Synthesis Of Biaryls Research Articles

Synthesis of Chiral Axially Diaryl Aldehydes by Chiral Phosphoric Acid Catalyzed Desymmetrization Reaction

Axially chiral biaryl aldehydes are precursors for the synthesis of axially chiral compounds and novel chiral catalysts of great interest, which play vital roles in extensive research fields. However, limited strategies exist for the efficient synthesis of axially chiral aldehydes, and the construction of structurally diverse axially chiral aldehydes remains challenging. Herein, a strategy is reported for the synthesis of biaryl axially chiral aldehydes with varying structures from biaryl dialdehydes and aromatic amines in the presence of a chiral phosphoric acid catalyst. This protocol features excellent enantioselectivity, mild conditions, and good functional‐group tolerance.

Palladium-Catalyzed Suzuki-Miyaura Reactions with Triazenyl-Tethered Aryl Bromides: Exploiting the Orthogonal Coupling Sites under Different Conditions.

Transition-metal-catalyzed cross-coupling of arenes bearing two or more potential coupling sites is often challenging because of the chemoselectivity issue. If orthogonal cross-couplings were applicable, one can develop a synthetically useful approach for consecutive functionalization of the starting arenes compounds. We herein reported a Suzuki-Miyaura coupling of triazenyl-substituted aryl bromides catalyzed by PdCl2(PCy3)2/PPh3 under basic conditions. The resultant polyfunctionalized aryl triazenes could undergo Suzuki-Miyaura couplings under acidic conditions or be converted to many other functionalized arenes. This orthogonal coupling strategy allows for a sequential functionalization of arenes with same type of nucleophilic reagents toward the synthesis of diverse biaryls and teraryls.

Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases

AbstractAxially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six‐membered aza‐acetal‐bridge‐promoted racemization followed by an imine reductase (IRED)‐catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S‐IRED‐Ss‐M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and >99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S‐IRED‐Ss‐M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts’ toolbox to construct challenging axially chiral molecules.

Bio‐Inspired Cu/Pd Bimetallic Catalysts Facilitating One‐Pot Relay Catalysis of Homo‐Couplings of Arylboronic Acids

ABSTRACTInspired by the multienzymatic relay catalysis in nature, herein, we reported a pioneering bio‐inspired Cu/Pd bimetallic composite microspheres (Cu/CMC@Pd/C) as a simple and efficient relay catalyst for the homo‐coupling of arylboronic acids. In this composite, Pd/C was encapsulated by Cu(II)‐crosslinking carboxymethyl cellulose (Cu/CMC). Cu/CMC@Pd/C microspheres were easily achieved by adding a mixture solution of Pd/C and carboxymethyl cellulose into a Cu(II) solution through an ion exchange reaction between carboxylate groups of CMC and Cu(II) ions. The morphology and composition of the as‐prepared Cu/CMC@Pd/C microspheres were well characterized using various analytical tools such as FT‐IR, XRD, XPS, SEM, TEM, elemental mapping, EDS, and ICP‐AES. The analysis indicated that the composite microspheres have a porous structure and Pd/C is uniformly distributed within the interior of the composite microspheres. The porous structure facilitates mass transfer of the substrate and increases the contact area of the catalyst, thus improving reaction efficiency. The performance of Cu/CMC@Pd/C microspheres was assessed in the homo‐coupling of arylboronic acid for the synthesis of symmetric biaryl without the need for an aryl halide as a partner. This process mimics a multienzyme catalysis through a relay Cu(I)‐catalyzed halogenation of one portion of arylboronic acid and a Pd(0)‐catalyzed Suzuki–Miyaura cross‐coupling between the in situ generated aryl halide and another portion of arylboronic acid. The results showed that this bio‐inspired Cu/CMC@Pd/C has excellent relay catalytic activity with tolerance of broad functional groups, producing the desired symmetrical biaryls in excellent yields within a short reaction time under mild conditions. Moreover, the catalyst can be easily recovered through simple filtration and still has good catalytic activity after six cycles. Consequently, this innovative pseudo‐homogeneous Cu/Pd relay catalyst emerges as a convenient and efficient alternative for the synthesis of asymmetric biaryls.

Ag-Cu2O Supported Biomass-Derived rGO for Catalyzing Suzuki-Miyaura Cross-Coupling.

