Grignard Reagents Research Articles

Regio‐ and Diastereoselective Conjugate Addition of Grignard Reagents to Chiral Fluoroalkyl α,β‐Unsaturated N‐tert‐Butanesulfinyl Ketimines: Synthesis of Optically Active Fluorinated Enamines and Derivatives

AbstractA regio‐ and diastereoselective conjugate addition reaction of Grignard reagents to fluoroalkyl α,β‐unsaturated N‐tert‐butanesulfinyl ketimines was disclosed. A range of different fluoroalkyls and Grignard reagents were well tolerated, giving up to 99% diastereomeric and regioisomeric ratios. This reaction provided a straightforward method for the synthesis of a variety of enantiomerically enriched α‐fluorinated enamines and derivatives which are difficult to achieve with other methods.

Multielectron Redox Afforded by a Pincer Ligand Promoting Kumada Cross-Coupling Reactions.

The redox-active nature of a pincer has been exploited to conduct C-C cross-coupling reactions under mild conditions. A nickel complex with a NNN pincer was dimeric in the solid state, and the structure displayed a Ni2 N2 diamond core. In the dimeric structure, both ligand backbones house an electron, in the iminosemiquinonate form, to keep the metal's oxidation state at +2. In the presence of an aryl Grignard reagent, only 3 mol % loading the nickel complex generates a Kumada cross-coupled product in good yield from a wide variety of aryl-X (X= I, Br, Cl) substrates. That the ligand-based radical remains responsible for promoting such a coupling reaction following a radical pathway is suggested by TEMPO quenching. Furthermore, a radical-clock experiment along with tracing product distribution unambiguously supported the radical's involvement through the catalytic cycle. A series of thorough mechanistic probation, including computational DFT analysis, disclosed the cooperative action of both redox-active pincer ligand and the metal centre to drive the reaction.

A Practical Synthesis of Homoallylic Diene Halides: Versatile Synthons for the Preparation of the Taxane A-Ring System

AbstractA concise and efficient synthesis of two homoallylic halides, which are useful precursors for the preparation of the taxane A-ring system is reported. Contrary to the synthetic routes reported in the literature, this procedure does not employ expensive tetramethylethylene as a starting material. The synthetic route uses readily available and inexpensive ethyl acetoacetate, 1,2-dibromoethane, methyltriphenylphosphonium iodide and methylmagnesium bromide as starting materials. The key step in the synthesis is the acid-mediated ring opening of a cyclopropyl tertiary alcohol to afford the corresponding homoallylic diene halides. The corresponding Grignard reagent, derived from the bromide, is used in the synthesis of an enone previously used as a precursor of taxadienone by reaction with the enol ethyl ether of 1,3-cyclohexanedione.

Synthesis of Octahydroperylene, the Framework of Altertoxin III

AbstractRoutes to the framework of perylenequinone‐derived mycotoxins of the dihydroanthracene type are described. Starting with anthracene derivatives, attachment of C3 units at positions 9 and 10 and twofold cyclization would furnish the required pentacycle. Heck‐type couplings, SN2 additions of enolates, alkynyl and allyl additions turned out to be not successful, while addition of a Grignard reagent prepared from acetal‐protected 3‐bromopropionaldehyde to anthraflavic acid methyl ester, subsequent acetal cleavage, and Birch reduction furnished octahydroperylene in only four steps.

Copper‐Catalyzed Stereoselective Defluoroalkylation or ‐arylation of gem‐Difluoroallenes To Form Monofluoroallenes under Mild Conditions

AbstractHerein, we demonstrate the formation of monofluoroallenes through copper‐catalyzed defluoroalkylation or defluoroarylation of gem‐difluoroallenes using affordable and readily available Grignard reagents. Additionally, alkyl lithium or alkyl zinc reagents proved successful in these transformations. Under mild conditions, monofluoroallenes can be converted into fluorinated olefinic compounds or non‐fluorinated alkyne compounds. Initial mechanistic studies suggest that the reaction may start with an organocopper reagent and undergo a rapid β‐F elimination step. Although the current enantiomeric excess is low, chiral ligands could facilitate the asymmetric transformation of this reaction.

Borylation-Reduction-Borylation for the Formation of 1,4-Azaborines.

