Methylmagnesium Iodide Research Articles

A Simple Strategy for the Preparation of 6-Substituted 3H-Benzoxazol-2-ones and 3H-Benzothiazol-2-ones

The double metallation of 6-bromo-3H-benzothiazol-2-one and 6-bromo-3H-benzoxazol-2-one with methyl magnesium bromide and alkyllithium bases is described. Alkylation with a variety of electrophiles occurs at the 6-position of the heterocycles in good yields.

3,6-Disubstituted Cyclohexenones in the Synthesis of New Three Ring Liquid Crystalline Compounds with the Negative Dielectric Anisotropy

New improved approach for preparation of the three ring liquid crystalline compounds with 2,3-difluorobenzene moiety is proposed. The key stage is the synthesis of 3,6-disubstituted cyclohex-2-en-1-ones via the condensation of the corresponding Mannich salts with 2-substituted acetoacetic esters (or methyl benzyl ketones) in the presence of base. The chlorination with phosphrous pentachloride of these cyclohexenones or methylation with methylmagnesium iodide followed oxidative aromatization give new three ring compounds, which could be used in the LC compositions with negative dielectric anisotropy.

Organomagnesium clusters: Structure, stability, and bonding in archetypal models

We have studied the molecular structure and the nature of the chemical bond in the monomers and tetramers of the Grignard reagent CH 3MgCl as well as MgX 2 (X = H, Cl, and CH 3) at the BP86/TZ2P level of theory. For the tetramers, we discuss the stability of three possible molecular structures of C 2 h , D 2 h , and T d symmetry. The most stable structure for (MgCl 2) 4 is D 2 h , the one for (MgH 2) 4 is C 2 h , and that of (CH 3MgCl) 4 is T d . The latter is 38 kcal/mol more stable with chlorines in bridge positions and methyl groups coordinated to a Mg vertex than vice versa. We find through a quantitative energy decomposition analysis (EDA) that the tetramerization energy is predominantly composed of electrostatic attraction Δ V elstat (60% of all bonding terms Δ V elstat + ∆ E oi) although the orbital interaction ∆ E oi also provides an important contribution (40%).

Stereoselective Addition of Grignard Reagents to New P‐Chirogenic N‐Phosphinoylbenzaldimines: Effect of the Phosphorus Substituents on the Stereoselectivity

AbstractSeveral phosphinoylimines have been synthesized in five steps by starting from the appropriate phosphane oxide and were then treated with methylmagnesium bromide to give both diastereoisomers in high yields and with promising diastereomeric ratios. Then N‐[(tert‐butyl)(phenyl)phosphinoyl]benzaldimine, which displayed the best results, was subjected to the 1,2‐addition of various Grignard reagents to evaluate the best chiral induction due to the stereogenic phosphorus atom. The corresponding adducts were obtained in excellent yields and with moderate to excellent diastereoisomeric ratios.

ChemInform Abstract: Facile Synthesis of 1‐Methyl‐1H‐benzo[b]azepines from 1‐Methylquinolinium Iodides and Diazo(trimethylsilyl)methylmagnesium Bromide.

AbstractStarting from iodide (I), the synthesis of benzoazepines (IV) is achieved via addition of magnesium salt (II), followed by sequential Cu‐catalyzed ring expansion and desilylation.

Asymmetric Synthesis of 1,1-Diarylethane Drugs

Syntheses of the sleep-inducing H1-antihistamine K and the tubulin polymerization inhibitor N exemplify a general enantioselective synthesis of 1,1-diarylethanes using the stereo­specific nickel-catalyzed cross-coupling reactions of alkyl ethers with methylmagnesium iodide. Further seven examples are reported giving yields of 70-96% and ee values of 85-99%.

ChemInform Abstract: Synthesis of 3‐Substituted 3H‐Indol‐3‐ols by the Reaction of 2‐Isocyanophenyl Ketones with Grignard Reagents.

Abstract A facile method for the synthesis of 3-substituted 3 H -indol-3-ols has been developed. Thus, 2-isocyanophenyl ketones are allowed to react with various Grignard reagents to give the corresponding desired indolol derivatives in generally fair to good yields. The formation of 3-aryl-2,3-dimethylindolin-3-ols by the reaction of 2-isocyanobenzophenones with 2 M amounts of methylmagnesium bromide is also reported.

