Suzuki Cross-coupling Reaction Research Articles

Resin-Immobilized Palladium Acetate and Alcohol Dehydrogenase for Chemoenzymatic Enantioselective Synthesis of Chiral Diarylmethanols.

The enantioselective synthesis of chiral diarylmethanols is highly desirable in synthetic chemistry and the pharmaceutical industry, but it remains challenging, especially in terms of green and sustainable production. Herein, a resin-immobilized palladium acetate catalyst was fabricated with high activity, stability, and reusability in Suzuki cross-coupling reaction of acyl halides with boronic acids, and the coimmobilization of alcohol dehydrogenase and glucose dehydrogenase on resin supports was also conducted for asymmetric bioreduction of diaryl ketones. Experimental results revealed that the physicochemical properties of the resins and the immobilization modes played important roles in affecting their catalytic performances. These two catalysts enabled the construction of a chemoenzymatic cascade for the enantioselective synthesis of a series of chiral diarylmethanols in high yields (83-90%) and enantioselectivities (87-98% ee). In addition, the asymmetric synthesis of the antihistaminic and anticholinergic drugs (S)-neobenodine and (S)-carbinoxamine was also achieved from the chiral diarylmethanol precursors, demonstrating the synthetic utility of the chemoenzymatic cascade.

5-(9-(p-Tolyl)-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazol-6-yl)thiophene-2-carbaldehyde

Donor–π spacer–acceptor (D–π–A) dyes are among the most attractive structures for the design of organic dye-sensitized solar cells (DSSCs). Typically, the key intermediates for these sensitizers are D–π compounds containing an aldehyde group to which an anchor acceptor group is attached via the Knoevenagel reaction. In this communication, 5-(9-(p-tolyl)-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazol-6-yl)thiophene-2-carbaldehyde was prepared via the Suzuki cross-coupling reaction. The structure of the newly synthesized compound was established by means of high-resolution mass spectrometry, 1H NMR, 13C NMR, IR, and UV–Vis spectroscopy. The title compound would be used in the synthesis of sensitizers for DSSCs.

Chitosan-functionalized poly(3-hydroxybutyrate) bead as a novel biosupport for palladium in the Suzuki cross-coupling reaction

The utilization of environmentally friendly biopolymer poly(3-hydroxybutyrate) (PHB) as a support for metal catalysts is an unexplored area. Herein, exploring a stable and recyclable heterogeneous palladium (Pd) catalyst based on PHB for the Suzuki cross-coupling reaction is an attractive topic. In this study, a novel hydrophobic and hydrophilic core-shell bead supported Pd catalyst was developed by using PHB particle as a hydrophobic rigid framework and hydrophilic chitosan (CS) as the surface of the supporting matrix to fix Pd nanoparticles (NPs). The results of structural characterization showed that the Pd NPs with a small average size of 2.3±0.82 nm were uniformly distributed on the surface of the PHB-CS bead with a Pd content of 0.12 wt%. This demonstrated that the PHB-CS bead created a stable coordinated environment for Pd fixation, preventing Pd leaching. Furthermore, the Pd@PHB-CS catalyst exhibited high catalytic efficiency with 99% conversion in the Suzuki reaction under mild conditions, using a solvent mixture of EtOH and H2O (1:1) for 0.5 h. It is worth noting that the catalyst exhibits excellent stability, and reusability. It can be reused five times without a significant reduction in activity while maintaining its structural integrity. The successful construction of Pd@PHB-CS will further expand the application of PHB in the field of metal catalysts and may help establish a green and environmentally friendly multifunctional platform for the development of highly recyclable heterogeneous catalysts containing metal nanoparticles.

Nanodiamond Supported Ultra-Small Palladium Nanoparticles as an Efficient Catalyst for Suzuki Cross-Coupling Reactions

A nanocatalyst comprising ultra-small palladium nanoparticles supported on nanodiamonds (ultra-small Pd/rNDs) was fabricated via a reduction of palladium (II) salt on oxidized nanodiamond. The prepared catalyst was characterized using XRD, XPS, ICP-MS, AAS, and TEM/HRTEM techniques, including STEM-EDS chemical mapping, which revealed that the modified material is a combination of reduced nanodiamond decorated with palladium nanoparticles. The as-prepared and well-characterized ultra-small Pd supported on rNDs displayed superb catalytic activity for Suzuki–Miyaura cross-coupling reactions at low temperature without any toxic solvents, to obtain the respective products in good-to-excellent yields (75–98%). The catalyst was easily separated from the reaction solution and was reused four times without loss of catalytic activity or chemical stability.

