Bench‐Stable Stock Solutions of Silicon Grignard Reagents: Application to Iron‐ and Cobalt‐Catalyzed Radical C(sp3)–Si Cross‐Coupling Reactions

A robust method for the preparation of silicon‐based magnesium reagents is reported. The MgBr₂ used in the lithium‐to‐magnesium transmetalation step is generated in situ from 1,2‐dibromoethane and elemental magnesium in hot THF. No precipitation of MgBr₂ occurs in the heat, and transmetalation at elevated temperature leads to homogeneous stock solutions of the silicon Grignard reagents that are stable and storable in the fridge. This method avoids the preparation of silicon pronucleophiles such as Si?Si and Si?B reagents. The new Grignard reagents were applied to unprecedented iron‐ and cobalt‐catalyzed cross‐coupling reactions of unactivated alkyl bromides. The functional‐group tolerance of these magnesium reagents is excellent.     

Reaction of polyepichlorohydrin with magnesium and grignard reagents

The reaction of polyepichlorohydrin with magnesium in tetrahydrofuran at reflux temperature was studied in the hope of obtaining a polymeric Grignard reagent. The polymeric Grignard reagent could not be obtained, but dechlorination occurred. It was confirmed that the Grignard reagent of polyepichlorohydrin was formed as an intermediate during the dechlorination. The reactions of polyepichlorohydrin with Grignard reagents were carried out in tetrahydrofuran at reflux temperature. Benzylmagnesium chloride and allylmagnesium chloride were used as Grignard reagents. It was found that the chlorine atom in polyepichlorohydrin can be replaced by benzyl and allyl groups. The extent of the substitution increased with increasing concentration of Grignard reagent. Dechlorination and scission of the ether linkage occurred simultaneously as side reactions.     

New polyfunctional magnesium reagents for organic synthesis

The iodine-magnesium exchange reaction allows the preparation of polyfunctional aryl, heteroaryl, or alkenyl magnesium reagents at low temperature. These reagents display the typical reactivity of Grignard compounds and undergo various copper-catalyzed reactions such as allylation or 1,4-addition. Using this halogen-metal exchange reaction, it was possible to generate polyfunctional magnesium reagents on the solid phase.     

The quest for chiral Grignard reagents

The involvement of single electron transfer, i.e. of free radicals in the reactions of organomagnesium reagents could be detected with the aid of a chiral secondary Grignard reagent, in which the magnesium-bearing carbon atom is the sole stereogenic centre. So far, however, such reagents have not been accessible, because the standard preparation of Grignard reagents proceeds via free radicals. We review and summarize here our efforts to generate such a Grignard reagent 36 by asymmetric synthesis starting from an enantiomerically pure alpha-chloroalkyl-sulfoxide 30b using a sulfoxide/magnesium exchange reaction to give 33 followed by a carbenoid homologation reaction. Grignard reagent 36 turned out to be an ideal probe to learn about the extent to which SET is involved in reactions of organomagnesium reagents.     

An improved preparation of 3,5-bis(trifluoromethyl)acetophenone and safety considerations in the preparation of 3,5-bis(trifluoromethyl)phenyl Grignard reagent

An improved and efficient bromination of 3,5-bis(trifluoromethyl)benzene was developed. A safe and reliable preparation of the potentially explosive 3,5-bis(trifluoromethyl)phenyl Grignard and 3-trifluoromethylphenyl Grignard reagents, from the precursor bromides, is described. Reaction System Screening Tool (RSST) and Differential Thermal Analysis (DTA) studies suggest these trifluoromethylphenyl Grignard reagents can detonate on loss of solvent contact or upon moderate heating. When prepared and handled according to the methods described herein, these Grignard reagents can be safely prepared and carried on to advanced intermediates.     

Generation of magnesium carbenoids from 1-chloroalkyl phenyl sulfoxides with a Grignard reagent and applications to alkylation and olefin synthesis

Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature gave magnesium carbenoids in quantitative yields. The generated magnesium carbenoids were found to be stable at lower than −60 °C for long periods of time and are reactive with Grignard reagents to give alkylated products. The reaction of the generated magnesium carbenoids with various kinds of lithium α-sulfonyl carbanions gave olefins with carbon-carbon bond-formation in good to high yields. This method offers a good way for the preparation of olefins. The scope and limitations of the above-mentioned reactions are described.     

