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A novel axially chiral all-hydrocarbon cyclo[7] (1,3-(4,6-dimethyl)benzene (CDMB-7) was designed and synthesized using atroposelective[2 + 5] cyclization through Suzuki-Miyaura coupling. CDMB-7 adopts an irregular bowl-like shape with C2 symmetry and exhibits two diastereoisomers in its crystallographic structure. The conformational isomers of CDMB-7 racemates remain stable at high temperatures (393 K). High-performance liquid chromatography (HPLC) confirmed that a single chiral isomer will spontaneously undergo racemization within 30 min at room temperature. This finding opens up possibilities for achieving adaptive chirality in all-hydrocarbon cyclo[7] m-benzene macrocycles.

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An Artificial Metalloenzyme (ArM) built employing the streptavidin-biotin technology has been used for the enantioselective synthesis of binaphthyls by means of asymmetric Suzuki-Miyaura cross-coupling reactions. Despite its success, it remains a challenge to understand how the length of the biotin cofactors or the introduction of mutations to streptavidin leads the preferential synthesis of one atropisomer over the other. In this study, we apply an integrated computational modeling approach, including DFT calculations, protein-ligand dockings and molecular dynamics to rationalize the impact of mutations and length of the biotion cofactor on the enantioselectivities of the biaryl product. The results unravel that the enantiomeric differences found experimentally can be rationalized by the disposition of the first intermediate, coming from the oxidative addition step, and the entrance of the second substrate. The work also showcases the difficulties facing to control the enantioselection when engineering ArM to catalyze enantioselective Suzuki-Miyaura couplings and how the combination of DFT calculations, molecular dockings and MD simulations can be used to rationalize artificial metalloenzymes.

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Despite the paramount importance of the Suzuki-Miyaura coupling (SMC) in academia and industry, and the great promise of iron to offer sustainable catalysis, iron-catalyzed SMC involving sp3-hybridized partners is still in its infancy. We herein report the development of a versatile, well-defined electron-deficient anilido-aldimine iron(II) catalyst. This catalyst effectively performed C(sp3)-C(sp2) and C(sp3)-C(sp3) SMC of alkyl halide electrophiles and (hetero)aryl boronic ester and alkyl borane nucleophiles respectively, in the presence of a lithium amide base. These couplings operated under mild reaction conditions and displayed wide functional group compatibility including various medicinally relevant N-, O- and S-based heterocycles. They also tolerated primary, secondary and tertiary alkyl halides (Br, Cl, I), electron-neutral, -rich and -poor boronic esters and primary and secondary alkyl boranes. Our methodology could be directly and efficiently applied to synthesize key intermediates relevant to pharmaceuticals and a potential drug candidate. For C(sp3)-C(sp2) couplings, radical probe experiments militated in favor of a carbon-centered radical derived from the electrophile. At the same time, reactions run with a pre-formed activated boron nucleophile coupled to competition experiments supported the involvement of neutral, rather than an anionic, (hetero)aryl boronic ester in the key transmetalation step.

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Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

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At first, an organometallic catalyst namely, Pd-DPyE@MCM-41@MNP was prepared through magnetic (Fe3O4) nanoparticles-doped into channels of mesoporous silica MCM-41 and then, anchoring a novel complex composed of di(4-pyridyl)ethylene and palladium on the inner surface of the support. This immobilized catalyst was successfully identified via VSM, ICP-OES, TEM, FTIR, TGA, SEM, BET, XRD, EDX and elemental mapping analyses. After that, it was used as a versatile, heterogeneous, and magnetically reproducible catalyst in the generation of N,N'-alkylidene bisamides (1a-13a, 8-20 min, 90-98%, 50 °C, solvent-free) and Suzuki-Miyaura coupling (SMC) reaction derivatives (1b-26b, 10-140 min, 86-98%, 60 °C, PEG-400). The VSM plot of Pd-DPyE@MCM-41@MNP displays that this nanocatalyst can be easily recycled by applying an external magnetic field. In both synthetic paths, this nanocatalyst was reused at least seven times without palladium leaching and significantly reducing its catalytic performance. Also, stability and heterogeneous nature of catalyst were approved via ICP-OES technique and hot filtration test.

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Palladium-catalyzed Suzuki-Miyaura (SM) coupling is a valuable method for forming C─C bonds, including those between aryl moieties. However, achieving atroposelective synthesis of axially chiral styrenes via SM coupling remains challenging. In this study, a palladium-catalyzed atroposelective Suzuki-Miyaura coupling between gem-diborylalkenes and aryl halides is presented. Using the monophosphine ligand Me-BI-DIME (L2), a range of axially chiral tetra-substituted acyclic styrenes with high yields and excellent enantioselectivities are successfully synthesized. Control experiments reveal that the gem-diboryl group significantly influences the product enantioselectivities and the coupling prefers to occur at sites with lower steric hindrance. Additionally, the alkenyl boronate group in the products proves versatile, allowing for various transformations while maintaining high optical purities.

