Reaction Of Grignard Reagents Research Articles

Copper‐Catalyzed Cross‐Coupling Reaction of Grignard Reagents with Primary‐Alkyl Halides: Remarkable Effect of 1‐Phenylpropyne

A general get-together: The Cu-catalyzed cross-coupling reaction of primary-alkyl halides with primary-, secondary-, and tertiary-alkyl and phenyl Grignard reagents proceeds efficiently in THF under reflux in the presence of 1-phenylpropyne (see scheme). The reaction is also applicable to alkyl mesylates (OMs) and tosylates (OTs). The reactivities of alkylX with a Grignard reagent increase in the order X=Cl<F<OMs<OTs<Br. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z603451_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Copper‐Catalyzed Cross‐Coupling Reaction of Grignard Reagents with Primary‐Alkyl Halides: Remarkable Effect of 1‐Phenylpropyne

Copper‐Catalyzed Cross‐Coupling Reaction of Grignard Reagents with Primary‐Alkyl Halides: Remarkable Effect of 1‐Phenylpropyne

Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions

2-Methyltetrahydrofuran (MeTHF) is a commercially available solvent that is produced from renewable resources. The properties of MeTHF place it between tetrahydrofuran (THF) and diethyl ether in solvent polarity and Lewis base strength. In many cases, MeTHF can replace THF in organometallic reactions. The formation and reaction of Grignard reagents in MeTHF and THF are similar. MeTHF can be used as a solvent for low-temperature lithiation, for lithium aluminum hydride reductions, for the Reformatsky reaction, and for metal-catalyzed coupling reactions. MeTHF is also a good substitute for dichloromethane in biphasic reactions.

Simple Method for the Preparation of Esters from Grignard Reagents and Alkyl 1-Imidazolecarboxylates

The reaction of Grignard reagents with alkyl imidazolecarboxylates, which were prepared from alcohols with carbonyl diimidazole, gave the corresponding esters in good to excellent yields. This method conveniently provides esters from alkyl halides and alcohols by C1-carbon chain extension.

Studies on the Titanium‐Catalyzed Cyclopropanation of Nitriles.

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REACTIONS OF 5-[1-(2-PHENYL)METHYLIDENE]-3-PHENYLIMIDAZOLIDINE-2,4-DIONES WITH SOME ORGANOMETALLIC REAGENTS

The reaction of Grignard reagents with 5-[1-(2-chlorophenyl)methylidene]-3-phenylimidazolidine-2,4-dione, 4 , and 5-[1-(2-bromophenyl)methylidene]-3-phenylimidazolidine-2,4-dione, 5 , gave exclusively 1,2-addition products, 6-8 , in 70-80% yields. Lithium dibutylcuprate reacted with 4 to yield exclusively 1,2-addition product 9 (92%). No conjugate or 1,4-addition products were obtained. These results indicate that 5-[1-(2-phenyl)methylidene]-3-phenylimidazolidine-2,4-diones do not react like normal unsaturated carbonyl compounds. KEY WORDS : Imidazolidine-2,4-diones, a,b-Unsaturated carbonyl compounds, 1,2-Addition, conjugate addition, Grignard reagents, Lithium dibutylcuprate Bull. Chem. Soc. Ethiop. 2005, 19(1), 55-60.

Researchers in This Field Still Have Many Challenges in Front of Them, but the Future is Indeed Very Bright

