Efficient Modular Synthesis of Isomeric Mono‐ and Bispyridyl[2.2]paracyclophanes by Palladium‐Catalyzed Cross‐ Coupling Reactions

Pyridyl‐substituted [2.2]paracyclophanes build a multifunctional structural motif that is useful in material chemistry, catalysis and for luminescent structures. Nonetheless, there is still a lack of general methods for the synthesis of these structures tolerating easily accessible bromides as well as different isomeric pyridyl groups. Hence the coupling of functionalized [2.2]paracyclophanes with various substituted and functionalized pyridyl derivatives was achieved using Stille, Suzuki and Kumada coupling conditions. Hereby the Stille coupling of a [2.2]paracyclophane is presented as a versatile reaction for the formation of heteromeric [2.2]paracyclophane‐containing biaryl structures.

     

Selective C3?C3 Oxidative Cross‐Coupling between Unactivated Anilines and Indoles

A selective C3 C3 oxidative cross‐coupling between unactivated anilines and indoles catalyzed by copper bromide together with iodobenzene diacetate as the oxidant is described. This methodology provides a novel approach to biaryl synthesis.     

Development of Biarylalkyl Carboxylic Acid Amides with Improved Anti-schistosomal Activity

The parasitic disease schistosomiasis is the cause of more than 200 000 human deaths per year. Although the disease is treatable, there is one major shortcoming: praziquantel has been the only drug used to combat these parasites since 1977. The risk of the emergence of resistant schistosomes is known to be increasing, as a reduced sensitivity of these parasites toward praziquantel has been observed. We developed a new class of substances, which are derived from inhibitors of human aldose reductase, and which showed promising activity against Schistosoma mansoni couples in vitro. Further optimisation of the compounds led to an increase in anti-schistosomal activity with observed phenotypes such as reduced egg production, vitality, and motility as well as tegumental damage and gut dilatation. Here, we performed structure–activity relationship studies on the carboxylic acid moiety of biarylalkyl carboxylic acids. Out of 82 carboxylic acid amides, we identified 10 compounds that are active against S. mansoni at 25 μm . The best five compounds showed an anti-schistosomal activity up to 10 μm and induced severe phenotypes. Cytotoxicity tests in human cell lines showed that two derivatives had no cytotoxicity at 50 or 100 μm . These compounds are promising candidates for further optimisation toward the new anti-schistosomal agents.     

Combinatorial Design of Copper‐Based Mixed Nanoclusters: New Catalysts for Suzuki Cross‐Coupling

Quantum dots (2–5 nm) of copper and copper/palladium mixtures are found to be good catalysts for Suzuki cross‐coupling. The catalysts are applicable to a wide range of iodo‐ and bromoaryl substrates, and give moderate yields using chloroaryl substrates. Cluster activity and stability is found to depend strongly on the preparation method and the reaction conditions. The mechanism of cluster deactivation and the sensitivity of the cluster‐catalysed reaction to substituent effects are studied and discussed.     

Highly Selective Pd‐Catalyzed Reductive Coupling of Substituted Haloarenes with Supported Phase‐Transfer Catalyst using Zn as the Reducing Agent

Highly selective reductive coupling of substituted haloarenes to biaryls is accomplished by Zn in N,N‐dimethylformamide (DMF) and in the presence of a catalytic amount of PdCl₂, PPh₃, and a carbon‐supported phase‐transfer catalyst (PTC). Selectivity as high as 100% is achieved with chlorotoluenes. It is realized that the supported PTC has a predominant role in minimizing the rate of the hydrodehalogenation reaction. The reaction is found to be selective only when homogeneous PdCl₂ is applied as the catalyst, whereas heterogeneous Pd/C‐catalyst selectively reduces chloroarenes to arenes under similar conditions. The role of PPh₃ is discussed and the effects of different process parameters such as temperature, PdCl₂ loading, PPh₃ to PdCl₂ ratio, amount of supported PTC, and solvents have been examined. A mechanism is proposed which is in good agreement with the experimental results obtained.     

Enantiomerization Kinetics of 2,2′-Disubstituted Biphenyls: A Dynamic Chiral HPLC Investigation

The enantiomers of eight axially chiral biaryls were separated by chiral HPLC. On-column enantiomerization of 1-(o-tolyl)naphthalene and 2-cyclohexyl-2′-dimethylaminobiphenyl was observed between 10 °C and 35 °C, generating characteristic HPLC elution profiles with a plateau between the resolved enantiomer peaks. Computer simulation of the experimentally obtained chromatograms allowed determination of the Gibbs free energies of activation, ΔG^≠, as 93.2 kJ/mol and 88.4 kJ/mol, respectively.     

Synthesis of Biaryls through Aromatic C?H Bond Activation: A Review of Recent Developments

This review describes recent progress made in the rapidly developing field of C H bond activation, in particular for syntheses of biaryls. The catalysts presented here provide convenient strategies for the direct arylation of arenes, via single or double C H bond activation, leading to inter‐, and intramolecular carbon‐carbon bond formation. The literature from mid‐2009 to December 2013 has been discussed.

     

Synthesis of Biaryls via Ligand‐Free Suzuki–Miyaura Cross‐Coupling Reactions: A Review of Homogeneous and Heterogeneous Catalytic Developments

This review describes the recent developments in the field of Suzuki–Miyaura cross‐coupling reaction, in particular with regard to ligand‐free catalysis. The catalysts outlined here allow convenient and green synthetic pathways specifically for the construction of C–C bonds. They enable the synthesis of biaryls by the coupling arylboronic acids with aryl halides. The literature reporting ligand‐free synthesis of biaryls from 2010 to May 2015 has been reviewed.

     

Tunable Phosphine‐Mediated Domino Reaction: Selective Synthesis of 2,3‐Dihydrofurans and Biaryls

We have developed a novel strategy to control the product distribution between 2,3‐dihydrofurans and biaryls from the same starting materials by tuning the catalytic or stoichiometric process. By controlling the loading of the phosphine PR₃, the Morita–Baylis–Hillman carbonates can be selectively used as a C₁ or a C₃ synthon, respectively. This investigation has given new insights into tunable domino reactions and will be useful in diversity‐oriented synthesis (DOS).     

Synthesis of Well‐Defined Diphenylvinyl(cyclopropyl)phosphine‐Palladium Complexes for the Suzuki–Miyaura Reaction and Buchwald–Hartwig Amination

The well‐defined diphenylvinylphosphine‐palladium complex 1 and the diphenylcyclopropylphosphine‐palladium complex 2 were successfully synthesized. The crystal structures of these complexes were obtained by X‐ray crystallographic analysis. Both complexes were air‐ and moisture‐stable, and could be prepared on a gram scale. These palladium complexes catalyzed the Suzuki–Miyaura reaction of aryl bromides [turnover numbers (TON) up to 196,000] and aryl chlorides (TON up to 50,000). Furthermore, complex 2 catalyzed the Buchwald–Hartwig amination of aryl chlorides and aromatic/aliphatic amines with a low catalyst loading. These complexes showed different reactivities for the coupling of 2‐chloropyridine, and the origin of this difference is discussed.