The search for cost-effective, efficient, and ecofriendly heterogeneous catalysts for the Suzuki-Miyaura reaction is crucial due to challenges with expensive, toxic homogeneous catalysts. This study centrally aims at crafting a pioneering green catalyst by adorning reduced graphene oxide (rGO), sourced from basil seeds (Ocimum basilicum L.), with an Ag-Cu2O composite structure. Comprehensive characterization of the Ag-Cu2O/rGO nanocomposite was conducted through FTIR, SEM, hHR-TEM, EDS, XPS, XRD, TGA, and N2 adsorption/desorption analyses. Results showed that nanosized Ag-Cu2O particles were partially integrated into rGO sheets derived from basil seeds, acting as active species for oxidative addition with aryl halides in the SMR. The catalytic efficacy of this robust nanocatalyst was assessed in Suzuki-Miyaura cross-coupling reactions, targeting the synthesis of biaryls employing various aryl halides and aryl boronic acids. The findings underscore that the Ag-Cu2O/rGO nanocatalyst manifests rapid reaction kinetics (15 min) alongside commendable yields (99%). The Ag-Cu2O/rGO demonstrates impressive recyclability, maintaining catalytic efficiency over four cycles. Utilizing it as a green substrate for metal loading highlights its potential, offering well-defined coordination sites. This approach facilitates stable heterogeneous catalyst fabrication, crucial for significant bond formations. Notable features include broad applicability, exceptional functional tolerance, scalability, and practicality. Moreover, it holds promise for automating safe processes and enabling efficient late-stage functionalization of complex molecules with moderate to high efficiency, presenting promising prospects for various applications in chemical synthesis.

Chemoselective C(sp2)–C(sp2) doubly decarbonylative cross-electrophile coupling enabled by palladium catalysis: Reaction development and mechanism studies

Transition metal-catalyzed cross-electrophile coupling of two electrophiles has proved to be a powerful and step-economic strategy for the construction of C–C bonds in organic synthesis. Despite the considerable advances, cross-electrophile coupling of sp2-hybridized carboxylic acid derivatives via a decarbonylative fashion remains a formidable challenge. Herein, we disclose a chemoselective C(sp2)–C(sp2) doubly decarbonylative cross-electrophile coupling of aroyl fluorides with a wide range of aryl and alkenyl thioesters by palladium catalysis. The catalytic protocol provides an alternative route for the efficient synthesis of biaryls and stilbene derivatives owing to wide accessibility, natural abundance and stability of carboxylic acid and relevant derivatives. The combination of a series of experiments and theoretical calculations reveals that conversion of aroyl fluorides into the corresponding thioesters, chloride anion in catalyst PdCl2 and in situ generated Zn(II) reagents play the crucial roles in the current cross-coupling reactions.

Palladium-Catalyzed/Copper-Mediated Decarbonylative Cross-Coupling of S-Pyrimidyl Thioesters for Biaryl Synthesis.

A palladium-catalyzed/copper-mediated cross-coupling of S-pyrimidinyl thioesters with arylboronic acids to yield biaryls is described. The reaction is likely to proceed via cleavage of the S-C(O) bond and subsequent release of CO, rather than via cleavage of the S-C(pyrimidine) bond and release of SCO, as supported by the results of both experimental and computational studies. The investigation of the reaction scope with various S-pyrimidinyl thioesters and arylboronic acids showed that the reaction is significantly affected by the substituent of the thioester and the presence of a chelatable ortho substituent was found to increase reaction efficiency.

Synthesis of (Hetero)biaryls via Nickel Catalyzed Reductive Cross-Electrophile Coupling Between (Hetero)aryl Iodides and Bromides.

(Hetero)biaryls are fundamental building blocks in the pharmaceutical industry and rapid access to these scaffolds is imperative for the success of numerous medicinal chemistry campaigns. Herein, a highly general, mild, and chemoselective reductive cross-electrophile coupling between (hetero)aryl iodides and heteroaryl bromides is reported. By employing more reactive (hetero)aryl halides, a broad range of successful substrates (45 examples) were identified. The reaction was also found to be chemoselective for C(sp2)-C(sp2) bond formation between (hetero)aryl iodides and bromides over (hetero)aryl chlorides, which were generally inert under the described reaction conditions. The efficiency of the procedure is also further demonstrated in parallel synthesis library format, on gram scale, as well as in the formal synthesis of Ruxolitinib, a potent JAK inhibitor. As such, we anticipate this method will find widespread utility in the assembly of (hetero)biaryls for medicinal chemistry efforts.

Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases.

Axially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal-bridge-promoted racemization followed by an imine reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and >99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules.

XAT-Catalysis for Intramolecular Biaryl Synthesis.

