Buchwald-Hartwig Cross-coupling Reaction Research Articles

Careful choice of carbonyl-containing cmps, and optimisation of Buchwald-Hartwig crosscoupling reaction conditions

In this study, new nitrogen-rich conjugated microporous polymers were synthesized using the Buchwald-Hartwig cross-coupling reaction. The synthesized polymers were characterized using various methods, including X-ray diffraction (XRD), ultraviolet-visible-near-infrared (UV-Vis-NIR) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, Brunauer-Emmett-Teller (BET) surface area analysis, and pore size distribution (PSD) determination using non-local density functional theory (NLDFT). The results provide important information about the structure and properties of synthesized materials, which contributes to a deeper understanding of their characteristics. The obtained characteristics of the material allow us to judge the quality and purity of the obtained polymers, which is important for further research, as well as serve as a basis for the development of new synthesis methods or improvement of existing technologies.

One-Step Catalyst-Transfer Macrocyclization: Expanding the Chemical Space of Azaparacyclophanes.

In this paper, we report on a one-step catalyst-transfer macrocyclization (CTM) reaction, based on the Pd-catalyzed Buchwald-Hartwig cross-coupling reaction, selectively affording only cyclic structures. This route offers a versatile and efficient approach to synthesize aza[1n]paracyclophanes (APCs) featuring diverse functionalities and lumens. The method operates at mild reaction temperatures (40 °C) and short reaction times (∼2 h), delivering excellent isolated yields (>75% macrocycles) and up to 30% of a 6-membered cyclophane, all under nonhigh-dilution concentrations (35-350 mM). Structural insights into APCs reveal variations in product distribution based on different endocyclic substituents, with steric properties of exocyclic substituents having minimal influence on the macrocyclization. Aryl-type endocyclic substituents predominantly yield 6-membered macrocycles, while polycyclic aromatic units such as fluorene and carbazole favor 4-membered species. Experimental and computational studies support a proposed mechanism of ring-walking catalyst transfer that promotes the macrocycle formation. It has been found that the macrocyclization is driven by the formation of cyclic conformers during the oligomerization step favoring an intramolecular C-N bond formation that, depending on the cycle size, hinges on either preorganization effect or kinetic increase of the reductive elimination step or a combination of the two. The CTM process exhibits a "living" behavior, facilitating sequential synthesis of other macrocycles by introducing relevant monomers, thus providing a practical synthetic platform for chemical libraries. Notably, CTM operates both under diluted and concentrated regimes, offering scalability potential, unlike typical macrocyclization reactions usually operating in the 0.1-1 mM range.

Linear Amine-Linked Oligo-BODIPYs: Convergent Access via Buchwald-Hartwig Coupling.

A convergent route toward nitrogen-bridged BODIPY oligomers has been developed. The synthetic key step is a Buchwald-Hartwig cross-coupling reaction of an α-amino-BODIPY and the respective halide. Not only does the selective synthesis provide control of the oligomer size, but the facile preparative procedure also enables easy access to these types of dyes. Furthermore, functionalized examples were accessible via brominated derivatives.

Self-Healing Conjugated Microporous Polyanilines for Effective and Continuous Catalytic Detoxification of 4-Nitrophenol to 4-Aminophenol.

Detoxification of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) with high efficiency and dynamic performance is challenging for a polymeric catalyst. Herein, a series of conjugated microporous polyanilines (CMPAs), capable of efficiently catalytically reducing 4-NP, were synthesized based on the Buchwald-Hartwig cross-coupling reaction mechanism. By adjusting the types of linkers and the molar ratios of linker to core, CMPAs with different Brunauer-Emmett-Teller (BET) specific surface areas and reduction degrees were obtained and used as the catalysts in reducing 4-NP. The ultrahigh catalytic reduction efficiency (K = 141.32 s-1 g-1, kapp = 0.00353 s-1) was achieved when using CMPA-3-0.7 as the catalyst (prepared with 4,4'-diaminodiphenylamine as the linker and a 0.7:1 molar ratio of linker to core). The catalytic reduction performance exhibited a strong correlation with the reduction degree and BET specific surface area of CMPAs. Furthermore, they also exhibit excellent cycling stability and dynamic performance. The coexistence of a microporous structure and high BET specific surface area endowed CMPAs with an increased number of catalytic active centers. The reversible redox transformation of CMPAs in the presence of NaBH4 and air enabled self-healing (the oxidation units in CMPAs were reduced to reduction units by NaBH4, and the newly generated reduction unit in CMPAs was subsequently oxidized to its original state by the O2 in the air), leading to the reduction reaction of 4-NP proceeded continuously and stably. The aforementioned factors resulted in the high efficiency of CMPAs for reducing 4-NP to 4-AP, enhancing the practical application prospects of CMPAs in the detoxification of 4-NP wastewater.