Synthesis, Reactions and Biological Activity of Pyrimido [5, 4-c] Quinolines based on (Thio)Barbituric Acid and their Analogous (Part IV)

Abstract: Pyrimido [5, 4-c] quinolone derivatives are significant synthetic targets that show numerous interesting biological activities. The pyrimido [4, 5-b] quinoline is the most famous source of these derivatives, which has been used in medicine to antitumor and target different diseases. Since the segregation of quinoline derivatives, many synthetic methodologies were advanced for their synthesis. Despite the current interesting findings on this class of pyrimidoquinoline, the chemical literature deficits a comprehensive summary of the synthetic methodologies and biological activities of pyrimido [5, 4-c] quinoline derivatives. This review focuses on recent advances in pyrimido [5, 4-c] quinolines chemistry via debating diverse synthetic ways developed for the preparation of pyrimido [5, 4-c] quinolines and other unique derivatives that exhibited promising biological activities. Also, it sheds light on the most widespread reactions of pyrimidoquinolines and the employment of these derivatives as the essential building blocks for different biologically active compounds:. Among these reactions used to prepare pyrimido [5, 4-c] quinoline derivatives are the following: Biginelli-type one or three-component reaction, Micheal addition, intermolecular cyclization, cyclo-condensation, acylation, Vielsmeir formylation, Suzuki cross-coupling reaction, transformation, oxidation-reduction, esterification, dehydration, decarboxylation, methylation, chlorination, alkylation.

Linkage Isomers of Triangular Pd Metallacycles and Catalysis in Aqueous Suzuki Coupling Reaction.

The water-soluble trinuclear Pd metallacycles [Pd(tmeda)(4-Spy)]3(X)3 (tmeda = tetramethylethylenediamine, X = OTf, 2; NO3, 3) were synthesized from the ambidentate ligand 4-pyridylthiolate (Spy-) and [Pd(tmeda)X2] in 80 and 70% yield, respectively. Two possible linkage isomers are found in solution (slow interconversion found in the NMR) and in the solid state. Density functional calculations showed that the energy of the isomer with a D3-symmetric arrangement of the SPy ligand and all Pd atoms having N∧NPdSN coordination is only 7 kcal/mol lower. When reacting [Pd(tmeda)(NO3)2] with 4,4'-biphenyldithiolate (S2bph2-), the tetranuclear [{Pd(tmeda)}4(μ-S2bph)2](NO3)4 (1) was formed. A new type of undecanuclear Pd cluster was separated as a minor product from an acetone solution of 2 in air. The new complexes represent the first examples of water-soluble Pd metallacycles constructed from a pyridine-thiolate ligand. They show catalytic activity with turnover numbers ranging from 9 to 420 in aqueous Suzuki cross-coupling reactions using phenyl boronic acid and a number of aryl halides. An optimized system gave a TON of 6,900,000 and a TOF of 492,857 h-1. The catalyst could be reused eight times, and the activity has been attributed to the formation of PdNPs.

Geometric deep learning-guided Suzuki reaction conditions assessment for applications in medicinal chemistry.

Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon-carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners. We show that the trained models support chemists in determining suitable catalyst-solvent-base combinations for individual transformations including an evaluation of the need for HTE screening. We introduce an algorithm for designing 96-well plates optimized towards reaction yields and discuss the model performance of zero- and few-shot machine learning. The best-performing machine learning model achieved a three-category classification accuracy of 76.3% (±0.2%) and an F 1-score for a binary classification of 79.1% (±0.9%). Validation on eight reactions revealed a receiver operating characteristic (ROC) curve (AUC) value of 0.82 (±0.07) for few-shot machine learning. On the other hand, zero-shot machine learning models achieved a mean ROC-AUC value of 0.63 (±0.16). This study positively advocates the application of few-shot machine learning-guided reaction condition selection for HTE campaigns in medicinal chemistry and highlights practical applications as well as challenges associated with zero-shot machine learning.

