Buchwald-Hartwig Coupling Reaction Research Articles

Aminative Suzuki-Miyaura coupling.

The Suzuki-Miyaura and Buchwald-Hartwig coupling reactions are widely used to form carbon-carbon (C-C) and carbon-nitrogen (C-N) bonds, respectively. We report the incorporation of a formal nitrene insertion process into the Suzuki-Miyaura reaction, altering the products from C-C-linked biaryls to C-N-C-linked diaryl amines and thereby joining the Suzuki-Miyaura and Buchwald-Hartwig coupling pathways to the same starting-material classes. A combination of a bulky ancillary phosphine ligand on palladium and a commercially available amination reagent enables efficient reactivity across aryl halides and pseudohalides, boronic acids and esters, and many functional groups and heterocycles. Mechanistic insights reveal flexibility on the order of bond-forming events, suggesting potential for expansion of the aminative cross-coupling concept to encompass diverse nucleophiles and electrophiles as well as four-component variants.

Total synthesis of natural pyrano[3,2-a]carbazole alkaloids

An efficient approach for the total synthesis of pyrano[3,2-a]carbazole alkaloids was reported, resulting in the synthesis of six natural pyrano[3,2-a]carbazole alkaloids, namely girinimbine (1), mukoenine C (2), koenimbine (3), koenigine (4), koenine (5), and koenidine (6). In the present study, the readily available 2-methyl-5-nitrophenol was employed as a starting material for the synthesis of aminochromenes. The intermediate diphenylamine was produced through the Buchwald-Hartwig coupling reaction, which ultimately facilitated the synthesis of pyrano[3,2-a]carbazole via the intramolecular palladium(II)-catalyzed oxidative cyclization of diphenylamine. In the palladium-catalyzed oxidative cyclization process, this approach successfully circumvents the Wacker oxidation by restricting the involvement of water, ultimately enabling the selective dehydrogenative oxidative cyclization of the C–C bond of the aryl ring. Consequently, this strategy simplifies the complexity of the reaction and reduces the synthesis steps.

Switching thermally activated delayed fluorescence to room temperature phosphorescence for oxygen sensing: Effect of donor substituents of trifluoromethylphenyl

Two compounds consisting of electron-accepting trifluoromethylphenyl moiety and electron-donating phenoxazine and phenothiazine moieties were designed and synthesized via Buchwald-Hartwig coupling reaction. Thermal, photophysical, and electrochemical properties of the compounds are discussed. Only compound with phenothiazine form molecular glass, with glass transition temperatures of 90 °C. The geometry and electronic characteristics of the compounds were substantiated within density functional theory (DFT). 10,10′-(2-(Trifluoromethyl)-1,4-phenylene)bis(10H-phenoxazine) shows efficient thermally activated delayed fluorescence with high spin-orbit coupling values. 10,10′-(2-(Trifluoromethyl)-1,4-phenylene)bis(10H-phenothiazine) as efficient room-temperature phosphor shows high oxygen sensitivity.

Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones.

The first access to polyfunctionnalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione derivatives is reported. The series were generated from diethyl acetylenedicarboxylate and arylhydrazines, which afforded the key intermediates bearing two functional positions. The annellation to generate the maleimide moiety of the bicycle was studied. Moreover, an efficient palladium-catalyzed C-C and C-N bond formation via Suzuki-Miyaura or Buchwald-Hartwig coupling reactions in C-6 position was investigated from 6-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. This method provides novel access to various 1,6 di-substituted pyrrolo[3,4-c] pyrazole-4,6-(2H,5H)-diones.

Carbon Nanotube Template-Assisted Synthesis of Conjugated Microporous Polytriphenylamine with High Porosity for Efficient Supercapacitive Energy Storage.