New antibacterial, antifungal and antioxidant agents bearing sulfonamide

The successful nickel catalyzed synthesis of N-(aryl) substituted p-toluene sulphonamides is reported. The intermediate 4-methylbenzenesulphonamide was obtained by the reaction of p-toluenesulphonyl chloride and ammonium hydroxide. Substituted p-toluene sulphonamides were obtained by coupling 4-methylbenzenesulphonamide with readily available aryl halides via Buchwald-Hartwig cross-coupling reaction. The structures of the compounds were confirmed using Fourier Transform Infrared (FT-IR), proton NMR, carbon-13 NMR and mass spectroscopy. The new compounds were screened for antibacterial and antifungal activities against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Aspergillus niger using agar diffusion technique. Some of the compounds showed improved antimicrobial activity when compared with ciprofloxacin and ketoconazole. The sulphonamides were further screened for antioxidant activity using 1,1-diphenyl-2-picrylhydrazide (DPPH), ferric reducing antioxidant potency (FRAP) and ferrous sulphate induced lipid peroxidation. The compounds showed improved antioxidant activity on comparison with ascorbic acid. Specifically, compound 20 was revealed by this study to be a lead antibacterial and antifungal agent whereas compound 17 showed a lead as antioxidant agent. The drug-likeness study indicated that none of the compounds violated Lipinski, Ghose, and Verber rules for drug-able molecules.

Conformational Locking as a Strategy to Reverse Ion Recognition Selectivity.

This study delves into the ion recognition capabilities of a novel host molecule, emphasizing the role of conformational locking in dictating ion selectivity. By employing the Buchwald-Hartwig cross-coupling reaction, we have notably shifted the ion receptor's selectivity from K+ to Na+. The findings are supported by computational simulations that reveal differences in binding energies and molecular strain impacting ion recognition. This innovative structural modification broadens the scope for alterations at the calix[4]arene's lower rim, paving the way for new methods and strategies in modulating ion recognition selectivity.

Synthesis of New 5- or 7-Substituted 3-Nitroimidazo[1,2-a]pyridine Derivatives Using SNAr and Palladium-Catalyzed Reactions To Explore Antiparasitic Structure–Activity Relationships

AbstractTo study the antikinetoplastid structure–activity relationships in a 3-nitroimidazo[1,2-a]pyridine series, we explored the substitution of positions 5 and 7 of the scaffold, developing nucleophilic aromatic substitution reactions and palladium-catalyzed Suzuki–Miyaura, Sonogashira, and Buchwald–Hartwig cross-coupling reactions that had never been reported at these positions in this series. In four steps from 2-amino(bromo)pyridines, 33 original compounds were obtained, allowing a better definition of the antiparasitic pharmacophore.

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues.

A series of novel N-aryl-debenzeyldonepezil derivatives (1-26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer's disease.

Boosting the generality of catalytic systems by the synergetic ligand effect in Pd-catalyzed C-N cross-coupling

In the areas of catalysis and organic chemistry, the development of versatile and efficient catalytic systems has long been a challenge, primarily due to the intricate relationship between ligands and transition metal centers. This study addresses this challenge by exploring the concept of ligand synergy to enhance the generality of catalytic systems, a crucial metric for their practical utility. By combining N-heterocyclic carbene (NHC) and phosphine ligands, we unveil a novel catalytic system that exhibits high level of generality in the Buchwald-Hartwig cross-coupling reaction. Our findings not only demonstrate the enhanced efficiency of this system, leading to the synthesis of valuable compounds with applications in organic electroluminescent devices and the pharmaceutical industry, but also shed light on the broader potential of ligand synergy in catalysis. Through machine learning analysis, we uncover the critical role of specific ligand properties, further paving the way for rational catalyst design.

