Aryl Halides Research Articles

Amination of Aryl Chlorides via Benzynes Catalyzed by Sodium Alkoxide Clusters

Amination of Aryl Chlorides via Benzynes Catalyzed by Sodium Alkoxide Clusters

Mechanical-Force-Induced Non-spontaneous Dehalogenative Deuteration of Aromatic Iodides Enabled by Using Piezoelectric Materials as a Redox Catalyst.

The development of green and efficient deuteration methods is of great significance for various fields such as organic synthesis, analytical chemistry, and medicinal chemistry. Herein, we have developed a dehalogenative deuteration strategy using piezoelectric materials as catalysts in a solid-phase system under ball-milling conditions. This non-spontaneous reaction is induced by mechanical force. D2O can serve as both a deuterium source and an electron donor in the transformation, eliminating the need for additional stoichiometric exogenous reductants. A series of (hetero)aryl iodides can be transformed into deuterated products with high deuterium incorporation. This method not only effectively overcomes existing synthetic challenges but can also be used for deuterium labelling of drug molecules and derivatives. Bioactivity experiments with deuterated drug molecule suggest that the D-ipriflavone enhances the inhibitory effects on osteoclast differentiation of BMDMs in vitro.

Mechanical‐Force‐Induced Non‐spontaneous Dehalogenative Deuteration of Aromatic Iodides Enabled by Using Piezoelectric Materials as a Redox Catalyst

AbstractThe development of green and efficient deuteration methods is of great significance for various fields such as organic synthesis, analytical chemistry, and medicinal chemistry. Herein, we have developed a dehalogenative deuteration strategy using piezoelectric materials as catalysts in a solid‐phase system under ball‐milling conditions. This non‐spontaneous reaction is induced by mechanical force. D2O can serve as both a deuterium source and an electron donor in the transformation, eliminating the need for additional stoichiometric exogenous reductants. A series of (hetero)aryl iodides can be transformed into deuterated products with high deuterium incorporation. This method not only effectively overcomes existing synthetic challenges but can also be used for deuterium labelling of drug molecules and derivatives. Bioactivity experiments with deuterated drug molecule suggest that the D‐ipriflavone enhances the inhibitory effects on osteoclast differentiation of BMDMs in vitro.

Oxalic acid as a dual C1 surrogate for heterogeneous palladium-catalyzed tandem four-component quinazolinone synthesis.

Herein, a heterogeneous Pd/C-catalyzed direct one-step four-component double carbonylative approach for cascade synthesis of 2-aryl quinazolinones has been reported for the first time starting from 2-iodoaniline derivatives and aryl iodides. The given reaction involves the simultaneous implementation of two different gaseous surrogates i.e., ammonium carbamate as an NH3 precursor and oxalic acid as a bi-functional reagent acting as a CO as well as a C-atom surrogate under ligand-free conditions.

Coupling of Aryl Chlorides with Lithium Nucleophiles Enabled by Molecularly Defined Alkynyllithium Palladium Catalysts

Palladium‐catalyzed cross‐couplings of aryl chlorides usually call for bulky, electron‐rich ligands such as phosphines or heterocyclic carbenes. We have now found that similarly powerful cross‐coupling catalysts are obtained by the reaction of palladium salts with alkynyllithium reagents. The species initially formed in this process was characterized as a dilithium tetraalkinyl palladate complex. It catalyzes the coupling of aryl chlorides with the lithium salts of various terminal alkynes to give alkynyl arenes. The isolated Li‐alkynyl‐Pd complex also efficiently promotes the reaction of aryl, and allyl chlorides with (hetero)aryl‐, alkyl‐, and allyllithium compounds as well as lithium amines. None of these reactions proceeded in the presence of palladium salts alone. The preparative utility of this approach was demonstrated by the synthesis of 49 molecules, including pharmaceutically relevant compounds.

Coupling of Aryl Chlorides with Lithium Nucleophiles Enabled by Molecularly Defined Alkynyllithium Palladium Catalysts.