Radical ipso-substitution offers an alternative to organometallic approaches for biaryl synthesis, but usually requires stoichiometric reagents such as tributyltin hydride. Here, we demonstrate that visible light photoredox catalysis can be used for ipso-biaryl synthesis, via a halogen-atom transfer (XAT) regime. Using amide substrates that promote ipso- over unwanted ortho-addition, we demonstrate smooth biaryl formation with no constraint on the electronic character of the migrating arene ring. The photoreaction can be combined in one operation to achieve a formal arylation of the inert aniline C-N bond.

XAT‐Catalysis for Intramolecular Biaryl Synthesis

AbstractRadical ipso‐substitution offers an alternative to organometallic approaches for biaryl synthesis, but usually requires stoichiometric reagents such as tributyltin hydride. Here, we demonstrate that visible light photoredox catalysis can be used for ipso‐biaryl synthesis, via a halogen‐atom transfer (XAT) regime. Using amide substrates that promote ipso‐ over unwanted ortho‐addition, we demonstrate smooth biaryl formation with no constraint on the electronic character of the migrating arene ring. The photoreaction can be combined in one operation to achieve a formal arylation of the inert aniline C−N bond.

Lewis Acid‐Base Interactions as a Racemization Strategy for the Atroposelective Synthesis of (Hetero)biaryls via Dynamic Kinetic Resolution

AbstractDue to their molecular topology, atropisomers serve as highly valuable chiral frameworks for diverse applications across academic research and industry. Despite the availability of numerous established catalytic methods for their synthesis, there is still a high demand for the development of novel and resourceful strategies. In this concept article, we will detail our studies on the use of transient Lewis acid‐base interactions (LABI) as a dynamization strategy for the synthesis of (hetero)biaryl atropisomers by Dynamic Kinetic Resolution (DKR). The formation of cyclic transition states, resulting from the interaction between an acidic functionality and a basic counterpart, plays a key role in facilitating racemization by substantially reducing the barrier to atropisomerization. In this scenario, we have employed transformations aimed at neutralizing the acidic nature of the Lewis acid, ultimately leading to the formation of configurationally stable enantioenriched compounds. The design of substrates and the employment of stereoselective strategies based on transition metal and biocatalysis for their resolution is detailed. Specific emphasis on the preparation of axially chiral motifs commonly found in catalysis or medicinal chemistry will also be given.

Solid‐state Suzuki–Miyaura cross‐coupling: A sustainable approach by DDIL‐stabilized magnetic separable and recyclable Pd nanoparticles with total solvent bypass

A new method for the sustainable synthesis of various functionalized biaryls through the solid‐state Suzuki–Miyaura cross‐coupling reaction has been developed. This solid‐state protocol employs a palladium catalyst anchored on diazabicyclo[2.2.2]octane silica ferrite composite (Pd‐DDIL@Fe3O4‐SiO2). The catalyst has been fully characterized using multiple techniques such as FTIR, XRD, FESEM, EDS, elemental mapping, HR‐TEM, XPS, BET, TGA‐DTA, and VSM. The Pd‐DDIL@Fe3O4‐SiO2 catalyst has a surface area of 60.17 m2 g−1 and a magnetization saturation of 40.95 emu g−1. The TEM analysis revealed the rough spherical morphology of PdNPs having a particle size of 7 nm. The catalyst has excellent activity and selectivity towards the synthesis of both symmetrical and unsymmetrical biaryls under solid‐state, solvent‐free grinding conditions using a mortar and pestle. This method is eco‐friendly, as it is performed at room temperature without any solvents. The method employs the excellent yield of the products (90–96%) in a short reaction time (3–20 min). The desired products are isolated easily without any use of organic solvents. The catalyst can be easily separated using an external magnet and reused at least six times with an admirable change in yield. Additionally, the catalytic system has been shown to have a high TON and TOF, thus confirming its sustainability.

Ultrasound-assisted Cu(II) Strecker-functionalized organocatalyst for green azide–alkyne cycloaddition and Ullmann reactions