Engineering of conjugated microporous polymers (CMPs) with high porosity, redox activity, and electronic conductivity is of significant importance for their practical applications in electrochemical energy storage. Aminated-multiwall carbon nanotubes (NH2 -MWNT) are utilized to modulate the porosity and electronic conductivity of polytriphenylamine (PTPA), which is synthesized via Buchwald-Hartwig coupling reaction of tri(4-bromophenyl)amine and phenylenediamine as constitutional units in a one-step in situ polymerization process. Compared to PTPA, the specific surface area of core-shell PTPA@MWNTs has been greatly improved from 32 to 484m2 g-1 . The PTPA@MWNTs exhibites an improved specific capacitance, with the highest value 410Fg-1 in 0.5M H2 SO4 at a current of 10Ag-1 achieve for PTPA@MWNT-4 due to the hierarchical meso-micro pores, high redox-activity and electronic conductivity. Symmetric supercapacitor assemble by PTPA@MWNT-4 has a capacitance of 216Fg-1 of total electrode materials and retains 71% of initial capacitance after 6000 cycles. This study gives new insights into the role of CNT templates in the adjustment of molecular structure, porosity, and electronic property of CMPs for the high-performance electrochemical energy storage.

Thermal-Responsive Conjugated Micropore Polymers for Smart Capture of Volatile Iodine.

The capture of radioiodine is crucial for nuclear security and environmental protection due to its volatility and superior environmental fluidity. Herein, we propose a strategy of "temperature-dependent gate" based on a swellable conjugated microporous polymer (SCMP) to significantly improve the capture of volatile iodine. The SCMP is constructed via the Buchwald-Hartwig coupling reaction of building monomers containing amines. It possesses a hierarchical pore structure with restricted pores, which can be "opened" and "closed" by changing the temperature. By virtue of the thermal-responsive pore structure, it reaches adsorption equilibrium for iodine in 2 h with a capacity of 4.3 g g-1 at 90 °C and retains 92.8% adsorbed iodine at room temperature. The SCMP also exhibits a high adsorption capacity up to 3.5 g g-1 for dissolved iodine within 10 min, as well as good radiation resistance and high selectivity for iodine against moisture, VOCs, and HNO3 vapor. The mechanism is clarified for effective iodine capture and caging based on the relationship between temperature and the pore structure. This work develops not only a strategy to enhance the capture of gaseous and dissolved iodine but also a new adsorption mechanism for iodine capture, which can be extended to the separation and caging of resources or volatile pollutants in other fields.

Probing the origin of higher efficiency of terphenyl phosphine over the biaryl framework in Pd-catalyzed C-N coupling: A combined DFT and machine learning study

The Pd-catalyzed Buchwald–Hartwig coupling reaction is important in the construction of the C-N bond due to various applications in organic synthesis. Quantum chemical calculations are widely used in understanding reaction mechanisms whereas the machine learning method is extremely popular in recognizing the relationships of data. Here, we combine density functional theory calculations with the support vector regression method to probe the origin of the higher efficiency of terphenyl phosphine ligand over the biaryl counterpart in the Buchwald–Hartwig C-N coupling reaction. By quantum chemical calculations, the turnover frequency-determining transition states are located and ligand features are calculated with high accuracy. By machine learning, the relationship between the reaction barrier and ligand features has been examined. It is found that the interplay of the charge on the metal center, the cone angle of the ligands, and the Sterimol L parameters of the ligand determines the catalytic performance of the palladium catalysts with different phosphine ligands. Our findings could help experimental chemists to design the ligands for Pd-catalyzed C-N coupling reactions with high efficiency.

Bulky, electron-rich, renewable: analogues of Beller's phosphine for cross-couplings.

In recent years, considerable progress has been made in the conversion of biomass into renewable chemicals, yet the range of value-added products that can be formed from biomass remains relatively small. Herein, we demonstrate that molecules available from biomass serve as viable starting materials for the synthesis of phosphine ligands, which can be used in homogeneous catalysis. Specifically, we prepared renewable analogues of Beller's ligand (di(1-adamantyl)-n-butylphosphine, cataCXium® A), which is widely used in homogeneous catalysis. Our new renewable phosphine ligands facilitate Pd-catalysed Suzuki-Miyaura, Stille, and Buchwald-Hartwig coupling reactions with high yields, and our catalytic results can be rationalized based on the stereoelectronic properties of the ligands. The new phosphine ligands generate catalytic systems that can be applied for the late-stage functionalization of commercial drugs.

