Conjugate Addition Of Organometallic Reagents Research Articles

Persistent guaiazulene arylmethylium ions as electrophilic traps for metal enolates.

Guaiazulene-stabilized cations reacted with metal enolates affording carbonyl compounds with an azulene moiety. Metal enolates generated by asymmetric conjugate addition of organometallic reagents led to enantioenriched products. Additionally, guaiazulene-substituted cations efficiently react with silyl enol ethers. DFT calculations allowed estimation of the electrophilicities of the carbocations. Reaction progress was monitored by a decrease in the reactant's Vis-light absorption and an increase in the product's anti-Kasha emission.

Synthetic Approaches to 2‐Alkylthiochroman‐4‐ones and Thioflavanones

2‐Alkylthiochroman‐4‐ones have been synthesized by acid‐catalyzed cyclodehydration of 3‐alkyl‐3‐(phenylthio)propanoic acids, Friedel–Crafts acylation of 3‐alkyl‐3‐(phenylthio)propanoyl chlorides with Lewis acids, direct reaction of thiophenols and acrylic acids using CF3SO3H, and 1,4‐addition of organometallic reagents to thiochromones. Furthermore, thioflavanones have been synthesized by cyclization of 3‐phenyl‐3‐(phenylthio)propanoyl chlorides with Lewis acids, incorporation of sulfur atoms into 2'‐halochalcones and subsequent cycloelimination, 1,4‐addition of S‐protected chalcones, direct condensation of 2'‐mercaptoacetophenone with arylaldehydes using lithium diisopropylamide, conjugate addition of organometallic reagents to thiochromones, and hydrogenation of thioflavones.

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors.

The copper-catalyzed enantioselective conjugate addition (ECA) of organometallic nucleophiles to electron-deficient alkenes (Michael acceptors) represents an efficient and attractive methodology for providing a wide range of relevant chiral molecules. In order to increase the attractiveness of this useful catalytic transformation, some Michael acceptors bearing challenging electron-deficient functions (i.e., aldehydes, thioesters, acylimidazoles, N-acyloxazolidinones, N-acylpyrrolidinones, amides, N-acylpyrroles) were recently investigated. Remarkably, only a few chiral copper-based catalytic systems have successfully achieved the conjugate addition of different organometallic reagents to these challenging Michael acceptors, with excellent regio- and enantioselectivity. Furthermore, thanks to their easy derivatization, the resulting chiral conjugated products could be converted into various natural products. The aim of this tutorial review is to summarize recent advances accomplished in this stimulating field.

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides.

The conjugate addition of organometallic reagents to α,β-unsaturated carbonyls represents an important method to generate C-C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild "one-pot" preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic α,β-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

Conjugate Addition of Perfluoroarenes to α,β-Unsaturated Carbonyls Enabled by an Alkoxide-Hydrosilane System: Implication of a Radical Pathway.

Conjugate addition of organometallic reagents to α,β-unsaturated carbonyls is a key strategy for the construction of carbon-carbon bond in organic synthesis. Although direct C-H addition to unsaturated bonds via transition metal catalysis is explored in recent years, electron-deficient arenes that do not bear directing groups continue to be challenging. Herein we disclose the first example of a conjugate addition of perfluoroarenes to α,β-unsaturated carbonyls enabled by an alkoxide-hydrosilane system. The reaction is convenient to carry out at room temperature over a broad range of substrates and reactants to furnish synthetically versatile products in high to excellent yields. Mechanistic experiments in combination with computational studies suggest that a radical pathway is most likely operative in this transformation. The hypervalent silicate and silanide species, which are relevant to the proposed mechanism, were observed experimentally by NMR and single crystal X-ray diffraction analyses.

Nickel-Catalyzed Reductive Conjugate Addition of Primary Alkyl Bromides to Enones To Form Silyl Enol Ethers.

Conjugate addition of organometallic reagents to enones to form silyl enol ether products is a versatile method to difunctionalize activated olefins, but the organometallic reagents required can be limiting. The reductive cross-electrophile coupling of unhindered primary alkyl bromides with enones and chlorosilanes to form silyl enol ether products is catalyzed by a nickel-complexed ortho-brominated terpyridine ligand. The conditions are compatible with a variety of cyclic/acyclic enones and functional groups.

Ultrasound-Assisted Conjugate Addition of Organometallic Reagents to 3-Diethylphosphonocoumarin

A comparative investigation on the 1,4-conjugate addition of various nucleophiles to diethyl ester of 2-oxo-2 H -1-benzopyran-3-phosphonic acid under thermal and ultrasound promoted conditions is presented. The approach enables the usage of a simpler experimental setup and mild reaction conditions as well as excellent yield reproducibility. The trans isomers isolated showed high diastereoselectivity and the absolute structure of one of the products was confirmed by X-ray diffraction analysis.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Conjugate Addition of Organometallic Reagents to Extended Michael Acceptors

AbstractReview: [42 refs.

