Cross-coupling Chemistry Research Articles

ChemInform Abstract: Cross‐Coupling Chemistry in Continuous Flow

AbstractReview: 102 refs.

ChemInform Abstract: O‐Arylation with Nitroarenes: Metal‐Catalyzed and Metal‐Free Methodologies

AbstractReview: [22 refs.

ChemInform Abstract: Immobilized Transition Metals as Catalysts for Cross‐Couplings in Continuous Flow — A Critical Assessment of the Reaction Mechanism and Metal Leaching

AbstractReview: [105 refs.

Reaction design, discovery, and development as a foundation to function-oriented synthesis.

Convergent C-C bond-forming reactions define the fabric of organic synthesis and, when applied in complex molecule synthesis, can have a profound impact on efficiency by decreasing the longest linear sequence of transformations required to convert simple starting materials to complex targets. Despite their well-appreciated strategic significance, campaigns in natural product synthesis typically embrace only a small suite of reactivity to achieve such bond construction (i.e., nucleophilic addition to polarized π-bonds, nucleophilic substitution, cycloaddition, and metal-catalyzed "cross-coupling"), therefore limiting the sites at which convergent coupling chemistry can be strategically employed. In our opinion, it is far too often that triumphs in the field are defined by chemical sequences that do not address the challenges associated with discovery, development, and production of natural product-inspired agents. We speculated that advancing an area of chemical reactivity not represented in the few well-established strategies for convergent C-C bond formation may lead to powerful new retrosynthetic relationships that could simplify approaches to the syntheses of a variety of different classes of natural products. Our studies ultimately embraced the pursuit of strategies to control the course of metallacycle-mediated "cross-coupling" between substrates containing sites of simple π-unsaturation (ubiquitous functionality in organic chemistry including alkenes, alkynes, allenes, aldehydes, and imines, among others). In just eight years since our initial publication in this area, we have defined over 20 stereoselective intermolecular C-C bond-forming reactions that provide access to structural motifs of relevance for the synthesis of polyketides, fatty acids, alkaloids, and terpenes, while doing so in a direct and stereoselective fashion. These achievements continue to serve as the foundation of my group's activity in natural product and function-oriented synthesis, where our achievements in reaction development are challenged in the context of complex targets. Among our early efforts, we achieved the most concise synthesis of a benzoquinone ansamycin ever described (macbecin I), and moved beyond this achievement to explore the role of our chemistry in function-oriented synthesis targeting the discovery of natural product-inspired Hsp90 inhibitors. These later efforts have led to the discovery of a uniquely selective benzoquinone ansamycin-inspired Hsp90 inhibitor that lacks the problematic quinone present in the natural series. This achievement was made possible by a concise chemical synthesis pathway that had at its core the application of metallacycle-mediated cross-coupling chemistry.

Palladium Catalysts for Cross-Coupling Reaction

Palladium-catalyzed cross-coupling reactions constitute one of the most important and useful transformations in transition metal-catalyzed reactions [1–3]. Although this research field emerged in the 1970s, it is still attracting considerable attention in synthetic and organometallic chemistry. New catalysts and catalytic systems are being developed to further expand the utility of the reactions. This Special Issue on “Palladium Catalysts for Cross-Coupling Reaction” covers the diverse aspects of the ever-evolving field of palladium catalysts in cross coupling chemistry.[...]

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling.

Non-aromatic nitrogen- and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp(2)-hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp(3)-hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2- and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.

(IPent)PdCl2(morpholine)]: a readily activated precatalyst for room-temperature, additive-free carbon-sulfur coupling.

A series of new, easily activated NHC-Pd(II) precatalysts featuring a trans-oriented morpholine ligand were prepared and evaluated for activity in carbon-sulfur cross-coupling chemistry. [(IPent)PdCl2(morpholine)] (IPent=1,3-bis(2,6-di(3-pentyl)phenyl)imidazol-2-ylidene) was identified as the most active precatalyst and was shown to effectively couple a wide variety of deactivated aryl halides with both aryl and alkyl thiols at or near ambient temperature, without the need for additives, external activators, or pre-activation steps. Mechanistic studies revealed that, in contrast to other common NHC-Pd(II) precatalysts, these complexes are rapidly reduced to the active NHC-Pd(0) species at ambient temperature in the presence of KOtBu, thus avoiding the formation of deleterious off-cycle Pd(II)-thiolate resting states.

Palladium-Catalyzed Direct α-Aryation of Benzyl Thioethers with Aryl Bromides.

The arylation of sp3-hybridized C-H's bonds is a powerful strategy to build molecular complexity and diversity. A novel and efficient palladium-catalyzed direct sp3 C-H arylation of aryl and alkyl benzyl thioether derivatives with aryl bromides is reported. The reaction involves reversible deprotonation of the benzylic C-H's of the thioether with either LiN(SiMe3)2 or NaN(SiMe3)2 and subsequent cross-coupling to provide the functionalized products in up to 97% yield. A screen of 24 of the most successful ligands in cross-coupling chemistry led to the identification of NiXantPhos as the only viable ligand for this challenging coupling.