Buchwald–Hartwig coupled conjugated microporous polymer for efficient removal COVID-19 antiviral drug famciclovir from waters: Adsorption behavior and mechanism

The consumption of famciclovir (FCV) has been increased dramatically since the outbreak of coronavirus in 2019, and the pollution and harm of FCV in waters are concerned. Here, by utilizing aryl halides on 2, 4, 6-tris(4-bromophenyl)− 1, 3, 5-triazine (BPT) and primary amine groups on benzidine (BZ), a novel conjugated microporous polymer, namely BPT-BZ-CMP, was synthesized by Buchwald–Hartwig coupling reaction and applied in the removal of FCV from aqueous solution firstly. The synthesized BPT-BZ-CMP were characterized by various methods, including FTIR, SEM, BET, and Zeta–potential. Due to the micropore structure and high specific surface area, it took only 30 min for BPT-BZ-CMP to adsorb FCV to reach an equilibrium, and the maximum adsorption capacity was 347.8 mg·g−1. The Liu and pseudo-second-order kinetic models properly fit the adsorption equilibrium and kinetic data, respectively. The adsorption process was a spontaneous process, and the hydrogen bonding, π–π interaction and C–H···π interaction enhanced the adsorption of FCV on BPT-BZ-CMP. BPT-BZ-CMP maintained a good adsorption capacity after four consecutive adsorption–desorption cycle experiments. This study confirmed the potential of BPT-BZ-CMP as efficient sorbent to remove FCV from aqueous solutions.

Machine learning for yield prediction for chemical reactions using in situ sensors

Machine learning models were developed to predict product formation from time-series reaction data for ten Buchwald-Hartwig coupling reactions. The data was provided by DeepMatter and was collected in their DigitalGlassware cloud platform. The reaction probe has 12 sensors to measure properties of interest, including temperature, pressure, and colour. Colour was a good predictor of product formation for this reaction and machine learning models were able to learn which of the properties were important. Predictions for the current product formation (in terms of % yield) had a mean absolute error of 1.2%. For predicting 30, 60 and 120 min ahead the error rose to 3.4, 4.1 and 4.6%, respectively. The work here presents an example into the insight that can be obtained from applying machine learning methods to sensor data in synthetic chemistry.

Solvent-Free Synthesis of Core-Functionalised Naphthalene Diimides by Using a Vibratory Ball Mill: Suzuki, Sonogashira and Buchwald-Hartwig Reactions.

Solvent‐free synthesis by using a vibratory ball mill (VBM) offers the chance to access new chemical reactivity, whilst reducing solvent waste and minimising reaction times. Herein, we report the core functionalisation of N,N’‐bis(2‐ethylhexyl)‐2,6‐dibromo‐1,4,5,8‐naphthalenetetracarboxylic acid (Br2‐NDI) by using Suzuki, Sonogashira and Buchwald–Hartwig coupling reactions. The products of these reactions are important building blocks in many areas of organic electronics including organic light‐emitting diodes (OLEDs), organic field‐effect transistors (OFETs) and organic photovoltaic cells (OPVCs). The reactions proceed in as little as 1 h, use commercially available palladium sources (frequently Pd(OAc)2) and are tolerant to air and atmospheric moisture. Furthermore, the real‐world potential of this green VBM protocol is demonstrated by the double Suzuki coupling of a monobromo(NDI) residue to a bis(thiophene) pinacol ester. The resulting dimeric NDI species has been demonstrated to behave as an electron acceptor in functioning OPVCs.

