Palladium-catalyzed Suzuki-Miyaura Cross-coupling Reaction Research Articles

Sadphos as Adaptive Ligands in Asymmetric Palladium Catalysis.

ConspectusPalladium catalysis, as one of the most important strategies in asymmetric synthesis, has continuously attracted the attention of organic chemists. With the development of chiral ligands, increasingly challenging reactions and substantial progress in asymmetric catalysis are being realized.Since 2014, we have focused on exploiting a series of sulfinamide phosphine ligands called "Sadphos," including Ming-Phos, Xu-Phos, Xiao-Phos, Xiang-Phos, TY-Phos, PC-Phos, GF-Phos, and WJ-Phos. These ligands can be easily prepared in two to four steps using commercial materials. These new types of ligands have shown remarkable performance in transition-metal-catalyzed reactions, especially in Pd-catalyzed transformations. X-ray diffraction analysis, mechanistic studies, and density functional theory calculations have revealed that Sadphos ligands can coordinate with the Pd0 and PdII species in the Pd0/P, Pd0/P,S, or PdII/P,O modes.This Account summarizes our recent efforts toward palladium-catalyzed enantioselective reactions using Sadphos ligands. These ligands were found to be privileged and very crucial to promote the reactions by increasing the reactivity and enantioselectivity. Ming-Phos is an effective ligand in Pd-catalyzed asymmetric coupling and intramolecular Heck reactions, providing highly enantioselective trisubstituted allenes, axially chiral anilides, gem-diarylmethine silanes, and disubstituted dihydroisoquinolinones. Incorporation of an electron-rich cyclohexyl group in the phosphine moiety afforded Xu-Phos, which showed a unique effect in a series of asymmetric transformations, including reductive Heck, dearomative Mizoroki-Heck, tandem Heck/Suzuki coupling, carboiodination, carboamination, and cross-coupling reactions. Using a similar strategy, our group synthesized more electron-rich TY-Phos and Xiang-Phos ligands bearing t-butyl and 1-adamantyl group at P atoms, respectively. Regarding stereoelectronic features, these two characteristic ligands were the best choice to satisfy the requirements of the palladium-catalyzed fluoroarylation of gem-difluoroalkenes, intermolecular α-arylation of aldehydes, carboetherification of alkenyl oximes, and carboheterofunctionalization of 2,3-dihydrofurans. Compared with the aforementioned Sadphos ligands, the attractive features of Xiao-Phos, including high nucleophilicity originating from the CH2PPh2 group and the ortho-substituent effect at the side of the aryl ring, are presumably responsible for its efficiency. The Pd/Xiao-Phos catalyst system shows good performance in a series of cross-coupling reactions of secondary phosphine oxides, affording P-stereogenic products bearing multiple types of molecular skeletons. The modification of the basic Sadphos backbone by introducing a xanthene skeleton motivated us to design and synthesize monophosphines, named PC-Phos and GF-Phos. PC-Phos is effective in various reactions, including arylation of sulfenate anions, denitrogenative cyclization of benzotriazoles, and dearomatization of indoles. The practicability of GF-Phos was validated in the Pd-catalyzed asymmetric three-component coupling of N-tosylhydrazones, aryl halides, and terminal alkynes, as well as in the cross-coupling of N-tosylhydrazones and vinyl iodides with pendent amines. In addition, ferrocene-derived WJ-Phos was employed in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction, affording axially chiral biaryl monophosphine oxides in excellent enantiomeric excesses.

Pyrimidine-morpholine hybrids as potent druggable therapeutics for Alzheimer’s disease: Synthesis, biochemical and in silico analyses

The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer’s disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman’s method revealed significantly strong potency. Compound 5h bearing a meta-tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer’s drugs.

Carbon monoxide surrogates for palladium-catalyzed Suzuki-Miyaura and Sonogashira carbonylative cross-coupling reactions

Palladium-catalyzed Suzuki-Miyaura and Sonogashira reactions are probably the best methods to create new sp2-sp2 and sp2-sp chemical bonds starting from aryl halides and aryl boronic acids or terminal alkynes. These cross-couplings are generally promoted by a palladium-based catalyst and due to their potentialities, they have been deeply investigated. In particular, the carbonylative version of this reactions is widely used for the synthesis of conjugated diaryl and alkynyl ketones, biologically active compounds, and important building blocks for the synthesis of pharmaceuticals, and organic materials. The insertion of a carbon monoxide molecule is generally achieved by means of high pressure of CO but nowadays the severe toxicity of this gas has led to the development of CO surrogates which must be non-toxic and easy to handle. In this context, the aim of this review is to give a detailed comprehensive overview of the scientific literature regarding carbonylative Suzuki-Miyaura and Sonogashira reactions performed employing a CO source. The content of this review will be divided into two main chapters according to the different approach to CO generation, i.e., -in situ and ex situ technique. For each chapter, a systematic analysis of the nature of the CO surrogate will be reported.

