Lipshutz Cuprate Research Articles

A Common C2 -Symmetric 2,2'-Biphenol Building Block and its Application in the Synthesis of (+)-di-epi-Gonytolide A.

A variety of biaryl polyketides exhibit remarkable bioactivities. However, their synthetic accessibility is often challenging. Herein, the enantioselective preparation and synthetic application of an axially chiral 2,2'-biphenol building block is outlined that represents a common motif of these intriguing natural products. Based on the highly regioselective and scalable bromination of a phenol precursor, a coupling process by Lipshutz cuprate oxidation was developed. A copper-mediated deracemization strategy proved to be superior to derivatization or kinetic resolution approaches. Key steps in the overall building block synthesis were rationalized through DFT studies. Utilizing the 2,2'-biphenol, a highly diastereoselective five step synthesis of formerly unknown (+)-di-epi-gonytolide A was developed, thus showcasing the building block's general potential for the synthesis of natural products and their derivatives. En route, the first enantioselective construction of a chromone dimer intermediate was established.

Cross-Coupling of Alkyl Fluorides with Lipshutz Cuprates under Aluminum Iodide-Mediated C–F Bond Activation

Cross-Coupling of Alkyl Fluorides with Lipshutz Cuprates under Aluminum Iodide-Mediated C–F Bond Activation

10-Mesityl-1,8-diphenylanthracene Dimer: Synthesis, Structure, and Properties.

Macrocyclic 10-mesityl-1,8-diphenylanthracene dimer 4 was synthesized by using the electron-transfer oxidation of Lipshutz cuprate derived from 1,8-bis(4-bromophenyl)-10-mesityl-anthracene 7 in moderate yield. This dimer 4 is a considerably fluorescent molecule (ΦF 0.40) with high thermal, photo, and air stability. The X-ray analysis of 4 revealed a unique structure with a small inner cavity which can incorporate a small molecule or atom. 1H NMR spectra in solution and emission spectra of 4 in the solid state showed that copper(I) ion was incorporated to form a 1:1 complex 4·CuOTf, whereas silver(I) ion only weakly interacted with 4 under similar conditions.

Synthesis of pentadecaphenylenes, their inclusion properties, and nanostructure formation with C60

Synthesis of macrocyclic pentadecaphenylene was carried out via electron-transfer oxidation of the corresponding Lipshutz cuprate. Pentadecaphenylene self-aggregated in solution to form a gel. Furthermore, it incorporated C60 in its cavity to produce a fibrous inclusion complex which showed a high gelation ability in benzene.

Copper‐Mediated Aryl‐Aryl Couplings for the Construction of Oligophenylenes and Related Heteroaromatics

Abstractmagnified imageEfficient methods for the syntheses of biaryls by the copper‐mediated homocoupling of arylmetals are summarized. First, a smooth transmetallation between arylzinc halides and copper(II) salts has been employed for the selective homocoupling of arylzinc halides to produce either biphenylenes or tetraphenylenes. This reaction has been applied to the synthesis of cyclic oligothiophenes. Second, an efficient method for the homocoupling of aryl halides by the electron‐transfer (ET) oxidation of Lipshutz cuprates [Ar2Cu(CN)Li2] with organic electron acceptors has been developed. The ET oxidation of cuprates with 1,4‐benzoquinones proceeds smoothly to afford the corresponding coupling products in moderate to high yields. The ET oxidation of cuprates has been applied to the synthesis of either thiophene‐ or benzene‐fused 10‐membered ring cyclophanes. For the synthesis of macrocyclic cyclophanes, a linear CCuC structure of Lipshutz cuprates should be maintained in the dimetallacyclic intermediates to efficiently produce large‐ring cyclophanes. Moreover, nonaphenylenes and dodecaphenylenes have been synthesized using the ET oxidation of cuprates with duroquinone. Interestingly, hexadodecyloxynonaphenylene exhibits different nanostructures between fibrous materials in solution and cast films on a surface. Films of this compound can detect vaporized nitroaromatics such as dinitrobenzene and trinitrobenzene.

