Alkylmagnesium Halides Research Articles

General and Scalable Synthesis of 2-Aryl and 2-Alkyl Pyrimidines via an Electronically Tuned SNAr Approach.

An efficient SNAr approach for generating a wide array of 2-aryl and 2-alkyl pyrimidines in good to high yields was developed. This methodology does not require precious metal catalysts and is compatible with aryl, heteroaryl, and alkyl magnesium halides as nucleophiles. This process is scalable and performed at room temperature well below the temperature of the competing decomposition of the activated 2-tert-butyl sulfonyl pyrimidine electrophile.

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.

Iron‐Catalyzed Magnesium‐Mediated Formal Hydroformylation of Alkynes and Alkenes

AbstractAlkynes and alkenes are routinely converted to corresponding synthetically versatile aldehydes using rhodium‐catalyzed hydroformylation. However, rhodium is rare, precious, costly, and depleting at a considerably high rate. Reported here is iron‐catalyzed, magnesium‐mediated, formal hydroformylation of alkynes and alkenes in the absence of syngas. Readily available FeCl2 in the presence of alkyl magnesium halide, and dimethyl formamide, catalyzes hydroformylation of various alkynes and selectively produces α,β‐unsaturated aldehydes in good to excellent conversion. Mechanistic investigations revealed the presence of vinyl magnesium intermediate, the kinetic study disclosed the first‐order dependence of the reaction on iron loading, and the control experiment authenticated the iron catalyst‘s homogeneous nature. The scope of this methodology was amplified, and 20 alkenes were examined. [Fe(acac)3] in the presence of ligand, alkyl magnesium halide, and dimethyl formamide catalyzed the hydroformylation of alkenes and displayed good to excellent conversion. An earth‐abundant iron catalyst offering a syngas cylinder‐free safe alternative to high‐pressure hydroformylation has been reported.

Синтез и воздействие третичных аминоспиртов пиперазинового ряда и их дигидрохлоридов на опухолевую ДНК в условиях <i>in vitro</i>

Взаимодействием 1-(4-бутоксифенил)-3-(4-замещенных пиперазин-1-ил)-2-фенилпропан-1-онов с алкил(арил)магнийгалогенидами синтезированы третичные аминоспирты пиперазинового ряда. Некоторые из конечных соединений переведены в дигидрохлориды. Изучено влияние синтезированных соединений на процессы метилирования опухолевой ДНК С-180 мышей в условиях in vitro: к гомогенату опухоли добавляли 3  10–6 М раствор исследуемых соединений и инкубировали в термостате при 37 °C в течение 24 ч. Сравнительно высокую активность (ингибирование метилирования на 51,6 %) показало соединение 1-(4-бутоксифенил)-3-[4-(4-фторфенил)пиперазин-1-ил]-1,2-дифенилпропан-1-ол, которое в положении 1 содержит фенильный радикал. Введение в орто-положение фенильного радикала метоксигруппы привело к снижению активности до 37,5 %.

Synthesis and Antitumor Activity of Piperazine-Based Tertiary Amino Alcohols and Their Dihydrochlorides

Aminomethylation of 1-(4-alkoxyphenyl)-2-phenyl(chlorophenyl)ethanones with paraformaldehyde and substituted piperazines in ethanol furnished 1-(4-alkoxyphenyl)-3-(4-R-piperazin-1-yl)-2-phenyl (chlorophenyl)propan-1-ones. Reaction of the latter with alkyl (aryl) magnesium halides resulted in the formation of tertiary amino alcohols of piperazine series, which were further converted to dihydrochlorides. The effect of synthesized compounds on the processes of tumor DNA methylation in vitro was studied.

Chromium(II)-Catalyzed Diastereoselective and Chemoselective Csp2-Csp3 Cross-Couplings Using Organomagnesium Reagents.

