Palladium-catalyzed Coupling Reaction Research Articles

Synthesis and photodynamic activity of new 5-[(E)-2-(3-alkoxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-2-phenyl-3H-indoles.

A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells. Evaluation revealed comparable anticancer activities of 8d in both breast and melanoma cancer cell lines within the submicromolar range. The treatment induced a massive generation of reactive oxygen species, leading to different types of cell death depending on the compound concentration and the irradiation intensity.

P,N-Coordinating Ylide-Functionalized Phosphines (NYPhos): A Ligand Platform for the Selective Monoarylation of Small Nucleophiles.

Palladium-catalyzed coupling reactions of small nucleophiles are of great interest, but challenging due to difficulties in selectivity control. Herein, we report the development of a new platform of P,N-ligands consisting of ylide-functionalized phosphines with aminophosphonium groups (NYPhos) to address this challenge. These phosphine ligands are easily accessible in a wide structural diversity with highly modular electronic and steric properties. Based on a family of 14 ligands the selective monoarylation of acetone as well as other challenging ketones and amides was accomplished with record-setting activities even for aryl chlorides at room temperature including late-stage functionalizations of drug molecules. Moreover, ammonia and other small primary amines could be coupled at mild conditions. Isolation and structure analyses of palladium complexes within the catalytic cycle confirmed that the P,N-coordination mode is necessary to achieve the observed selectivities. It also demonstrated the facile adjustability of the N-donor strength, which is beneficial for the targeted design of tailored P,N-ligands for future applications.

5-Trifluoromethoxy-substituted Nicotinic Acid, Nicotinamide and Related Compounds

A practical and convenient method for synthesizing nicotinic acid and nicotinamide with the trifluoromethoxy group in position 5 of the ring has been developed. A series of related compounds, for example, nicotinic aldehyde and nicotinic alcohol, have been synthesized. It has been shown that 3-bromo-5-trifluoromethoxypyridine is a convenient and efficient synthon for palladium-catalyzed coupling reactions. The trifluoromethoxy group has been found to be remarkably stable against hydroiodic acid in contrast to the methoxy group.

Synthesis of Unsymmetrically Condensed Benzo- and Thienotriazologermoles.

Germoles and siloles unsymmetrically condensed with heteroaromatic units are attracting much interest. In this study, compounds containing a triazologermole core unit condensed with a benzene or thiophene ring were prepared. Thienotriazologermole was subjected to bromination to obtain the bromide, which underwent transformation via the palladium-catalyzed Stille coupling reaction to form triphenylamine-substituted thienotriazolegermole, with an effective extension of conjugation. The electronic states and properties of these triazologermole derivatives are discussed on the basis of optical and electrochemical measurements and density functional theory calculations. Triphenylamine-substituted thienotriazolegermole showed clear solvatochromic properties in photoluminescence measurements, suggesting that intramolecular charge transfer occurs at the photo-excited state. This clearly indicates that the triazologermole unit is useful as an acceptor of donor-acceptor compounds. The potential application of triphenylamine-substituted thienotriazolegermole as a sensing material was also explored.

Synthesis and Evaluation of diaryl ether modulators of the leukotriene A4 hydrolase aminopeptidase activity

Activation of the aminopeptidase (AP) activity of leukotriene A4 hydrolase (LTA4H) presents a potential therapeutic strategy for resolving chronic inflammation. Previously, ARM1 and derivatives were found to activate the AP activity using the alanine-p-nitroanilide (Ala-pNA) as a reporter group in an enzyme kinetics assay. As an extension of this previous work, novel ARM1 derivatives were synthesized using a palladium-catalyzed Ullmann coupling reaction and screened using the same assay. Analogue 5, an aminopyrazole (AMP) analogue of ARM1, was found to be a potent AP activator with an AC50 of 0.12 μM. An X-ray crystal structure of LTA4H in complex with AMP was refined at 2.7 Å. Despite its AP activity with Ala-pNA substrate, AMP did not affect hydrolysis of the previously proposed natural ligand of LTA4H, Pro-Gly-Pro (PGP). This result highlights a discrepancy between the hydrolysis of more conveniently monitored chromogenic synthetic peptides typically employed in assays and endogenous peptides. The epoxide hydrolase (EH) activity of AMP was measured in vivo and the compound significantly reduced leukotriene B4 (LTB4) levels in a murine bacterial pneumonia model. However, AMP did not enhance survival in the murine pneumonia model over a 14-day period. A liver microsome stability assay showed metabolic stability of AMP. The results suggested that accelerated Ala-pNA cleavage is not sufficient for predicting therapeutic potential, even when the full mechanism of activation is known.