Autooxidation of Δ17(20)-20-hydroxy derivatives of steroids. Synthesis of 3β-acetoxy-17α-hydroperoxy-16α-methylpregn-5-en-20-one and its reduction to 17α-hydroxy derivative

An efficient procedure was proposed for the synthesis of 3β-acetoxy-17α-hydroperoxy-16α-methylpregn-5-en-20-one. Optimal conditions were found for the combined process including 1,4-addition of methylmagnesium bromide at the Δ16-20-oxo fragment of dehydropregnenolone acetate and autooxidation of resulting bromomagnesium 3β-acetoxy-16α-methylpregna-5,17(20)-dien-20-olate. The subsequent reduction of the 17α-hydroperoxy group and hydrolysis of the 3β-acetoxy group afforded 17α-hydroxy-16α-methyl-substituted dehydropregnenolone acetate and its 3-hydroxy analog in high yield.

Development of an automated modular system for the synthesis of [11C]acetate

Carboxylation reactions offer a straightforward method for the synthesis of carbon-11 labelled carboxylic acids. Among these, the preparation of carbon-11 (C)-acetate is receiving increasing attention because of diagnostic applications in oncology in addition to its well-established use as a probe for myocardial oxidative metabolism. Although a number of dedicated modules are commercially available, the development of the synthesis on flexible platforms would be beneficial to widen the number of tracers, in particular for preclinical assessment and testing. In this study, the carboxylation reaction was implemented for the synthesis of sodium 1-[C]acetate after the classic route of carboxylation of methylmagnesium chloride by [C]carbon dioxide, followed by the acidic hydrolysis, purification and sterile filtration. This was performed using a commercially available kit of preassembled hardware units and fully compatible components of radiochemistry automation (VarioSystem). The system proved be to highly versatile and inexpensive and allowed a quick translation of the radiochemistry project into a working system even by less experienced personnel, because of predefined interfaces between electronic parts and operating software (preloaded on a laptop and included in the kit). The automatic module proved to be a simple and reliable system for the production of 1-[C]acetate that was prepared in 24 min (total synthesis time) with stable radiochemical yields (20% nondecay corrected) and high radiochemical purity (>97%). The module is used routinely to produce 1-[C]acetate for preclinical studies and is being implemented for the production of the labelled fatty acids.

The preparation of [pentane‐5,5,5‐3H3]‐abnormal‐cannabidiol

AbstractA bromoalkane precursor was synthesized in six steps, and its copper catalysed coupling with methylmagnesium chloride to provide unlabelled abnormal‐cannabidiol (1a) was optimized. The methodology was used for an analogous coupling using [3H3]‐methylmagnesium iodide to provide [pentane‐2H3]‐abnormal‐cannabidiol (1b). Copyright © 2010 John Wiley & Sons, Ltd.

Facile Synthesis of 1-Methyl-1H-benzo[b]azepines from 1-Methylquinolinium Iodides and Diazo(trimethylsilyl)methylmagnesium Bromide

The reaction of diazo(trimethylsilyl)methylmagnesium bromide,TMSC(MgBr)N 2 , with 1-methylquinolinium iodides followedby sequential ring expansion using copper(I) chloride gives 1-methyl-3-(trimethylsilyl)-1 H-benzo[ B]azepinesin moderate to good yields. Moreover, the trimethylsilyl group canbe removed or converted into a hydroxy(phenyl)methyl group.

Asymmetric Allylic Alkylation in Combination with Ring-Closing Metathesis for the Preparation of Chiral N-Heterocycles

Asymmetric copper-catalyzed allylic substitution with methylmagnesium bromide is employed in combination with ring-closing olefin metathesis or ene-yne metathesis to achieve the synthesis of chiral, unsaturated nitrogen heterocycles. The resulting six- to eight-membered chiral heterocycles are accessible in high yields and with excellent enantioselectivities.

