Carbocupration Reaction Research Articles

Unveiling the Reaction Mechanism of the Das/Chechik/Marek Synthesis of Stereodefined Quaternary Carbon Centers

The reaction mechanism of the Cu+-catalyzed introduction of two all-carbon-substituted stereocenters in an ynamide system using a Grignard reagent, a zinc carbenoid, and an aldehyde, was investigated using density-functional theory. In contrast to the formation of an organocopper(I) compound and subsequent carbocupration reaction, previously postulated as the initial step, the reaction proved to instead proceed through an initial complexation of the substrate alkyne bond by the Cu+-catalyst, which primes this bond for reaction with the Grignard reagent. Subsequent addition of the zinc carbenoid then enables the nucleophilic attack on the incoming aldehyde, which is revealed as the rate-limiting step. Our computations have also identified the factors governing the regio- and setereoselectivity of this interesting reaction, and suggest possible paths for its further development.

Diastereo- and enantioselective preparation of cyclopropanol derivatives.

The diastereoselective carbocupration reaction of alkoxy-functionalized cyclopropene derivatives, followed by a subsequent trapping of the resulting cyclopropylmetal species with an electrophilic source of oxygen (oxenoid) afforded various tetrasubstituted cyclopropanol derivatives in high diastereo- and enantiomeric ratios. Similarly, the enantioselective copper-catalyzed carbomagnesiation/oxidation (or amination) sequence on achiral nonfunctionalized cyclopropenes provided the desired cyclopropanol (and cyclopropylamine) derivatives in excellent diastereo- and enantiomeric excesses.

Cyclopropene derivatives as precursors to enantioenriched cyclopropanols and n-butenals possessing quaternary carbon stereocenters.

The diastereoselective carbocupration reaction of cyclopropenylmethyl ethers followed by addition of oxenoid leads to the formation of diastereo- and enantiomerically enriched 2,2,3,3-tetrasubstituted cyclopropanol derivatives. Ring fragmentation of the copper cyclopropanolate leads to acyclic butenal derivatives possessing enantiomerically enriched α-quaternary carbon stereocenters in a single-pot operation.

Cyclopropene Derivatives as Precursors to Enantioenriched Cyclopropanols and n‐Butenals Possessing Quaternary Carbon Stereocenters

AbstractThe diastereoselective carbocupration reaction of cyclopropenylmethyl ethers followed by addition of oxenoid leads to the formation of diastereo‐ and enantiomerically enriched 2,2,3,3‐tetrasubstituted cyclopropanol derivatives. Ring fragmentation of the copper cyclopropanolate leads to acyclic butenal derivatives possessing enantiomerically enriched α‐quaternary carbon stereocenters in a single‐pot operation.

Air-stable solid aryl and heteroaryl organozinc pivalates: syntheses and applications in organic synthesis.

A wide range of air-stable, solid, polyfunctional aryl and heteroarylzinc pivalates were efficiently prepared by either magnesium insertion or Hal/Mg exchange followed by transmetalation with Zn(OPiv)2 (OPiv = pivalate). By reducing the amount of LiCl the air stability could be significantly enhanced compared with previously prepared reagents. An alternative route is directed magnesiation using TMPMgCl⋅LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) followed by transmetalation with Zn(OPiv)2 or, for very sensitive substrates, direct zincation by using TMPZnOPiv. These zinc reagents not only show excellent stability towards air, but they also undergo a broad range of C-C bond-formation reactions, such as allylation and carbocupration reactions, as well as addition to aldehydes and 1,4-addition reactions. Acylation reactions can be performed by using an excess of TMSCl to overcome side reactions of the omnipresent pivalate anion.

ChemInform Abstract: Stereoselective Synthesis of CF3‐Substituted trans‐ and cis‐Enediynes via Carbocupration or Hydrostannation Reactions of CF3‐Containing Diyne.

Abstract CF 3 -containing diyne, readily prepared from ( Z )-2,3,3,3-tetrafluoro-1-iodoprop-1-ene in two steps, was smoothly subjected to carbocupration reaction with various organocuprates, followed by treatment of the resultant carbocupration adducts with iodine, the corresponding vinyl iodides being formed in good yields in a cis -addition manner. Thus obtained iodide could be successfully converted into CF 3 -substituted trans -enediynes in high yields. Also, hydrostannation reaction of the diyne proceeded well in a trans -addition manner to give the corresponding vinylstannane in high yield. The vinylstannane was also found to be effectively convertible to CF 3 -substituted cis -enediynes in high yields.

