Arylation Reactions Research Articles

Recent Advances in 1,2-Amino(hetero)arylation of Alkenes.

Alkene amino(hetero)arylation presents a highly efficient and straightforward strategy for direct installation of amino groups and heteroaryl rings across a double bond simultaneously. An extensive array of practical transformations has been developed via alkene difunctionalization approach to access a broad range of medicinally valuable (hetero)arylethylamine motifs. This review presents recent progress in 1,2-amino(hetero)arylation of alkenes organized in three different modes. First, intramolecular transformations employing C, N-tethered alkenes will be introduced. Next, two-component reactions will be discussed with different combination of precursors, N-tethered alkenes and external aryl precursor, C-tethered alkenes and external amine precursor, or C, N-tethered reagents, and alkenes. Last, three-component intermolecular amino(hetero)arylation reactions will be covered.

Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3-Csp2 coupling.

Cross-electrophile coupling (XEC) reactions of aryl and alkyl electrophiles are appealing but limited to specific substrate classes. Here, we report electroreductive XEC of previously incompatible electrophiles including tertiary alkyl bromides, aryl chlorides, and aryl/vinyl triflates. Reactions rely on the merger of an electrochemically active complex that selectively reacts with alkyl bromides through 1e- processes and an electrochemically inactive Ni0(phosphine) complex that selectively reacts with aryl electrophiles through 2e- processes. Accessing Ni0(phosphine) intermediates is critical to the strategy but is often challenging. We uncover a previously unknown pathway for electrochemically generating these key complexes at mild potentials through a choreographed series of ligand-exchange reactions. The mild methodology is applied to the alkylation of a range of substrates including natural products and pharmaceuticals.

Modified chitosan-zeolite supported Pd nanoparticles: A reusable catalyst for the synthesis of 5-substituted-1H-tetrazoles from aryl halides

A novel heterogeneous catalyst has been developed using chitosan-zeolite supported Pd nanoparticles (PdNPs@CS-Zeo) and used in an efficient synthesis of 5-substituted-1H-tetrazoles from aryl halides with high yields for relatively short reaction times with an easy work-up procedure. In this method, highly effective and reusable PdNPs@CS-Zeo catalyst was used in the reaction of various aryl iodides/bromides with K4[Fe(CN)6] as a non-toxic cyanide source to catalyze the [2 + 3] cycloaddition of the corresponding aryl nitriles with NaN3 in the sequential one-pot preparation of 5-substituted-1H-tetrazoles. The synthesized PdNPs@CS-Zeo nanocatalyst was characterized using XRD, FTIR, TEM, HRTEM, XPS, Raman, TG-DTG, ICP-OES, BET, and EDS mapping. Additionally, the nanocatalyst could be effectively separated by filtration and reused for multiple times without significant decrease of catalytic activity.

Ruthenium(II)-Catalyzed Chelation-Assisted Desulfitative Arylation of Benzo[h]quinolines with Arylsulfonyl Chlorides.

Herein, a novel chelation-assisted C-H arylation reaction of benzo[h]quinoline is described. This transformation, using [RuCl2(p-cymene)]2 as the catalyst and cheap and easily accessible arylsulfonyl chlorides as the arylation source, featured simple reaction conditions, a broad substrate scope, and functional group tolerance. The successful application of some bioactive-molecule-based sulfonyl chlorides further highlighted the potential utility and importance of this desulfitative C-H arylation protocol.

Visible-Light-Mediated (sp 3)Cα-H Functionalization of Ethers Enabled by Electron Donor-Acceptor Complex.

A synthetically beneficial visible-light-mediated protocol has been disclosed to achieve C-H amination of readily available feedstocks cyclic and acyclic ethers. A rarely identified N-bromosuccinamide-tetrahydrofuran electron donor-acceptor complex served as an initiator to functionalize both α-diazoketones and dialkyl azodicarboxylates. This developed methodology gives an alternative and milder way to construct the C-N bond and can be explored for the formation of C-C bond to perform arylation and allylation reactions.

Electrochemical Oxidative C–H Arylation of Quinoxalin(on)es with Arylhydrazine Hydrochlorides under Mild Conditions

A practical and scalable protocol for electrochemical arylation of quinoxalin(on)es with arylhydrazine hydrochlorides under mild conditions has been developed. This method exhibits high efficiency, easy scalability, and broad functional group tolerance. Various quinoxalin(on)es and arylhydrazines underwent this transformation smoothly in an undivided cell, providing the corresponding aryl-substituted quinoxalin(on)es in moderate to good yields. A radical mechanism is involved in this arylation reaction.

