Reaction Of Organocuprates Research Articles

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.

Diastereoselective conjugate addition of organocuprates to N-[4-(Dibenzylaminobutenoyl)]oxazolidinone. Synthesis of chiral β-substituted γ-aminoacids

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a γ-nitrogen atom is present into α,β-unsaturated system is described. The reaction gave syn-products in moderate yields and high diastereomeric ratios. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral β-substituted γ -amino acids.

Csp3-Csp3 Bond-Forming Reductive Elimination from Well-Defined Copper(III) Complexes.

Carbon-carbon bond-forming reductive elimination from elusive organocopper(III) complexes has been considered the key step in many copper-catalyzed and organocuprate reactions. However, organocopper(III) complexes with well-defined structures that can undergo reductive elimination are extremely rare, especially for the formation of Csp3-Csp3 bonds. We report herein a general method for the synthesis of a series of [alkyl-CuIII-(CF3)3]- complexes, the structures of which have been unequivocally characterized by NMR spectroscopy, mass spectrometry, and X-ray crystal diffraction. At elevated temperature, these complexes undergo reductive elimination following first-order kinetics, forming alkyl-CF3 products with good yields (up to 91%). Both kinetic studies and DFT calculations indicate that the reductive elimination to form Csp3-CF3 bonds proceeds through a concerted transition state, with a Δ H⧧ = 20 kcal/mol barrier.

Intermediates Formed in the Reactions of Organocuprates with α,β-Unsaturated Nitriles.

Conjugate additions of organocuprates are of outstanding importance for organic synthesis. To improve our mechanistic understanding of these reactions, we have used electrospray ionization mass spectrometry for the identification of the ionic intermediates formed upon the treatment of LiCuR2 ⋅LiCN (R=Me, Bu, Ph) with a series of α,β-unsaturated nitriles. Acrylonitrile, the weakest Michael acceptor included, did not afford any detectable intermediates. Fumaronitrile (FN) yielded adducts of the type Lin-1 Cun R2n (FN)n (-) , n=1-3. When subjected to fragmentation in the gas phase, these adducts were not converted into the conjugate addition products, but re-dissociated into the reactants. In contrast, the reaction with 1,1-dicyanoethylene furnished the products of the conjugate addition without any observable intermediates. Tri- and tetracyanoethylene proved to be quite reactive as well. The presence of several cyano groups in these substrates opened up reaction pathways different from simple conjugate additions, however, and led to dimerization and substitution reactions. Moreover, the gas-phase fragmentation behavior of the species formed from these substrates indicated the occurrence of single-electron transfer processes. Additional quantum-chemical calculations provided insight into the structures and stabilities of the observed intermediates and their consecutive reactions.

Ionic Aggregates of Lithium Organocuprates

We have used a combination of electrospray ionization mass spectrometry and electrical conductivity measurements to analyze solutions of the Gilman cuprates LiCuR2·LiX, with R=Ph, Bu and X=Cl, Br, I, in tetrahydrofuran and have compared our findings with previous results on cyanocuprates LiCuR2·LiCN. Among the various polynuclear organocuprate ions observed, Li2Cu3Ph6(-), LiCu4Ph6(-), and Cu5Ph6(-) are of particular interest because aggregates of the same composition are known from X-ray crystal structures. Control experiments have indicated that the polynuclear organocuprate anions detected in solution are indeed identical to those formed in the solid state. As abundant ions of the type Li2Cu3R6(-) are found in solutions of Gilman cuprates and cyanocuprates alike, their possible involvement in organocuprate reactions should be considered. For comparison, we have also included solutions of LiCu(R)I, LiCuX2·LiX, LiCuX2, and CuCN·2LiX in the present study.

Dimethylcuprate-Catalyzed Decarboxylative Coupling of Allyl Acetate

Allylic alkylation of organocuprates represents an important class of C–C bond forming reactions. A drawback of these reactions is their stoichiometric nature. Although metal-catalyzed decarboxylative coupling reactions offer new opportunities for formation of C–C bonds, catalytic allylic alkylation reactions of organocuprates have not been previously reported. Here, multistage mass spectrometry experiments performed on ion trap mass spectrometers in conjunction with electronic structure calculations are used to demonstrate that the dimethylcuprate anion, [CH3CuCH3]−, can catalyze decarboxylative coupling of allyl acetate in the gas phase via a simple two-step catalytic cycle. In step 1, [CH3CuCH3]− undergoes a cross-coupling reaction with allyl acetate to yield [CH3CuO2CCH3]− as the major product ion. Step 2 involves subjecting the product ion to collision-induced decarboxylation to re-form [CH3CuCH3]−, thereby closing the catalytic cycle. Since the details of step 2 have been previously described (Rijs, N.; Khairallah, G. N.; Waters, T.; O’Hair, R. A. J. J. Am. Chem. Soc. 2008, 130,1069−1079), here the focus is on step 1. Comparison of the reactivity of dimethylcuprate toward allylic susbtrates reveals that while allyl acetate reacts around 70 times more slowly than allyl iodide, it is more selective for cross-coupling. This is rationalized by DFT calculations, which reveal that an increase in kinetic barrier is responsible for both reactivity trends. The lowest energy path was found to involve a stepwise π-oxidative addition proceeding via an η2-C3H5O2CCH3 intermediate and extrusion of a leaving group (LG) anion, followed by a reductive elimination where this LG is recomplexed to the copper center. Finally, DFT calculations were used to shed light on the role of leaving groups LG = CH3CO2–, I–, Br–, Cl– in the allylic alkylation. While selectivity is indeed achieved at the cost of reactivity, the LG effects were more complex than can be accounted for by a simple consideration of the anion proton affinity (APA) of the LG.