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Recent development in photocatalysis is increasingly focused on transforming organic compounds toward producing fine chemicals. Simple, non-selective oxidation reactions (degradation of pollutants) and very demanding solar-to-chemical energy conversion processes (production of solar fuels) face severe economic limitations influenced by still low efficiency and insufficient stability of the systems. Synthesis of fine chemicals, including reductive and oxidative selective transformations, as well as C-C and C-N coupling reactions, can utilise the power of photocatalysis. Herein, we present the recent progress in photocatalytic systems designed to synthesise fine chemicals. In particular, we discuss the factors influencing the efficiency and selectivity of the organic transformations, dividing them into intrinsic (related to individual properties of photocatalysts) and extrinsic (originating from the reaction environment). A rational design of the photocatalytic systems, based on a deep understanding of these factors, opens new perspectives for applied photocatalysis.

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Catalytic reduction of p-nitrophenol is usually carried out using transition metal nanoparticles such as gold, palladium, silver, and copper, especially palladium nanoparticles (Pd NPs), which are characterized by fast reaction rate, high turnover frequency, good selectivity, and high yield. However, the aggregation and precipitation of the metals lead to the decomposition of the catalyst, which results in a significant reduction of the catalytic activity. Therefore, the preparation of homogeneous stabilized palladium nanoparticles catalysts has been widely studied. Stabilized palladium nanoparticles mainly use synthetic polymers. Cellulose microspheres, as a natural polymer material with low-cost and porous fiber network structure, are excellent carriers for stabilizing metal nanoparticles. Cellulose microspheres impregnated with palladium metal nanoparticles were carbonized to have a larger specific surface area and highly dispersed palladium nanoparticles, which exhibited excellent catalytic activity in the catalytic reduction of p-nitrophenol. In this work, the cellulose carbon-based microspheres palladium (Pd@CCM) catalysts were designed and characterized by SEM, TEM, EDS, XRD, FTIR, XPS, TGA, BET, and so on. Furthermore, the catalytic performance of Pd@CCM catalysts was investigated via p-nitrophenol reduction, which showed high catalytic activity. This catalyst also exhibited excellent catalytic performance in the Suzuki-Miyaura coupling reaction. Linking aromatic monomer and benzene through Suzuki-Miyaura coupling was presented as an effective route to obtaining biaryls, and the synthesis method is low-cost and simple. In addition, Pd@CCM showed desirable recyclability while maintaining its catalytic activity even after five recycles. This work is highly suggestive of the design and application of the heterogeneous catalyst.

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The branched structures of dendronized polymers can provide good steric stabilization for metal nanoparticle catalysts. In this work, an amphiphilic dendronized copolymer containing hydrophilic branched triethylene glycol moieties and hydrophobic branched ferrocenyl moieties is designed and prepared by one-pot ring-opening metathesis polymerization, and is used as the stabilizer for metal (Au, Ag and Pd) nanoparticles. These metal nanoparticles (Au nanoparticles: 3.5 ± 3.0 nm; Ag nanoparticles: 7.2 ± 4.0 nm; Pd nanoparticles: 2.5 ± 1.0 nm) are found to be highly active in both the 4-nitrophenol reduction and Suzuki-Miyaura reactions. In the 4-nitrophenol reduction, Pd nanoparticles have the highest catalytic ability (TOF: 2060 h-1). In addition, Pd nanoparticles are also an efficient catalyst for Suzuki-Miyaura reactions (TOF: 1980 h-1) and possess good applicability for diverse substrates. The amphiphilic dendronized copolymer will open a new door for the development of efficient metal nanoparticle catalysts.

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Palladium-catalyzed coupling reactions are versatile and powerful tools for the construction of carbon-carbon bonds in organic synthesis. Although these reactions have favorable features that proceed selectively in mild reaction conditions using aqueous organic solvents, no attention has been given to their application in the field of biomedical analysis. Therefore, we focused on these reactions and evaluated the scope and limitations of their analytical performance. In this review, we describe the pros and cons and future trends of fluorescence derivatization of pharmaceuticals and biomolecules based on palladium-catalyzed coupling reactions such as Suzuki-Miyaura coupling, Mizoroki-Heck coupling, and Sonogashira coupling reactions for HPLC analysis.

