Highly functionalized organomagnesium reagents prepared through halogen-metal exchange

Organomagnesium reagents occupy a central position in synthetic organic and organometallic chemistry. Recently, the halogen-magnesium exchange has considerably extended the range of functionalized Grignard reagents available for synthetic purposes. Functional groups such as esters, nitriles, iodides, imines, or even nitro groups can be present in a wide range of aromatic and heterocyclic organomagnesium reagents. Also various highly functionalized alkenyl magnesium species can be prepared. These recent developments as well as new applications of organomagnesium reagents in cross-coupling reactions and amination reactions will be covered in this Review.     

35 years of palladium-catalyzed cross-coupling with Grignard reagents: how far have we come?

This tutorial review is intended to provide the reader with a timely review of major developments and the current state-of-the-art of palladium-catalyzed cross-coupling reactions with Grignard reagents. Organomagnesium reagents, the most reactive and most easily accessible nucleophiles for carbon-carbon bond forming cross-coupling reactions, were the first nucleophiles ever employed in cross-coupling reactions, but have only recently been re-discovered for highly efficient and (stereo)selective coupling reactions. This is mostly a consequence of improved catalyst systems with bulky phosphine, phosphonate or carbene ligands and new metal-halogen exchange procedures for the generation of functionalized Grignard reagents.     

Total Synthesis of Carpacin and its Geometric Isomer as a Cancer Chemopreventer

Carpacin ( 1a ), an antidepressant in Asiatic folk medicine from the Carpano tree, is achieved in which the longest linear sequence is only four steps in over all yield 67% from commercially available Sesamol. The key transformations in the synthesis are the selective palladium‐catalyzed coupling reactions of aryl bromide with Grignard reagents. The first preparation of its geometric isomer ( 1b ) is described. Highlights of the synthesis include Pd‐catalyzed coupling, selective hydrogenation, and Wittig reactions. Carpacin was examined as a potential inhibitor of carcinogenesis.     

Grignard Reactions Involving Halogenated Pyrimidines

Generally, there are two pathways that involve Grignard reagents and halogenated pyrimidines. The more common approach shows cross‐coupling reactions that utilize a Grignard reagent, either alkyl or aryl, with a variety of halogenated pyrimidines. Typically, these reactions are catalyzed by Fe, Co, Ni, Pd, Mn, or Zn species. Alternatively, but to a lesser degree, halogenated pyrimidines form pyrimidyl Grignard reagents, which then further react either in a cross‐coupling manner or via a standard addition process. Finally, there are a few examples in which Grignard reagents react with pyrimidines via an addition process that does not involve a halogen.     

Kinetically Controlled,Highly Chemoselective Acylation of Functionalized Grignard Reagents with Amides by N−C Cleavage

The direct transition-metal-free acylation of amides with functionalized Grignard reagents by highly chemoselective N−C cleavage under kinetic control has been accomplished. The method offers rapid and convergent access to functionalized biaryl ketones through transient tetrahedral intermediates. The direct access to functionalized Grignard reagents by in situ halogen–magnesium exchange promoted by the versatile turbo-Grignard reagent (iPrMgCl ⋅ LiCl) permits excellent substrate scope with respect to both the amide and Grignard coupling partners. These reactions enable facile, operationally simple and chemoselective access to tetrahedral intermediates from amides under significantly milder conditions than chelation-controlled intermediates. This novel direct two-component coupling sets the stage for using amides as acylating reagents in an alternative paradigm to the metal-chelated approach, acyl metals and Weinreb amides.     

Synthesis of carboxylic amides by ring-opening of oxazolidinones with Grignard reagents

Treatment of N-alkyl-oxazolidin-2-ones with Grignard reagents gives tertiary carboxylic amide products. Various substituted oxazolidinones can be used as illustrated with phenyl, benzyl or isopropyl groups on the 4-position, and methyl, benzyl or p-methoxybenzyl groups on the 3-position (the nitrogen atom). A selection of Grignard reagents were successful, including allyl, benzyl, alkyl and phenyl magnesium halides. The organomagnesium species attacks the carbonyl group and promotes ring-opening of the oxazolidinone. The product tertiary amides are useful substrates for stereoselective transformations and were applied to a highly selective enolate alkylation and to a ring-closing metathesis reaction to a six-membered lactam and hence a formal synthesis of the alkaloids (-)-coniine and (+)-stenusine.     