A Simple Preparation of a Stable CdS-Polyacrylamide Nanocomposite: Structure, Thermal and Optical Properties

A facile approach was employed for the preparation of stable luminescent nanocomposites of CdS quantum dots (QDs) and polyacrylamide (PAM) through the cross coupling chemistry. Initially, CdS QDs were synthesized in a well controlled manner using 3-mercaptopropionic acid as a capping agent. Then, carboxylic acid groups on CdS QDs were chemically incorporated into PAM matrices with the assistance of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and N-hydroxysulfosuccinimide coupling agents. FT-IR analysis was used to investigate the chemical incorporation of CdS QDs in PAM matrices via the covalent protocol. The XPS elemental mapping studies further suggested the formation of CdS-PAM nanocomposites. FE-SEM and TEM images were engaged to study the morphologies, and distribution of CdS QDs in the PAM networks. The physical structure of the CdS-PAM nanocomposites was investigated by XRD analysis. Thermal stability of the nanocomposites was observed to be enhanced in compare to PAM as evidenced from TGA data. The UV-vis and photoluminescence studies of the CdS-PAM nanocomposites suggested their promising optical applications.

Formal Ring‐Opening/Cross‐Coupling Reactions of 2‐Pyrones: Iron‐Catalyzed Entry into Stereodefined Dienyl Carboxylates

Open access: Despite the exceptional level of sophistication in cross-coupling chemistry, reactions of substrates that incorporate the leaving group as an integral part into a heterocyclic scaffold are scarce. The title reaction outlines the utility of this reaction format (see scheme; acac=acetylacetonate), provides a convenient entry into stereodefined diene carboxylates, and adds a new chapter to the field of iron catalysis.

ChemInform Abstract: The Complementary Competitors: Palladium and Copper in C—N Cross‐Coupling Reactions

AbstractReview: 671 refs.

Recycling Pd colloidal catalysts using polymeric phosphine ligands and polyethylene as a solvent

Polyisobutylene (PIB)-bound azo dyes were prepared from aryl amine terminated polyisobutylene oligomers and used to form palladacycle precatalysts that can be used for catalytic carbon–carbon cross coupling reactions. The catalysts so formed were recyclable using thermomorphic heptane–DMF solutions that are monophasic at 80 °C and biphasic at room temperature. Under these conditions, the Pd catalyst can be recycled but some Pd leaches into the product solution. Using a low melting polyethylene oligomer as a solvent in place of the volatile heptane solvent reduces this leaching by roughly an order of magnitude. Further modification that involves using a second polyisobutylene (PIB)-bound phosphine ligand both increases the activity of the colloidal Pd catalyst and decreases the total Pd leaching by almost two orders of magnitude with 99.88% of the Pd being recovered. In this case, the Pd content in the solution of the product was ca. 0.3 ppm. These two modifications together lead to a much more sustainable strategy for the use of Pd colloidal catalysts in catalytic cross coupling chemistry.

Synthesis and Single-Molecule Imaging of Highly Mobile Adamantane-Wheeled Nanocars

The synthesis and single-molecule imaging of two inherently fluorescent nanocars equipped with adamantane wheels is reported. The nanocars were imaged using 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) as the chromophore, which was rigidly incorporated into the nanocar chassis via Sonogashira cross-coupling chemistry that permitted the synthesis of nanocars having different geometries. In particular, studied here were four- and three-wheeled nanocars with adamantane wheels. It was found that, for the four-wheeled nanocar, the percentage of moving nanocars and the diffusion constant show a significant improvement over p-carborane-wheeled nanocars with the same chassis. The three-wheeled nanocar showed only limited mobility due to its geometry. These results are consistent with a requisite wheel-like rolling motion. We furthermore developed a model that relates the percentage of moving nanocars in single-molecule experiments with the diffusion constant. The excellent agreement between the model and the new results presented here as well as previous single-molecule studies of fluorescent nanocars yields an improved understanding of motion in these molecular machines.

The Complementary Competitors: Palladium and Copper in C–N Cross-Coupling Reactions

The C–N cross-coupling chemistry intensely developed since the late 1990s has supplied synthesists with an overwhelming number of methods to effectively combine carbon and nitrogen residues. This new chemistry relies on complexes of mainly two metals, copper and palladium, used as catalysts or stoichiometric agents. The development of new methods has revealed both similarities and differences in the principles used for the design of new catalytic systems and analysis of their reactivity and selectivity. The discussion of cross-coupling chemistry of these two metals can be performed within a common mechanistic paradigm, helping to elucidate the key factors governing the behavior of the transition-metal complexes involved.