Photoinduced Palladium-Catalyzed Radical Heck-Type Coupling of Cyclobutanone Oxime Esters with Vinyl Arenes.

A palladium-catalyzed radical Heck-type coupling reaction of cyclobutanone oxime esters with olefins under visible-light irradiation has been developed. The cyanoalkyl/Pd(I) hybrid species generated by selected ring-opening C-C bond cleavage of imino/Pd(I) species reacted smoothly with vinyl arenes, delivering the cyanoalkylation olefins under mild conditions. This elegant strategy has a broad scope and functional group tolerance. Subsequently, late-stage functionalization of bioactive molecules and synthetic transformations of the product further confirm the practicality.

Triple Role of Proton Sponge (DMAN) in the Palladium-Catalyzed Direct Stereoselective Synthesis of C-Aryl Glycosides from Glycals.

The triple role of 1,8-bis(dimethylamino)naphthalene (proton sponge) as a reductant, ligand precursor, and organic base in the palladium-catalyzed Heck-type coupling reaction of glycals with aryl iodides affords the rapid and stereoselective synthesis of 2',3'-unsaturated α-C-aryl glycosides in excellent yields. The role of the proton sponge in reducing palladium(II) to (0) has been studied using cyclic voltammetry, UV-vis, HRMS, and other spectroscopic techniques. This is the first example of a palladium proton sponge complex utilized in coupling reactions. The method is observed to be tolerant of various functional groups, as demonstrated by the huge substrate scope. Moreover, the 2',3'-unsaturated α-C-aryl glycosides were also converted to 3-keto-β-C-glycosides under sterically hindered pyridinium salt catalysis via a ring-opening and -closing mechanism.

Unique biomedical application of fluorescence derivatization based on palladium-catalyzed coupling reactions for HPLC analysis of pharmaceuticals and biomolecules.

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.

Synthesis and optical properties of dithieno-1,4-thiaborins bearing electron-donating amino groups

Abstract Dibenzo-1,4-heteraborins and their π-extended derivatives have been paid increased attention to because of their potential as optical and electronic functional materials such as organic electroluminescence emitters. However, 1,4-heteraborin compounds with heteroaromatic ring systems remain scarce, even though Liu et al. recently reported the synthesis, properties, and functionalization of dithieno-1,4-thiaborins (DTTBs). In this work, DTTBs with 10H-phenothiazine-10-yl (Pz), 9H-carbazol-9-yl (Cz), and p-(Ph2N)C6H4 groups as electron-donating amino groups at the α-positions of their thiophene moieties were synthesized using palladium-catalyzed coupling reactions. X-ray crystallographic analysis revealed the molecular structure of a DTTB substituted with Pz groups. This analysis showed that the 2 Pz moieties adopted extra (quasi-axial) conformations. The Cz- and p-(Ph2N)C6H4-substituted DTTBs showed red-shifted absorption and emission when compared to the original DTTBs. This shift is due to donor–acceptor interactions between the amino groups and the DTTB cores. The Pz-substituted DTTB exhibited dual fluorescence emissions, originating from the locally excited (LE) and twisted intramolecular charge transfer (TICT) states. The intensity and nature of these emissions varied based on solvent polarity, temperature, and viscosity, suggesting the potential of the Pz-substituted DTTB to act as a fluorescent environment sensor.

Decarboxylative Iodination and Suzuki-Miyaura Coupling Reactions to Access Chiral 3,3'-Diaryl-1,1'-bi-2-naphthols.

An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOLs is accomplished through decarboxylative iodination of the dimethyl ether derivative of BINOL-3,3'-dicarboxylic acid followed by Suzuki-Miyaura coupling using a one-pot protocol. The decarboxylative iodination is effected with the dimethyl ether derivative of BINOL-3,3'-dicarboxylic acid using iodine as a terminal oxidant and the cheaply available K3PO4 as a base under neat conditions. This protocol facilitated the introduction of the aryl group at the 3,3'-position on the binaphthyl system using aryl boronic acid through a palladium-catalyzed Suzuki-Miyaura coupling reaction.