Direct Addition of Grignard Reagents to Aliphatic Carboxylic Acids Enabled by Bulky turbo-Organomagnesium Anilides

The synthesis of ketones through addition of organometallic reagents to aliphatic carboxylic acids is a straightforward strategy that is limited to organolithium reagents. More desirable Grignard reagents can be activated and controlled with a bulky aniline-derived turbo-Hauser base. This operationally simple procedure allows the straightforward preparation of a variety of aliphatic and perfluoroalkyl ketones alike from functionalized alkyl, aryl and heteroaryl Grignard reagents.     

Copper-catalyzed electrophilic amination of functionalized diarylzinc reagents

The copper-catalyzed electrophilic amination of functionalized diarylzinc reagents with O-acyl hydroxylamines allows for the preparation of functionalized tertiary arylamines in high yields, and is noteworthy for the mild reaction conditions employed. The functionalized diarylzinc reagents were prepared via an iodine/magnesium exchange of the corresponding aryl iodide followed by transmetalation of the resultant Grignard species with ZnCl(2).     

A Short,Convenient Synthesis of 2-Arylglycidates via Aryl-Grignard Addition to an α-Bromopyruvate

A simple procedure has been developed for the preparation of a series of 2-arylglycidates required for herbicidal evaluation. Treatment of the α-bromopyruvate 5 with various aryl Grignard reagents at low temperature gave directly the glycidates 4. Saponification of these then afforded the desired sodium salts 7.     

Grignard Reagent Utilization Enables a Practical and Scalable Construction of 3-Substituted 5-Chloro-1,6-naphthyridin-4-one Derivatives

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition–acidolysis–cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.     

Stereospecific nucleophilic substitution of optically pure H-phosphinates: a general way for the preparation of chiral P-stereogenic phosphine oxides

Contrary to the generally held view, it is found that the rapid epimerization of (-)-menthyl (RP)-phenylphosphinate under basic conditions is not due to the so far believed inherent stereolability of its corresponding anion but due to a reaction of the hydrogen phosphinate ester with a metal alkoxide. This finding successfully leads to a discovery that, by adding an H-phosphinate to organolithiums or Grignard reagents at a low temperature, the nucleophilic substitution of the alkoxy group of the H-phosphinate with organolithiums or Grignard reagents proceeds stereospecifically with inversion of configurations at phosphorus to give a wide range of P-stereogenic secondary phosphine oxides and tertiary phosphine oxides, by quenching the reaction mixture with water and alkyl halides, respectively. This finding establishes a general protocol for the preparation of optically active secondary phosphine oxides and tertiary phosphine oxides from the easily accessible optically pure H-phosphinates. Mechanistic studies show that the substitution reactions of H-phosphinates with organolithiums and Grignard reagents proceed via two competing reaction paths, that is, a two-step reaction path involving first a deprotonation of H-phosphinates followed by a substitution of the corresponding anion with inversion of configuration at phosphorus and a direct substitution of RM with H-phosphinates generating the SPO directly.     

Oligoarenes as molecular backbones of catalysts: synthesis and applications

This feature article highlights our recent work on oligoarene-type catalysts. We developed a synthetic method for multifunctionalized oligoarenes using a repetitive two-step strategy. The method was then applied to the preparation of oligoarene-type phosphines, which were used for palladium-catalyzed cross-coupling of halobenzenes with Grignard reagents.     

Transformation of aromatic bromides into aromatic nitriles via formations of grignard reagents and their DMF adducts

Various aromatic bromides were efficiently transformed into the corresponding aromatic nitriles in good yields via the formations of Grignard reagents and subsequently N,N-dimethyl formamide (DMF) adducts, followed by treatment with molecular iodine (I₂) in aq NH₃ at room temperature. The present reaction is an easy and practical method for the preparation of aromatic nitriles from aromatic bromides with less toxic reagents, such as Mg, DMF, I₂, and aq NH₃.     

