Palladium-catalyzed Cross-coupling Research Articles

Palladium-Catalyzed Conjunctive Cross-Coupling with Electronically Asymmetric Ligands.

Palladium-catalyzed conjunctive cross-coupling can be accomplished with the use of chiral phosphine-oxazoline based ligand structures. Of note, the reaction can be conducted on Grignard-based boron ate complexes and operates without the use of halide-scavenging additives, which are required for other catalyst systems.

Efficient syntheses of KLS-13019 using palladium mediated cross couplings

KLS-13019 is a structural analogue of cannabidiol, that shows improved bioavailability and potency in both preventing and reversing paclitaxel-induced neurotoxicity in vitro and in vivo. KLS-13019 was selected as a development candidate and attention was turned to development of a scalable synthesis. The original synthesis of KLS-13019 was not efficient, regioselective, or high yielding. Two new syntheses are reported that make use of the palladium catalyzed cross couplings to a chemically advanced intermediate 5, dramatically shortening (3–4 steps) and improving the overall yield. In addition, a convenient one pot Boc-cleavage and acetylation procedure is described to avoid impurities generated from a step-wise process.

Palladium-Catalyzed Cross-Coupling of Aryl Halides with Carboxylic Acids by Photoinduced Reductive Elimination

Key words acridines - aryl halides - carboxylic acids - palladium catalysis - photoexcitation

Copper-Catalyzed Stereoselective Borylation and Palladium-Catalyzed Stereospecific Cross-Coupling to Give Aryl C-Glycosides.

Metabolically stable C-glycosides are an essential family of compounds in bioactive natural products, therapeutic agents, and biological probes. For their application, development of synthetic methods by connecting glycosides and aglycons with strict stereocontrol at the anomeric carbon, as well as with high functional-group compatibility and environmental compatibility is a pivotal issue. Although Suzuki-Miyaura-type C(sp3 )-C(sp2 ) cross-coupling using glycosyl boronates is a potential candidate for the construction of C-glycosides, neither the cross-coupling itself nor the facile synthesis of the coupling precursor, glycosyl boronates, have been achieved to date. Herein, it was succeeded to develop a copper-catalyzed stereoselective one-step borylation of glycosyl bromides to glycosyl boronates and palladium-catalyzed stereospecific cross-coupling of β-glycosyl borates with aryl bromides to give aryl β-C-glycosides, in which the β-configuration of the anomeric carbon of the glycosyl trifluoroborates is stereoretentively transferred to that of the resulting aryl C-glycosides.

What is a cross-coupling? An argument for a universal definition

Despite amazing advances in cross-coupling technologies over the past several decades, there is not a consistent definition of what a cross-coupling reaction is. Often, definitions rely on comparison to “traditional” palladium-catalyzed cross-couplings pioneered in the 1970s by chemists such as Suzuki, Negishi, and Heck. While these reactions provide a basis for a cross-coupling definition, they do not define this type of transformation, originally described by Linstead almost 20 years prior. Rather than modify and compartmentalize modern transformations to categorize them into either a synthetic or mechanistic definition, we make an argument for broadening the cross-coupling definition to the union of two distinct molecular entities in a covalent-bond-forming process, to encourage discussion around exploring novel reactivity and disconnections. In addition to making a case for a universal cross-coupling definition, we cite specific examples of reactions that break the mold of prior cross-coupling definitions. We believe this perspective will stimulate dialog around what it means to be a cross-coupling and in turn inspire future developments within this field.

The Hirao Reaction: Palladium-Catalyzed Cross-Coupling of Dialkyl Phosphites with Aryl Halides

Key words C(sp2)–P bond formation - palladium catalysis - phosphonates

Palladium-Catalyzed Cross-Coupling of Silicon-Masked Diazenyl Anions and (Hetero)Aryl Halides

Palladium-Catalyzed Cross-Coupling of Silicon-Masked Diazenyl Anions and (Hetero)Aryl Halides

Development of a General Method for the Hiyama-Denmark Cross-Coupling of Tetrasubstituted Vinyl Silanes.