Synthesis of Nonaphenylenes and Dodecaphenylenes Using Electron-Transfer Oxidation of Lipshutz Cuprates and Formation of Nanostructural Materials from Hexadodecyloxynonaphenylene

Nonaphenylenes and dodecaphenylenes have been synthesized by using electron-transfer oxidation of Lipshutz cuprates with duroquinone. Oxidation of the Lipshutz cuprate derived from 4,4''-dibromo-o-terphenyl 3a in THF produced nonaphenylene 1a in 46% yield, whereas the similar oxidation of the Lipshutz cuprates derived from 4,4''-diiodo-4',5'-dialkyl-o-terphenyls 3b-d in ether afforded the corresponding nonaphenylenes 1b-d and dodecaphenylenes 2b-d in moderate total yields. In the case of 4,4''-diiodo-4',5'-didodecyloxy-o-terphenyl 3e as the starting material, oxidation of the corresponding Lipshutz cuprate in ether or THF only led to the formation of nonaphenylene 1e. Both nonaphenylenes 1a-e and dodecaphenylenes 2b-d are unreactive to light, atmospheric oxygen, and prolonged heating. These oligophenylenes showed strong UV absorption and fluorescent emission and exhibited some redox properties on CV analysis. Moreover, hexadodecyloxynonaphenylene 1e exhibits different nanostructures on the surface and in solution to form a film by casting a solution of 1e in cyclohexane, benzene, chloroform, THF, or diisopropyl ether (IPE) and nanofibers from IPE-MeOH (1:1), indicating different absorption and emission spectra and XRD patterns. The absorption maxima of THF solution, fiber, and film are in the order of 1e film (315 nm) > fiber (302 nm) > solution (295 nm), whereas the emission maxima are in the order of 1e fiber (425 m) > solution (418 nm) > film (401 nm). XRD analysis revealed that 1e aligns laterally on a glass or silicon surface to form a thin film with a lamella structure; however, it forms a nanofiber with a Lego-like stacking structure without pi-pi stacking interaction of the aromatic rings. Reflecting the different nanostructures of the 1e film and fiber, a spin-coated 1e film is found to be effective in detecting the vapor of explosives due to the intercalation of nitroaromatics to the cracked surface of the loosely stacked 1e. In contrast, the 1e fiber is not effective in detection of nitroaromatics but exhibits fluorescence anisotropy. The maximum fluorescence intensity is obtained in a direction perpendicular to the longitudinal axis of the fiber, indicating the stacking direction to be parallel to the longitudinal axis of the fiber.

Efficient Construction of Biaryls and Macrocyclic Cyclophanes via Electron‐Transfer Oxidation of Lipshutz Cuprates.

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Tellurium in organic synthesis: an approach to the synthesis of ( Z, E)-dienic precursors of insect pheromones

A simple and straightforward route to ( Z, E)-dienic precursors of insect pheromones was developed. The route features a cross-coupling of a ( Z, E)-dienic telluride with an alkyl Lipshutz cuprate.

Efficient Construction of Biaryls and Macrocyclic Cyclophanes via Electron-Transfer Oxidation of Lipshutz Cuprates

An efficient method for the homocoupling of aryl halides by electron-transfer oxidation of Lipshutz cuprates (Ar2Cu(CN)Li2) with organic electron acceptors is disclosed. Thus, various types of Lipshutz cuprates are prepared by successive treatment of aryl or heteroaryl bromides with tert-butyllithium and CuCN. The electron-transfer oxidation of Lipshutz cuprates with p-benzoquinones proceeds smoothly to afford the corresponding homocoupling products in moderate to good yields. Furthermore, it can be applied to the construction of either thiophene- or benzene-fused 10-membered ring cyclophanes. For the synthesis of 10-membered cyclophanes, the linear C-Cu-C structure of Lipshutz cuprates should be maintained in the dimetallacyclic intermediates, producing the large ring cyclophanes efficiently. The X-ray analysis of the cyclophanes reveals that the difference in the bridging atoms results in the different conformations of the macrocyclic rings. Thus, the silicon-bridged cyclophane 5a adopts a D2-symmetric structure with a twisted rhombic arrangement of four thiophene rings, whereas the methylene- and oxygen-bridged cyclophanes 5b and 5c possess C2h- and C2-symmetric structures with chair- and boatlike conformations, respectively. The 1H NMR spectrum of C2-symmetric 5c is temperature-dependent, and the activation energy (DeltaG) for the conformational change is 10.1 kcal/mol.