The cross-coupling reaction is old enough that even I, no longer a young scientist, learned about it in college. Indeed, the problem of coupling sp-based carbon nucleophiles and electrophiles was recognized as being important but difficult as long ago as 1941 by Kharasch, who found that coupling reactions of Grignard reagents worked better when traces of transition metals were present in the system. As it often happens in science, the seeds for the discovery of this excitingmodern synthetic tool lay dormant in the fertile soil of the scientific literature until the groups of Kochi, Corriu, and Kumada, among others, realized in 1971–1972 that discrete transition metal catalysts (Ag, Fe, Ni) can be devised to carry out these reactions in good yield and with some generality. Palladium rose to center stage more slowly a few years later, through thework ofMurahashi, followedbymanyothers. But Grignard reagents were not the only organometallic species in the world, and indeed not the most synthetically useful. Negishi and co-workersmust be credited with bringing more practical reagents into the menu of the synthetic organic chemist, i.e., Al, Zr and the now very popular Zn derivatives. Indeed, among practitioners, cross-coupling reactions involving organozinc reagents are now referred to as “Negishi couplings”. In 1968, even before the cross-coupling reactionmade it to the forefront of organic synthesis, Richard Heck had brought to light the reaction that now bears his name. His first entry into the field was a stunning series of seven consecutive papers with his name as the only author. The innumerable important observations contained in these early papers and those which soon followed transformed this unusual reaction into a general synthetic method. It has taken the synthetic community many years to realize the immense potential of theHeck reaction, and in the last 20 years countless refinements, extensions (e.g., enantioselective cyclizations), and applications have been reported. In 1975, Sonogashira found that alkynes could be coupled directly with carbon electrophiles, without preparing first an organometallic reagent, if both a Pd and aCu catalyst were used in tandem. The Sonogashira coupling is now a very popular synthetic tool in academia as well as in industry. In the late 1970s, tin derivativeswere shown to also undergo Pd-catalyzed coupling with a broad range of electrophiles, mainly through the work of Kosugi and Migita and Stille. These couplings are now referred to as the “Stille reaction”, and constitute an extremely important tool in the discovery of pharmaceuticals, the total synthesis of complex natural products, the synthesis of materials and devices, etc. It turned out to be more difficult to induce boron to undergo this reaction. I was a graduate student at the University of Alberta when I saw Akira Suzuki lecture for the first time. I was told by the organizers that Prof. Suzuki was going to disclose an important unpublished result. I listened carefully as he told us how he andNorio Miyaura had just found that organoboron compounds, easily available through a variety of synthetic means, can be made to cross-couple through the formation of “ate” complexes. The Suzuki reaction had been born. For us in the pharmaceutical industry, this is now the most practical way to cross-couple aromatics and heteroaromatics, and we have become quite skilled COMMENTARIES

Selective Iron‐Catalyzed Cross‐Coupling Reactions of Grignard Reagents with Enol Triflates, Acid Chlorides, and Dichloroarenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Selective Iron‐Catalyzed Cross‐Coupling Reactions of Grignard Reagents with Enol Triflates, Acid Chlorides, and Dichloroarenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

AB INITIO MO CALCULATION STUDIES FOR SEVERAL NOVEL ENTRIES TO TROPANE COMPOUNDS

Tropane alkaloids are generally known as anticholinergics. Radiolabeled tropane compounds could be brain imaging agents used in biomedical imaging technique positron emission tomography (PET). A novel entry to aryltropane analogs of cocaine was developed based on the conjugate addition reaction of Grignard reagents phenylmagnesium (10), (4'-isopropenylphenyl)magnesium (11), or 2-naphthylmagnesium bromide (12) to α,β-unsaturated esters anhydroecgonine methyl ester (9) or t-butyl ester (13) which gave several aryltropanes (1–8) with high binding affinities for dopamine and serotonin transporters. Basic conditions are frequently employed in the radiolabeling chemistry of many aryltropane cocaine analogs (1–8b, 14–24b). However, isomerization at C-2 position can also occur under basic conditions, resulting in loss of the biologically potent 2β-isomers (1–8b, 14–24b) by conversion to the much less active 2α-isomer (1–8a, 14–24a). Tropinone (25) could be envisaged as a convenient starting material for the synthesis of diverse tropane alkaloids. A novel entry into tropane alkaloid intermediates was developed based on the ring-opening reaction of tropinone. In this reaction, the enolate of tropinone, resulting from deprotonation with lithium diisopropylamide [ LDA , LiN ( CHMe 2)2] or sodium bis(trimethylsilyl)amide [ NaN ( SiMe 3)2] was treated with alkyl chloroformate to give a novel, structurally unique class of tropane alkaloid intermediates 6-N-carboalkyoxy-N-methyl-2-cycloheptenone (26), 1-alkyoxycarboxy-6-N-carboalkoxy-N-methyl-2,7-cyclohept-dien (27) and 6-N-carboalkyoxy-N-methyl-7-carboalkoxy-2,7-cyclohept-dien-ol (28). In this paper we study the conjugate addition reaction of Grignard reagents to α,β-unsaturated esters, the isomerization of aryltropane cocaine analogs, and the ring-opening reaction of tropinone by ab initio MO calculation at the Hartree–Fock (HF) level. The calculation results solely in terms of energetics indicate that the 2α-isomers (equatorial configurations) of aryltropane cocaine analogs are more stable than their 2β-isomers (axial configurations), at the AM1, STO-3G and 3-21G(*) levels, and the Grignard 1,4- and then 1,2-addition (double addition) products (2, 4, 5 and 7) are likely more stable than the Grignard 1,4-addition (single addition) products (1, 3, 6 and 8), respectively, at the STO-3G and 3-21G(*) levels except at the AM1 level. Therefore the tendency of Grignard addition toward double addition is competitive with single addition, and the isomerization tends to the formation of more stable 2α-isomers. Likewise, the calculation results solely in terms of energetics indicate that the stability of the reaction product forms is 28&gt;27&gt;26, at the AM1, STO-3G and 3-21G(*) levels, and the tendency of alkyl chloroformate addition toward double addition to the products 27 and 28 is competitive with single addition to the products 26. Ab initio MO calculations provide a theoretical rationalization for the chemoselectivity of the conjugate addition reaction and the ring-opening reaction, the most stable configurations of reaction products (1–8, 14–24, 26–28), and the isomerization between 1–8b, 14–24b and 1–8a, 14–24a, and between 27 and 28.