ChemInform Abstract: Organocopper‐Mediated Two‐Component SN2′‐Substitution Cascade Towards N‐Fused Heterocycles.

AbstractThe title compounds are obtained in an efficient reaction of organocuprates with heterocyclic propargyl mesylates which are in situ obtained from the corresponding propargyl alcohols.

ChemInform Abstract: Reactions of Organocuprates with Vinyl Triflates and Related Cephems: A Novel Approach to 3-Substituted Cephalosporins.

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ChemInform Abstract: Effects of Dimethyl Sulfide on the Reaction of Dibutylcopper Reagents with α,β-Unsaturated Ketones.

Abstract Addition of Me 2 S to a 1:2 CuI/BuLi mixture in toluene promotes 1,4- over 1,2-addition in reactions with a representative selection of α,β-unsaturated ketones. Unlike similar reactions studied with dialkyl ethers, the effect of Me 2 S is not related to the amount of lithium salts in the reaction medium. The results are related to current mechanistic theories of organocuprate reactions.

Reaction Pathway of Conjugate Addition of Lithium Organozincates to s-trans-Enones

Density functional theory (DFT) calculations were performed to understand the reaction mechanism of organozincates in 1,4-addition to methyl vinyl ketone (MVK). Examination of the addition of Me3ZnLi to MVK as compared with that of (MeLi)2 showed that the precise transition state structures critically determine the reaction selectivity for α,β-unsaturated carbonyl compounds. In the case of organozincates, the 1,4-addition proceeds smoothly through an open form TS, whereas alkyllithiums favor 1,2-addition through a closed TS. This 1,4-addition mechanism of Zn-ates does not involve an electron transfer process and is different from the reaction of organocuprates, in which oxidation/reduction of the copper atom occurs.

Toward the total synthesis of lophotoxin — New methodologies and synthetic strategies

Our recent progress toward the synthesis of the furanocembranolide lophotoxin (1) is disclosed. Strategies for the stereoselective incorporation of the C13stereocenter by a catalytic desymmetrization of a cyclic meso-anhydride, as well as a novel 1,6-addition reaction of organocuprates to unsaturated [1,3]dioxin-4-ones are discussed. Preliminary results on the development of a rhodium-catalyzed asymmetric 1,6-addition reaction are also mentioned. Finally, modifications of a previously reported transition-metal-catalyzed cyclization reaction involving α-propargyl β-keto esters allow furan ring formation either under thermal conditions or by microwave irradiation.Key words: 1,6-addition, organocuprates, catalytic desymmetrization, furan cyclization, microwave.

Selectivity Guidelines and a Reductive Elimination‐Based Model for Predicting the Stereochemical Course of Conjugate Addition Reactions of Organocuprates to γ‐Alkoxy‐α,β‐enoates.

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Selectivity Guidelines and a Reductive Elimination-Based Model for Predicting the Stereochemical Course of Conjugate Addition Reactions of Organocuprates to γ-Alkoxy-α,β-enoates

Current models used to predict the stereochemical outcome of organocopper conjugate addition processes focus on the nucleophilic addition step as stereochemistry-determining. Recent kinetic, NMR, kinetic isotope effect, and theoretical density functional studies strongly support the proposal that stereochemical preferences in these processes are dictated by the reductive elimination step, transforming Cu(III) to Cu(I) intermediates. A new model that considers various steric and stereoelectronic factors involved in the transition state of the reductive elimination step is proposed and then used to interpret the results of systematic studies of arylcuprate conjugate addition reactions with cis and trans gamma-alkoxy-alpha,beta-enoates. The results give rise to the following selectivity guidelines for this process. To achieve high anti-addition diastereoselectivities the use of trans esters with a bulky nonalkoxy substituent at the gamma-position is recommended. While stereoelectronics disfavor syn-addition, a judicious choice of properly sized gamma-substituents may lead to the predominant formation of syn-products, especially with cis enoates. However, high syn-selectivities may be achieved by using gamma-amino-alpha,beta-enoates.