Gradient Hierarchically Porous Structure for Rapid Capillary-Assisted Catalysis.

Synthesis of hierarchically porous structures with uniform spatial gradient and structure reinforcement effect still remains a great challenge. Herein, we report the synthesis of zeolite@mesoporous silica core-shell nanospheres (ZeoA@MesoS) with a gradient porous structure through a micellar dynamic assembly strategy. In this case, we find that the size of composite micelles can be dynamically changed with the increase of swelling agents, which in situ act as the building blocks for the modular assembly of gradient mesostructures. The ZeoA@MesoS nanospheres are highly dispersed in solvents with uniform micropores in the inner core and a gradient tubular mesopore shell. As a nanoreactor, such hierarchically gradient porous structures enable the capillary-directed fast mass transfer from the solutions to inner active sites. As a result, the ZeoA@MesoS catalysts deliver a fabulous catalytic yield of ∼75% on the esterification of long-chain carboxylic palmitic acids and high stability even toward water interference, which can be well trapped by the ZeoA core, pushing forward the chemical equilibrium. Moreover, a very remarkable catalytic conversion on the C-H arylation reaction of large N-methylindole is achieved (∼98%) by a Pd-immobilized ZeoA@MesoS catalyst. The water tolerance feature gives a notable enhancement of 26% in catalytic yield compared to the Pd-dendritic mesoporous silica without the zeolite core.

Chiral Phosphoric Acid-Catalyzed Asymmetric Arylation of Indolizines: Atroposelective Access to Axially Chiral 3-Arylindolizines.

We report herein a highly straightforward strategy for the synthesis of a new axially chiral 3-arylindolizine scaffold via organocatalytic asymmetric arylation reactions of indolizines and p-quinone esters. Using the chiral phosphoric acid catalyst, a series of axially chiral 3-arylindolizines were accessed in good to excellent yields and atropo-enantioselectivities. This approach features a broad substrate scope, mild reaction conditions, good scalability, and facile derivatization. Moreover, preliminary investigations based on nonlinear effects and a thermal racemization study demonstrated the intrinsic pathway for the formation of axial chirality and its potential utility.

Exploring metallic and plastic 3D printed photochemical reactors for customizing chemical synthesis

Visible light photocatalysis is a rapidly developing branch of chemical synthesis with outstanding sustainable potential and improved reaction design. However, the challenge is that many particular chemical reactions may require dedicated tuned photoreactors to achieve maximal efficiency. This is a critical stumbling block unless the possibility for reactor design becomes available directly in the laboratories. In this work, customized laboratory photoreactors were developed with temperature stabilization and the ability to adapt different LED light sources of various wavelengths. We explore two important concepts for the design of photoreactors: reactors for performing multiple parallel experiments and reactors suitable for scale-up synthesis, allowing a rapid increase in the product amount. Reactors of the first type were efficiently made of metal using metal laser sintering, and reactors of the second type were successfully manufactured from plastic using fused filament fabrication. Practical evaluation has shown good accuracy of the temperature stabilization in the range typically required for organic synthesis for both types of reactors. Synthetic application of 3D printed reactors has shown good utility in test reactions—furan C–H arylation and thiol-yne coupling. The critical effect of temperature stabilization was established for the furan arylation reaction: heating of the reaction mixture may lead to the total vanishing of photochemical effect.

Discovery of tricyclic HIV-1 integrase-LEDGF/p75 allosteric inhibitors by intramolecular direct arylation reaction

We have been conducting exploratory research to develop human immunodeficiency virus type-1 (HIV-1) integrase-LEDGF/p75 allosteric inhibitors (INLAIs). Here, we report on a newly designed compound with a tricyclic scaffold that shows promise as an inhibitor. Various scaffolds were synthesized by intramolecular direct arylation reaction to fix the position of a lipophilic side chain required for antiviral activity. Among these, the compound having an N-mesyl dihydrophenanthridine ring showed the best antiviral activity. Compound 42i, prepared by side chain optimization of the C-4 and C-6 positions, exhibited high antiviral activity against wild-type (WT) and the T174I mutant (EC50 (WT) = 4.6 nM, EC50 (T174I) = 83 nM) with a good PK profile. Based on co-crystal structural analysis of compound 42i and WT HIV-1 IN CCD, we discuss the interaction important for high antiviral activity.