A novel magnetic nanoparticle as an efficient and recyclable heterogeneous catalyst for the Suzuki cross-coupling reaction

A novel magnetically recyclable heterogeneous palladium catalyst Fe3O4@FSM@Pd was constructed and characterized, which is highly efficient and reusable for the Suzuki–Miyaura cross-coupling reaction.

Synthesis and Fluorescent Properties of Some Benzothiazole Derivatives Synthesized via Suzuki Cross Coupling Reaction

Synthesis and Fluorescent Properties of Some Benzothiazole Derivatives Synthesized via Suzuki Cross Coupling Reaction

Application of Palladium Single Atoms in C−C Coupling Reactions of Pharmaceutical Synthesis

Designing highly active and structurally well-defined catalysts while reducing the amount of catalyst has become a key issue in heterogeneous catalytic reactions. In this study, palladium single-atom catalysts were prepared for efficient catalysis in the Suzuki cross-coupling reaction of iodobenzene and phenylboronic acid, which was prepared by one-step high-temperature pyrolysis. The palladium single-atom catalysts have high activity as well as stability in Suzuki cross-coupling reactions and have great potential in catalyzing organic reactions.

Green Synthesis of CuO Nanoparticles Using Agaricus bisporus Extract as a Highly Efficient Catalyst for the Suzuki Cross-Coupling Reaction.

Copper oxide nanoparticles (CuONPs) were synthesized using a rapid, eco-friendly, cost-effective, efficient, and biological method employing aqueous Agaricus bisporus extract as a capping and reducing agent. The formation of CuONPs was checked by UV-vis spectroscopy and was characterized by X-ray diffraction analysis (XRD), dynamic light scattering spectroscopy (DLS), transmission electron microscopy (TEM), and surface area and porosimetry analyzer. The characterization results showed that the synthesized nanoparticles had a spherical-like appearance and a crystal structure with 40-100 nm particle size. The green synthesized CuONPs were found to be an excellent and sustainable heterogeneous catalyst (TOF up to 29700 h-1 ) for the Suzuki C-C coupling of aryl halides with phenylboronic acid in a very short reaction time (10 minutes). Moreover, the easily recovered catalyst can be reused five times with just a negligible reduction in catalytic behavior.

CuNPs@Al2O3-cellulose composite for the ligand-free Suzuki cross-coupling reactions in batch and continuous flow process

In the present work, we synthesized recyclable CuNPs@Al2O3-CELL composite from an inexpensive and commercially available synthetic reagent by a simple method. The catalyst was characterized by various techniques such as TGA (Thermogravimetric analysis), SEM (Scanning electron microscope), TEM (Transmission electron microscopy), XPS (X-ray photoelectron spectroscopy), EDS (Energy dispersive spectroscopy), and AAS (Atomic Absorption Spectroscopy). The composite was applied for the Suzuki coupling reactions in the batch and flow process. The aryl halides were easily coupled with arylboronic acids in 95 % ethanol at 78 °C. We systematically investigated the role of reaction temperature, solvent, and catalyst loading, on the transient and steady-state behavior of the flow reactor through an automated flow chemistry platform. The CuNPs@Al2O3-CELL catalytic particles demonstrate minimal deactivation and leaching over a continuous Suzuki coupling reaction at a 20 min nominal residence time at 100 °C. Moreover, the catalyst can be recovered by simple filtration and reused at least five times with a moderate decrease in product yield. The excellent activity and stability of the catalyst have been attributed to the strong chelation of the Cu species with hydroxyl functional groups of the Al2O3-CELL composite. The catalytic system was highly efficient in Suzuki coupling of various aryl bromides with different aryl boronic acids, yielding good to excellent product yields (80–96 %) with a TON of 15.914–19.066 and TOF of 2.649–9.533 h−1.

