Grignard Reagents Research Articles

Synthesis of Boronic Esters from Organometallic Reagents and Bis(pinacolato)diboron.

Synthesis of alkyl, aryl, and vinyl boronic esters carrying various chiral and achiral diol-protecting groups were synthesized starting from the corresponding alkyl, aryl, and vinyl lithium or Grignard reagents. Good to excellent yields were obtained for a large range of substrates. The reaction can be conducted in a gram scale to obtain the product over 80 % yield. This approach provides direct access to neopentyl, pinene, and other boronic esters that are difficult to achieve. Using trimethoxyborane or 2-isopropoxy pinacolboronic ester. Detailed mechanistic studies have been conducted to understand the mechanism behind the formation of boronic ester starting from organometallic reagents.

Rapid access to diverse indoles by addition/SNAr with Grignard reagents and 2-fluorophenyl acetonitriles

Indoles are essential heterocycles in natural products, biological chemistry, and medicinal chemistry. Efficient approaches to their synthesis, therefore, remain in demand. Herein is reported a novel and scalable method to produce a wide variety of indoles by combining Grignard reagents and 2-fluorobenzyl cyanides (59 examples, 45%–95% yields). The Grignard reagent adds to the nitrile to give a metalated imine that undergoes SNAr with unactivated C–F bonds. This strategy installs the R group of RMgX at the indole 2-position, and it is noteworthy that a diverse array of Grignard reagents (aryl, alkyl, vinyl, and cyclopropyl) provide the desired heterocyclic products. The resulting N-magnesiated indole can be in situ functionalized at the 3-position with alkyl halides or functionalized on the nitrogen with silyl chlorides. This method enables the synthesis of indoles with functional groups at each position of the indole backbone (C4–C7), providing handles for further functionalization.

Infrared Spectroscopy as Process Analytics to Identify and Quantify Grignard Reagents

Infrared Spectroscopy as Process Analytics to Identify and Quantify Grignard Reagents

N,O-Bidentated difluoroboron complexes based on pyridine-ester enolates: Facile synthesis, post-complexation modification, optical properties, and applications

An array of pyridine-ester enolate based organoboron complexes has been designed and synthesized via a one-pot cascade of Pd-catalyzed α-arylation and BF2 complexation. The rapid structure-activity relationship (SAR) studies indicated that unsymmetrical N,O-chelated BF2 complexes were highly fluorescent in solid state, and exhibited large Stokes shifts, excellent photostability, along with insensitivity to pH. The α-aryl group could not only modulate the electronic effect but also inhibit the intermolecular π-π stacking to promote the aggregation-induced emission (AIE) effect. DFT calculations and experiments identified that the intramolecular charge transfer properties of these N,O-chelates could be switched by the modification of substituents, resulting tunable fluorescence wavelengths. Furthermore, post-complexation modification was accomplished, including Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination, oxidative cleavage, along with a unique triple substitution reaction involving propargyl Grignard reagents. The exemplificative application of dimethylamine substituted boron complex as a reversible acidic vapor sensor was also demonstrated.

Sp2–sp3 Coupling of Unprotected Halogenated Anilines with Grignard Reagents

sp2–sp3 Coupling of Unprotected Halogenated Anilines with Grignard Reagents

Copper‐Catalyzed Asymmetric Synthesis of Silicon‐Stereogenic Benzoxasiloles

AbstractA Cu‐catalyzed asymmetric synthesis of silicon‐stereogenic benzoxasiloles has been realized via intramolecular Si−O coupling of [2‐(hydroxymethyl)phenyl]silanes. Cu(I)/difluorphos is found to be an efficient catalytic system for enantioselective Si−C bond cleavage and Si−O bond formation. In addition, kinetic resolution of racemic substituted [2‐(hydroxymethyl)phenyl]silanes using Cu(I)/ PyrOx (pyridine‐oxazoline ligands) as the catalytic system is developed to afford carbon‐ and silicon‐stereogenic benzoxasiloles. Ring‐opening reactions of chiral benzoxasiloles with organolithiums and Grignard reagents yield various enantioenriched functionalized tetraorganosilanes.