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Diabetes mellitus, one of the major health challenges of the 21st century, is associated with numerous biomedical complications including retinopathy, neuropathy, nephropathy, cardiovascular diseases and liver disorders. To control the chronic hyperglycemic condition, the development of potential inhibitors of drug targets such as α-glucosidase and α-amylase remains a promising strategy and focus of continuous efforts. Therefore, in the present work, a concise library of isobenzofuranone derivatives (3a-q) was designed and synthesized using Suzuki-Miyaura cross-coupling approach. The biological potential of these heterocyclic compounds against carbohydrate-hydrolyzing enzymes; α-glucosidase and α-amylase, was examined. In vitro inhibitory results demonstrated that the tested isobenzofuranones were considerably more effective and potent inhibitors than the standard drug, acarbose. Compound 3d having an IC50 value of 6.82 ± 0.02 µM was emerged as the lead candidate against α-glucosidase with ⁓127-folds strong inhibition than acarbose. Similarly, compound 3g demonstrated ⁓11-folds higher inhibition strength against α-amylase when compared with acarbose. Both compounds were tested in vivo and results demonstrate that the treatment of diabetic rats with α-amylase inhibitor show more pronounced histopathological normalization in kidney and liver than with α-glucosidase inhibitor. The Lineweaver-Burk plot revealed an uncompetitive mode of inhibition for 3d against α-glucosidase whereas compound 3g exhibited mixed inhibition against α-amylase. Furthermore, in silico molecular docking and dynamics simulations validated the in vitro data for these compounds whereas pharmacokinetics profile revealed the druglike properties of potent inhibitors.

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This work establishes the first direct mechanocatalytic reaction protocol within an extruder, focusing on the Suzuki-Miyaura reaction. Through the coating of either the extruder screws or barrel with Pd, we executed the cross-coupling reaction without the reliance on molecular catalyst compounds or powders, and solvents continuously. We identified the influence and interplay of crucial reaction parameters such as temperature, mechanical energy input, residence time, rheology, and catalyst contact time and finally obtained 36 % and 75 % of the reaction product after one and four reactor passes respectively.

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N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage diversification of 3-bromopyrazoles 10 A/B and 14 A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electron-withdrawing properties of the cyano moiety in 4-position of the pyrazole ring limited the acylation of the primary amino moiety in 5-position. A large set of pyrazoles bearing diverse aryl and alkynyl substituents in 3-position was prepared and the antileishmanial and antitrypanosomal activity was recorded. The urea 38 lacking the electron withdrawing cyano moiety in 4-position and containing the large 4-benzylpiperidinoo moiety exhibited a modest antileishmanial (IC50=19 µM) and antitrypanosomal activity (IC50=7.9 µM)). However, its considerable toxicity against the PMM and MRC-5 cells indicates low selectivity, i. e. a small gap between the desired antiparasitic activity and undesired cytotoxicity of <2- to 4-fold.

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The rising costs of pharmaceutical research are currently limiting the productivity of drug discovery and development, but can potentially be diminished via miniaturization of the synthesis and screening of new compounds. As droplet microarrays already present themselves as a versatile tool for highly miniaturized biological screening of various targets, their use for chemical synthesis is still limited. In this study, the influential palladium-catalyzed Suzuki-Miyaura reaction is successfully implemented at the nanoliter scale on droplet microarrays for the synthesis of an 800-compound library of biphenyls. Each reaction is carried out in individual 150 nL droplets. Remarkably, the synthesis of these 800 compounds requires a minimal amount of reagents, totaling 80 µmol, and a solvent volume of 400 µL. Furthermore, the cleavage kinetics and purity of the obtained biphenylic compounds are investigated. Via the solid-phase synthesis approach, the compounds could be purified from excess reactants and catalyst prior to the analysis and a UV-cleavable linker allows for fast and additive-free cleavage of each compound into the individual 100 nL droplet. This novel approach expands the toolbox of the droplet microarray for miniaturized high-throughput chemical synthesis and paves the way for future synthesis and screening of chemical compounds in a single platform.

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Zeolitic imidazolate frameworks (ZIFs) are a subclass of metal-organic framework that have attracted considerable attention as potential functional materials due to their high chemical stability and ease of synthesis. ZIFs are usually composed of zinc ions coordinated with imidazole linkers, with some other transition metals, such as Cu(II) and Co(II), also showing potential as ZIF-forming cations. Despite the importance of nickel in catalysis, no Ni-based ZIF with permanent porosity is yet reported. It is found that the presence and arrangement of the carbonyl functional groups on the imidazole linker play a crucial role in completing the preferred octahedral coordination of nickel, revealing a promising platform for the rational design of Ni-based ZIFs for a wide range of catalytic applications. Herein, the synthesis of the first Ni-based ZIFs is reported and their high potential as heterogeneous catalysts for Suzuki-Miyaura cross-coupling C─C bond forming reactions is demonstrated.