Experimental and computational study of the catalytic activity of Pd and PdCu nanoparticle catalysts and clusters supported on reduced graphene oxide and graphene acid for the suzuki cross-coupling reaction

The catalytic activity of Pd and PdCu nanoparticle catalysts and clusters supported on reduced graphene oxide (RGO) and graphene acid (GA) toward the Suzuki cross-coupling reaction between bromobenzene and phenylboronic acid is investigated experimentally and computationally. The experimental results indicate that the bimetallic PdCu nanoparticle catalysts supported on RGO or GA outperform the supported Pd catalysts and that the PdCu/RGO catalyst exhibits superior activity, reaching a full conversion to the biphenyl product in only 15 min under ambient conditions. The experimental results show that both the Pd and PdCu catalysts have higher activities when supported on RGO than when supported on GA. The computational results using density functional theory show that the RGO provides relatively better support for the C-C coupling reaction than GA. Investigations based on the charge analysis have further revealed that the RGO is a better charge donor and acceptor than GA, facilitating both the reaction's oxidative addition and reductive elimination steps by reducing the respective barrier heights. Doping a Cu atom near the Pd reaction site is shown to enhance this effect further. The relative reactivity trends of RGO- and GA-supported Pd and PdCu clusters obtained from the DFT calculations show exact agreement with the experimental results.

Palladium/1,3-bis(ferrocenylmethy)imidazolinium chloride catalyst for Suzuki cross-coupling reactions

We describe here the first results of catalytic performance of in situ prepared [Pd(O2CCH3)2] / 1,3-bis(ferrocenylmethy)imidazolinium chloride involving a saturated imidazole ring were successfully employed to Suzuki cross-coupling reactions of different aryl bromides (bromobenzene, 2-bromobenzonitrile, 2-bromotoluene, p-bromobenzaldehyde, p-bromoacetophenone, p-bromoanisole, p-bromotoluene and p-bromobenzotrifluoride) with phenylboronic acid under the optimum conditions. Optimum conditions were choosed, as 24 h, 80 oC, K2CO3 as base, dioxane as solvent, 1,3-bis(ferrocenylmethy)imidazolinium chloride as auxiliary ligand. Under these optimum conditions, 2- bromobenzonitrile, p-bromoacetophenone and p- bromobenzaldehyde react with phenyl boronic acid in moderate yields 57%, 50%, and 46% respectively. Catalytic experiments showed that [Pd(O2CCH3)2] / 1,3-bis(ferrocenylmethy)imidazolinium chloride catalytic system was moderately effficent in the Suzuki cross coupling reaction of aryl bromides in dioxane.

Reduced Tiara-like Palladium Complex for Suzuki Cross Coupling Reactions.

The design of highly active and structurally well-defined catalysts has become a crucial issue for heterogeneous catalysed reactions while reducing the amount of catalyst employed. Beside conventional synthetic routes, the employment of polynuclear transition metal complexes as catalysts or catalyst precursors has progressively intercepted a growing interest. These well-defined species promise to deliver catalytic systems where a strict control on the nuclearity allows to improve the catalytic performance while reducing the active phase loading. This study describes the development of a very active and reusable palladium-based catalyst on alumina (Pd8/Al2O3) for Suzuki cross coupling reactions. An octanuclear tiara-like palladium complex was selected as active phase precursor to give isolated Pd-clusters of ca. 1 nm in size on Al2O3. The catalyst was thoroughly characterised by several complementary techniques to assess its structural and chemical nature. The high specific activity of the catalyst has allowed to carry out the cross-coupling reaction in 30 minutes using only 0.12 mol% of Pd loading under very mild and green reaction conditions. Screening of various substrates and selectivity tests, combined with recycling and benchmarking experiments, have been used to highlight the great potentialities of this new Pd8/Al2O3 catalyst.

Sonogashira coupling reactions with ligand-free heterogeneous nanoporous Pd catalyst

The Sonogashira coupling reaction is one of the most important protocols for the production of aryl alkynes. In order to solve the problems existing in Sonogashira cross-coupling reaction, according to the application of nanoporous palladium in Suzuki and Heck cross-coupling reactions, nanoporous palladium was used as the sustainable catalyst for the Sonogashira cross-coupling reaction. A sustainable catalyst system was tested and optimized without cuprous ion, phosphine ligand, or amine additives. Nanoporous palladium catalyst remained stable over five cycles without significant leaching or loss of catalytic activity, and the desired alkynes were obtained in high yields.

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library.

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.