General conditions for the Hiyama-Denmark cross-coupling of tetrasubstituted vinyl silanes and aryl halides are reported. Prior reports of Hiyama-Denmark reactions of tetrasubstituted vinyl silanes have required the use of vinyl silanols or silanolates, which are challenging to handle, or internally activated vinyl silanes, which lack structural generality. Now, unactivated tetrasubstituted vinyl silanes, bearing bench-stable tetraorganosilicon centers, and aryl halides can be coupled. The key to this discovery is the identification of dimethyl(5-methylfuryl)vinylsilanes as bench stable and easily prepared cross-coupling partners that are readily activated under mild conditions in Hiyama-Denmark couplings. These palladium-catalyzed cross-couplings proceed well with aryl chlorides, though aryl bromides and iodides are also tolerated, and the reactions display high stereospecificity in the formation of tetrasubstituted alkenes. In addition, only a mild base (KOSiMe3) and common solvents (THF/DMA) are required, and importantly toxic additives (such as 18-crown-6) are not needed. We also show that these conditions are equally applicable to Hiyama-Denamrk coupling of trisubstituted vinyl silanes.

Visible-Light-Induced Palladium-Catalyzed Cross-Coupling of Iodocarboranes with (Hetero)Arenes.

This work describes a general method for the efficient production of a class of cage B-centered carboranyl radicals at the B3, B4, and B9 sites via a visible-light-promoted palladium(0)/palladium(I) pathway using readily available iodo-o-carboranes as the starting materials. The electrophilicities of these hypervalent boron-centered radicals decrease in the following order: B3 > B4 > B9. They are useful intermediates for the preparation of a family of cage B-(hetero)arylated o-carboranes at ambient temperature.

Construction of Heterobiaryl Skeletons through Pd-Catalyzed Cross-Coupling of Nitroarenes and Heterocyclic Arylborononate Esters with a Sterically Demanding NHC Ligand.

The palladium-catalyzed Suzuki-Miyaura cross-couplings of nitroarenes and heteroarylboronate esters has been developed. A number of heterobiaryl compounds containing pyridine, pyrimidine, quinoline, furan, thiophene, and pyrazole were prepared using [Pd(cinnamyl)Cl]2/2-aryl-5-(2,4,6-triisopropylphenyl)-2,3-imidazolylidene[1,5-a]pyridines as the catalysts in good to excellent yields. The synthetic practicality of this approach is demonstrated through the synthesis of druglike molecules.

The Road Less Traveled: Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dihalogenated N-Heteroarenes.

The vast majority (≥90%) of literature reports agree on the regiochemical outcomes of Pd-catalyzed cross-coupling reactions for most classes of dihalogenated N-heteroarenes. Despite a well-established mechanistic rationale for typical selectivity, several examples reveal that changes to the catalyst can switch site selectivity, leading to the unconventional product. In this Perspective, we survey these unusual cases in which divergent selectivity is controlled by ligands or catalyst speciation. In some cases, the mechanistic origin of inverted selectivity has been established, but in others the mechanism remains unknown. This Perspective concludes with a discussion of remaining challenges and opportunities for the field of site-selective cross-coupling. These include developing a better understanding of oxidative addition mechanisms, understanding the role of catalyst speciation on selectivity, establishing an explanation for the influence of ring substituents on regiochemical outcome, inverting selectivity for some "stubborn" classes of substrates, and minimizing unwanted over-reaction of di- and polyhalogenated substrates.

Palladium-Catalyzed Sequential Three-Component Cross-Coupling to 1,3-Dienes: Employing Alkenes as Hydride and Alkenyl Donors.

This report discloses a novel Pd-catalyzed sequential three-component multiple reaction of alkenes, bromoalkynes, and boronic acids using alkenes as hydride and alkenyl donors, leading to highly stereoselective assembly of (Z,E)-1,3-diene derivatives. Mechanistic studies demonstrate that the generation and reutilization of palladium hydride species are critical to the success of this transformation. In addition, the good functional group compatibility, late-stage modification, and investigation of photophysical properties of 1,3-diene products illustrate the synthetic value of this strategy.

Synthesis and Properties of Pyridine-Fused Triazolylidene-Palladium: Catalyst for Cross-Coupling Using Chloroarenes and Nitroarenes.

The synthesis and catalytic activity of pyridine-fused triazolylidene as a novel abnormal N-heterocyclic carbene (aNHC) ligand is described. The evaluation of physical properties using X-ray crystallographic analysis and infrared spectroscopy revealed that these triazolylidenes have a high electron-donating ability toward the metal center. The application of this triazolylidene to the palladium-catalyzed cross-coupling of chloroarenes and nitroarenes with arylboronic acids showcased its ability to activate C-Cl and C-NO2 bonds.