Total Synthesis of the Pyrrole Alkaloids Strychnuxinal and Strychnuxin

AbstractThe first asymmetric total syntheses of the fused-pyrrole alkaloids strychnuxinal and strychnuxin have been achieved in 6 and 7 steps, respectively, starting from commercially available (±)-4-chlorostyrene oxide. Key steps in the synthetic route include a regioselective epoxide opening, a reductive etherification sequence to form the central 1,4-oxazine ring, and a late-stage phenol synthesis using a mild palladium-catalyzed coupling reaction. Notably, the optimized synthetic sequence presented avoids the use of traditional protecting groups. Total synthesis of these two structurally related natural products confirmed both their constitution (via NMR and X-ray crystallography) and their absolute configuration (via optical rotation).

Well-Balanced Ambipolar Charge Transport of Diketopyrrolepyrrole-Based Copolymers: Organic Field-Effect Transistors and High-Voltage Logic Applications.

A poly (3,6-bis(thiophen-2-yl)-2,5-bis(2-decyltetradecyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione-co-(2,3-bis(phenyl)acrylonitrile)) (PDPADPP) copolymer, composed of diketopyrrolopyrrole (DPP) and a cyano (nitrile) group with a vinylene spacer linking two benzene rings, is synthesized via a palladium-catalyzed Suzuki coupling reaction. The electrical performance of PDPADPP in organic field-effect transistors (OFETs) and circuits is investigated. The OFETs based on PDPADPP exhibit typical ambipolar transport characteristics, with the as-cast OFETs demonstrating low field-effect hole and electron mobility values of 0.016 and 0.004cm2 V-1 s-1 , respectively. However, after thermal annealing at 240°C, the OFETs exhibit improved transport characteristics with highly balanced ambipolar transport, showing average hole and electron mobility values of 0.065 and 0.116cm2 V-1 s-1 , respectively. To verify the application of the PDPADPP OFETs in high-voltage logic circuits, compact modeling using the industry-standard small-signal Berkeley short-channel IGFET model (BSIM) is performed, and the logic application characteristics are evaluated. The circuit simulation results demonstrate excellent logic application performance of the PDPADPP-based ambipolar transistor and illustrate that the device annealed at 240°C exhibits ideal circuit characteristics.

Synthesis of Polysubstituted Pyrimidines through Palladium-Catalyzed Isocyanide Insertion to 2H-Azirines.

The domino process of the palladium-catalyzed coupling reaction of isocyanides with 2H-azirine provides various tetrasubstituted pyrimidines via one C-C bond and two C-N bond formations with satisfactory yields. The title compounds are obtained with good functional group tolerance, high atom economy, and broad substrate scopes.

Incorporating Domain Knowledge and Structure-Based Descriptors for Machine Learning: A Case Study of Pd-Catalyzed Sonogashira Reactions.

Machine learning has revolutionized information processing for large datasets across various fields. However, its limited interpretability poses a significant challenge when applied to chemistry. In this study, we developed a set of simple molecular representations to capture the structural information of ligands in palladium-catalyzed Sonogashira coupling reactions of aryl bromides. Drawing inspiration from human understanding of catalytic cycles, we used a graph neural network to extract structural details of the phosphine ligand, a major contributor to the overall activation energy. We combined these simple molecular representations with an electronic descriptor of aryl bromide as inputs for a fully connected neural network unit. The results allowed us to predict rate constants and gain mechanistic insights into the rate-limiting oxidative addition process using a relatively small dataset. This study highlights the importance of incorporating domain knowledge in machine learning and presents an alternative approach to data analysis.

N-Heterocyclic Carbene-Palladium Polymers Network: Recyclable Pre-catalyst for Effective Suzuki-Miyaura Coupling Reaction in Water.

Rational design of high-efficiency N-heterocyclic carbene (NHC) palladium catalyst is of great importance to modern organic synthesis, especially in chemical and pharmaceutical industries. Herein, we fabricate a polymer network containing N-heterocyclic carbene palladium (PNNHC-Pd) catalytic active sites via an immobilization process. The N-heterocyclic carbene palladium can serve as a promising linkage of polymer network as well as an effective catalytic active site owing to its structural preference and strong σ-donating ability with palladium species. The results display that N-heterocyclic carbene palladium disperses homogeneously in polymer network, thus rendering PNNHC-Pd excellent catalytic activity, high stability and superior reusability in palladium-catalyzed Suzuki-Miyaura coupling reaction in aqueous medium. This work provides a new insight into the development of heterogenization of homogeneous catalysts based on polymer network.