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Bicyclol, an innovative hepatoprotective drug, was approved by the Chinese National Medical Products Administration (NMPA) in 2001 to treat Hepatitis B and drug-induced liver injury. Two active metabolites of bicyclol have been identified as M2 and M3. To evaluate the impact on drug safety and efficacy of possible drug-drug interactions (DDIs) associated with these metabolites, a sufficient quantity of these metabolites is required. Herein, we report a concise novel route for the synthesis of M2 and M3 using the Suzuki-Miyaura coupling as the key step. Furthermore, we complete the gram-scale syntheses of M2 and M3.

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Phosphine periodic mesoporous organosilicas (R-P-PMO-TMS: R=Ph, tBu), which possess electron-donating alkyl substituents on the phosphorus atom, were synthesized using bifunctional compounds with alkoxysilyl- and phosphino groups, bis[3-(triethoxysilyl)propyl]phenylphosphine borane (1 a) and bis[3-(triethoxysilyl)propyl]-tert-butylphosphine borane (1 b). Immobilization of Pd(0) species was performed to give R-P-Pd-PMO-TMS: R=Ph (2 a), tBu (3 a), respectively. The Pd(0) immobilized 2 a and 3 a were applicable as catalysts for Suzuki-Miyaura cross-coupling reactions of aryl chlorides with phenylboronic acid. It was revealed that 3 a bearing more electron-donating tBu groups exhibited higher catalytic activity. Various functional groups including both electron withdrawing and donating substituents were compatible in the system. The recyclability of 3 a was examined to support its moderate utility for the recycle use.

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The Suzuki-Miyaura cross-coupling (SMCC) involves the coupling of organohalides and organoboron molecules in the presence of Pd(II)-based catalysts. Often SMCC reactions employ homogenous catalysts. However, such homogenous SMCC reactions are associated with certain limitations which has motivated design of effective and sustainable Pd(II)-based heterogeneous catalytic systems. Herein, we report a systematic development of a Pd(II)-immobilized and triptycene based ionic hyper crosslinked polymer (Pd@TP-iHCP) and explored its application as a heterogeneous catalyst for SMCC reaction. Pd@TP-iHCP has ample N-heterocyclic carbene (NHC) pendants that anchor Pd(II) centres on the polymeric matrix. Pd@TP-iHCP was characterized satisfactorily using FT-IR, 13 C CP-MAS NMR, BET surface area analysis, SEM, EDX and HRTEM. The performance of Pd@TP-iHCP as a heterogeneous catalyst for SMCC reactions was explored using various combinations of aryl boronic acids and aryl halides. Experimental results show that Pd@TP-iHCP is associated with a moderately high surface area. It is an efficient catalyst for SMCC (in aqueous media) with a modest loading of 0.8 mol % Pd(II)-catalyst since high yields of the expected products were obtained in shorter time intervals. Pd@TP-iHCP also features excellent stability and catalyst recyclability since it could be re-used for several cycles without any significant decrease in catalytic efficiency.

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Di(p-benzi)[40]decaphyrin(1.0.0.0.0.1.0.0.0.0) BF2 complex and tris(p-benzi)[60]pentadecaphyrin(1.0.0.0.0.1.0.0.0.0.1.0.0.0.0) BF2 complex were synthesized by Suzuki-Miyaura coupling of α,α'-diborylated tetrapyrrole BF2 -complex with 1,4-diiodobenzene. Bis-BF2 complex was converted to bis-PdII complex via its free base. Macrocycles bis-BF2 and tris-BF2 complex take Möbius topology but are nonaromatic, since the macrocyclic conjugation is disrupted by the locally aromatic 1,4-phenylene units. In contrast, bis-PdII complex is a weakly Hückel 38π-aromatic macrocycle as evinced by its red-shifted, enhanced, and structured Q-like bands and a small electrochemical HOMO-LUMO gap. Interestingly, one 1,4-pheylene part of bis-PdII complex takes a quinonoidal distorted structure and the other takes a usual benzene structure in a figure-eight conformation with Hückel topology.

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Practical advances in Ni-catalyzed Suzuki-Miyaura cross-coupling (SMC) have been limited by a lack of mechanistic understanding of phosphine ligand effects. While bisphosphines are commonly used in these methodologies, we have observed instances where monophosphines can provide comparable or higher levels of reactivity. Seeking to understand the role of ligation state in catalysis, we performed a head-to-head comparison study of C(sp2)-C(sp2) Ni SMCs catalyzed by mono and bisphosphine precatalysts using six distinct substrate pairings. Significant variation in optimal precatalyst was observed, with the monophosphine precatalyst tending to outperform the bisphosphines with electronically deactivated and sterically hindered substrates. Mechanistic experiments revealed a role for monoligated (P1Ni) species in accelerating the fundamental organometallic steps of the catalytic cycle, while highlighting the need for bisligated (P2Ni) species to avoid off-cycle reactivity and catalyst poisoning by heterocyclic motifs. These findings provide guidelines for ligand selection against challenging substrates and future ligand design tailored to the mechanistic demands of Ni-catalyzed SMCs.