High-efficiency PdNi single-atom alloy catalyst toward cross-coupling reaction

The preparation of Pd-based catalysts with rich electrons and a high atom dispersion rate is of great significance for improving the reactivity of cross-coupling reactions, which is a powerful tool for pharmaceutical and fine chemical synthesis. Here, we report a PdNi single-atom alloy (SAA) catalyst in which isolated Pd single atoms are anchored onto the surface of Ni nanoparticles (NPs) applied for Suzuki coupling reactions and Heck coupling reactions. The 0.1% PdNi SAA exhibits extraordinary catalytic activity (reaction rate: 17,032.25 mmol h−1 gPd−1) toward the Suzuki cross-coupling reaction between 4-bromoanisole and phenylboronic acid at 80 °C for 1 h. The excellent activity is supposed to attribute to the 100 percent utilization rate of Pd atoms and the highly stable surface zero-valance Pd atoms, which provides abundant sites and electrons for the adsorption and fracture of the C-X (X = Cl, Br, I) bond. Moreover, our work demonstrates the excellent application prospect of SAAs for cross-coupling reactions.

Synthesis of 1-(4-Bromobenzoyl)-1,3-dicyclohexylurea and Its Arylation via Readily Available Palladium Catalyst-Their Electronic, Spectroscopic, and Nonlinear Optical Studies via a Computational Approach.

In this study, we reported the synthesis of 1-(4-bromobenzoyl)-1,3-dicyclohexylurea by the reaction of DCC (N,N'-dicyclohexylcarbodiimide) with 4-bromobenzoic acid. Subsequently, we further synthesized a new series of 1-(4-arylbenzoyl)-1,3-dicyclohexylurea (5a-g) derivatives using a Suzuki cross-coupling reaction between 1-(4-bromobenzoyl)-1,3-dicyclohexylurea (3) and various aryl/heteroaryl boronic acids (4). Thus, density functional theory (DFT) calculations have been performed to examine the electronic structure of the synthesized compounds (3, 5a-g) and to calculate their spectroscopic data. Moreover, optimized geometries and thermodynamic properties, such as frontier molecular orbitals (HOMO, LUMO), molecular electrostatic potential surfaces, and reactivity descriptors, were also calculated at the PBE0-D3BJ/def2-TZVP/SMD1,4-dioxane level of theory to validate the structures of the synthesized compounds.

Exploration of catalytic activity of newly developed Pd/KLR and Pd-Cu/KLR nanocomposites (NCs) for synthesis of biologically active novel heterocycles via Suzuki cross-coupling reaction

The present articles aimed at the synthesis of biologically active novel heterocycles via selective construction of CC bond through a cross-coupling reaction between a heterocyclic aryl halide and phenylboronic acid catalyzed by the newly developed Pd-KLR (Palladium-Kaphal leaves residue) and Pd-Cu-KLR nanocomposites (NCs). The biological properties of the newly synthesized heterocycles were examined using molecular docking studies. Pd-KLR nanocomposites (NPs) and Pd-Cu/KLR nanoparticles (NCs) were synthesized using kaphal (box berry) leaves extract, the extracted residue of kaphal leaves is used as a carrier and reducing agent in the cross-coupling reaction. The synthesized Pd NCs and Pd-Cu NPs were characterized using FT-IR, UV-visible, X-ray diffraction, X-ray photoelectron spectroscopy, and scanning electron microscopy. Molecular docking results revealed that the newly synthesized heterocycles exhibit impressive affinity towards bacterial topoisomerase II that indicated their antibacterial properties. The cluster Pd-KLR NCs and spherical Pd-Cu-KLR NPs had a mean particle size of around 110 nm and 53 nm. The comparative study of both Pd-KLR and Pd-Cu-KLR nanocatalysts is studied. However, the heterogeneous Pd-KLR nanocomposite showed excellent catalytic activity for the heterocyclic Suzuki Cross-Coupling reaction. The yield of the reaction of 3-amino-2-chloropyridine with phenylboronic acid using EtOH solvent in the presence of NaOH base and a very little amount of Pd0.02/KLR (0.1 mmol%) catalyst at 78 °C temperature under microwave irradiations for 10 min is noticed as 96.7%. Furthermore, the catalyst could be recycled for up to seven cycles without any significant activity loss.