Palladium-Catalyzed Three-Component Cross-Coupling of Conjugated Dienes with Indoles Using Ethynylbenziodazolones as Electrophilic Alkynylating Reagents.

A palladium-catalyzed regioselective 1,2-alkynyl-carbonalization of conjugated dienes with ethynylbenziodazolone (EBZ) and indoles has been developed for the first time. Various molecules containing alkenyl, alkynyl, and indole groups were readily obtained. Moreover, the resulting products can be applied to various derivatizations. This protocol uses EBZ as an electrophilic alkynylating reagent, avoiding the byproduct of dimerization of alkynes.

Synthesis of 2-Aryl Azetidines through Pd-Catalyzed Migration/Coupling of 3-Iodoazetidines and Aryl Boronic Acids.

A palladium-catalyzed cross-coupling of 3-iodoazetidines and nonheteroaryl boronic acids was reported. The [1,1'-biphenyl]-2-yldicyclohexylphosphane ligand enabled the reaction that favored the formation of 2-aryl azetidines. The control experiments indicated that the reaction can proceed through either a palladium-hydride/dihydroazete complex or free dihydroazete intermediate followed by hydropalladation.

Palladium-Catalyzed Cross-Coupling of Cyanohydrins with Aryl Bromides: Construction of Biaryl Ketones

AbstractThe palladium-catalyzed cross-coupling of the lithium anion of aryl tert-butyldimethylsilyl-protected cyanohydrins with aryl bromides followed by in situ deprotection with fluoride ion provides a convenient and versatile approach to biaryl ketones. This protocol represents the first example of a palladium-catalyzed arylation of a cyanohydrin, which functions as an acyl anion equivalent. Hence, in contrast to classical cross-coupling reactions, the pronucleophile component is incorporated in the product to permit further functionalization. We then highlight the synthetic utility of the new method with applications to bioactive biaryl ketones and the construction of a triaryl diketone that has been used to prepare an extended tetrathiafulvalene.

Palladium-Catalyzed Cross-Coupling Reactions of Borylated Alkenes for the Stereoselective Synthesis of Tetrasubstituted Double Bond

The stereoselective formation of tetrasubstituted alkenes remains one of the key goals of modern organic synthesis. In addition to other methods, the stereoselective synthesis of tetrasubstituted alkenes can be achieved by means of cross-coupling reactions of electrophilic and nucleophilic alkene templates. The use of electrophilic templates for the stereoselective synthesis of tetrasubstituted alkenes has previously been described. Therefore, the present review summarizes the procedures available for the stereoselective preparation of tetrasubstituted alkenes using stable and isolable nucleophilic templates.

Palladium-Catalyzed Oxidative Cross-Coupling of Two Alkenes Using tert-Leucine as Transient Directing Group

Palladium-Catalyzed Oxidative Cross-Coupling of Two Alkenes Using tert-Leucine as Transient Directing Group

Palladium-catalyzed solid-state borylation of aryl halides using mechanochemistry.

This study describes the solid-state palladium-catalyzed cross-coupling between aryl halides and bis(pinacolato)diboron using ball milling. The reactions were completed within 10 min for most aryl halides to afford a variety of synthetically useful arylboronates in high yields. Notably, all experimental operations could be performed in air, and did not require the use of large amounts of dry and degassed organic solvents. The utility of this method was further demonstrated by gram-scale synthesis under solvent-free, mechanochemical conditions.

Synthesis and Theoretical Studies of Aromatic Azaborines

Organoboron compounds are well known for their use as synthetic building blocks in several significant reactions, e.g., palladium-catalyzed Suzuki-Miyaura cross-coupling. As an element, boron is fascinating; as part of a molecule it structurally resembles a three-valent atom, but if there is a lone pair of electrons nearby, the boron atom’s empty p-orbital may capture the lone pair and form a covalent bond. This is the main aspect that is challenging chemistry during the synthesis of boron containing molecules and may lead into unexpected reactions and products. To study this, we synthesized and studied novel aromatic azaborines for better understanding of their structures and reactions. Here, we report a one-pot method for the synthesis of substituted aromatic azaborines and computational studies of their structure to explain their observed chemical properties.