Simple Double Hetero[5]helicenes Realize Highly Efficient and Narrowband Circularly Polarized Organic Light-Emitting Diodes

Simple Double Hetero[5]helicenes Realize Highly Efficient and Narrowband Circularly Polarized Organic Light-Emitting Diodes

Prediction of the Chemical Context for Buchwald‐Hartwig Coupling Reactions

We present machine learning models for predicting the chemical context for Buchwald‐Hartwig coupling reactions, i. e., what chemicals to add to the reactants to give a productive reaction. Using reaction data from in‐house electronic lab notebooks, we train two models: one based on single‐label data and one based on multi‐label data. Both models show excellent top‐3 accuracy of approximately 90 %, which suggests strong predictivity. Furthermore, there seems to be an advantage of including multi‐label data because the multi‐label model shows higher accuracy and better sensitivity for the individual contexts than the single‐label model. Although the models are performant, we also show that such models need to be re‐trained periodically as there is a strong temporal characteristic to the usage of different contexts. Therefore, a model trained on historical data will decrease in usefulness with time as newer and better contexts emerge and replace older ones. We hypothesize that such significant transitions in the context‐usage will likely affect any model predicting chemical contexts trained on historical data. Consequently, training context prediction models warrants careful planning of what data is used for training and how often the model needs to be re‐trained.

Scalable Fabrication of Conjugated Microporous Polymer Sponges for Efficient Solar Steam Generation.

Seawater evaporation realized by solar-thermal conversion represents one of the most sustainable and effective strategies to obtain fresh water. Many approaches have been proposed to achieve high efficiencies of solar-thermal conversion, but their practical applications are limited by the low scalability. Herein, novel porphyrin/aniline-based conjugated microporous polymers (PACMPs) are synthesized via a Buchwald-Hartwig coupling reaction, which are then integrated with polyurethane sponges via a simple dip-coating technique. The PACMP-modified sponges (PACSs) retain the high porosity of the sponge substrate and excellent solar-thermal conversion properties of PACMPs. Under standard solar irradiation (1 kW m-2), PACSs achieve a high seawater evaporation rate of 1.31 kg m-2 h-1 with a solar-thermal conversion efficiency of 86.3%. PACSs show no salt accumulation and high performance of desalination and dye decolorization, removing >99.9% salt and >99.2% dye, respectively. The self-floating characteristic, recyclability, and durable solar-thermal evaporation efficiencies enable PACSs to be promising candidate materials for seawater desalination and sewage purification.

Thioarylation of anilines using dual catalysis: two-step synthesis of phenothiazines.

A two-step synthesis of phenothiazines has been developed using a dual-catalytic ortho-thioarylation reaction of anilines as the key step. Activation of N-(2-bromophenylthio)succinimide was achieved using the super Lewis acid, iron(III) triflimide and the Lewis base, diphenyl selenide, resulting in an accelerated and efficient ortho-thioarylation reaction of various protected aniline derivatives and less reactive, unprotected analogues. The thioarylated adducts were then cyclised to the desired phenothiazines using either an Ullmann-Goldberg or Buchwald-Hartwig coupling reaction. The dual catalytic thioarylation and copper(I)-catalysed cyclisation approach was used for the four-step synthesis of methopromazine, a neuroleptic agent with antipsychotic activity.

Deep Forest-Based Intelligent Yield Predicting of Buchwald-Hartwig Coupling Reaction

Buchwald-Hartwig coupling reaction is widely used in organic chemical synthesis, yield prediction is particularly important. In 2018, Science reported a yield prediction method based on random forest, but this method lacks feature learning. Therefore, an intelligent prediction and analysis method of coupling reaction yield based on deep forest is proposed. Combined with the advantages of deep learning and ensemble learning, the new deep model in the form of non-neural network is explored, which has good characterization learning ability and low difficulty in adjusting parameters, realizes the efficient prediction of chemical reaction, and analyzes the factors that have a significant impact on the prediction of reaction yield.