Reactions of Grignard reagents with 1,3-dicyanoadamantane

Reactions of Grignard reagents RMgX (R = Me, Et, Pr, Bu; X = Br, I) with 1,3-dicyanoadamantane (1) were studied. Optimum conditions for the synthesis of monoaddition products of Grignard reagents to compound 1 were established. The first stage of the reaction of cyanoadamantane 1 with MeMgBr was studied by the MNDO-PM3 method. According to calculations, the more preferable reaction mechanism involves formation of a six-membered cyclic intermediate containing two Mg atoms, two C atoms, and one Br and one N atom.

Reactions of a phosphavinyl Grignard reagent with main group mono-halide compounds

The reactions of a phosphavinyl Grignard reagent, [CyPC(Bu t )MgCl(OEt 2)] Cy=cyclohexyl, with a variety of main group 13, 14 and 16 mono-halide compounds have been investigated. When the Grignard reagent is reacted with bromocatecholborane the terminal phosphavinyl complex, [(C 6H 4O 2)B{C(Bu t )PCy}], is formed. Related terminal phosphavinyl tin and gallium complexes, [R 3Sn{C(Bu t )PCy}], R=Me or Bu n and [IGa{C(Bu t )PCy} 2], have been prepared by similar routes. The reaction of the Grignard reagent with PhSeCl has afforded a new λ 5,λ 5-diphosphete, [{(Bu t )CP(Cy)(SePh)} 2], the mechanism of formation of which is discussed. The preparation of a phosphavinyl selenium compound, [(C 8H 4O 2N)PC(Bu t )(SePh)], is also described. All compounds have been spectroscopically characterised and several have been crystallographically authenticated.

Reaction of Grignard Reagents with Diethyl Perfluoroacyl (1‐Cyanoethyl) phosphonates. Synthesis of Perfluoroalkylated α, β‐Unsaturated Nitriles with Predominant Z‐Selectivity

AbstractDiethyl (1‐cyanoethyl) phosphorate 1 was reacted with n‐butyl‐lithium in tetrahydrofuran (THF) at ‐ 78 °C and the resulting carbanion 2 reacted with perfluoroalkanoic add anhydride to afford perfluoroacylated phosphorate 3. Without isolation 3 was attacked by Grignard reagents giving perfluoroalkylated α, β‐unsaturated nitriles in 46%‐88% yields with high Z‐stereoselectivity (Z: E = 89–62:11–38).

ChemInform Abstract: Highly Enantioselective Desymmetrization of Anhydrides by Carbon Nucleophiles: Reactions of Grignard Reagents in the Presence of (‐)‐Sparteine.

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The interaction of phosphavinyl Grignard reagents with group 15 halides: synthesis and structural characterisation of novel heterocyclic and heterocage compounds