A simple protocol for performing chromium-catalyzed highly diastereoselective alkylations of arylmagnesium halides with cyclohexyl iodides at ambient temperature has been developed. Furthermore, this ligand-free CrCl2 enables efficient electrophilic alkenylations of primary, secondary, and tetiary alkylmagnesium halides with readily available alkenyl acetates. Moreover, this chemoselective C-C coupling reaction with stereodefined alkenyl acetates proceeds in a stereoretentive fashion. A wide range of functional groups on alkyl iodides and alkenyl acetates are well tolerated, thus furnishing functionalized Csp2-Csp3 coupling products in good yields and high diastereoselectivity. Detailed mechanistic studies suggest that the in situ generated low-valent chromium(I) species might be the active catalyst for these Csp2-Csp3 cross-couplings.

Palladium-Catalyzed Cross-Coupling of Monochlorosilanes And Grignard Reagents.

Using a palladium catalyst supported by DrewPhos, the alkylation of monochlorosilanes with primary and secondary alkyl-magnesium halides is now possible. Arylation with sterically demanding aromatic magnesium halides is also enabled. This transformation overcomes the high bond strength of the Si-Cl bond (113 kcal/mol) and is a rare example of a transition-metal catalyzed process involving its activation. Due to the availability of both chlorosilanes and organomagnesium halide reagents, this method allows for the preparation of a wide range of alkyl and aryl silanes.

Iron‐Catalyzed Cross‐Coupling of 1‐Alkynylcyclopropyl Tosylates and Related Substrates

Abstract1‐Alkynylcyclopropyl tosylates react with alkylmagnesium halides in the presence of catalytic ferric acetylacetonate [Fe(acac)3] under net propargylic substitution; allene formation, which is the prevalent reactivity mode of propargylic substrates otherwise, was noticed as a side reaction only when branched alkyl‐ or aryl‐Grignard reagents were used. These transformations represent the first successful iron‐catalyzed cross‐coupling reactions of tert‐alkyl electrophiles.magnified image

Nickel-Catalyzed Alkylative Cross-Coupling of Anisoles with Grignard Reagents via C–O Bond Activation

We report nickel-catalyzed cross-coupling of methoxyarenes with alkylmagnesium halides, in which a methoxy group is eliminated. A wide range of alkyl groups, including those bearing β-hydrogens, can be introduced directly at the ipso position of anisole derivatives. We demonstrate that the robustness of a methoxy group allows this alkylation protocol to be used to synthesize elaborate molecules by combining it with traditional cross-coupling reactions or oxidative transformation. The success of this method is dependent on the use of alkylmagnesium iodides, but not chlorides or bromides, which highlights the importance of the halide used in developing catalytic reactions using Grignard reagents.

Solution Structure and Magnesium Deposition Electrochemistry of Mixing Alkylmagnesium Halide with Magnesium Sulfonyl Amide/Glyme Solution

Solution Structure and Magnesium Deposition Electrochemistry of Mixing Alkylmagnesium Halide with Magnesium Sulfonyl Amide/Glyme Solution

Ring-opening of cyclic ethers with carbon–carbon bond formation by Grignard reagents

The ring-opening of cyclic ethers with concomitant C–C bond formation was studied with a number of Grignard reagents. The transformation was performed in a sealed vial by heating to ∼160 °C in an aluminum block or at 180 °C in a microwave oven. Good yields of the product alcohols were obtained with allyl- and benzylmagnesium halides when the ether was tetrahydrofuran or 3,3-dimethyloxetane. Lower yields were obtained with substituted tetrahydrofurans while no ring-opening was observed with tetrahydropyran. Only highly reactive allyl and benzyl Grignard reagents participated in the transformation while no reaction occurred with other alkylmagnesium halides.

The retro Grignard addition reaction revisited: the reversible addition of benzyl reagents to ketones

The Grignard addition reaction is known to be a reversible process with allylic reagents, but so far the reversibility has not been demonstrated with other alkylmagnesium halides. By using crossover experiments it has been established that the benzyl addition reaction is also a reversible transformation. The retro benzyl reaction was shown by the addition of benzylmagnesium chloride to di-tert-butyl ketone followed by exchange of both the benzyl and the ketone moiety with another substrate. Similar experiments were performed with phenylmagnesium bromide and tert-butylmagnesium chloride, but in these two cases the Grignard addition reaction did not show any sign of a reverse transformation.