Palladium-catalyzed cross-couplings of aryl chlorides usually call for bulky, electron-rich ligands such as phosphines or heterocyclic carbenes. We have now found that similarly powerful cross-coupling catalysts are obtained by the reaction of palladium salts with alkynyllithium reagents. The species initially formed in this process was characterized as a dilithium tetraalkinyl palladate complex. It catalyzes the coupling of aryl chlorides with the lithium salts of various terminal alkynes to give alkynyl arenes. The isolated Li-alkynyl-Pd complex also efficiently promotes the reaction of aryl, and allyl chlorides with (hetero)aryl-, alkyl-, and allyllithium compounds as well as lithium amines. None of these reactions proceeded in the presence of palladium salts alone. The preparative utility of this approach was demonstrated by the synthesis of 49 molecules, including pharmaceutically relevant compounds.

Recyclable Palladium-Catalyzed Carbonylative Coupling of Aryl Halides and Organoaluminum Compounds with tert-Butyl Iso­cyanide as CO Equivalent Leading to 1,2-Diketones

AbstractAn efficient heterogeneous palladium-catalyzed carbonylative coupling of aryl halides and organoaluminum compounds has been developed using tert-butyl isocyanide as CO equivalent. The carbonylation reaction proceeds smoothly in toluene with KOtBu as a base at 100 °C by using 10 mol% of an SBA-15-anchored bidentate phosphine palladium(0) complex [2P-SBA-15-Pd(0)] as the catalyst and provides a general and practical approach for the assembly of 1,2-diketones in good to excellent yields. This heterogenized palladium catalyst can be readily separated and recovered via a simple centrifugation process and reused for more than seven cycles with almost consistent catalytic efficiency.

NHC-Cu Three-Coordinate Complex as a Promising Photocatalyst for Energy and Electron Transfer Reactions.

Herein, we describe a simple three-coordinate complex of Cu(I) with an NHC and 1,10-phenanthroline ligands as an effective photocatalyst for energy (e.g., olefin E/Z isomerization) and electron transfer (e.g., aryl halide dehalogenation) reactions under blue-light irradiation. This complex can be obtained in a one-pot procedure starting from commercially available reagents and green solvents (EtOH, water). We hereby present a study of its activity and mechanistic insight into its mode of operation.

A nickel-catalyzed Suzuki-Miyaura coupling reaction of aryl halides facilitated by pyridine derivatives

A nickel-catalyzed Suzuki-Miyaura coupling reaction facilitated by pyridine derivative ligands is reported. A wide range of (hetero) aryl halides and (hetero) aryl boronic acids were compatible, which led to the corresponding products in moderate to good yields. A gram-scale reaction proceeded well and afforded an efficient route to prepare methyl [1,1′-biphenyl]-4-carboxylate.

Synthesis of Methyl N-phenylcarbamate Derivatives by Xphos Pd G2 Catalyzed Intermolecular Amidation Reaction

Abstract: The utilization of palladium catalysts in cross-coupling reactions has emerged as a highly promising method for the facile formation of aryl C-N bonds, operating under mild conditions. In this study, we present an efficient approach for the synthesis of methyl N-phenyl carbamate derivatives through the intermolecular amidation of aryl chlorides, catalyzed by Xphos Pd G2. The developed protocol has demonstrated remarkable efficacy, offering several advantages. Notably, the intermolecular amidation reaction exhibited good chemoselectivity, allowing for the precise targeting of desired C-N bond formations while maintaining the integrity of other functional groups. Additionally, this methodology showcases exceptional functional group compatibility, accommodating a diverse array of moieties, including sensitive groups that are traditionally challenging to handle. The Xphos Pd G2 catalyst has proven to be instrumental in orchestrating this transformation, exhibiting high catalytic activity and selectivity. Furthermore, this protocol stands out for its operational simplicity, making it a practical choice for synthetic chemists seeking a straightforward and reliable route to access methyl N-phenyl carbamate derivatives. Overall, this study not only expands the synthetic toolbox for C-N bond formations, but also underscores the significance of palladium-catalyzed methodologies in modern organic synthesis. The reported findings hold substantial promise for applications in medicinal chemistry and material science, where the facile construction of aryl C-N bonds is of paramount importance.