Asymmetric Synthesis of Saturated and Unsaturated Hydroxy Fatty Acids (HFAs) and Study of Their Antiproliferative Activity.

Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression.

Copper-Catalyzed Asymmetric Synthesis of Silicon-Stereogenic Benzoxasiloles.

A Cu-catalyzed asymmetric synthesis of silicon-stereogenic benzoxasiloles has been realized via intramolecular Si-O coupling of [2-(hydroxymethyl)phenyl]silanes. Cu(I)/difluorphos is found to be an efficient catalytic system for enantioselective Si-C bond cleavage and Si-O bond formation. In addition, kinetic resolution of racemic substituted [2-(hydroxymethyl)phenyl]silanes using Cu(I)/ PyrOx (pyridine-oxazoline ligands) as the catalytic system is developed to afford carbon- and silicon-stereogenic benzoxasiloles. Ring-opening reactions of chiral benzoxasiloles with organolithiums and Grignard reagents yield various enantioenriched functionalized tetraorganosilanes.

Grignard reagents as simple precatalysts for the dehydrocoupling of amines and silanes.

Methyl magnesium bromide is a precatalyst for the dehydrocoupling of silanes and amines to produce aminosilane products under mild conditions. As a commercially available Grignard reagent, this precatalyst represents a simplification over previous magnesium-containing catalysts for Si-N bond formation while displaying similar activity to other magnesium-based catalysts. This observation is consistent with the hypothesis that competitive Schlenk equilibrium can be addressed by not using an ancillary ligand. While the activity of MeMgBr is lower than some reported catalysts, including other commercially available precatalysts, unique selectivity was observed for MeMgBr that may allow for directed synthesis of aminosilane products. This work continues to increase the accessibility of Si-N heterodehydrocoupling through a growing family of commercially available precatalysts that balance activity and selectivity.

Synthesis of cytochalasan analogues with aryl substituents at position 10.

Cytochalasans are fungal metabolites that are known to inhibit actin polymerization. Despite their remarkable bioactivity, there are few studies on the structure-activity relationship (SAR) of the cytochalasan scaffold. The full potential of structural modifications remains largely unexplored. The substituent at position 10 of the cytochalasan scaffold is derived from an amino acid incorporated into the cytochalasan core, thus limiting the structural variability at this position in natural products. Additionally, modifications at this position have only been achieved through semisynthetic or mutasynthetic approaches using modified amino acids. This paper introduces a modular approach for late-stage modifications at position 10 of the cytochalasan scaffold. Iron-mediated cross-coupling reactions with corresponding Grignard reagents were used to introduce aryl or benzyl groups in position 10, resulting in the synthesis of six new cytochalasan analogues bearing non-natural aromatic residues. This methodology enables further exploration of modifications at this position and SAR studies among cytochalasan analogues.

Surefire generation of stannylpotassium: highly reactive stannyl anions and applications.

Organometallic reagents such as organolithium and Grignard reagents have long been esteemed in chemical synthesis for their exceptional reactivity. In contrast, the application of their sodium and potassium counterparts has been comparatively sluggish, notwithstanding their augmented reactivity stemming from their heightened ionic character. This inertia persists due to the constrained accessibility of these heavy alkali metal reagents. In this study, our focus was directed towards devising a convenient and pragmatic approach for fabricating heavy alkali metal-based reagents, particularly those grounded in potassium. Herein, we present a novel, direct method for generating stannylpotassium (Sn-K) reagents through the simple combination of readily available silylstannanes and t-BuOK. Subsequently, the generated Sn-K reagents were effectively harnessed for stannylative substitution of aryl halides, furnishing an array of arylstannanes straightforwardly under transition metal-free conditions. This application distinctly underscores the potential utility of highly reactive Sn-K species, hitherto sparingly tapped into within the realm of synthetic organic chemistry. Furthermore, our investigation confirms that Sn-K reagents manifest notably superior reactivity compared with their well-established stannyllithium (Sn-Li) counterparts. This heightened reactivity can be ascribed to the increasing ionic character of Sn-K, which was supported by computational experiments.