Formation and characterization of palladium ethyl 2-aminoazulene-carboxylate complexes

We tried to synthesize an intermolecular cyclic compound with ethyl 2-amino-3-bromoazulene-carboxylate (EABA) using a Buchwald–Hartwig cross-coupling reaction in the presence of palladium acetate and Cs2CO3. The consumption of EABA was confirmed; however, no target compound was produced and a palladium-EABA complex (Pd-EABA) was formed. Pd complexes with diethyl 2-aminoazulene-1,3-carboxylate (DEAA) were synthesized and characterized using single-crystal X-ray structural analysis, nuclear magnetic resonance, Fourier transform infrared (FTIR) spectroscopy, and density functional theory calculations. Oligomer composed of Pd and 2,2′-diamino-1,1′,3,3′-tetrakis(ethoxycarbonyl)-6,6′-biazulene (2DEAA) was synthesized and characterized by matrix assisted laser desorption/ionization time-of-flight mass spectrometry and FTIR. Because of the expansion of the conjugation between p-orbital of the azulenyl moiety and d-orbital of the Pd atom, Pd complexes exhibit bathochromic shifts and hyperchromic effects. When DEAA was mixed with other metal sources (Ti4+, Fe3+, Co2+, Ni2+, Cu2+, Cu+, Zn2+, and Ru3+), no coordination was observed between DEAA and the cations.

Desymmetric Reductive Amination of 1,3-Cyclopentadiones to Single Stereoisomer of β-Amino Ketones with an All-Carbon Quaternary Stereocenter by Engineered Amine Dehydrogenases

Regio- and stereoselective reductive amination of diketones offers an attractive method to access chiral β-amino ketones with multiple stereocenters which are unique scaffolds and building blocks for bioactive molecules, but it is still a great challenge in organic chemistry. In this study, mutant amine dehydrogenases (LsAmDHs) were created by directed evolution of a l-phenylalanine dehydrogenase from Lysinibacillus sphaericus to catalyze the desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones. Using these beneficial LsAmDHs, the corresponding (2R, 3R)-β-amino ketones with an all-carbon quaternary stereocenter were prepared with up to 99% de and ee and up to 84% isolated yields. A cyclopenta[b]hydroquinoline derivative was obtained from 2-methyl-2-(2′-bromobenzyl)-1,3-cyclopentadione or 2-methyl-2-(2′-chlorobenzyl)-1,3-cyclopentadione via sequential enzymatic desymmetric reductive amination and an intramolecular Buchwald–Hartwig cross coupling reaction. Molecular docking and dynamics simulations provided some insights into the roles of key mutations on the improved activity and excellent stereoselectivity toward these un-native substrates. This study not only developed biocatalysts to realize the unprecedented desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones to the single stereoisomer of the corresponding β-amino ketones but also suggested that engineering of amine dehydrogenase provides a useful tool to address the challenges in asymmetric reductive amination of diketones.

Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N-Aryl Galantamine Analogues.

A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC50 = 0.19 μM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.

Derivatives of Pyridazine with Phenoxazine and 9,9-Dimethyl-9,10-dihydroacridine Donor Moieties Exhibiting Thermally Activated Delayed Fluorescence.

Two compounds based on pyridazine as the acceptor core and 9,9-dimethyl-9,10-dihydroacridine or phenoxazine donor moieties were designed and synthesized by Buchwald-Hartwig cross-coupling reaction. The electronic, photophysical, and electrochemical properties of the compounds were studied by ultraviolet-visible spectroscopy (UV-vis), photoluminescence spectrometry, differential scanning calorimetry, thermogravimetric analysis, and cyclic voltammetry. The compounds are characterized by high thermal stabilities. Their 5% weight loss temperatures are 314 and 336 °C. Complete weight loss of both pyridazine-based compounds was detected by TGA, indicating sublimation. The derivative of pyridazine and 9,9-dimethyl-9,10-dihydroacridine is capable of glass formation. Its glass transition temperature is 80 °C. The geometries and electronic characteristics of the compounds were substantiated using density functional theory (DFT). The compounds exhibited emission from the intramolecular charge transfer state manifested by positive solvatochromism. The emission in the range of 534-609 nm of the toluene solutions of the compounds is thermally activated delayed fluorescence with lifetimes of 93 and 143 ns, respectively.

4,7-Bis(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine

Donor-acceptor-donor (D-A-D) type molecules are of interest as components in organic light emitting diodes (OLEDs). In this communication, 4,7-bis(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine was obtained by two successive reactions—aromatic nucleophilic substitution SNAr and Buchwald-Hartwig cross-coupling reaction. The structure of newly synthesized compounds was established by elemental analysis, high resolution mass-spectrometry, 1H, 13C NMR, IR and UV spectroscopy and mass-spectrometry. The luminescent properties of the title compound were studied.