Synthesis, Molecular Docking and Biological Evaluation of Novel 3-substituted Pyrido[2,3-b]pyrazine Derivatives

A novel series of 3-substituted pyrido[2,3-b]pyrazine derivatives were synthesized using Suzuki and Buchwald-Hartwig coupling reactions. All the synthesized derivatives were screened for in-vitro anti-inflammatory activities as inhibitors of pro-cytokines TNF-alpha and IL-6. Among them, compounds 7a, 7b, 7d, 9a and 9c showed LPS-induced TNF-α secretion of 79 ± 1.2, 98.5 ± 1.6, 95.5 ± 2.1, 92.4 ± 1.9, and 88.9 ± 1.2 pg mL-1 respectively at a concentration of 20 μM. Similarly, compounds 7a, 7b and 7d, 9a and 9c showed LPS-induced IL-6 secretion of 59.5 ± 2.1, 77 ± 2.1, 89 ± 2.4, 65.4 ± 2.1, and 74 ± 1.9 pg mL-1 respectively at a concentration of 20 μM. In addition, the compounds were tested for cytotoxic activity against A549, MCF-7, K562 & Hela cancer cell lines and all the compounds showed good biological profiles on cancer cell lines. In silico studies revealed that compounds 9a and 9b could bind strongly with the active site of the TNF-α protein structure and formed three hydrogen bonds with Gln61, Tyr151 amino acids with binding energies of -5.9 and -5.7 kcal/mol. Compound 9b formed three strong hydrogen bonds with amino acids of the TGF-β protein with a binding energy of -6.0 kcal/mol. Compound 7e bound strongly with the KRAS protein structure, making seven strong hydrogen bonds with amino acids Gly13, Val29, Asn116, Asp119, Ser145 and Ala146, each with a binding energy of -8.0 kcal/mol. Compound 7b bound strongly with the KRAS protein structure, making four strong hydrogen bonds with amino acids Asn116, Lys117, Asp119, Ser145, each with a binding energy of -8.2 kcal/mol.

Synthesis, Structures, and Electronic Properties of 2,7-Anthrylene-Based Azacyclophanes Bearing o-, m-, and p-Phenylenediamine Linkers.

A series of novel azacyclophanes consisting of 2,7-anthrylene and phenylene units were designed and synthesized by the Buchwald-Hartwig coupling reaction to investigate their unique electronic properties in multiple oxidized states. Cyclic voltammetry showed that the p-phenylene derivative exhibited three reversible oxidation waves, whereas the o- and m-phenylene derivatives showed two quasi-reversible oxidation waves due to the complicated intramolecular interaction between the oxidized units and neutral units. Moreover, the absorption spectra of the p-phenylene derivative in different oxidation states showed absorption bands at 865 and 1025 nm, which were attributed to intramolecular charge-transfer interactions. The photophysical and electrochemical properties of the p-phenylene analog were also compared with those of the o- and m-phenylene derivatives based on theoretical calculations for further evaluation of the intramolecular electronic interactions.

Atroposelective Synthesis, Structure and Properties of a Novel Class of Axially Chiral N‐Aryl Quinolinium Salt

AbstractInspired by naturally occurring molecules containing atropisomeric N+‐C axes, we have developed a novel synthetic approach to generate a library of axially chiral N‐aryl quinolinium salts. Enantiopurities up to 93 % ee were obtained via a four‐step route from commercially available precursors. Axial stereochemistry was controlled through an enantioselective ring‐closing Buchwald–Hartwig coupling reaction. The structure and properties of the salts were examined by X‐ray crystallography, DFT, UV‐Vis, and fluorescence spectroscopy, revealing high rotational barriers and solvatochromic behaviour.

Microtiter Plate (MTP) Reaction Screening and Optimization of Surfactant Chemistry: Examples of Suzuki–Miyaura and Buchwald–Hartwig Cross-Couplings in Water

A screening method to evaluate Suzuki–Miyaura and Buchwald–Hartwig coupling reactions under aqueous surfactant conditions has been established, leading to high yielding and highly selective Suzuki–Miyaura and Buchwald–Hartwig reactions under mild reaction temperatures and ecologically improved conditions. The screening method highlighted the utility of Buchwald–Hartwig third generation precatalysts for unprecedented high conversion Buchwald–Hartwig C–N coupling reactions in water.