Palladium-catalyzed synthesis and acetylcholinesterase inhibitory activity evaluation of 1-arylhuperzine A derivatives

A series of arylated huperzine A (HPA) derivatives (1–24) were efficiently synthesized in good yields (45–88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer’s disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues.

Functionalization of Framboidal Phenylboronic Acid-Containing Nanoparticles via Aqueous Suzuki-Miyaura Coupling Reactions.

Polymeric nanoparticles with reactive functional groups are an attractive platform for drug carriers that can be conjugated with drugs through a cleavable covalent linkage. Since the required functional groups vary depending on the drug molecule, there is a need for development of a novel post-modification method to introduce different functional groups to polymeric nanoparticles. We recently reported phenylboronic acid (PBA)-containing nanoparticles (BNP) with a unique framboidal morphology created via one-step aqueous dispersion polymerization. Since BNPs have high surface area due to their framboidal morphology and contain a high density of PBA groups, these particles can be used as nanocarriers for drugs that can bind to PBA groups such as curcumin and a catechol-bearing carbon monoxide donor. To further explore the potential of BNPs, in this article we report a novel strategy to introduce different functional groups to BNPs via the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction between the PBA groups and iodo- and bromo-coupling partners. We developed a new catalytic system that efficiently catalyzes Suzuki-Miyaura reactions in water without the need for an organic solvent, as confirmed by NMR. Using this catalyst system, we show that BNPs can be functionalized with carboxylic acids, aldehyde, and hydrazide groups while keeping their original framboidal morphology as confirmed via IR, alizarin red assay, and TEM. Furthermore, the potential of the functionalized BNP in drug delivery applications was demonstrated by conjugating the hydrogen sulfide (H2S)-releasing compound anethole dithiolone to carboxylic acid-functionalized BNPs and show their H2S-releasing capability in cell lysate.

Caffeine and theophylline as sustainable, biosourced NHC ligand precursors for efficient palladium-catalyzed Suzuki–Miyaura cross-coupling reactions

The alkylation of caffeine with methyl iodide afforded 1,3,7,9-tetramethylxanthinium iodide, which was further reacted with PdCl2, KI, and K2CO3 in neat pyridine to afford the [PdI2(NHC)(Py)] complex 1 in two steps and 73% overall yield. An intermediate anion exchange afforded the corresponding dichlorido complex 2 in 70% overall yield. Theophylline was successfully converted into a new xanthinium salt bearing an isobutyl group on its N7 atom, which was further employed to prepare the [PdCl2(NHC)(Py)] complex 3. These three Pd-PEPPSI catalyst precursors were fully characterized and the molecular structure of complex 2 was determined. Complexes 1–3 displayed a high catalytic activity in the Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic acids. Aryl bromides and iodides bearing either electron-donating or withdrawing substituents afforded a wide range of biaryl derivatives that were isolated in 40–93% yields (30 examples). The reactions required only a low catalyst loading (0.25 mol%) and were carried out in a green, water-based solvent mixture using K2CO3 as a base in the presence of air. Although less reactive, aryl chlorides were also successfully activated under more forcing conditions, provided that an electron-withdrawing group was present on their aromatic ring.

Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Oxygen-Substituted Allylboronates with Aryl/Vinyl (Pseudo)Halides.

An efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of oxygen atom-substituted allylboronates with aryl/vinyl bromides, iodides, and triflates has been developed. The present coupling reactions proceeded smoothly to provide a variety of allylic siloxanes with high efficiency and excellent regioselectivity. This protocol features broad substrate scope, excellent functional group tolerance, and easy gram-scale preparation, and offers an alternative approach for the synthesis of allylic alcohols and their derivatives.

Functionalized styrene synthesis via palladium-catalyzed C[sbnd]C cleavage of aryl ketones

We report herein the synthesis of functionalized styrenes via palladium-catalyzed Suzuki–Miyaura cross-coupling reaction between aryl ketone derivatives and potassium vinyltrifluoroborate. The employment of pyridine-oxazoline ligand was the key to the cleavage of unstrained CC bond. A variety of functional groups and biologically important moleculars were well tolerated. The orthogonal Suzuki–Miyaura coupling demonstrated the synthetic practicability.

Arylketones as Aryl Donors in Palladium-Catalyzed Suzuki-Miyaura Couplings.

Herein, we report the arylation, alkylation, and alkenylation of aryl ketones via a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The use of the pyridine-oxazoline ligand is the key to the cleavage of the unstrained C-C bond. The late-stage arylation of aryl ketones derived from drugs and natural products demonstrated the synthetic utility of this protocol.

Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction.

The story of C−C bond formation includes several reactions, and surely Suzuki‐Miyaura is among the most outstanding ones. Herein, a brief historical overview of insights regarding the reaction mechanism is provided. In particular, the formation of the catalytically active species is probably the main concern, thus the preactivation is in competition with, or even assumes the role of the rate determining step (rds) of the overall reaction. Computational chemistry is key in identifying the rds and thus leading to milder conditions on an experimental level by means of predictive catalysis.

Synthesis of Xylyl-Linked Bis-Benzimidazolium Salts and Their Application in the Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reaction of Aryl Chlorides

A new series of xylyl-linked bis-benzimidazolium salts were efficiently prepared using a simple preparation method from bis-benzimidazolium precursors featuring highly tunable linkers and wingtips. A highly efficient Suzuki–Miyaura cross-coupling reaction of aryl chlorides within the range of 0.5–2.0 mol% Pd-catalyst loading was observed. Also, di-ortho-substituted biaryl synthesis was achieved.

Stereoselective Palladium-Catalyzed Base-Free Suzuki–Miyaura Cross-Coupling of Tetrasubstituted gem-Difluoroalkenes: An Experimental and Computational Study

Palladium-catalyzed Suzuki–Miyaura cross-coupling reactions are among the most powerful tools for constructing carbon–carbon bonds. Moreover, the selective coupling between gem-difluoroalkenes and ...

High-Throughput Peptide Derivatization toward Supramolecular Diversification in Microtiter Plates.

The evolution of life on earth eventually leads to the emergence of species with increased complexity and diversity. Similarly, evolutionary chemical space exploration in the laboratory is a key step to pursue the structural and functional diversity of supramolecular systems. Here, we present a powerful tool that enables rapid peptide diversification and employ it to expand the chemical space for supramolecular functions. Central to this strategy is the exploitation of palladium-catalyzed Suzuki–Miyaura cross-coupling reactions to direct combinatorial synthesis of peptide arrays in microtiter plates under an open atmosphere. Taking advantage of this in situ library design, our results unambiguously deliver a fertile platform for creating a set of intriguing peptide functions including green fluorescent protein-like peptide emitters with chemically encoded emission colors, hierarchical self-assembly into nano-objects, and macroscopic hydrogels. This work also offers opportunities for quickly surveying the diversified peptide arrays and thereby identifying the structural factors that modulate peptide properties.

Synthesis of novel coumarin containing conjugated fluorescent polymers by Suzuki cross-coupling reactions and their chemosensing studies for iron and mercury ions

Conjugated fluorescent polymers are very useful materials for chemical and biochemical sensors. Herein we report the synthesis of four novel conjugated coumarin-containing fluorescent co-polymers (P1–P4) by palladium catalyzed Suzuki-Miyaura cross-coupling reaction. 4-Methyl/phenyl coumarin ditriflates and diboronic acids such as benzene-1,4-diboronic acid and 9,9-dioctylfluorene-2,7-diboronic acid were used as coupling partners. All the polymers were well-characterized using NMR and gel permeation chromatography. TGA studies revealed that these polymers are stable over 300 °C. The photophysical properties of these novel polymers were studied by UV–Vis and fluorescence spectroscopy. Among these four polymers, polymer P3 having 4-methylcoumarin and dioctylfluorene as alternating monomers showed intense fluorescence with 0.73 quantum yield in the DMF medium. Polymer P3 was also found as selective fluorescence “turned-off” chemosensor for the detection of Hg(II) and Fe(II)/Fe(III) ions over the other metal ions dissolved in water.

Anchored Pd(0) Nanoparticles on Synthetic Talc for the Synthesis of Biaryls and a Precursor of Angiotensin II Inhibitors

AbstractThe palladium-catalyzed Suzuki–Miyaura cross-coupling reaction is one of the most important and efficient reactions to prepare a variety of organic compounds, including biaryls. Despite the overwhelming number of reports related to this topic, some methodological difficulties persist in terms of catalyst handling, recovery, and reuse, as well as the reaction media. This work reports the rational design of new, efficient, cost-effective, and reusable palladium catalysts supported on synthetic talc for the Suzuki–Miyaura reaction. From the results, key points were identified: both designed catalysts accelerated the reaction in EtOH and an open-flask setup, affording moderate to excellent yields within a short time (e.g., 30 min) even for deactivated aryl halides; the protocol can be applied to a great number of both cross-coupling partners, showing an excellent functional group tolerance; the catalysts can be recovered and reused without significant loss of activity. This protocol was used for the synthesis of a precursor of angiotensin II inhibitors such as valsartan, losartan, irbesartan, and telmisartan.