Synthesis, Carbonic Anhydrase II/IX/XII Inhibition, DFT, and Molecular Docking Studies of Hydrazide-Sulfonamide Hybrids of 4-Methylsalicyl- and Acyl-Substituted Hydrazide

Carbonic anhydrases (CAs and EC 4.2.1.1) are the Zn2+ containing enzymes which catalyze the reversible hydration of CO2 to carbonate and proton. If they are not functioning properly, it would lead towards many diseases including tumor. Synthesis of hydrazide-sulfonamide hybrids (19-36) was carried out by the reaction of aryl (10-11) and acyl (12-13) hydrazides with substituted sulfonyl chloride (14-18). Final product formation was confirmed by FT-IR, NMR, and EI-MS. Density functional theory (DFT) calculations were performed on all the synthesized compounds to get the ground-state geometries and compute NMR properties. NMR computations were in excellent agreement with the experimental NMR data. All the synthesized hydrazide-sulfonamide hybrids were in vitro evaluated against CA II, CA IX, and CA XII isozymes for their carbonic anhydrase inhibition activities. Among the entire series, only compounds 22, 32, and 36 were highly selective inhibitors of hCA IX and did not inhibit hCA XII. To investigate the binding affinity of these compounds, molecular docking studies of compounds 32 and 36 were carried out against both hCA IX and hCA XII. By using BioSolveIT's SeeSAR software, further studies to provide visual clues to binding affinity indicate that the structural elements that are responsible for this were also studied. The binding of these compounds with hCA IX was highly favorable (as expected) and in agreement with the experimental data.

Effects of Electrolytes on the Dediazoniation of Aryldiazonium Ions in Acidic MeOH/H2O Mixtures

Aryldiazonium, ArN2+, ions decompose spontaneously through the formation of highly reactive aryl cations that undergo preferential solvation by water, showing a low selectivity towards the nucleophiles present in their solvation shell. In this work, we investigate the effects of electrolytes (NaCl, LiCl, and LiClO4) on the dediazoniation of 2-, 3-, and 4-methylbenzenediazonium ions in acidic MeOH/H2O mixtures. In the absence of electrolytes, the rates of dediazoniation, kobs, increase modestly upon increasing the MeOH content of the reaction mixture. At any solvent composition, the rate of ArN2+ loss is the same as that for product formation. The main dediazoniation products are cresols (ArOH) and methyl phenyl ethers (ArOMe). Only small amounts (less than 5%) of the reduction product toluene (ArH), which are detected at high percentages of MeOH. Quantitative yields of are obtained at any solvent composition. The addition of LiCl or NaCl ([MCl] = 0–1.5 M) to the reaction mixtures has a negligible effect on kobs but leads to the formation, in low yields (<10%), of the ArCl derivative. The addition of LiClO4 (0–1.5 M) to 20% MeOH/H2O mixtures has a negligible effect on both kobs and on the product distribution. However, at 99.5% MeOH, the addition of the same amounts of LiClO4 leads to a modest decrease in kobs but to a significant decrease in the yields of ArOMe. Results are interpreted in terms of the preferential solvation of perchlorate ions by the aryl cations, removing MeOH molecules from the solvation shell.

Cover Feature: Face‐Directed Tetrahedral Organic Cage Anchored Palladium Nanoparticles for Selective Homocoupling Reactions (Eur. J. Inorg. Chem. 7/2022)

The Cover Feature shows the formation of two face-directed truncated tetrahedral enantiopure organic cages by employing dynamic imine condensation reactions of a hexa-aldehyde precursor with trans-oriented enantiopure diamines separately. In view of its intrinsic porosity combined with the presence of multiple vicinal di-imine corners and stable aromatic backbones, one of the cages was used as a template for nucleation of ultrafine Pd-nanoparticles (PdNPs). The cage-PdNPs hybrid was further utilized as a suitable catalyst for selective and additive-free C−C homocoupling reactions of aryl and heteroaryl halides under heterogeneous conditions. Moreover, the composite material exhibited high durability and thermal stability for several catalytic cycles without any agglomeration. More information can be found in the Research Article by P. S. Mukherjee and co-workers.