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

The copper-catalyzed asymmetric conjugate addition (ACA) of nucleophiles onto polyenic Michael acceptors represents an attractive and powerful methodology for the synthesis of relevant chiral molecules, as it enables in a straightforward manner the sequential generation of two or more stereogenic centers. In the last decade, various chiral copper-based catalysts were evaluated in combination with different nucleophiles and Michael acceptors, and have unambiguously demonstrated their usefulness in the control of the regio- and enantioselectivity of the addition. The aim of this review is to report recent breakthroughs achieved in this challenging field.

ChemInform Abstract: Enantio‐ and Regioselective Conjugate Addition of Organometallic Reagents to Linear Polyconjugated Nitroolefins.

AbstractThe copper‐catalyzed addition of trialkylaluminum reagents to polyconjugated olefins using a ferrocene‐based phosphine ligand affords selectively 1,4‐addition products with high enantioselectivity.

Enantio‐ and Regioselective Conjugate Addition of Organometallic Reagents to Linear Polyconjugated Nitroolefins

The copper-catalysed conjugate addition of trialkylaluminium and dialkylzinc reagents to polyconjugated nitroolefins (nitrodiene and nitroenyne derivatives) is reported. A reversed Josiphos ligand L7 allows for the selective 1,4- or 1,6-addition with high enantioselectivities.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Conjugate Addition to Challenging Michael Acceptors and Synthesis of Relevant Target Molecules

AbstractReview: 56 refs.

Copper-catalyzed Asymmetric Conjugate Addition to Challenging Michael Acceptors and Synthesis of Relevant Target Molecules

We report herein the enantioselective Cu-catalyzed conjugate addition of organometallic reagents to sensitive Michael acceptors and their application to the synthesis of relevant target molecules. This is one of the most important methodologies to form a C-C bond in an enantioselective manner. A wide range of α,β-unsaturated aldehydes and β,γ-unsaturated-α-ketoesters has been successfully used. Reactivity, regio- and enantioselectivities were strongly dependent on the reaction conditions, therefore moderate to very good results were obtained. Furthermore, γ-substituted-α-ketoesters were used as chiral building blocks for further derivatization with complete retention of the chiral information to obtain key compounds.

Enantioselective Copper‐Catalyzed Conjugate Addition of Trimethylaluminium to β,γ‐Unsaturated α‐Ketoesters

Not a cop out: The copper-catalyzed asymmetric conjugate addition of organometallic reagents to Michael acceptors is an important methodology for forming a CC bond in an enantioselective manner. Such an addition of Me3Al to β,γ-unsaturated α-ketoesters is described to proceed in high yield and selectivity. CuTC=copper(I) thiophene-2-carboxylate.

ChemInform Abstract: Asymmetric Conjugate Addition of Organometallic Reagents to Chiral . alpha.,β-Unsaturated Esters.

ChemInform Abstract: Asymmetric Conjugate Addition of Organometallic Reagents to Chiral . alpha.,β-Unsaturated Esters.

ChemInform Abstract: Enantioselective Conjugate Addition of Organometallic Reagents to Cycloalkenones by the Aid of Chiral Lactam-Phosphine Ligand.

ChemInform Abstract: Enantioselective Conjugate Addition of Organometallic Reagents to Cycloalkenones by the Aid of Chiral Lactam-Phosphine Ligand.

ChemInform Abstract: Copper-Catalyzed Asymmetric Conjugate Addition of Organometallic Reagents to Enones Using S,O-Ligands with a Xylofuranose Backbone.

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Copper‐Catalyzed Enantioselective Conjugate Addition of Organometallic Reagents to Acyclic Dienones.

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Conjugate Addition of Organometallic Reagents to Acyclic Dienones

The Feringa group describes the conjugate addition to acyclic dienones. This is an interesting class of compounds for which controlled single addition products are obtained in high yields. The products can be used for a moderately diastereoselective second addition or be subjected to ring-closing metathesis to generate substituted cyclopentenones. The diastereoselective second addition of the allyl moiety is likely due to stereoselective generation of the intermediary enolate.

Copper‐Catalyzed Enantioselective Conjugate Addition of Organometallic Reagents to Acyclic Dienones

AbstractThe enantioselective, copper/phosphoramidite‐catalyzed 1,4‐addition of dialkylzinc reagents to acyclic dienones is described. The products of this reaction, obtained with enantioselectivities of up to 95 %, can be further functionalized by a second conjugate addition, or employed in an enolate trapping, ring‐closing metathesis protocol.