The reactions of a phosphavinyl Grignard reagent, [CyPC(But)MgCl(OEt2)], Cy = cyclohexyl, with a variety of group 15 halide compounds in a number of stoichiometries have been investigated. When the Grignard reagent is reacted with Ph2PCl or CyPCl2, Cy = cyclohexyl, in a 1∶1 and 2∶1 stoichiometry respectively, the 1,3-diphosphapropene, Ph2PC(But)PCy, and triphosphabicyclo[2.1.0]pentane compound, CyP{C2(But)2P2Cy2}, are formed. The 2∶1 and 3∶1 reactions of the Grignard reagent with either PCl3 or AsCl3 lead to the strained triphospha- and arsadiphosphabicyclo[1.1.1]pentanes, ButC{μ-P(Cy)}2{μ-ECl}CBut, E = P or As in moderate yield. The related 1∶1 reaction of the Grignard reagent with PCl3 affords two products, a phosphino-substituted phosphorus ylide, Cl2PC(But)P(Cy)(Cl)2, and a tetraphosphabicyclo[2.1.1]hexane, ButC{μ-P(Cl)P(Cy)}{μ-P(Cy)}{μ-P(Cl)}CBut, the mechanism of formation of which is discussed. An analogous 1∶1 reaction of the Grignard reagent with SbCl3 led to an unusual heterocyclic compound, (Cl2Sb)(But)CSb(Cl)C(But)P(Cl)(Cy)P(Cy), which quantitatively decomposes in solution to yield the known 1,2-dihydro-1,2-diphosphete, P2(Cy)2C2(But)2. All prepared compounds have been crystallographically characterised.

Highly enantioselective desymmetrization of anhydrides by carbon nucleophiles: reactions of Grignard reagents in the presence of (-)-sparteine.

Highly enantioselective desymmetrization of anhydrides by carbon nucleophiles: reactions of Grignard reagents in the presence of (-)-sparteine.

Highly Enantioselective Desymmetrization of Anhydrides by Carbon Nucleophiles: Reactions of Grignard Reagents in the Presence of (−)-Sparteine

Wo andere chirale Liganden scheiterten, konnte (−)-Spartein erfolgreich zur Komplexierung von Grignard-Reagentien verwendet werden, mit denen die Desymmetrisierung einer Reihe von Anhydriden mit guter Enantioselektivität gelang (bis zu 92 % ee; siehe Schema). Durch (−)-Spartein chiral modifizierte Organolithiumreagentien sind in der asymmetrischen Synthese gut etabliert, doch entsprechende (−)-Spartein-kontrollierte Reaktionen mit Grignard-Reagentien sind noch selten.

Grignard reactions of 4-substituted-2-keto-1,3-dioxanes: highly diastereoselective additions controlled by a remote alkyl group.

[see reaction]. The reactions of Grignard reagents with a representative series of simple cis-2-keto-4-substituted-1,3-dioxanes have been investigated. The stereochemical outcome of these highly diastereoselective additions (dr > 90:10) is consonant with Cram's chelate model on the assumption that RMgX coordinates preferentially with the ring oxygen remote from the C(4) substituent.

The bisected s-trans conformation-controlled highly stereoselective addition of Grignard reagents to C-cyclopropylaldonitrone. An efficient synthesis of 1-phenyl-2-[(S )-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides, a new class of potent NMDA receptor antagonists

An efficient synthesis of 1-phenyl-2-[(S)-1-aminoethyl]- and 1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamides [1a (PEDC) and 1b (PPDC), respectively], potent NMDA receptor antagonists having a cyclopropane structure, was achieved. We have shown for the first time that C-cyclopropylaldonitrone preferentially exists in the bisected s-trans conformation, due to the characteristic stereoelectronic effects of the cyclopropane ring, by X-ray crystallographic analysis, NMR studies, and theoretical calculations. Based on these findings, the highly stereoselective addition reaction of Grignard reagents to C-cyclopropylaldonitrone 6 was developed, and the reaction was successfully used as the key step for the preparation of the NMDA receptor antagonists 1a and 1b as well as for a newly designed isopropyl-type congener 1c. The facial selectivity of the addition of Grignard reagents can be explained by the attack of the reagents from the less hindered side of the substrate in the predicted bisected s-trans conformation. This Grignard reaction is the first example of a highly stereoselective addition to a nitrone via a non-chelation controlled pathway.

ChemInform Abstract: Reactions of Grignard Reagents with Bis- and Monophosphonium Ions in situ Generated from Bu3P and Dicarboxylic Acid Dichlorides or ω-Ethoxycarbonyl Alkanoyl Chlorides as a Novel Method to Obtain Diketones and Ketoesters.

ChemInform Abstract: Reactions of Grignard Reagents with Bis- and Monophosphonium Ions in situ Generated from Bu3P and Dicarboxylic Acid Dichlorides or ω-Ethoxycarbonyl Alkanoyl Chlorides as a Novel Method to Obtain Diketones and Ketoesters.