldiazenes (tBu–N=N–Si) as silylating reagents and inexpensive sodium alkoxides as catalytic promoters yields a range of aromatic organosilicon compounds under ambient conditions. Mechanistic studies provide solid evidence for the involvement of tert‐butyl sodium as the C(sp2)–Br metalating agent.

Iron‐Catalyzed Reductive Coupling of Nitro Compounds with Grignard and Organozinc Reagents for Synthesis of Functionalized Secondary Amines

The treatment of nitro compounds with Grignard reagents in the presence of a catalytic amount of FeCl<sub>2</sub>/4 <i>t</i>‐BuMgCl produced various types of secondary amines in good yields. This reductive coupling most likely involves the compatibility of functional groups such as chlorine, benzyl ether, olefin, and acetylene. Moreover, the corresponding poly‐substituted amines were not observed under these conditions. When the Grignard reagents were replaced with organozinc reagents, functionalized secondary amines containing ester and nitrile groups were obtained in good yields.

Nickel‐Catalyzed Reductive Protocol to Access Silacyclobutanes with Unprecedented Functional Group Tolerance

AbstractWhile significant progress has been made in the area of transition metal‐catalyzed ring‐opening and formal cycloaddition reactions of 1,1‐disubstituted silacyclobutanes (SCBs), synthesizing these SCBs—particularly those bearing additional functional groups—continues to present synthetic challenges. In this context, we present a novel Ni‐catalyzed reductive coupling reaction that combines 1‐chloro‐substituted silacyclobutanes with aryl or vinyl halides and pseudohalides, thereby obviating the need for organometallic reagents. This method facilitates the generation of 1,1‐disubstituted silacyclobutanes with a remarkable tolerance for various functional groups. This approach serves as a complementary and more step‐economical alternative to the commonly used yet moisture‐ and air‐sensitive nucleophilic substitution reactions involving Grignard or lithium reagents. Our initial mechanistic studies indicate that this reaction is initiated by oxidative cleavage of the Si−Cl bond in 1‐chlorosilacyclobutanes, which represents a distinct mechanism from the previously documented reductive coupling processes involving carbon electrophiles and chlorosilanes.

Nickel-Catalyzed Reductive Protocol to Access Silacyclobutanes with Unprecedented Functional Group Tolerance.

While significant progress has been made in the area of transition metal-catalyzed ring-opening and formal cycloaddition reactions of 1,1-disubstituted silacyclobutanes (SCBs), synthesizing these SCBs-particularly those bearing additional functional groups-continues to present synthetic challenges. In this context, we present a novel Ni-catalyzed reductive coupling reaction that combines 1-chloro-substituted silacyclobutanes with aryl or vinyl halides and pseudohalides, thereby obviating the need for organometallic reagents. This method facilitates the generation of 1,1-disubstituted silacyclobutanes with a remarkable tolerance for various functional groups. This approach serves as a complementary and more step-economical alternative to the commonly used yet moisture- and air-sensitive nucleophilic substitution reactions involving Grignard or lithium reagents. Our initial mechanistic studies indicate that this reaction is initiated by oxidative cleavage of the Si-Cl bond in 1-chlorosilacyclobutanes, which represents a distinct mechanism from the previously documented reductive coupling processes involving carbon electrophiles and chlorosilanes.

Iron‐N,N,N’,N’‐Tetramethylethylenediamine‐Catalyzed Selective Substitution of Functionalized Diene and Triene Monoepoxides with Aliphatic Grignard Reagents

AbstractWhen γ,δ‐epoxy‐α,β‐unsaturated esters were treated with 3 equiv. of aliphatic Grignard reagents in the presence of 10 and 20 mol% FeCl2 and N,N,N’,N’‐tetramethylethylenediamine, regio‐ and stereoselective substitution of the epoxide moiety with the aliphatic Grignard reagent occurred, producing exclusively δ‐hydroxy‐γ‐alkyl‐α,β‐unsaturated esters. Similarly, γ,δ‐epoxy‐α,β,ϵ,ζ‐unsaturated esters and amides underwent transformation to the corresponding δ‐hydroxy‐γ‐alkyl‐α,β,ϵ,ζ‐unsaturated esters and amides as single isomers, respectively.