Remarkable Effect of Silyl Groups on Asymmetric Induction in a Conjugate Addition Reaction with O-Methylnorephedrine-Based N-Silylamidocuprates

Scalemic N-silylamidocuprates, prepared from O-methylnorephedrine in a two-flask procedure, are exceedingly reactive and give excellent enantiomeric excesses with chalcone, a classic substrate for studies of organocuprate conjugate addition. For example, the butyl N-diphenylmethylsilylamidocuprate (T = Bu) affords a 99.2% ee (99% yield) of (S)-3-butyl-1,3-diphenyl-1-propanone. The remarkably high yields with this and other silyl ligands are attributed to the extraordinary activating effect of a beta-silicon atom on organocuprate reactions. The high ee is a consequence of the larger size of the silyl ligands compared to that of the unsubstituted or methyl-substituted analogues.

Mechanism of substitution reaction on sp2-carbon center with lithium organocuprate.

Theory and experiments suggest that the substitution reaction of a lithium dialkylcuprate(I) with an alkenyl bromide takes place through a pi-complex (cuprio(III)cyclopropane) that directly breaks down to the alkenylated product rather than via a conventional three-centered transition state. This mechanism is consistent with the broader mechanistic picture of the organocuprate reactions and accounts for the retentive stereochemistry and the kinetic isotope effect observed in the experiments.

Mechanism and ligand-transfer selectivity of 1,2-addition of organozincate complexes to aldehyde.

Density functional theory (DFT) calculations have been performed to investigate the origin of the reactivity and ligand-transfer selectivity of organozincates in the 1,2-addition to carbonyl compounds. Examination of the addition of Me(3)ZnLi to formaldehyde as compared with that of Me(2)Zn showed that the addition reaction is facilitated by the push-pull synergy of the Lewis acidic Li atom and the negatively charged Me(3)Zn moiety. This analysis then provided an answer to the mechanistic question about the experimentally established ligand-transfer selectivity in the 1,2-addition of heteroleptic organozincate Me(2)Zn(X)Li (X = H-, R(2)N-, and R(3)Si-). The addition of these heteroleptic zincate compounds results in selective transfer of H, R(2)N, and R(3)Si groups owing to the favorable orbital interaction between these groups and the carbonyl pi-system. The addition reaction of the zincate compounds conforms to the mechanistic framework of the conventional nucleophilic reaction, such as the addition reaction of MeLi dimer, and is different from the reaction of organocuprates, where oxidation/reduction of the copper atom is involved.

Rapid-Injection NMR Study of Iodo- and Cyano-Gilman Reagents with 2-Cyclohexenone: Observation of π-Complexes and Their Rates of Formation

Rapid-injection is a very useful technique for the preparation of temperature-sensitive and air-sensitive compounds in the cold, nitrogen-filled probe of an NMR spectrometer. We have used this method to prepare solutions of pi-complexes from 2-cyclohexenone and prototypical cuprates Me2CuLi.LiI and Me2CuLi.LiCN, and we have assigned structures on the basis of 1H and 13C NMR. In each case two pi-complexes were observed, and in the former, their rates of formation were measured by rapid-injection 1H NMR and EXSY spectroscopy. These results provide insights into the normal and anomalous conjugate addition reactions of organocuprates.

Mechanism of 1,6-addition reactions of organocuprates: detailed NMR spectroscopic study of a cuprate-enyne pi complex.

A detailed NMR-spectroscopic study of the multiply 13C-labeled cuprate pi complexes 2, 2a and 2b was carried out. The 13C,13C coupling constants observed were interpreted in terms of a deformation of the cuprate-alkene complex from the expected idealized square plane. This conclusion is in agreement with NOESY and ROESY data acquired with unlabeled material.

Wherefore Art Thou Copper? Structures and Reaction Mechanisms of Organocuprate Clusters in Organic Chemistry.

Organocopper reagents provide the most general synthetic tools in organic chemistry for nucleophilic delivery of hard carbanions to electrophilic carbon centers. A number of structural and mechanistic studies have been reported and have led to a wide variety of mechanistic proposals, some of which might even be contradictory to others. With the recent advent of physical and theoretical methodologies, the accumulated knowledge on organocopper chemistry is being put together into a few major mechanistic principles. This review will summarize first the general structural features of organocopper compounds and the previous mechanistic arguments, and then describe the most recent mechanistic pictures obtained through high-level quantum mechanical calculations for three typical organocuprate reactions, carbocupration, conjugate addition, and S(N)2 alkylation. The unified view on the nucleophilic reactivities of metal organocuprate clusters thus obtained has indicated that organocuprate chemistry represents an intricate example of molecular recognition and supramolecular chemistry, which chemists have long exploited without knowing it. Reasoning about the uniqueness of the copper atom among neighboring metal elements in the periodic table will be presented.

Effects of dimethyl sulfide on the reaction of dibutylcopper reagents with α,β-unsaturated ketones

Addition of Me 2S to a 1:2 CuI/BuLi mixture in toluene promotes 1,4- over 1,2-addition in reactions with a representative selection of α,β-unsaturated ketones. Unlike similar reactions studied with dialkyl ethers, the effect of Me 2S is not related to the amount of lithium salts in the reaction medium. The results are related to current mechanistic theories of organocuprate reactions.