Diastereoselective Synthesis of Pyridone ribo‐C‐Nucleosides via Heck Reaction and Oxidation

Nucleosides find applications in medicinal chemistry, chemical biology and diagnostics. Among the nucleosides, C‑nucleosides have attracted particular attention because their carbon‐carbon bond between nucleobase and ribose provides stability against degradation. While several well‐established methods exist for the synthesis of 2'‐deoxy‐C‐nucleosides, the preparation of their ribofuranosyl counterparts is more challenging. Established methods for their synthesis give mixtures of anomers and require harsh reagents or conditions. Here we report a diastereoselective glycosylation method involving a Heck reaction between a glycal and an aryl iodide, followed by oxidation of the silyl enol ether with methyl(trifluoromethyl)dioxirane (TFDO). The resulting ketone is then diastereoselectively reduced to the ribonucleoside. The new route has been applied to pyridones and is expected to also yield other ribo‐C‑nucleosides in diastereoselective fashion.

Ruthenium/η5-Phenoxo-Catalyzed Amination of Phenols with Amines.

Ruthenium(II) complexes are known to form η6-arene complexes with benzene-containing compounds through π-coordination, a property extensively utilized to initiate reactions not typically observed with free arenes. A prime example is nucleophilic aromatic substitution, where ruthenium-complexed aryl halides undergo nucleophilic attack, allowing the direct synthesis of diverse aromatic compounds by displacing halides with nucleophiles. However, this activation relies on the electron-withdrawing effect of the Ru(II) species, as well as is hindered by the resistance of η6-arenes to arene exchange. In the previous pursuit of catalysis, the emphasis of ligand design has centered on promoting arene exchange. In this study, we extended the ruthenium activation strategy to umpolung substitution reactions of phenols. The amination proceeds through a direct condensation between phenols and amines, with a key intermediate identified as [bis(η5-phenoxo)Ru], which is in situ generated from a commercially available ruthenium catalyst. In comparison with the well-studied cyclopentadienyl (Cp) type ligands, we demonstrated that an η5-phenoxo motif, as a superior alternative to Cp, contributes to the amination of phenols in two crucial ways: its less electron-donating nature enhances the withdrawing effect of the ruthenium unit, facilitating substitution on the phenol complex; its distinctive behavior in arene exchange allows for conducting the amination with a catalytic amount of metal. Additionally, hydrogen bonding, wherein the phenoxo serves as the acceptor, was found to be important for the substitution. The versatility of this ruthenium-catalyzed amination was validated by performing reactions with a diverse array of phenols exhibiting various electronic properties, in combination with a wide range of primary amines. This work exemplifies the expansion of the scope of π-coordination activation in catalysis through innovative ligand development.

A Dual Ni/Photoredox Cross-Coupling Approach toward Mandelic Acids.

Mandelic acid derivatives represent a valuable class of compounds due to their wide use in synthetic organic chemistry and the pharmaceutical sector. Herein, we report a novel reductive Ni/photoredox cross-coupling of readily accessible, bench stable N-alkoxyphthalimides and aryl halides to prepare unprotected mandelic acid ester derivatives. Mechanistic experiments suggest that this cross-coupling likely proceeds via a pathway that is distinct from previous reports using similar redox-active alkoxy radical precursors.

Triazine-wingtips accelerated NHC-Pd catalysed carbonylative Suzuki cross-coupling reaction

Triazine conjugated N-heterocyclic carbene palladium complexes were synthesized for reducing the Pd amount in the catalysts to the ppm levels. This work reports the carbonylative Suzuki-Miyaura coupling of aryl iodides catalyzed by N-heterocyclic carbenes palladium with triazine wingtips (T-NHC-Pd). More importantly, the palladacycles have been used to generate high turnover numbers (TON's) and turnover frequencies (TOF's).

Triple Radical Sorting: Aryl-Alkylation of Alkenes.