Stereoselective synthesis of CF3-substituted trans- and cis-enediynes via carbocupration or hydrostannation reactions of CF3-containing diyne

CF3-containing diyne, readily prepared from (Z)-2,3,3,3-tetrafluoro-1-iodoprop-1-ene in two steps, was smoothly subjected to carbocupration reaction with various organocuprates, followed by treatment of the resultant carbocupration adducts with iodine, the corresponding vinyl iodides being formed in good yields in a cis-addition manner. Thus obtained iodide could be successfully converted into CF3-substituted trans-enediynes in high yields. Also, hydrostannation reaction of the diyne proceeded well in a trans-addition manner to give the corresponding vinylstannane in high yield. The vinylstannane was also found to be effectively convertible to CF3-substituted cis-enediynes in high yields.

Modulable and Highly Diastereoselective Carbometalations of Cyclopropenes

The copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 leads to various substituted cyclopropanes species 3 in good yields with very high diastereoselectivities. The reaction proceeds through a syn-chelated carbomagnesiation reaction and could be extended to various cyclopropenylmethyl ester derivatives 5. The potential of this approach was illustrated by the preparation of two consecutive all-carbon quaternary stereocenters. However, the carbometalation reaction needs to be performed at temperature ranging from -35 to -20 °C to avoid subsequent fragmentation reaction into stereodefined β,γ-nonconjugated unsaturated esters 4. Alternatively, the carbocupration reaction with organocopper species could also be performed to leads to configurationally stable cyclopropyl copper species 2[Cu]. Additionally, when the Lewis acid character of the copper center is decreased (i.e., RCuCNLi), the reaction proceed with an anti-selectivity. The diastereodivergent behavior of these organometallic species is of synthetic interest, since both diastereomers syn-3 and anti-3 can be obtained, at will, from the same precursor cyclopropenyl esters 1.

Stereodefined trisubstituted enolates as a unique entry to all-carbon quaternary stereogenic centers in acyclic systems

This protocol describes a new approach for the preparation of stereodefined trisubstituted chiral enolate species, avoiding conventional asymmetric enolization of carbonyl compounds. This protocol was developed as a single-flask synthetic sequence and therefore does not require isolation or purification of intermediate compounds. The sequence starts from a regioselective carbocupration reaction of readily accessible chiral ynamides; this is followed by oxidation of the generated vinylcuprate with a commonly available oxidizing reagent (tert-butyl hydroperoxide) in order to generate an enolate that completely retains its configuration. This synthetic protocol has been applied to the preparation of aldol and Mannich-type adducts. The procedure reported here requires a simple reaction setup commonly available in all synthetic laboratories and takes ∼6 h for completion and 2 h for isolation and purification. Final products are valuable diastereomerically and enantiomerically enriched building blocks for organic synthesis containing all-carbon quaternary stereocenters in acyclic systems.

Regio- and stereoselective carbometallation reactions of N-alkynylamides and sulfonamides

The carbocupration reactions of heterosubstituted alkynes allow the regio- and stereoselective formation of vinyl organometallic species. N-Alkynylamides (ynamides) are particularly useful substrates for the highly regioselective carbocupration reaction, as they lead to the stereodefined formation of vinylcopper species geminated to the amide moiety. The latter species are involved in numerous synthetically useful transformations leading to valuable building blocks in organic synthesis. Here we describe in full the results of our studies related to the carbometallation reactions of N-alkynylamides.

ChemInform Abstract: Carbocupration of Alkynes

AbstractReview: 144 refs.

ChemInform Abstract: Synthesis and Selective Carbocupration Reaction of Fluorine‐Containing Enynic Esters, Enynylphosphine Oxides, and Enynylphosphates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and selective carbocupration reaction of fluorine-containing enynic esters, enynylphosphine oxides, and enynylphosphates

Some new fluorine-containing enynic esters, enynylphosphine oxides, and enynylphosphates were synthesized stereoselectively in good yields by the dehydrohalogenation reaction of fluoroalkylated 3-iodoacrylates, 2-iodovinylphosphonates, and 2-iodovinylphosphine oxides under basic conditions. These fluorine-containing enynic compounds could undergo carbocupration reaction with organocopper reagents and the vinylcopper intermediates formed in situ could further react with some electrophiles such as allyl bromide, phenylselenyl bromide, and iodine to give the corresponding polysubstituted fluorine-containing dienoic esters, phosphates, and phosphine oxides with high regio- and stereoselectivity.