A highly efficient and selective fluorescent probe for Pd (II) based on benzotriazole-coumarin derivative and its catalytic application in Sonogashira reaction

Palladium-catalyzed coupling reactions have become effective tools for forming new carbon–carbon bonds. In this work, a novel fluorescence active benzotriazole-coumarin derivative, (E)-N'-((1H-benzo[d][1,2,3]triazol-6-yl)methylene)-7-(diethylamino)-2-ox o-2H-chromene-3-carbohydrazide (BTANC), was synthesized as ligand in Pd(II) cation coordination. It is shown that BTANC has a strong fluorescent emission at 483 nm and Pd(II) can effectively quench the fluorescence of BTANC and BTANC shows excellent sensitivity and selectivity towards Pd (II) ions. Otherwise, the BTANC-Pd(II) complex was also tested in the Sonogashira coupling reaction of phenylacetylene and aryl halides. The desired product was obtained with high yield (up to 99%) under the optimized reaction conditions. More to that, Low fluorescence emission was observed during the Pd-catalyzed reaction process and the fluorescent emission of BTANC was recovered at the end of the Pd-catalyzed reaction because the oxidative addition of the aryl halide towards Pd (0) was shut down at the end of the Pd-catalyzed reaction. This fluorescence properties of BTANC indicates the feasibility of using fluorescence signal as a potential tool to monitor the completion of the Sonogashira coupling reaction.

Post-Modification of Pyrrolopyrrole Aza-BODIPY toward High Near-Infrared Fluorescence Brightness

Pyrrolopyrrole aza-BODIPYs (PPABs), dimeric aza-BODIPY analogues, exhibit intense absorption and fluorescence in the visible and near-infrared (NIR) regions. Here, we developed a facile postmodification by palladium-catalyzed coupling reactions to synthesize a series of donor-acceptor-donor (D-A-D) PPABs. Despite the possible fluorescence quenching dictated by the energy-gap low, D-A-D PPABs exhibit high-fluorescence brightness in the NIR region, implying their potential use as a bright NIR emitter.

Synthesis, Photophysical properties and OFET application of thienothiophene and benzothiadiazole based Donor-π-Acceptor-π (D-π -A-π) type conjugated polymers

Novel conjugated donor- π -acceptor- π (D- π -A- π) type polymers (P1-P3), possessing thieno[3,2-b]thiophene (TT) with different aromatic substituents as donors, benzo[1–3]thiadiazole (BT) as an acceptor and thiophene as a π -linker, were designed and synthesized via palladium-catalyzed Stille coupling reaction. Their electronic, optical and thermal properties were investigated using UV–vis and fluorescence spectroscopies, cylic voltammetry, and thermal gravimetric analysis. Photophysical characterizations of these novel polymers showed a remarkable mega Stokes shift, reaching up to 130 nm and optic/electronic band gaps between 1.70 and 2.00 eV, as well as good thermal stability of degradation temperature at around 260 °C. To study the effect of electron donating and withdrawing groups on the electronic properties of the π -extended polymers, their organic field-effect transistors (OFETs) were fabricated and charge transport characteristics were investigated. While all three polymers showed a p-type field-effect behaviour, dimethylamine substituted P3 exhibited the highest average saturated hole mobility, μsat, 0.04 cm2 V−1 s−1, on/off current ratio, Ion/Ioff = 3.0 × 103, and the smallest subthreshold swing, SS, 250 mV dec-1, outperforming similar p-type D- π -A- π semiconducting polymers reported in the literature. The results presented in this work corroborate that the three novel TT-BT polymers have promising potential for electronic and optoelectronic applications, in particular where the tunability of field-effect behaviour is essential for performance.

A Team for Accelerating Catalyst and Reaction.

This invited Team Profile was created by the Gessner and Gooßen research groups at Ruhr-University Bochum (Germany). They recently published a series of articles in Angewandte Chemie on the application of ylide-substituted phosphines (YPhos) in palladium-catalyzed coupling reactions. Owing to their inherently strong sigma-donating ability and their modular synthesis, YPhos ligands can be tailored to fit the demands of various catalytic transformations. In the most recent article, machine learning methods were applied to identify a YPhos catalyst that enables the previously elusive Hiyama coupling of aryl chlorides. "Computer-Driven Development of Ylide Functionalized Phosphines for Palladium-Catalyzed Hiyama Couplings", J. F. Goebel, J. Löffler, Z. Zeng, J. Handelmann, A. Hermann, I. Rodstein, T. Gensch, V. H. Gessner, L. J. Gooßen, Angew. Chem. Int. Ed. 2023, e202216160; Angew. Chem. 2023, e202216160.

Recent advances and prospects in palladium-catalyzed Hiyama coupling reaction

Recent advances and prospects in palladium-catalyzed Hiyama coupling reaction