Diversity‐Oriented Enantioselective Synthesis of Highly Functionalized Cyclic and Bicyclic Alcohols

The copper‐catalyzed hetero‐allylic asymmetric alkylation (h‐AAA) of functionalized Grignard reagents that contain alkene or alkyne moieties has been achieved with excellent regio‐ and enantioselectivity. The corresponding alkylation products were further transformed into a variety of highly functionalized cyclic and bicyclic alcohols with excellent control over the chemo‐, regio‐, and stereoselectivity.     

Reactifs de Grignard vinyliques γ fonctionnels : III. Addition a quelques derives carbonyles

Δt^α,β-Butenolides can be obtained by carbonation of γ-functionally substituted vinylic Grignard reagents, prepared by addition of organomagnesium compounds to α-acetylenic or α-allenic alcohols. By addition to aldehydes and ketones, these vinylic Grignard reagents yield diols, which give unsaturated ethers by cyclization reactions.     

Chemoselective Chromium(II)‐Catalyzed Cross‐Coupling Reactions of Dichlorinated Heteroaromatics with Functionalized Aryl Grignard Reagents

Chromium(II) chloride catalyzes the chemoselective cross‐coupling reaction of dichloropyridines with a range of functionalized (hetero)aromatic Grignard reagents at room temperature. Functional groups, such as esters and acetals, are well tolerated in this transformation. Previously challenging substrates, quinolines and isoquinolines, participate in the selective Cr‐catalyzed cross‐coupling in cyclopentyl methyl ether (CPME) as the solvent. The effective purging of Cr salts is demonstrated by using various solid supports.     

Effective and Selective Mild Catalytic Hydrodehalogenation of Halocyclopropanes: Preparative Capabilities and Mechanistic Aspects

This review surveys both data obtained by the authors and published data on the partial or full hydrodehalogenation of di- and polyhalocyclopropanes (chlorides and bromides) with Grignard reagents catalyzed by titanium or zirconium compounds. The factors affecting the efficiency and selectivity of the hydrodebromination of bromocyclopropanes are considered: the nature of Grignard reagents (including isotopically labeled reagents), their transformations and effects in catalyzed and uncatalyzed reactions, the participation of solvents, catalytic and stoichiometric amounts of the catalyst, etc. A scheme is proposed in which the key steps of the mechanism of hydrodebromination of bromocyclopropanes includes three blocks of reactions: (a) the generation of a catalytically active Ti(II) species; (b) the hydrodehalogenation of bromocyclopropanes involving electron transfer from a low-valent catalyst species, formation of the cyclopropyl radical, and stabilization of this radical as a result of hydrogen atom transfer from the solvent molecule; and (c) transformations of previously formed radical species, such as dimerization and disproportionation (for example, of radical species generated from Grignard reagents or ether molecules) or the linking of alkyl radicals to radical species produced from solvent molecules.     

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.     

Gold‐Catalyzed Synthesis of Iodofulvenes

We report the gold‐catalyzed synthesis of highly functionalized iodofulvenes from iododialkynes under mild conditions. The catalytic cycle involves the formation of gold acetylides and vinylgold intermediates. These intermediates can then undergo an unprecedented iodine/gold exchange. This new pathway for catalyst transfer in dual gold catalysis opens up the possibility of highly regioselective transformations directed by the gold in the organogold intermediates. The resulting products are well suited for further metal‐mediated coupling reactions, allowing the synthesis of extended π‐systems.     

Palladium‐Catalyzed Dearomative syn‐1,4‐Carboamination with Grignard Reagents

A protocol for palladium‐catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one‐pot method features a visible‐light‐mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium‐catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn‐1,4‐selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.     