Ultrasound-promoted iodination of pyrazoles in aqueous medium

Several pharmacological activities have been devoted to pyrazole containing molecules. In particular, 4-iodopyrazoles have been employed as key starting materials in cross-coupling chemistry and metal-iodine exchange reactions that focus on the synthesis of such biologically important compounds. Unfortunately, existing methods for the synthesis of 4-iodopyrazoles are not in agreement with the environmental requirements due to a series of drawbacks including the use of large excess of reagents, the generation of toxic waste and long reaction times. Recently, we developed a fast and mild reaction condition for the iodination of aromatic compounds using an I 2 /H 2 O 2 system water as a nonflammable and innocuous solvent and ultrasonic irradiation as energy source. In this work, we present the application of this methodology for the iodination of pyrazoles (Scheme). Initially, a series of pyrazoles were efficiently prepared starting from 1,3-dicarbonyl compounds and hydrazines under ultrasonic irradiation. Three examples from the pyrazoles were subjected to the iodination condition shown above. Iodopyrazoles were obtained in 63-65% yields.

Redox Reactions in Palladium Catalysis: On the Accelerating and/or Inhibiting Effects of Copper and Silver Salt Additives in Cross‐Coupling Chemistry Involving Electron‐rich Phosphine Ligands

Challenging a catalytic cycle: Pd(0) catalysts are readily oxidized by Cu and Ag salts to give dinuclear Pd(I) complexes and Cu(I) or Ag(I) cubanes (see scheme). The reactivities of the resulting Pd(I) dimers are consistent with several observations of additive effects in cross-coupling chemistry. The results indicate the possibility for alternative catalytic cycles involving dinuclear Pd(I) complexes over the currently accepted synergistic cycles involving Pd(0)/Pd(II) intermediates and Cu or Ag.

Catalytic enantioselective transformations of borylated substrates: Preparation and synthetic applications of chiral alkylboronates

Organoboronic acid derivatives are well-established intermediates for the preparation of alcohols and amines, and in the formation of C–C bonds via different reactions, including homologations, carbonyl allylboration, or transition-metal-catalyzed cross-coupling chemistry. In the past decade, there has been great interest in the development of catalytic enantioselective methods for the preparation of chiral, optically enriched organoboronates as precursors of enantioenriched compounds. While the mainstream strategy remains the late-stage borylation of organic functional groups, our group has focused on an alternate strategy focused on modification of boron-containing substrates. In this way, acyclic and cyclic secondary alkyl- and allyl-boronates were prepared through catalytic enantioselective processes such as [4 + 2] cycloadditions, isomerizations, allylic substitutions, and conjugate additions. The resulting optically enriched boronates have been successfully utilized in the syntheses of complex natural products and drugs. One remaining challenge in the chemistry of secondary alkylboronate derivatives is their cross-coupling, especially with control of stereoselectivity. In this regard, our recent approach featured the conjugate asymmetric borylation of β-boronyl acrylates, providing the first enantioselective preparation of highly optically enriched 1,1-diboronyl derivatives. The chirality of these geminal diboron compounds is conferred through the use of two distinct boronate adducts, which can be coupled chemo- and stereoselectively with a variety of aryl and alkenyl halides under palladium catalysis.

Synthesis of C8‐Arylamine‐Modified 2′‐Deoxyadenosine Phosphoramidites and their Site‐Specific Incorporation into Oligonucleotides

Adducts of C8-(N-acetyl)-arylamines and 2'-deoxyadenosine were synthesised by palladium-catalysed C--N cross-coupling chemistry. These 2'-dA adducts were converted into the corresponding 3'-phosphoramidites and site-specifically incorporated into DNA oligonucleotides, which were characterised by mass spectrometry, UV thermal-stability assays and circular dichroism. These modified oligonucleotides were also used in EcoRI restriction assays and in primer-extension studies with three different DNA polymerases. The incorporation of the 2'-dA lesion close to the EcoRI restriction site dramatically reduced the susceptibility of the DNA strand to cleavage; this indicates a significant local distortion of the DNA double helix. The incorporation of the acetylated C8-2'-dA-phosphoramidites into 20-mer oligonucleotides failed, however, because the N-acetyl group was lost during the deprotection process. Instead the corresponding C8-NH-2'-dA-modified oligonucleotides were obtained. The effect of the C8-NH-arylamine-dA lesion on the replication by DNA polymerases was clearly dependent both on the polymerase used and on the arylamine-dA damage.

Combined oxypalladation/C-H functionalization: palladium(II)-catalyzed intramolecular oxidative oxyarylation of hydroxyalkenes.

Combined oxypalladation/C-H functionalization: palladium(II)-catalyzed intramolecular oxidative oxyarylation of hydroxyalkenes.

ChemInform Abstract: Direct Arylation: Alternative to Classic Cross‐Coupling Chemistry and a Fruitful Synthetic Tool for the Access to Novative Bioactive Molecules

AbstractReview: 43 refs.