Selective Mechanochemical Monoarylation of Unbiased Dibromoarenes by in Situ Crystallization.

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of liquid, unbiased dibromoarenes under mechanochemical conditions selectively afford the monoarylated products. The lower reactivity of the crystalline monoarylated products relative to the liquid starting materials should be attributed predominantly to the low diffusion efficiency of the former in the reaction mixture, which results in a selective monoarylation. The present study sheds light on a novel approach using in situ phase transitions in solids to design selective organic transformations that are difficult to achieve via conventional solution-based synthesis.

Polyphenylene networks containing triptycene units: Promising porous materials for CO2, CH4, and H2 adsorption

The synthesis of triptycene-based three-dimensional networks and their uptake towards various gases are described. The target polymers TPP1-3 were synthesized by employing a convenient palladium-catalyzed Suzuki-Miyaura cross-coupling reaction between a triptycene synthon bearing two peripheral dibromotetraphenyl benzene ( TBT ) units and various arylboronic acid/ester moieties. Polymers TPP1-3 were characterized by several instrumental analysis techniques, namely, solid-state 13 C nuclear magnetic resonance (SSNMR), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR), and emission spectrophotometry. Brunauer-Emmett-Teller (BET) nitrogen adsorption investigation of TPP1-3 revealed surface areas up to 468 m 2 g −1 and an average pore volume of ~0.25 cm 3 g −1 . Interestingly, low-pressure gas adsorption studies of TPP1-3 disclosed a CO 2 uptake for TPP1 of 78.4 mg g −1 (273 K) and a gas adsorption capacity for TPP2 towards H 2 and CH 4 of 10 mg g −1 (77 K) and 7.9 mg g −1 (273 K), respectively. • Synthesis of new polyhenylene networks TPP1-3 bearing triptycene units is reported. • Gas sorption study show BET surface area up to 468 m 2 /g and pore volume of 0.25 cm 3 /g. • CO 2 adsorption capacity discloses a promising uptake of 78.4 mg g −1 at 273 K for TPP1 . • TPP2 uptakes 10 mg g −1 of H 2 at 77 K and 7.9 mg g −1 of CH 4 at 273 K.

Mild and Metal-Free Protocol toward the Synthesis of Triarylmethanes by Reactions of (Hetero)Arylboronic Acids and ortho-Hydroxyarylaldehydes.

Herein, we have reported a metal-free, mild, and novel protocol for the synthesis of various triarylmethanes (TRAMs) in moderate to good yields via the reactions of aryl boronic acids and ortho-hydroxyarylaldehydes in the presence of stoichiometric amounts of Et3N in dichloroethane at 80 °C. Additionally, the synthetic utilities of few synthesized TRAMs were proven by carrying out bromination on the -OH-containing aryl part and followed by functionalization of bromine through a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with arylboronic acids in good yields. The -OH group was also alkylated and arylated through simple alkylation and Chan-Lam reaction, respectively.

Interface Interactions in Conjugated Polymer Composite with Metal Oxide Nanoparticles.

This study presents the preparation, characterization, and properties of a new composite containing cerium oxide nanoparticles and a conjugated polymer. CeO2 nanoparticles prepared using the co-precipitation method were dispersed into the conjugated polymer, prepared using the palladium-catalyzed Suzuki–Miyaura cross-coupling reaction. The interface interactions between the two components and the resultant optoelectronic properties of the composite are demonstrated. According to transmission electron microscopy and X-ray absorption spectroscopy, the dispersion of CeO2 nanoparticles in the polymer matrix strongly depends on the CeO2 nanoparticle concentration and results in different degrees of charge transfer. The photo-induced charge transfer and recombination processes were studied using steady-state optical spectroscopy, which shows a significant fluorescence quenching and red shifting in the composite. The higher photo-activity of the composite as compared to the single components was observed and explained. Unexpected room temperature ferromagnetism was observed in both components and all composites, of which the origin was attributed to the topology and defects.

Facile synthesis of novel amino acid-like building blocks by N-alkylation of heterocyclic carboxylates with N-Boc-3-iodoazetidine.

An efficient protocol providing easy access to highly functionalized heterocyclic compounds as novel organic building blocks was developed by coupling alkyl pyrazole-, indazole- and indolecarboxylates with N-Boc-3-iodoazetidine. The synthesized compounds are representatives of constrained non-chiral synthetic azole carboxylates in their N-Boc protected ester forms. Diversification of the prepared heterocyclic building blocks was achieved via application of palladium-catalyzed Suzuki-Miyaura cross-coupling reactions. In total, 34 building blocks were obtained to form a highly diversified small molecule collection. The structure of the novel heterocyclic compounds was investigated and verified by advanced NMR spectroscopy methods.