Silylene acetals from cheap reagents: synthesis and regioselective opening.

In this communication, a practical method for using cheap and easily available silylene chlorides for diol protection is presented. The method is based on activation of the reagents using Finkelstein-like conditions. Silylene acetals of carbohydrates are synthesized, and it is furthermore shown how these can be regioselectively opened using Grignard reagents.

Dearomative spirocyclization of ynamides.

Spiro N-heterocycles, particularly aza-spiro piperidines, have shown significant promise in pharmaceutical applications due to their ability to enhance physicochemical properties. Despite their potential, the preparation of these complex structures poses significant challenges. To address this, we propose a one-pot dearomative spirocyclization reaction of ynamides. This method involves a copper-catalyzed carbomagnesiation reaction, achieving chemo-, regio-, and stereoselective formation of vinyl metal intermediates. Upon the addition of a Lewis acid, these intermediates undergo a regioselective nucleophilic dearomatization event, facilitating the synthesis of diverse aza-spiro dihydropyridine scaffolds with multiple functional handles. Various Grignard reagents, diverse ynamides, and acylating reagents have been explored. A subsequent hydrogenation reaction provides access to both partially and fully reduced spirocyclic frameworks, broadening the scope of spirocyclic structures with potential medicinal applications.

Mechanochemical generation of aryl barium nucleophiles from unactivated barium metal.

Organobarium reagents are of interest as homologues of the Grignard reagents based on organomagnesium compounds due to their unique reactivity as well as regio- and stereoselectivity. However, reactions involving organobarium reagents are less developed in comparison to reactions involving Grignard reagents due to the lack of a simple and economical synthetic method and their high reactivity. To the best of our knowledge, there is no established method for the direct synthesis of organobarium compounds from commercially available bulk barium metal and organic halides. So far, the generation of organobarium compounds usually requires the use of activated barium (Rieke barium), which significantly reduces the practical utility of organobarium reagents and hinders the development of new organobarium-mediated transformations. Here, we present a mechanochemical strategy based on ball-milling that facilitates the direct generation of various aryl barium nucleophiles from commercially available unactivated barium metal and aryl halides without complicated pre-activation processes. Our simple mechanochemical protocol allows the rapid development of novel carbon-silicon-bond-forming reactions with hydrosilanes mediated by aryl barium nucleophiles; importantly, these reactions are difficult to achieve using other Grignard-type carbon nucleophiles. To the best of our knowledge, this is the first example of a nucleophilic substitution reaction involving an aryl barium species. Furthermore, this mechanochemical strategy established the first example of a nucleophilic addition to a carbonyl compound involving an aryl barium nucleophile. Preliminary theoretical calculations using the artificial force-induced reaction (AFIR) method to reveal the reaction mechanism of the hydrosilane arylation are also described.

Grignard reagents as deprotonation agents for oxazoline-amido-phenolate ligands: structural and catalytic implications with the role of halogen ions.

In this study, various halogen-substituted Grignard reagents were assessed as deprotonating agents for the oxazoline-amido-phenolate ligand, leading to the formation of magnesium complexes. The newly synthesized complexes with halogen substituents displayed three distinct coordinative modes, all extensively characterized through crystallographic methods. The introduction of halogen substituents induced changes in the Lewis acid properties of the complexes, thereby impacting their structural attributes and catalytic behavior during the initiation and propagation of ring polymerization of cyclic esters.

Direct arylation of alkyl fluorides using in situ mechanochemically generated calcium-based heavy Grignard reagents

Here, we report the reaction of calcium-based heavy Grignard reagents, which are easily generated by a mechanochemical method, with unactivated alkyl fluorides to produce the arylated products in moderate to good yields.