ChemInform Abstract: Construction of Quaternary Carbon Centers by Using Substitution of γ,γ‐Disubstituted Secondary Allylic Picolinates with Alkylcopper Reagents.

AbstractA convenient protocol using ZnI2 as promotor is developed for the regio‐ and stereoselective substitution of allylic picolinates with alkyl copper reagents, generated from alkylmagnesium halides and CuBr2·Me2S.

Olefin‐Assisted Iron‐Catalyzed Alkylation of Aryl Chlorides

AbstractA selective and operationally simple iron‐catalyzed cross‐coupling of aryl chlorides with alkylmagnesium halides has been developed. The reaction tolerates various functional groups and exhibits high chemoselectivity even in the presence of aryl bromides. Mechanistic studies indicate the essential role of the olefin substituent for substrate activation. Competing polymerization and reduction are effectively suppressed.magnified image

ChemInform Abstract: Preparation of Alkylmagnesium Reagents from Alkenes Through Hydroboration and Boron—Magnesium Exchange.

AbstractA general protocol for the generation of various primary and secondary alkylmagnesium halides is presented, involving a sequence of alkene boration and boron—magnesium exchange.

Preparation of Alkylmagnesium Reagents from Alkenes through Hydroboration and Boron–Magnesium Exchange

A general protocol for the generation of various primary and secondary alkylmagnesium halides is presented, involving a sequence of alkene boration and boron—magnesium exchange.

ChemInform Abstract: Nickel‐Catalyzed Kumada Cross‐Coupling Reactions of Tertiary Alkylmagnesium Halides and Aryl Bromides/Triflates.

AbstractKumada cross‐coupling of tertiary alkylmagnesium halides with aryl bromides, triflates and alkenyl halides proceeds smoothly in the presence of a Ni—NHC catalyst.

Nickel-Catalyzed Kumada Cross-Coupling Reactions of Tertiary Alkylmagnesium Halides and Aryl Bromides/Triflates

We report a Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides. This process is extremely general for a wide range of electrophiles and generally occurs with a ratio of retention to isomerization >30:1. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component.

ChemInform Abstract: Synthesis of Benzotriazine and Aryltriazene Derivatives Starting from 2‐Azidobenzonitrile Derivatives.

AbstractThe reactions of 2‐azidobenzonitrile derivatives (I) with alkyl magnesium halides give benzotriazines in moderate yields accompanied by aminobenzonitriles (IV).

ChemInform Abstract: Quaternary Carbon Stereogenic Centers Through Copper‐Catalyzed Enantioselective Allylic Substitutions with Readily Accessible Aryl‐ or Heteroaryllithium Reagents and Aluminum Chlorides.

Catalytic enantioselective allylic substitution (EAS) reactions[i] are among the most versatile classes of transformations in organic chemistry: such processes convert readily available achiral substrates to enantiomerically enriched products bearing a stereogenic center adjacent to a readily functionalizable alkene. We have devised chiral amino acid-based[ii] and bidentate N-heterocyclic carbene (NHC) Cu complexes[iii] that promote EAS processes with dialkylzinc reagents and generate quaternary carbon stereogenic centers[iv] with high site- and enantioselectivity. Catalytic enantioselective Cu-free additions of alkylmagnesium halides to allylic halides,[v] as well as dialkylzinc and trialkylaluminum reagents[vi] to phosphates, have also been developed. Nonetheless, significant and compelling problems remain unaddressed. Catalytic EAS transformations involving aryl nucleophiles and which deliver quaternary carbon centers are notoriously scarce, and protocols that involve hetero-arylmetals do not exist (including those that furnish tertiary C–C bonds). The only reported cases of aryl additions by catalytic EAS that generate quaternary carbons correspond to Si-substituted alkenes and involve diarylzinc reagents,[vii] which are relatively difficult to prepare in high purity and offer only one of the two aryl units. Such considerations underline a shortcoming in the state-of-the-art: the absence of EAS methods that deliver quaternary carbon stereogenic centers through reactions with mono-arylmetal reagents, in particular those that are easily accessible and atom-economical.[i]