Palladium-Catalysed Intermolecular Direct C–H Bond Arylation of Heteroarenes with Reagents Alternative to Aryl Halides: Current State of the Art

Abstract: This unprecedented review with 322 references provides a critical up-to-date picture of the Pd-catalysed intermolecular direct C–H bond arylation of heteroarenes with arylating reagents alternative to aryl halides that include aryl sulfonates (aryl triflates, tosylates, mesylates, and imidazole-1-sulfonates), diaryliodonium salts, [(diacetoxy)iodo]arenes, arenediazonium salts, 1-aryltriazenes, arylhydrazines and N’-arylhydrazides, arenesulfonyl chlorides, sodium arenesulfinates, arenesulfinic acids, and arenesulfonohydrazides. Particular attention has been paid to summarise the preparation of the various arylating reagents and to highlight the practicality, versatility, and limitations of the various developed arylation protocols, also comparing their results with those achieved in analogous Pd-catalysed arylation reactions involving the use of aryl halides as electrophiles. Mechanistic proposals have also been briefly summarised and discussed. However, data concerning Pd-catalysed direct C–H bond arylations involving the C–H bonds of aryl substituents of the examined heteroarene derivatives have not been taken into account.

One-Pot Dual Catalysis of a Photoactive Coordination Polymer and Palladium Acetate for the Highly Efficient Cross-Coupling Reaction via Interfacial Electron Transfer.

We report herein an exploration of the straightforward one-pot dual-catalysis strategy, i.e., direct combination of a photoactive coordination polymer (CP) with another metal catalyst, for carrying out the desirable photoinduced organic transformation. The strategy overcomes the necessity of the presynthesis of the metal/CP composite that has been demonstrated to be invalid in our case. A new two-dimensional CP showing the desirable properties of wide-range visible-light absorption and efficient photoinduced charge generation was synthesized via a solvothermal reaction. The synthesized CP was successfully applied to the photocatalytic C-C cross-coupling reaction via the one-pot dual-catalysis method, in combination with the simple and ligand-free palladium salt of Pd(OAc)2 as a metal catalyst. The reaction features a short reaction time, mild reaction conditions, good recyclability, and a high yield of Heck products from a broad variety of substrates. A comparative experiment showed the presynthesized Pd/CP composite was invalid for the reaction, demonstrating the significance of the one-pot dual-catalysis strategy. Mechanistic studies suggest the one-pot reaction depends on the synergy between the photocatalysis of a synthesized CP to generate reactive aryl radicals and Pd catalysis to generate target products, in which the interfacial electron transfer has been demonstrated to be vital for producing the transient and catalytically active Pd(0) species near the surface of the CP. The study shows the direct combination of a CP photocatalyst and a metal catalyst is a highly feasible method for the photochemical reaction and enhances the prospects of application of photoactive CPs.

Palladium-Catalyzed C–H Bond Arylation and O- to N-Alkyl Migratory Rearrangement of 2-Alkoxythiazoles: One-Pot Access to 2-Alkoxy-5-arylthiazoles or 3-Alkyl-5-arylthiazol-2(3H)-ones

AbstractPd-catalyzed direct arylation of 2-alkylthiazoles is a well-known reaction affording the corresponding 2-alkyl-5-arylthiazoles in very high yields. Conversely, the reactivity of 2-alkoxythiazoles has not been described yet. Herein, we report conditions for the Pd-catalyzed regioselective C5-arylation of 2-alkoxythiazoles. Moreover, we also found reaction conditions leading to 3-alkyl-5-arylthiazol-2(3H)-ones via a one-pot direct arylation with an O- to N-alkyl migratory rearrangement. The judicious choice of reaction temperature and time allows control over the selectivity of the reaction. In general, at 100 °C, 2-alkoxy-5-arylthiazoles were the major products, whereas, at 120 °C with a longer reaction time, 3-alkyl-5-arylthiazol-2(3H)-ones were obtained with good selectivities. The arylation reaction is promoted by a ligand-free air-stable palladium catalyst and a simple and inexpensive base, without oxidant or further additives, and tolerates a variety of useful substituents on the aryl bromide and also heteroaryl bromides.

Bulky Selenium Ligand Stabilized Trans-Palladium Dichloride Complexes as Catalyst for Silver-Free Decarboxylative Coupling of Coumarin-3-Carboxylic Acids.