Synthesis of unsymmetrical dialkoxydiarylsilanes and diarylsilanediols from tetraalkoxysilane having a dioxasilepane unit.

The tetraalkoxysilane carrying a stable seven-membered dioxasilepane moiety and two trifluoroethoxy groups undergoes reliable iterative substitution of the two trifluoroethoxy groups by sequential treatment with different aryl Grignard reagents while keeping the seven-membered structure intact. The process results in the synthesis of unsymmetrical dialkoxydiarylsilanes and eventually diarylsilanediols after proper hydrolysis.

PREPARATION, CHARACTERIZATION, AND STUDY OF THE BIOLOGICAL ACTIVITY OF 5-CHLORO-8-QUINOLINOL DERIVATIVES AND ITS COORDINATION WITH THE NICKEL (II) AND DIPHOSPHINES

Nickel complexes are effective catalysts for cross-coupling reactions between alkyl Grignard reagents and alkenyl–S and alkenyl–Se compounds. In this study, various organic compounds were prepared. Ethylnyl 2-((5-chloro-8-quinolinol)oxy) acetate compound (designated as A1) was synthesized by adding potassium carbonate to quinoline and ethyl chloroacetate. The second compound 2-((5-chloro-8- quinolinol)oxy) acetohydrazide (A2) were obtained by reacting A1with hydrazide. Complex compound A3 were obtained by reacting equimolar amounts of compound A2 with the nickel salt solution, using ethanol as the solvent. Phosphinate complexes were prepared by reacting equal moles of the A3 with the various phosphines and using ethanol as a solvent. The synthesized compounds and complexes were characterized using various spectroscopic techniques, including (FT-IR) spectroscopy, (31P-{ 1H}- 13C-NMR) spectroscopy, and C.H.N. analysis. Additionally, their melting points, purity, molar conductivity, and magnetic susceptibility were determined. The impact of some prepared compounds and complexes on the growth of two antibiotic-resistant bacterial strains, namely the Gram-negative Staphylococcus and the Gram-positive Escherichia coli, was studied. Amoxicillin was used as control antibiotics. Some of the synthesized compounds exhibited significant inhibitory activity against the tested bacterial strains. The A2 compound readily forms complexes, especially with nickel, manganese, and copper salts. The prepared compounds and complexes exhibited high stability and strength, maintaining their structure, color, and melting point even under varying laboratory temperatures between winter and summer

Enabling organometallic libraries by flow: a tale of two metals

We present, to our knowledge, the first library synthesised from on-demand Grignard reagents: a 76-member library. We also present a matrix library of 21 Negishi products, both libraries giving a success rate of >90% at the organometallic step.

Addition of allyl Grignard to nitriles in air and at room temperature: experimental and computational mechanistic insights in pH-switchable synthesis.

A straightforward and selective conversion of nitriles into highly substituted tetrahydropyridines, aminoketones or enamines by using allylmagnesium bromide as an addition partner (under neat conditions) and subsequent treatment with different aqueous-based hydrolysis protocols is reported. Refuting the conventional wisdom of the incompatibility of Grignard reagents with air and moisture, we herein report that the presence of water allows us to promote the chemoselective formation of the target tetrahydropyridines over other competing products (even in the case of highly challenging aliphatic nitriles). Moreover, the careful tuning of both the reaction media employed (acid or basic aqueous solutions for the hydrolysis protocol) and the electronic properties of the starting nitriles allowed us to design a multi-task system capable of producing either β-aminoketones or enamines in a totally selective manner. Importantly, and for the first time in the chemistry of main-group polar organometallic reagents in non-conventional protic solvents (e.g., water), both experimental and computational studies showed that the excellent efficiency and selectivity observed in aqueous media cannot be replicated by using standard dry volatile organic solvents (VOCs) under inert atmosphere conditions.