Cobalt-Catalyzed Three-Component Alkyl Arylation of Acrylates with Alkyl Iodides and Aryl Grignard Reagents.

A highly regioselective cobalt-catalyzed three-component alkyl arylation of acrylates with alkyl iodides and aryl Grignard reagents has been established. The reaction efficiently provides an alternative strategy for the construction of α-aryl esters with a broad substrate scope and good yields under mild conditions. The practical applicability of this protocol is shown by the scaled-up reaction and further transformations of the products. In addition, the preliminary mechanistic explorations demonstrated that the alkyl radicals generated by the efficient cobalt catalysis are instantaneously added to the acrylates to finally afford the desired products.

Reductive‐Transmetalation Reactions of ZnR2/(AlCp*)4 Heterobimetallic Combinations and Application Towards CO2 Insertion

AbstractOrgano‐aluminum compounds are usually derived via salt metathesis reactions starting from aluminum halides and s‐block organometallics such as organolithiums or Grignard reagents. Herein, an alternative route is reported using an Cp*Al(I)/Zn(II)R2 (Cp* = C5Me5; R = aryl) system which facilitates the formation of a range of halide and donor free heteroleptic triorgano‐alanes of the general formula [Al(Cp*)R2]. Exposing the obtained alanes to an atmosphere of CO2 enables for the selective insertion of CO2 in their AlCp* moieties. State of the art quantum chemical calculations support experimental observations providing mechanistic insights on the observed reactivity of the [Al(Cp*)R2] compounds towards this unsaturated organic molecule.

Ring-Opening Reactions of Imidazolidines and Hexahydropyrimidines with Grignard Reagents.

We herein report an unprecedented ring-opening of unstrained cyclic aminals such as imidazolidines and hexahydropyrimidines by the use of Grignard and cuprate reagents to give secondary sulfonamides bearing diversely substituted tertiary amines in the β- or γ-position. This synthetic procedure can be carried out in a one-pot fashion without collateral reactions that are commonly associated with sp3-organometallic multicomponent Mannich-type reactions, indicating the fundamental role of sulfonamide protection of the second nitrogen atom in the generation of the cyclic aminal and in the ring-opening process. Computational density functional theory (DFT) data point to the formation of a transient iminium ion intermediate, in which the Lewis acidity of the cationic component of the organometallic reagent triggers the ring-opening process by coordination. The presented method allows the nucleophilic decoration of diamines including those bearing an adjacent chiral center to the tertiary amine not easily achievable by means of alternative standard synthetic procedures.

Nickel-Catalyzed Cross-Coupling of Cyclic Sulfones and Grignard Reagents

Nickel-Catalyzed Cross-Coupling of Cyclic Sulfones and Grignard Reagents

Modular Synthesis of Heterobenzylic Amines via Carbonyl Azinylative Amination.

Transformations enabling the synthesis of α-alkyl, α'-2-azinyl amines by addition of 2-heteroaryl-based nucleophiles to in situ-generated and non-activated alkyl-substituted iminium ions are extremely rare. Approaches involving classical 2-azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2-azinyl indium nucleophile, generated in situ from the corresponding 2-iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction. This modular carbonyl azinylative amination (CAzA) displays a broad scope and only a metal reductant is needed to generate a reactive 2-azinyl nucleophile. Beyond the addition to iminium ions, the 2-azinyl addition to polyfluoromethyl ketones forms the corresponding tertiary alcohols. Together, the products of these reactions possess a high degree of functionality, are typically challenging to synthesize by other methods, and contain motifs recognized as privileged in the context of pharmaceuticals and agrochemicals.