Transition metal catalyzed carbon-silicon bond forming reactions using chlorosilanes promoted by Grignard reagents

New catalytic C--Si bond-forming reactions using chlorosilanes are described. These reactions proceed efficiently under mild conditions by the combined use of Grignard reagents and transition metal catalysts, such as Ti, Zr, Ni, and Pd. It is proposed that ate complex intermediates formed by the reaction of transition metals with Grignard reagents play important roles as the active catalytic species. The present study demonstrates the practical use of chlorosilanes in transition metal catalyzed silylation reactions providing convenient methods for allyl- or vinylsilane synthesis. The reaction pathways of these transformations as well as the scope and limitations are discussed.     

新型有机镁试剂的研究进展

介绍了双格氏试剂、镁杂碳环化合物和含有多官能团的格氏试剂的制备、反应化学及在有机合成中的应用等。     

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.     

Functionalized magnesium organometallics as versatile intermediates for the synthesis of polyfunctional heterocycles

In the last few years, we have demonstrated that the halogen/magnesium-exchange reaction is a unique method for preparing a variety of new functionalized aryl, alkenyl, heteroaryl magnesium compounds which has considerably extended the range of functionalized Grignard reagents available for synthetic purposes. A variety of functional groups such as an ester, nitrile, iodide, imine and even sensitive groups like nitro, hydroxyl and boronic ester can be tolerated in these organomagnesium compounds. We wish to describe the application of this halogen/magnesium-exchange reaction for the preparation of a broad range of five- and six-membered functionalized heteroaryl magnesium compounds and their reactions with various electrophiles providing a new entry to a range of polyfunctional heterocycles such as thiophene, furan, pyrrole, imidazole, thiazole, antipyrine, pyridine, quinoline and uracil derivatives.     

Iron‐Catalyzed Stereoselective Cross‐Coupling Reactions of Stereodefined Enol Carbamates with Grignard Reagents

A practical and highly stereoselective iron‐catalyzed cross‐coupling reaction of stereodefined enol carbamates and Grignard reagents to yield tri‐ and tetrasubstituted acrylates is reported. A facile method for the stereoselective generation of these enol carbamates has also been developed.     

Reactivite des organomagnesiens vis-a-vis de composes acetyleniques en presence du complexe de nickel (PPh3)2NiCl2

In the presence of dichlorobis(triphenylphosphine) nickel, acetylenic compounds undergo stereospecific or stereoselective syn addition of non recuding Grignard reagent. With reducing Grignard reagents, addition and reduction reactions are observed. These reactions yield vinylic organomagnesium compounds. A catalytic process is proposed to explain the experimental results.     

Iron-copper cooperative catalysis in the reactions of alkyl Grignard reagents: exchange reaction with alkenes and carbometalation of alkynes

Iron-copper cooperative catalysis is shown to be effective for an alkene-Grignard exchange reaction and alkylmagnesiation of alkynes. The Grignard exchange between terminal alkenes (RCH═CH(2)) and cyclopentylmagnesium bromide was catalyzed by FeCl(3) (2.5 mol %) and CuBr (5 mol %) in combination with PBu(3) (10 mol %) to give RCH(2)CH(2)MgBr in high yields. 1-Alkyl Grignard reagents add to alkynes in the presence of a catalyst system consisting of Fe(acac)(3), CuBr, PBu(3), and N,N,N',N'-tetramethylethylenediamine to give β-alkylvinyl Grignard reagents. The exchange reaction and carbometalation take place on iron, whereas copper assists with the exchange of organic groups between organoiron and organomagnesium species through transmetalation with these species. Sequential reactions consisting of the alkene-Grignard exchange and the alkylmagnesiation of alkynes were successfully conducted by adding an alkyne to a mixture of the first reaction. Isomerization of Grignard reagents from 2-alkyl to 1-alkyl catalyzed by Fe-Cu also is applicable as the first 1-alkyl Grignard formation step.