Synthesis of N,N‐Dimethylamines via Barbier–Grignard‐Type Electrophilic Amination

Aryl Grignard reagents react with N,N‐dimethyl O‐(mesitylenesulfonyl)hydroxylamine in THF under Barbier conditions at room temperature and give N,N‐dimethylanilines with high yields in a 2‐h reaction. The amination yield of in situ Grignard reagents were not lower than those of preformed aryl Grignard reagents. In situ cycloalkyl‐, allyl‐, and benzylmagnesium bromides did not react with N,N‐dimethyl O‐(mesitylenesulfonyl)hydroxylamine, except that amination of in situ n‐hexylmagnesium bromide resulted in a medium yield. Grignard–Barbier‐type amination of aryl bromides with N,N‐dimethyl O‐(mesitylenesulfonyl)hydroxylamine provides a new alternative route for the synthesis of N,N‐dimethylanilines.     

Synthesis of Cyclohexyl and Isopropyl Ketones from Benzimidazole Methiodide Salt and Grignard Reagents

The reaction of 2-alkyl-l, 3-dimethylbenzimidazolinm salts with Grignard reagents gave addition products which were hy-drelyzed to give ketones. A new method for the preparation of cyclohexyl ketones and isopropyl ketones is provided.     

Methodology for the preparation of 2-argininylbenzothiazole

An efficient process to produce kilogram quantities of a key argininylbenzo[d]thiazole intermediate was developed for the preparation of the tryptase inhibitor RWJ-56423. A variety of activated arginine esters and benzo[d]thiazole nucleophiles were evaluated as coupling partners. Our work led to the selection and optimization of an argininyl imidazolide ester and benzothiazol-2-yl MgCl nucleophile. This paper focuses on the preparation, use, and stability of the benzothiazol-2-yl Grignard reagents.     

Effects of water content on magnesium deposition from a Grignard reagent-based tetrahydrofuran electrolyte

It is well known that water causes decomposition of Grignard reagents. When these reagents are used, water or moisture should be eliminated. However, it is possible that a very small amount of water, for example, trapped in the walls of the glassware used, can enter the system even in a well-controlled Ar glove box. Therefore, in this work, the effect of very low concentrations of water on Mg deposition from a Grignard reagent-based electrolyte was studied. It was shown that a minute amount of water, although insufficient to cause destruction of the Grignard reagent, affects the overpotential for Mg deposition, resulting in Mg deposits of different morphology. For reproducible and reversible Mg deposition and dissolution, it is desirable that the water content of the electrolyte is kept as low as possible and the electrolyte is left to stand for at least several hours after preparation.     

Noncryogenic I/Br-Mg exchange of aromatic halides bearing sensitive functional groups using i-PrMgCl-bis[2-(N,N-dimethylamino)ethyl] ether complexes

[reaction: see text] Iodo- and bromoaromatics bearing sensitive carboxylic ester and cyano groups underwent a selective halide-magnesium exchange with isopropylmagnesium chloride at ambient temperature in the presence of bis[2-(N,N-dimethylamino)ethyl] ether to afford the corresponding Grignard reagents. The newly formed reactive Grignard reagents were allowed to react with electrophiles such as trimethylborate to afford arylboronic acids in good to excellent yields.     

双烷基膦酸的合成和性质研究

用格氏试剂与三氯化磷反应,继而水解、氧化,合成了3个高位阻双烷基膦酸,发现制备高位阻格氏试剂用叔氯代烷比叔溴代烷效果好;同时还用格氏试剂与亚磷酸酯反应,然后用Todd方法制备了二正辛基膦酸,发现亚磷酸二正丁酯比亚磷酸二乙酯反应效果好。此外,还考察了其1H、¹³C、³¹PNMR和酸电离性质与其取代基结构效应的关系。     

Moderne Magnesiumorganische Chemie. Neues von der Grignard‐Reaktion

Organomagnesium reagents can be employed for a variety of useful transformations, which are also of relevance for industrial processes. Recent protocols for syntheses of highly functionalized Grignard reagents highlight fascinating new perspectives for organic synthesis. Particularly, the addition of superstoichiometric amounts of LiCl allowed for the preparation of organomagnesium compounds, employing haloarenes or arenes at very mild reaction conditions. These highly functionalized Grignard reagents can be used as starting materials for transition metal‐catalyzed cross‐coupling reactions. New developments in the ligand design resulted in highly active palladium and nickel catalysts for efficient transformations of inexpensive chlorides or tosylates, as well as challenging fluorides. Economically attractive iron‐catalyzed coupling reactions of organomagnesium reagents bear great potential for further developments.