Given the current interest in materials containing 1,4-azaborine units, the development of new routes to these structures is important. Carbonyl directed electrophilic borylation using BBr3 is a facile method for the ortho-borylation of N,N-diaryl-amide derivatives. Subsequent addition of Et3SiH results in carbonyl reduction and then formation of 1,4-azaborines that can be protected in situ using a Grignard reagent. Overall, borylation-reduction-borylation is a one-pot methodology to access 1,4-azaborines from simple precursors.

Selectivity of Grignard Reagent Formation: From Semibatch to Continuous Lab and Pilot Scale

Selectivity of Grignard Reagent Formation: From Semibatch to Continuous Lab and Pilot Scale

Kumada-Tamao-Corriu Type Reaction of Aromatic Bromo- and Iodoamines with Grignard Reagents.

The first example of the Kumada-Tamao-Corriu type reaction of unprotected bromoanilines with Grignard reagents is described. The method uses a palladium source and a newly designed Buchwald-type ligand as the catalytic system. Secondary and tertiary bromo- and iodoamines were also successfully coupled to alkyl Grignard reagents. The products of the competitive β-hydride elimination reaction were successfully reduced using a highly efficient electron-deficient phosphine ligand (BPhos). Mechanistic considerations allowed us to establish that the less electron-rich phosphine ligands stabilize the transition state much better than the electron-rich ones; hence, they increase the reaction yield and reduce the amount of β-hydride elimination products. The developed method proved to be tolerant of many functional groups and can be applied to many different aromatic bromo- and iodoamines. Multigram synthesis of p-toluidine from 4-bromoaniline was achieved with a palladium catalyst loading of only 0.03 mol%.

A Sulfur Monoxide Surrogate Designed for the Synthesis of Sulfoxides and Sulfinamides.

Sulfur monoxide (SO) is a highly reactive species that cannot be isolated in bulk. However, SO can play a pivotal role as a fundamental building block in organic synthesis. Reported herein is the design and application of a sulfinylhydrazine reagent as an easily prepared sulfur monoxide surrogate. We show facile thermal SO transfer from this reagent to dienes where a reaction using a mechanistic probe suggests the generation of singlet SO. Combined with Grignard reagents and appropriate carbon or nitrogen electrophiles, the reagent serves as an effective "SO" donor to enable the one-pot, three-component synthesis of sulfoxides and sulfinamides.

A Sulfur Monoxide Surrogate Designed for the Synthesis of Sulfoxides and Sulfinamides**

AbstractSulfur monoxide (SO) is a highly reactive species that cannot be isolated in bulk. However, SO can play a pivotal role as a fundamental building block in organic synthesis. Reported herein is the design and application of a sulfinylhydrazine reagent as an easily prepared sulfur monoxide surrogate. We show facile thermal SO transfer from this reagent to dienes where a reaction using a mechanistic probe suggests the generation of singlet SO. Combined with Grignard reagents and appropriate carbon or nitrogen electrophiles, the reagent serves as an effective “SO” donor to enable the one‐pot, three‐component synthesis of sulfoxides and sulfinamides.

Iron-catalyzed regio- and stereoselective substitution of 2,4-alkadienyl carboxylates with aryl Grignard reagents

Treatment of 2,4-alkadienyl carboxylates with an aryl Grignard reagent in the presence of a catalytic amount of FeCl2 affords diene derivatives in high yields with regio- and cis-stereoselectivity. Additionally, optically active 2,4-alkadienyl carboxylates afford the corresponding optically active dienes in high yields and with excellent degrees of chiral transfer. More importantly, the absolute structures of both starting material and product clarified the stereochemical pathway.

Opportunities with calcium Grignard reagents and other heavy alkaline-earth organometallics.

More than a century old, magnesium Grignard reagents remain essential to the toolbox of organic chemists. Although similar reagents with the neighbouring group 2 metal Ca have been explored, the considerably higher polarity and reactivity of the Ca-C bond result in undesired decomposition pathways. Ca Grignard reagents have found academic interest but have never fully developed into an established synthetic tool. Recent research activities, however, provide facile access to these highly reactive organocalcium species, including in situ preparation and ball milling approaches to tackle the challenge of controlling their extreme sensitivity. Heavier Grignard reagents are not just more reactive but profit from unique chemical transformations. Insight into the transition metal-like properties of Ca, Sr and Ba is only just emerging. Considering the rapidly developing field of alkaline-earth metal-mediated catalysis, heavy Grignard reagents will probably have a bright future.