Optimization of cation structure of imidazolium-based ionic liquids as ionic solvents for rechargeable magnesium batteries

A series of imidazolium cation-based ionic liquids (ILs) have been synthesized and examined as ionic solvents for rechargeable magnesium batteries. The electrolyte solutions consist of these ILs dissolving methylmagnesium bromide with tetrahydrofuran (MeMgBr/THF). The chemical structure of imidazolium cation much influenced the ionic conductivity and the electrochemical window of the system. A reversible process of cathodic deposition and anodic dissolution of magnesium has been successfully achieved at room temperature. The highest value of anodic peak current for magnesium dissolution was obtained in an optimized-structure IL with allyl and methoxyethyl groups as the substituents.

Modern Friedel-Crafts chemistry. Part 32. Facile synthesis of some new fused heteropolycycles via direct intramoleclar Friedel-Crafts cyclialkylations of suitable heteroarylalkanols

This study provides expedient methods for the synthesis of some novel fused heteropolycycles. Thus, a variety of fused di-, tri- and tetracyclic nitrogen and nitrogen-sulfur heteropolycycles 8, 9, 11-15 were smoothly synthesized by Friedel-Crafts intramolecular alkylations of heteroarylalkanols 1-7 in the presence of both Bronsted (PPA and PTSA) and Lewis (AlCl3/CH3NO2) acid catalysts. The precursor alkanols were readily prepared by reaction of the corresponding carboxylic acid esters with methylmagnesium iodide. The structures of the compounds are established using both spectral and analytical data. A plausible carbocation mechanism is proposed to account for the results.

Formal Synthesis of the Anti-Angiogenic Polyketide (−)-Borrelidin under Asymmetric Catalytic Control

Borrelidin (1) is a polyketide that possesses extremely potent anti-angiogenesis activity. This paper describes its formal total synthesis by the most efficient route to date. This modular approach takes optimal benefit of asymmetric catalysis and permits the synthesis of analogues; in addition, the high yields and selectivities obtained eliminate the need for separation of stereoisomers. The upper half of borrelidin has been accessed by iterative copper-catalysed asymmetric conjugate addition of methylmagnesium bromide, whereas synthesis of the lower half of the molecule was achieved by relying on asymmetric hydrogenation and cross-methathesis as key steps.

Enantioselective Copper‐Catalysed Allylic Alkylation of Cinnamyl Chlorides by Grignard Reagents using Chiral Phosphine‐Phosphite Ligands

AbstractThe copper(I)‐catalysed SN2′‐type allylic substitution of E‐3‐aryl‐allyl chlorides (cinnamyl chlorides) using Grignard reagents represents a powerful method for the synthesis of compounds carrying a benzylic stereocentre. By screening a small library of modular chiral phosphine‐phosphite ligands a new copper(I)‐based catalyst system was identified which allows the performance of such reactions with exceptional high degrees of regio‐ and enantioselectivity. Best results were obtained using TADDOL‐derived ligands (3 mol%), copper(I) bromide⋅dimethyl sulfide (CuBr⋅SMe2) (2.5 mol%) and methyl tert‐butyl ether (MTBE) as a solvent. Various (1‐alkyl‐allyl)benzene derivatives were prepared with up to 99% ee (GC) in isolated yields of up to 99%. In most cases the product contained less than 3% of the linear regioisomer (except for ortho‐substituted substrates). Both electron‐rich and electron‐deficient cinnamyl chlorides were successfully employed. The absolute configuration of the products was assigned by comparison of experimental and calculated CD spectra. The substrates were prepared from the corresponding alcohols by reaction with thionyl chloride. Initially formed mixtures of regioisomeric allylic chlorides were homogenised by treatment with CuBr⋅SMe2 (2.5 mol%) in the presence of triphenyl phosphine (PPh3) (3 mol%) in MTBE at low temperature to give the pure linear isomers. In reactions with methylmagnesium bromide (MeMgBr) an ortho‐diphenylphosphanyl‐arylphosphite ligand with an additional phenyl substituent in ortho′‐position at the aryl backbone proved to be superior. In contrast, best results were obtained in the case of higher alkyl Grignard reagents (such as ethyl‐, n‐butyl‐, isopropyl‐, and 3‐butenylmagnesium bromides) with a related ligand carrying an isopropyl substituent in ortho′‐position. The method was tested on a multi‐mmol scale and is suited for application in natural product synthesis.