Convenient and Efficient Access to Fluoroalkylated Vinylphosphonates via Highly Regio- and Stereoselective Hydrometalation or Carbometalation Reactions of Fluorine-Containing Alkynylphosphonates

The hydrostannation, carbocupration, and carbozincation reactions of fluorinated alkynylphosphonates were investigated. The hydrostannation reaction proceeded smoothly without an additive (e.g., BEt 3 /O 2 , AIBN) to give the corresponding vinylstannanes in a highly regio- and stereoselective manner. Various cuprates, prepared from organolithium, Grignard, and organozinc reagents, could participate nicely in the carbocupration reactions, the corresponding adducts were obtained in good to high yields. Dialkylzinc reagents reacted smoothly with the alkynylphosphonates even in the absence of copper salt to afford the corresponding adducts in good yields.

Efficient, Transition Metal Mediated, Sequential, Two‐ and Three‐Component Coupling Reactions for the Synthesis of Highly Substituted Five‐Membered Ring Carbocycles

AbstractA Cu‐catalysed method for the preparation of highly substituted methylenecyclopentanes, through a sequence involving a Michael addition of stabilized enolates to activated enynes followed by an intramolecular carbocupration reaction, is presented. This method was also successfully combined with a Pd‐mediated coupling reaction to perform a new three‐component reaction through a transmetallation pathway on the vinylcopper intermediate. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

An Experimental and Theoretical Study of the Mechanism of Stannylcupration of α,β‐Acetylenic Ketones and Esters

The title reaction has been investigated by experimental and computational (DFT) techniques, and subsequently compared to the corresponding carbocupration reaction, with particular emphasis on the stereoselectivity. For stannylcupration of an ynone substrate, only the anti-addition product is observed, whereas for the corresponding ynoate substrate, the stereoselectivity can be affected by the reaction conditions: in the presence of methanol as proton donor, the initial syn-addition product can be trapped, whereas a syn/anti mixture is obtained in a non-protic solvent. This is in sharp contrast to the carbocupration of the same ynone substrate with a cyanocuprate (RCu(CN)Li), which is highly selective for syn-addition. The product selectivities can be understood from a detailed computational characterization of the reaction paths, and in particular from the relative stabilities of the vinyl cuprate and allenolate intermediates. It is suggested that the stereodetermining step is protonation of vinyl cuprate intermediates.

Highly regio- and stereo-selective carbometallation reaction of fluorine-containing internal acetylenes with organocopper reagents

The carbometallation reactions of fluoroalkylated internal alkynes with various organocopper reagents derived from organolithium, Grignard, and organozinc reagents were examined. All carbocupration reactions proceeded smoothly in a highly regio- and stereo-selective manner to give the corresponding vinylcopper intermediates. The intermediates reacted with H + smoothly, leading to the trisubstituted alkenes in high to excellent yields, whereas they reacted only with strictly limited carbon electrophiles such as allyl-, crotyl-, methallyl bromide, etc, probably due to the low reactivity exerted by an electron-withdrawing fluoroalkyl group. Treatment of vinylcopper with iodine resulted in a high yield of the corresponding vinyl iodide, which was employed successfully for Suzuki–Miyaura and Sonogashira cross-coupling reactions. In addition, two key reactions, the carbocupration and the Suzuki–Miyaura cross-coupling reaction realized the first highly stereoselective total synthesis of anti-estrogen drug, panomifene.

Preparation and Synthetic Transformation of Alkenyl Carbamates into Vinyl Zirconocene Derivatives

The carbocupration reaction of alkynyl carbamates leads to the stereospecific preparation of polysubstituted alkenyl carbamates. Subsequent treatment of these enol carbamates with the Negishi reagent gave the corresponding vinyl zirconocene species.

Regio‐ and Stereoselective Synthesis of Novel (E)‐1‐Alkenyl Carbamate via Carbocupration Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

ChemInform Abstract: Intramolecular Carbocupration Reaction of Unactivated Alkynes Bearing a Stabilized Nucleophile: Application to the Synthesis of Iridoid Monoterpenes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.