This report describes the syntheses of three new trans-palladium dichloride complexes of bulky selenium ligands. These complexes possess a Cl-Pd-Cl rotor spoke attached to a Se-Pd-Se axle. The new ligands and palladium complexes (C1-C3) were characterized with the help of NMR, HRMS, UV-Vis., IR, and elemental analysis. The single-crystal structure of metal complex C2 confirmed a square planar geometry of complex with trans-orientation. The X-ray structure revealed intramolecular secondary interactions (SeCH-Cl) between chlorine of PdCl2 and CH2 proton of selenium ligand. Variable-temperature NMR data shows coalescence of diastereotopic protons, which indicates pyramidal inversion of selenium atom at elevated temperature. The relaxed potential energy scan of C2 suggests a rotational barrier of ∼12.5 kcal/mol for rotation of chlorine atom through Cl-Pd-Cl rotor. The complex C3 possesses dual intramolecular secondary interactions (OCH2 -Cl and SeCH2 -Cl) with stator ligand. Molecular rotor C2 was found to be a most efficient catalyst for the decarboxylative Heck-coupling under mild reaction conditions. The protocol is applicable to a broad range of substrates with large functional group tolerance and low catalyst loading (2.5 mol %). The mechanism of decarboxylative Heck-coupling reaction was investigated through experimental and computational studies. Importantly the reaction works under silver-free conditions which reduces the cost of overall protocol. Further, the catalyst also worked for decarboxylative arylation and decarboxylative Suzuki-Miyaura coupling reactions with good yields of the coupled products.

Functionalization of filled radioactive multi-walled carbon nanocapsules by arylation reaction for in vivo delivery of radio-therapy.

Functionalized multi-walled carbon nanotubes (MWCNTs) containing radioactive salts are proposed as a potential system for radioactivity delivery. MWCNTs are loaded with isotopically enriched 152-samarium chloride (152SmCl3), the ends of the MWCNTs are sealed by high temperature treatment, and the encapsulated 152Sm is neutron activated to radioactive 153Sm. The external walls of the radioactive nanocapsules are functionalized through arylation reaction, to introduce hydrophilic chains and increase the water dispersibility of CNTs. The organ biodistribution profiles of the nanocapsules up to 24 h are assessed in naïve mice and different tumor models in vivo. By quantitative γ-counting, 153SmCl3@MWCNTs-NH2 exhibite high accumulation in organs without leakage of the internal radioactive material to the bloodstream. In the treated mice, highest uptake is detected in the lung followed by the liver and spleen. Presence of tumors in brain or lung does not increase percentage accumulation of 153SmCl3@MWCNTs-NH2 in the respective organs, suggesting the absence of the enhanced permeation and retention effect. This study presents a chemical functionalization protocol that is rapid (∼one hour) and can be applied to filled radioactive multi-walled carbon nanocapsules to improve their water dispersibility for systemic administration for their use in targeted radiotherapy.

Acenaphthylene-fused ullazines: fluorescent π-extended monopyrroles with tunable electronic gaps

π-Extended ullazines were obtained using complementary synthetic approaches based on direct arylation and cycloaddition reactions, respectively. Their strong fluorescence can be tuned by appropriate modifications of substitution and edge expansion.

Synthesis of Conjugated Molecules Based on Dithienopyrrole Derivatives and Pyrene as Chemosensor for Mesotrione Detection

The conjugated molecules based on pyrene and dithienopyrrole derivatives including 4-(2-ethylhexyl)-2-(pyren-1-yl)-4H-dithieno[3,2-b:2’,3’-d]pyrrole (EP4HP) and 4-(2-ethylhexyl)- 2,6-di(pyren-1-yl)-4H-dithieno[3,2-b:2’,3’-d]pyrrole (EDP4HP) have been successfully synthesized via C–H direct arylation reaction. The structures of these conjugated molecules were determined via nuclear magnetic resonance and Fourier-transform infrared spectroscopy (FTIR). The optical properties of conjugated molecules were evaluated via ultraviolet visible (UV-Vis) and fluorescence spectroscopies. The conjugated molecules exhibited the efficient fluorescence quenching toward herbicide mesotrione as nitroaromatic pesticides that could be promising candidates as the chemosensor for tracing of nitroaromatic pesticides.