Magnesium 4, 5, and 6 coordinate complexes with ligands bound via sp or sp2 hybridized atoms

As a metallic element of high natural abundance, magnesium finds a wide range of uses in both stoichiometric and more recently catalytic applications. This often takes advantage of the basic or nucleophilic properties of its compounds or their ability to co-complex with other organometallic compounds. However, the homoleptic chemistry of Mg(II) is heavily skewed towards alkyl and aryl ligands bound via sp2 and sp3 hybridized atoms. Here, we report our combined NMR spectroscopic and X-ray crystallographic study into much rarer alternative THF solvates of homoleptic magnesium complexes using ligands which bind via sp (alkynyl) and sp2 (imido) atoms. Specifically, we exploit the high acidity of terminal alkynes and diphenylacetonitrile to prepare tetra-solvated distorted octahedral complexes Mg(CCC6H4R-p)2(THF)4 (R = Me, CF3) and Mg(NCCPh2)2(THF)4 starting from the commercial alkyl reagent MgBu2. Adopting a similar deprotonative strategy using benzophenoneimine Ph2CNH affords the heteroleptic trinuclear complex Mg3(NCPh2)4nBu2(THF)2 with distorted tetrahedral Mg centres. Related imidomagnesium halide complexes can be accessed either by deprotonation of the imine with a Grignard reagent, or nucleophilic addition of a Grignard reagent to a nitrile, but these unusual five-coordinate complexes are unresponsive to a 1,4-dioxane induced Schlenk equilibrium shift. Employing a higher reflux temperature switching from a THF to a toluene medium permits access to the THF solvate of a homoleptic imido complex which also possesses a trinuclear constitution in Mg3(NCPh2)6(THF)2.

Use of Tetrakis(2-ethoxyethoxy)silane for the Preparation of Ethylalkoxysilanes of a Single Structure by the Organomagnesium Methods

A new method for obtaining individual ethylalkoxysilanes of various types of substitution without using chlorosilanes is proposed based on the reactions of tetrakis(2-ethoxyethoxy)silane with the Grignard reagents. The structures of the compounds obtained are confirmed by NMR spectroscopy and GLC.

Iron‐Catalyzed Cross‐Coupling Reactions of Alkyl Grignard Reagents with Alkenyl Carbonate

Herein, we report the alkylation of alkenyl carbonates using alkyl Grignard reagents and iron catalysis to generate C(sp2)–C(sp3) bonds and provide synthetically useful yields over a range of substrates. The transformation allows the alkylation of a wide range of substrates, including aromatic rings, alkanes, cycloalkanes, heterocycles. This reaction has introduced a new family of electrophiles to the iron‐catalyzed cross‐coupling reactions.

Distinguishing Organomagnesium Species in the Grignard Addition to Ketones with X-Ray Spectroscopy.

The addition of Grignard reagents to ketones is a well-established textbook reaction. However, a comprehensive understanding of its mechanism has only recently begun to emerge. X-ray spectroscopy, because of its high selectivity and sensitivity, is the ideal tool for distinguishing between an ensemble of competing pathways. With this aim in mind, we investigated the concerted mechanism of the addition of methylmagnesium chloride (CH3MgCl) to acetone in tetrahydrofuran by simulating the X-ray spectra of different molecules in solution. We used electronic structure methods to calculate the X-ray absorption spectra at the Mg K- and L1-edges and the X-ray photoelectron spectra at the Mg K-edge for different organomagnesium species, which coexist in solution due to the Schlenk equilibrium. The simulated spectra show that individual species can be distinguished throughout the different stages of the reaction. Each species has a distinct spectral feature which can be used as a fingerprint in solution. The absorption and photoelectron spectra consistently show a blue shift as the reaction progressed from reagents to products.

Modular Synthesis of Heterobenzylic Amines via Carbonyl Azinylative Amination

AbstractTransformations enabling the synthesis of α‐alkyl, α′‐2‐azinyl amines by addition of 2‐heteroaryl‐based nucleophiles to in situ‐generated and non‐activated alkyl‐substituted iminium ions are extremely rare. Approaches involving classical 2‐azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2‐azinyl indium nucleophile, generated in situ from the corresponding 2‐iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction. This modular carbonyl azinylative amination (CAzA) displays a broad scope and only a metal reductant is needed to generate a reactive 2‐azinyl nucleophile. Beyond the addition to iminium ions, the 2‐azinyl addition to polyfluoromethyl ketones forms the corresponding tertiary alcohols. Together, the products of these reactions possess a high degree of functionality, are typically challenging to synthesize by other methods, and contain motifs recognized as privileged in the context of pharmaceuticals and agrochemicals.