Dialkyl magnesium compounds from (-)-menthyl chloride and reactions with 1,4-dioxane, TMEDA, and diphenylchlorophosphane

1,4-Dioxane (dx) reacts with the well-known Grignard reagent, prepared via reduction of (-)-menthyl chloride with magnesium in diethyl ether, to a mixture of the three diastereomeric magnesium compounds R2Mg(dx)x, R'2Mg(dx)x and RR'Mg(dx)x (R = (1R)-menthyl and R' = (1S)-neomenthyl). Addition of N,N,N’,N’-tetramethylethylenediamine (TMEDA) to this solution yields (tmeda)Mg(R/R’)2 (R : R’ ≈ 3 : 1) (1) via substitution of ligated dx ligands. The reaction of (R/R’)2Mg(dx)x with diphenylchlorophosphane (molar ratio 1 : 1) in diethyl ether at a temperature regime of 0 °C to reflux and subsequent oxidation with elemental sulfur leads to formation of pure (-)-menthyldiphenylphosphane sulfide RPh2P(S) (2). Compounds 1 and 2 have been authenticated by X-ray crystal structures determinations.

A SNAr‐Active External Initiator that Enables Heterobifunctional Clickable Polythiophenes

AbstractPoly(3‐hexylthiophene) (P3HT) is a well‐studied conjugated polymer; however, the end‐group functionalization of these polymers is limited by fundamental synthetic challenges. Generally, end‐capping agents are used to terminate the Kumada catalyst transfer polycondensation (KCTP) to install functional end‐groups at the propagating chain end. In this work, it is shown that P3HT can be prepared with a novel SNAr‐active external initiator, followed by end capping to afford heterobifunctional end‐groups that exhibit orthogonal chemical reactivity. This orthogonal chemistry can be leveraged in sequential “click”‐type reactions to ultimately achieve the synthesis of triblock copolymers. More specifically, it is shown that the synthesis of a new pentafluorophenyl initiator allows one to append this readily functionalized group at the initiating end during P3HT synthesis. After reaching the desired degree of polymerization, an ethynyl group is incorporated at the polymer terminus using an end‐capping Grignard reagent. Critically, this heterobifunctional P3HT allows for both orthogonal para‐fluoro thiol reactions, a subset of nucleophilic aromatic substitution (SNAr), and copper‐catalyzed alkyne‐azide cycloadditions (CuAAC). The efficacy of this heterobifunctional polymer design is demonstrated by assessing sequential “click” reactions with different nonconjugated polymer blocks to either end of the P3HT polymer block.

The Ring‐Opening Reaction of Benzofuran Involving the Cleavage of C−O Bond

AbstractRing‐opening of (di)benzofurans is a significant area of research in organic chemistry, offering versatile and direct synthetic strategies to access valuable functional phenol derivatives. Transition metal catalysis, particularly nickel‐catalyzed reactions, has been extensively explored for the selective cleavage of the C−O bond in (di)benzofuran. Metal‐free methods, such as acid catalysis and strong base‐mediated process, have also emerged as important alternatives. Organometallic reagents, including Grignard and organolithium reagents, play a pivotal role in promoting efficient C−O bond activation. The field of (di)benzofuran ring opening holds great promise for the synthesis of complex molecules with diverse applications in pharmaceuticals, materials science, and fine chemical synthesis. Continued research efforts will pave the way for innovative strategies and broaden the utility of (di)benzofuran derivatives in various fields.