A new aminonitrile-functionalized Fe3O4 has been synthesized via the Strecker reaction, the designed aminonitrile ligand on the surface of the magnetic core coordinated to copper(II) to obtain the final new catalyst. The fabricated nanocatalyst was characterized by Fourier transform Infrared (FT-IR), Field Emission Scanning Electron Microscopy (FESEM), Energy-Dispersive X-ray spectroscopy (EDX), Transmission Electron Microscopy (TEM), Vibrating-Sample Magnetometer (VSM), Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), and Thermogravimetric Analysis (TGA). The high tendency of nitrogens in the aminonitrile functional group to make a complex with Cu(II) has caused the practical activity of this nucleus in this catalyst. This nanocatalyst performance was investigated in azide–alkyne Huisgen cycloaddition (3 + 2) reaction for achieving to 1,4-disubstituted 1,2,3-triazoles in water as a green media at room temperature. In another try, Classic Ullmann Reaction was investigated for the synthesis of biaryls at 85 °C promoted by ultrasonic condition (37 kHz). The reaction scope was explored using different reactants and the results of using this developed catalytic system demonstrated its capacity to reduce the reaction time and enhance the reaction efficiency to provide good to excellent product yield. Conversely, the simple recycling and reusability of this catalyst for at least six times without any noticeable leaching of copper makes it a potential future catalyst for synthesizing such compounds.

Expression of Concern: One‐Step Synthesis of Biaryls under Mild Conditions

Expression of Concern: One‐Step Synthesis of Biaryls under Mild Conditions

Photosensitizers Enable the Formation of Biphenyls with UV-LEDs and Sunlight.

The regioselective synthesis of biphenyls, which are economically important pharmaceuticals, agrochemicals, and liquid crystals, is a challenging task. Current methods rely on metal-dependent cross-coupling reactions, which unfortunately require the use of harmful halogenated aryls and heavy metal catalysts that are toxic and difficult to remove from the final products. Recently, we have circumvented these problems by developing a metal-free and broadly applicable photochemical method for biphenyl synthesis using UV-C light, called photosplicing. Here we present an improved method using photosensitizers in combination with UV-B, UV-A light, or sunlight. Using a high-precision flow reactor with deep-UV LEDs, we investigated the ability of commonly available organic photosensitizers to enhance the photosplicing reaction and identified a number of suitable photosensitizers with the required triplet energy. This method allows for easy batch synthesis of biaryls in borosilicate glassware and paves the way for their large-scale production without the need for flow reactors.

Catalytic π-π Interactions Triggered Photoinduced Synthesis of Biaryls.

A highly regioselective photocatalytic method to access a variety of biaryl motifs under metal-free conditions has been developed. The organophotocatalyst is involved in π-π stacking interactions with the alkyne species, which promotes this photocatalytic process with thiophene. Mechanistic studies have shed light on these interactions and the overall process. Along with a broad functional-group tolerance and excellent regioselectivity, this protocol has been utilized in the late-stage functionalization of pharmaceuticals and other natural products.

Recyclable LaF3·Pd nanocatalyst in Suzuki coupling: green synthesis of biaryls from haloarenes and phenylboronic acids.

Herein we prepared the novel LaF3·Pd nanocatalyst characterized by XRD and TEM analysis. The nanocatalyst was applied in Suzuki coupling reaction for the synthesis of biaryls in aqueous medium from readily available aryl halides (bromides and iodides) and substituted phenylboronic acids in the presence of K2CO3 as the base at 70 °C. The present method is capable of giving the C-C coupled product in good to excellent yields (up to 97%). The reactions were conducted under green conditions in aqueous medium and the nanocatalyst used in this study was recyclable. The recyclability and reusability of the catalyst was checked for seven consecutive cycles without significant loss in reactivity.

Chiral amino acids: evolution in atroposelective C-H activation.

This review covers the journey of chiral amino acids as ligands in atroposelective C-H bond activation/functionalization via transition metal catalysis. Herein, we intend to demonstrate how these chiral amino acids have evolved and flourished in this stimulating field. Unprotected amino acids, mono-N-protected amino acids, and di-N-protected amino acids have been devised for atroposelective C-H activation. In each section, we have briefly discuss the key successes of amino acids in the atroposelective synthesis of biaryls, heterobiaryls, and non-biaryl atropisomers and their advantages in atroposelective C-H activation.

C–C and C–N bond formation in electro-oxidation reactions of aromatic compounds

Atom-economical, eco-efficient, metal- and chemical oxidant-free formation of C–C and C–N bond from C(sp2)−H and C(sp3)−H of arenes toward the direct synthesis of biaryls and anilides or N-benzylamides under mild electro-oxidative conditions is described. The products of C–C and C–N coupling are obtained in up to 88% yields. Aromatic substrates that are oxidized at potentials less positive than +2 V or have bulky bromine or iodine substituents undergo homo-coupling reactions by anodic oxidation to form biaryls or dimers. Aromatic substrates that are difficult to oxidize (Eox > +2 V) preferentially form anilides and N-benzylamides upon anodic oxidation. The presence of a chlorine substituent on the aromatic ring leads to the formation of both biaryls and anilides during electro-oxidation.