Synthesis of Nonaphenylenes and Dodecaphenylenes Using Electron-transfer Oxidation of Lipshutz Cuprate Intermediates

Abstract Nonaphenylene and its hexaalkyl derivatives have been synthesized using electron-transfer oxidation of Lipshutz cuprates with duroquinone. Oxidation of the Lipshutz cuprate derived from dibromo-o-terphenyl in THF produced nonaphenylene in moderate yield, whereas the similar oxidation of the Lipshutz cuprate derived from diiododiethyl-o-terphenyl in ether afforded the corresponding nonaphenylene and dodecaphenylene. Furthermore, oxidation of Lipshutz cuprate derived from diiododibutyl-o-terphenyl only gave the nonaphenylene.

Novel Electron‐Transfer Oxidation of Lipshutz Cuprates with 1,4‐Benzoquinones: An Efficient Homo‐Coupling Reaction of Aryl Halides and Its Application to the Construction of Macrocyclic Systems.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Novel electron-transfer oxidation of Lipshutz cuprates with 1,4-benzoquinones: an efficient homo-coupling reaction of aryl halides and its application to the construction of macrocyclic systems

The electron transfer reaction from Lipshutz cuprates, which can be easily prepared from aryl bromides, to 1,4-benzoquinones was found to proceed smoothly, affording either the corresponding homo-coupling products, in modest to excellent yields, or macrocyclic products selectively.

On the Reaction Mechanism of “Higher‐Order Cuprate”, Alias “Lipshutz Cuprate”

AbstractFor Abstract see ChemInform Abstract in Full Text.

On the Reaction Mechanism of “Higher-Order Cuprate”, Alias “Lipshutz Cuprate”

Abstract An organocuprate reagent of the R2Cu(CN)Li composition introduced by Lipshutz has been frequently used in organic synthesis because its reactivity in some reactions is higher than that of the standard Gilman reagent R2CuLi. The higher reactivity of the Lipshutz cuprate was once ascribed to a dianionic tri-coordinated copper(I) (“higher-order”) structure, but numerous structural studies over the last ten years have shown that the Lipshutz cuprate exists as a “cyano-Gilman” (R2CuLi·LiCN) cuprate. This conclusion notwithstanding, our recent theoretical study indicated that a minor and undetectable species such as R(CN)CuLi·LiR may play some roles in the substitution and the addition reactions of the Lipshutz cuprate. The high reactivity of the minor species originates from the anisotropic and multi-coordination capability of the cyanide ligand to metals. Our result accounts for the higher or anomalous reactivity of the Lipsthuz cuprate in some reactions, and further demonstrates the importance of computational study on poly-metallic reaction pathways, where experimental mechanistic information may be difficult to obtain.

Density Functional Studies on Kinetic Reactivity of “Higher Order” Lipshutz Cuprate in Addition Reaction to Acetylene

Abstract There is a frequently used organocuprate species that was introduced by Lipshutz and possesses a molecular structure written as CuLi2R2(CN). This species was previously called “higher order cuprate”, but is now considered to exist as an equilibrating mixture of various isomers of R2CuLi·LiCN and R(CN)CuLi·LiR, among which R2Cu−·Li2CN+ is known to be dominant in solution. The present studies on the kinetic reactivity of these species in the addition reaction to acetylene suggest that the minor species R(CN)CuLi·LiR may be more reactive than the major species, thereby making it equally possible that addition reaction products may arise through both the major and the minor reactive species. The reason for the high reactivity of the minor species has been ascribed to the anisotropic and multi-coordination capability of the cyanide ligand to metals; such capability is not available for a halide or alkyl anion ligand.