Chemistry of new polyfluorinated oxiranyl anions and epoxy silanes

The reaction of partially fluorinated epoxides with strong, hindered bases in the presence of electrophiles resulted in functionalization of the epoxy ring. For example, the reaction of hexafluoroisobutene epoxide with LDA and trimethyl- or triethychlorosilanes at low temperature led to the formation of the corresponding epoxy silanes. In the case of the E- and Z-epoxides of 1,1,1,3,3,3-hexafluorobutene-2, the deprotonation step can be successfully carried out using i-PrMgCl.LiCl (Turbo Grignard reagent), and the reaction with chlorosilanes can be carried out at ambient temperature, which significantly simplifies the synthetic protocol. The process was found to be stereospecific, proceeding with complete retention of configuration of the epoxide ring and giving access to pure E- or Z-isomers of the corresponding epoxy silanes. Using this protocol, the corresponding epoxy silanes were also prepared from the epoxides of E-3,3,3,1-tetrafluoropropene-1 and 3,3,3-trifluoropropene-1.The new silanes were demonstrated to be convenient reagents for the transfer of a fluorinated epoxy moiety to carbonyl compounds under fluoride anion catalysis. This process was shown to proceed with complete retention of the geometry of the epoxy ring.

Hybrid Modeling of an Active Pharmaceutical Ingredient Flow Synthesis in a Ring-Opening Reaction of an Epoxide with a Grignard Reagent

Hybrid Modeling of an Active Pharmaceutical Ingredient Flow Synthesis in a Ring-Opening Reaction of an Epoxide with a Grignard Reagent

A high-throughput femtosecond laser-engineered 3D microfluidic chip for efficient chemical transformation of carbon dioxide to value-added chemicals

Efficient conversion of low reactive CO2 within a short residence time of flow chemistry presents a challenge. We have tackled this issue by developing 3D microfluidic chips (MFCs) with high-density, small-diameter, and large-volume for CO2 gas–liquid reactions using femtosecond laser technology. Our innovative design effectively shortens reaction times while satisfying the required temperature and pressure conditions. One of the key features is the integration of the 3D Barker's transform structure, which provides an efficient gas–liquid contact area for mass and heat transfer, even at low Reynolds numbers. As a proof of concept, we synthesize 2,4,5-trifluorobenzoic acid and various other fluorinated carboxylic acids in 3D MFCs using Grignard reagents and CO2. Impressively, the Grignard reagents can be generated in situ and utilized at room temperature, and the CO2 carboxylation reaction with 3D MFCs takes only 40 s with a yield of 97 %. Our findings highlight the feasibility of this multifunctional, efficient, and fast CO2 flow conversion process, providing a valuable tool to produce value-added chemicals via 3D MFCs techniques.

Grignard Reagent-Catalyzed Hydroboration of Esters, Nitriles, and Imines.

The reduction in esters, nitriles, and imines requires harsh conditions (highly reactive reagents, high temperatures, and pressures) or complex metal-ligand catalytic systems. Catalysts comprising earth-abundant and less toxic elements are desirable from the perspective of green chemistry. In this study, we developed a green hydroboration protocol for the reduction in esters, nitriles, and imines at room temperature (25 °C) using pinacolborane as the reducing agent and a commercially available Grignard reagent as the catalyst. Screening of various alkyl magnesium halides revealed MeMgCl as the optimal catalyst for the reduction. The hydroboration and subsequent hydrolysis of various esters yielded corresponding alcohols over a short reaction time (~0.5 h). The hydroboration of nitriles and imines produced various primary and secondary amines in excellent yields. Chemoselective reduction and density functional theory calculations are also performed. The proposed green hydroboration protocol eliminates the requirements for complex ligand systems and elevated temperatures, providing an effective method for the reduction in esters, nitriles, and imines at room temperature.

Regio- and stereoselective nucleophilic addition reactions of Swaminathan ketone and its methylated analog using organometallic reagents

Herein, we report the regio- and stereoselective nucleophilic addition reactions of Swaminathan ketone 2a and its methylated analog 2b, both of which contain a 6–7 fused carbocyclic enedione moiety. Nucleophilic additions to 2 using generic organometallic reagents, such as Grignard and organolithium reagents, preferentially occurs at the conjugated carbonyl group to afford a range of tert-alcohols with high stereoselectivity. The selectivity observed with 2 was notable when compared to that observed with Wieland–Miescher ketone 1a bearing a decalin framework. A variety of substituents, such as alkyl, alkenyl, alkynyl and aryl groups, can be introduced into 2 using this method. Exceptionally, the allylation reaction of 2 occurred at both the conjugated and non-conjugated carbonyl groups, but this regioselectivity problem was solved using organocopper reagents.