The cross-coupling of aryl bromides with alkenes can provide access to diverse combinatorial chemical space. Two-component couplings between these partners are well-known, but three-component aryl-functionalizations of unactivated alkenes remain underdeveloped. In particular, the aryl-alkylation of unactivated alkenes would allow for rapid construction of molecular complexity and the expedient exploration of a pharmaceutically relevant and C(sp3)-rich structural landscape. Herein, we report a general approach toward the aryl-alkylation of alkenes through a triple radical sorting mechanism. Over the course of the reaction, a high energy aryl radical, a primary radical, and a hindered alkyl radical are simultaneously formed. Through mediation by a nickel-based catalyst, the three radicals are sorted into productive bond-forming pathways toward the efficient aryl-alkylation of alkenes. A wide range of electronically and sterically differentiated alkenes and aryl radical precursors can be used to access complex scaffolds. This method was further applied to the synthesis of highly substituted semisaturated fused heterocycles.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)–C(sp3) Couplings via Nickel Catalysis

The development of robust and reliable methods for the construction of C(sp2)–C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious‐metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross‐coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single‐electron‐transfer (SET) and energy‐transfer (EnT) processes for the formation of C–X bonds, and in this manuscript we overcome previous limitations to furnish C–C over C–O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)-C(sp3) Couplings via Nickel Catalysis.

The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Host-Guest Approach to Promoting Photocatalysis Based on Consecutive Photo-Induced Electron-Transfer Processes via Efficient Förster Resonance Energy Transfer.

Supramolecular artificial light-harvesting system with highly efficient host-guest energy transfer pathway provides an ideal platform for optimizing the photochemistry process. The consecutive photo-induced electron transfer (conPET) process overcomes the energy limitation of visible-light photocatalysis, but is often compromised by mismatching between the absorption of ground state dye and its radical, weakening the efficiency of photoredox reaction. By encapsulating a conPET photocatalyst rhodamine 6G into metal-organic cage, the supramolecular approach was undertaken to tackle the intrinsic difficulty of matching the light absorption of photoexcitation between rhodamine 6G and its radical. The highly efficient Förster resonance energy transfer from the photoexcited cage to rhodamine 6G forced by host-guest encapsulation facilitates the conPET process for the single-wavelength light-driven activation of aryl halides by stabilizing and accelerating the production and accumulation of the rhodamine 6G radical intermediate. The tunable and flexible nature of the supramolecular host-guest complex renders the cage-based encapsulation strategy promising for the development of ideal photocatalysts toward the better utilization of solar energy.

Host‐Guest Approach to Promoting Photocatalysis Based on Consecutive Photo‐Induced Electron‐Transfer Processes via Efficient Förster Resonance Energy Transfer

Supramolecular artificial light‐harvesting system with highly efficient host‐guest energy transfer pathway provides an ideal platform for optimizing the photochemistry process. The consecutive photo‐induced electron transfer (conPET) process overcomes the energy limitation of visible‐light photocatalysis, but is often compromised by mismatching between the absorption of ground state dye and its radical, weakening the efficiency of photoredox reaction. By encapsulating a conPET photocatalyst rhodamine 6G into metal‐organic cage, the supramolecular approach was undertaken to tackle the intrinsic difficulty of matching the light absorption of photoexcitation between rhodamine 6G and its radical. The highly efficient Förster resonance energy transfer from the photoexcited cage to rhodamine 6G forced by host‐guest encapsulation facilitates the conPET process for the single‐wavelength light‐driven activation of aryl halides by stabilizing and accelerating the production and accumulation of the rhodamine 6G radical intermediate. The tunable and flexible nature of the supramolecular host‐guest complex renders the cage‐based encapsulation strategy promising for the development of ideal photocatalysts toward the better utilization of solar energy.

A Merger of Relay Catalysis with Dynamic Kinetic Resolution Enables Enantioselective β-C(sp3)-H Arylation of Alcohols.

The conceptual merger of relay catalysis with dynamic kinetic resolution strategy is reported to enable regio- and enantioselective C(sp3)-H bond arylation of aliphatic alcohols, forming enantioenriched β-aryl alcohols typically with >90:10 enantiomeric ratios (up to 98:2 er) and 36-74% yields. The starting materials bearing neighbouring stereogenic centres can be converted to either diastereomer of the β-aryl alcohol products, with >85:15 diastereomeric ratios determined by the catalysts. The reactions occur under mild conditions, ensuring broad compatibility, and involve readily available aryl bromides, an inorganic base, and commercial Ru- and Pd-complexes. Mechanistic experiments support the envisioned mechanism of the transformation occurring through a network of regio- and stereoselective processes operated by a coherent Ru/Pd-dual catalytic system.