Synthesis of 3-substituted 3H-indol-3-ols by the reaction of 2-isocyanophenyl ketones with Grignard reagents

Abstract A facile method for the synthesis of 3-substituted 3 H -indol-3-ols has been developed. Thus, 2-isocyanophenyl ketones are allowed to react with various Grignard reagents to give the corresponding desired indolol derivatives in generally fair to good yields. The formation of 3-aryl-2,3-dimethylindolin-3-ols by the reaction of 2-isocyanobenzophenones with 2 M amounts of methylmagnesium bromide is also reported.

New Dual Initiators To Combine Quasiliving Carbocationic Polymerization and Atom Transfer Radical Polymerization

New dual initiators, 3,3,5-trimethyl-5-chlorohexyl 2-bromopropionate (IB2BP) and 3,3,5-trimethyl-5-chlorohexyl 2-bromo-2-methylpropionate (IB2BMP), which contain initiating sites for both carbocationic polymerization and atom transfer radical polymerization (ATRP), were synthesized and used to create poly(isobutylene-b-methyl acrylate) (PIB-b-PMA) diblock copolymers. Initiator synthesis involved reaction of methyl 3,3-dimethyl-4-pentenoate with 2 equiv of methylmagnesium bromide, followed by hydroboration−oxidation of the double bond to yield 1,5-dihydroxy-3,3,5-trimethylhexane (DHTMH). IB2BP was synthesized by reaction of the primary hydroxyl group of DHTMH with 2-bromopropionyl bromide, followed by chlorination of the tertiary hydroxyl group with anhydrous HCl. IB2BMP was synthesized analogously using 2-bromo-2-methylpropionyl bromide. Both initiators displayed slow cationic initiation of isobutylene, leading to moderate initiation efficiencies (0.50 < Ieff < 0.80) at low temperature (−70 °C) and low mo...

Novel nucleosides as potent influenza viral inhibitors

Influenza virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified ((2 R,3 S,4 R,5 R)-3-acetoxy-5-(4-benzamido-2-oxopyrimidin-1(2 H)-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl) methyl benzoate ( 18c) as a potent influenza virus inhibitor. We now here report the synthesis and evaluation of a series of C-3′ modified ribose nucleosides. These novel compounds were prepared, primarily by taking known ((2 R,3 R,4 R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate ( 1) and converting it in to C-3 keto sugar ( 7), reacting C-3 keto group with methyl magnesium bromide, followed by coupling these sugars with purine and pyrimidine bases. Anti influenza viral activity was determined by screening against both A and B viral strains.

2-Isoxazolinium Salts and 3-Isoxazolines: Exploratory Chemistry and Uses for the Synthesis of Branched Amino Polyols and Amino Acids

2-Isoxazolines represent a well known class of heterocycles, readily accessible in particular by 1,3-dipolar cycloaddition of nitrile oxides to alkenes. 2-Isoxazolines are easily transformed into 2- isoxazolinium salts by N-methylation, and further into 3-isoxazolines by deprotonation. In contrast to the parent system, less is known concerning the chemistry of the derived classes, and potential applications in synthesis. - 2-Isoxazolinium salts, due to their iminium part, are prone to the attack of nucleophiles, and examples for this, addition of hydride (reduction) and C-nucleophiles like methylmagnesium bromide, cyanide, methane nitronate, and malonate are given. With these adducts, syntheses of β - and α-amino acids with OH-containing side chains have been effected. The cyanide products also are useful as precursors of branched, unsymmetrical 1,2-diamino polyols. - On the other hand, 3-isoxazolines due to their oxy-enamine part, represent species with nucleophilic sites and therefore react with electrophilic reagents. Examples given are [3+2] cycloadditions with nitrile oxides, [2+2] cycloadditions with dimethyl acetylenedicarboxylate, and [2+1] cycloaddition in the form of epoxidation which, however, led to a dihydro-1,3-oxazine nitrone by initial attack at the nitrogen atom, in an unprecedented oxidation/N-dealkylation/rearrangement sequence.