Regression Prediction of Coupling Reaction Yield Based on Attention-Driven Convolutional Neural Network

The traditional method to improve the yield of Buchwald-Hartwig cross coupling reaction is to change the reactants or reaction conditions, but the reaction has many problems, such as harsh reaction conditions, complex synthetic route. In 2018, Doyle reported a yield prediction method based on random forest in Science. However, the predicted value of the regression tree in the random forest is the average value of the target variable of the leaf node, which treats the feature as equally important. We focused on the important characteristic information in order to obtain a more accurate yield prediction value. Therefore, it is of interest to apply some advanced deep learning methods to the performance prediction of chemical reactions, during which less training data may be required.

Reusing meta-terphenyl ligands: Synthesis, metalation and recycling of 5-pyrrolidino-m-terphenyl

5-pyrrolidino-m-terphenyl (1) is synthesized via a Buchwald-Hartwig cross-coupling reaction. This terphenyl is readily halogenated under ambient conditions with tetrabutylammonium tribromide to generate 4-pyrrolidino-2,6-diphenylbromobenzene (2). The reaction of (2) with magnesium results in the conversion to its corresponding Grignard reagent (3). Quenching of (3) with water results in the recovery of (1), demonstrating the ability to recycle this m-terphenyl ligand through a halogenation-metalation-hydrolysis cycle. The structure of all three compounds were confirmed by 1H and 13C NMR and by single-crystal X-ray diffraction.

Construction and Functionalization of Highly Strained N -Doped Zigzag Hydrocarbon Belts

Construction and Functionalization of Highly Strained <i>N</i> -Doped Zigzag Hydrocarbon Belts

General Method of Synthesis of 5-(Het)arylamino-1,2,3-triazoles via Buchwald-Hartwig Reaction of 5-Amino- or 5-Halo-1,2,3-triazoles.

An efficient access to the novel 5-(het)arylamino-1,2,3-triazole derivatives has been developed. The method is based on Buchwald–Hartwig cross-coupling reaction of 5-Amino or 5-Halo-1,2,3-triazoles with (het)aryl halides and amines, respectively. As result, it was found that palladium complex [(THP-Dipp)Pd(cinn)Cl] bearing expanded-ring N-heterocyclic carbene ligand is the most active catalyst for the process to afford the target molecules in high yields.

Synthesis of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines and their photodynamic properties in the human skin melanoma cell line G361

A small series of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines was synthesized from easily accessible 1-phenyl-1H-pyrazol-3-ol via 7-iodo-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine and 7-iodo-4-methyl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine intermediates and their subsequent use in palladium catalyzed Buchwald-Hartwig cross-coupling reaction with various anilines. Majority of the compounds were not significantly cytotoxic to melanoma G361 cells in the dark up to 10 µM concentration, but their activity could be increased by irradiation with visible blue light (414 nm). The most active compound 10 possessed EC50 values of 3.5, 1.6 and 0.9 µM in cells irradiated with 1, 5 and 10 J/cm2, respectively. The treatment caused generation of reactive oxygen species in cells and extensive DNA damage, documented by the comet assay and by detection of phosphorylated histone H2A.X, followed by apoptotic cell death. Our results suggest that N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines could serve as a potential source of photosensitizing compounds with anticancer activities.

Donor disubstituted trifluoromethyl benzenes for various electroluminescent devices

New derivatives of trifluoromethyl benzene and tert-butyl disubstituted acridan or phenothiazine were designed and obtained by single-step synthesis, i.e., by Buchwald-Hartwig cross-coupling reactions of 1,3-dibromo-5-(trifluoromethyl)benzene with 3,7-di-tert-butyldimethylacridan, or 3,7-di-tert-butyl-10H-phenothiazine. The advantages in high thermal and photophysical characteristics were utilized in exciplex emission based OLEDs. In the optimal case, device showed maximum current, power, and external quantum efficiencies of 27.4 cd/A, 28.6 lm/W and 7.6%, respectively. Taking into account that successful employment of acridan or phenothiazine derivatives as donors in exciplex-forming systems remains scarce, the proposed design of donor compounds in this work shows their potential for successful implementation in complex emissive systems of OLEDs.