Cross-coupling Research Articles

Co-Catalyzed Suzuki-Miyaura Coupling of Organoboronic Acids and Alkynyl Chlorides Using Potassium Bicarbonate as Base.

Organoboronic acids, some of the most common and widely used organoboron compounds, have not yet been used in the cobalt-catalyzed cross coupling reactions, despite cobalt demonstrating good reactivity with zinc reagents, Grignard reagents, and metal organoborates that are formed by n-butyl lithium or alkaline metal alkoxide salts and organoboron esters. Herein, a highly efficient and practical cobalt-catalyzed coupling reaction of aryl/alkenyl boronic acids and alkynyl chloride under mild reaction conditions is reported. The advantages of the organoboronic acids, along with a broad functional group compatibility and the reaction's tolerance to moisture and air, enable this reaction to be a synthetically useful protocol for the construction of a C(sp2)-C(sp) bond. Lastly, the synthesis of two natural products and a key intermediate of roxadustat was effectively accomplished using the methodology to construct the critical alkynyl-aryl bond.

Synthesis of core-functionalised naphthalene diimides from naphthalenetetracarboxylic dianhydride using a vibratory ball mill: bromination, imidization and Heck-type reactions.

The synthesis of 9 core-functionalised naphthalene diimide (c-NDI) residues is reported via a 3-step solvent free synthesis from naphthalenetetracarboxylic dianhydride using only mechanochemical activation. Selective dibromination and subsequent dimidiation were achieved for the first time in a vibratory ball mill, resulting in the key structural intermediate, 2,6-dibromonaphthalenediimide (DBND), which is the basis for elaboration into a multitude of organic electronic materials. Our new synthesis of DBND is achieved in just 5 hours' reaction time over two steps compared to typical solution state times of 24 hours. Subsequent Heck-type cross coupling reactions, with a range of styrene residues, produced a series of c-NDIs in good yields. The Heck-type reactions are rapid (1.5 hours), require no additional heating or solvent and are tolerant of atmospheric moisture and air.

Copper‐Catalyzed Cross Coupling Reaction of Alkyl Bromides with (DMPU)2Zn(Rf)2 Reagent: A Method for the Synthesis of Perfluoroalkylated Compounds

AbstractA method for the copper‐catalyzed cross‐coupling of alkyl bromides with a range of (DMPU)2Zn(Rf)2 reagents has been developed. This protocol tolerates multiple functional groups and provides broad access to aliphatic perfluoroalkylated compounds. The applicability of this procedure is demonstrated in the late‐stage functionalization of drug analogues.

Palladium immobilized on functionalized halloysite: A robust catalyst for ligand free Suzuki–Miyaura cross coupling and synthesis of pyrano[2,3-c]pyrazole motifs via four component cascade reaction and their in-silico antitubercular screening

This research introduces a novel organically functionalized halloysite-supported palladium catalyst, HMF-EDA-TMS@HAL-Pd(II) that was synthesized and thoroughly characterized using various analytical techniques like HR-TEM, FEG-SEM, EDX, XPS, FTIR, XRD, TGA, ICP-AES, EXAFS and DFT studies. The catalyst exhibited exceptional performance in Suzuki–Miyaura cross coupling reactions, demonstrating high efficiency and reusability up to seven cycles in aqueous ethanol medium. Motivated by its promising catalytic activity, we extended our investigation to explore its applicability in the synthesis of pyrano[2,3-c]pyrazole motifs via a four-component cascade reaction affording the desired products in good to excellent yields with broad substrate scope under green reaction conditions. In-silico antitubercular screening of pyrano[2,3-c]pyrazole motifs against DprE1 enzyme have shown promising results with inhibition constants ranging between 0.030 and 0.1 μM for compounds 5b, 5k and 5 l. This protocol has the advantages of wide substrate scope, high yield, excellent functional group tolerance, high efficiency and environmental benign procedure. These findings emphasized the catalyst's versatility and potential in diverse organic transformations, highlighting its importance in advancing sustainable synthetic methodologies.

Effects of fluorination of benzothiadiazole units on the properties of alternating cyclopentadithiophene/benzothiadiazole donor/acceptor polymers

AbstractA set of narrow bandgap conjugated polymers was prepared, using cyclopentadithiophene (CDT) donor units coupled with benzothiadiazole (BT) acceptor units substituted with either no fluorine atoms (A1), one fluorine atom (A2) or two fluorine atoms (A3), using the Stille cross coupling reaction. The addition of two electron‐withdrawing fluorine atoms to the BT units was observed to deepen the HOMO energy level of the resulting copolymer, while only slightly affecting the LUMO level, as evidenced by cyclic voltammetry examination. The alternating copolymers (CDT‐A1, CDT‐A2 and CDT‐A3) possess small optical bandgaps of 1.37, 1.43 and 1.51 eV (which should efficiently harvest a broad part of the solar spectrum), and a moderate HOMO level of −5.00, −5.05 and −5.12 eV, respectively. CDT‐A3 displayed the highest optical/electrochemical‐bandgap and the deepest HOMO level, a consequence of the addition of the fluorine atoms on the BT moieties. Inclusion of two fluorine atoms resulted in sharper X‐ray diffraction peaks in the CDT‐A3 copolymer with respect to its analogues CDT‐A1 and CDT‐A2 copolymer indicating a greater crystallinity. These findings clearly demonstrate that fluorination of BT units is an effective approach for adjusting the energy levels and optical properties of BT‐based materials for use in organic solar cells devices as well as for other applications.

NiII, PdII and PtII pincer complexes of 2-(diphenylphosphanyl)-N-(2-(diphenyl-phosphanyl)benzyl)benzamide: synthesis, reactivity and catalytic studies.

In this article, the synthesis of bis(phosphine), o-Ph2PC6H4C(O)N(H)CH2C6H4PPh2-o (1) (hereafter referred to as "PCNHCP" and its anionic form as "PCNCP") and its group 10 metal chemistry and catalytic studies are described. PCNHCP (1) on reaction with NiCl2(DME) and PdCl2(COD) afforded pincer complexes, [MCl{(PCNCP)κ3-P,N,P}] (M = Ni, 2; Pd, 3). A similar reaction of 1 with PtCl2(COD) yielded a chelate complex, [PtCl2{(PCNHCP)κ2-P,P}] (4), which on further treatment with LiHMDS produced the 1,2-azaphospholene-phosphine complex, [PtCl(Ph){(o-P(Ph)C6H4CONCH2C6H4PPh2-o)κ2-P,P}] (5) via P-C/P-N bond metathesis. Passing dry HCl gas through the solution of 5 resulted in benzene elimination to form [PtCl2{(o-P(Ph)C6H4CONCH2C6H4PPh2-o)κ2-P,P}] (6). Treatment of 1 with PtCl2(COD) and Pt(Cl)(Me)(COD) in the presence of a base resulted in pincer complexes [PtX{(PCNCP)κ3-P,N,P}] (X = Cl, 7; Me, 8). Nickel complex 2 catalyzed the Suzuki-Miyaura cross coupling reaction between bromobenzene and phenyl boronic acid to give the corresponding biphenyls in good yield. The platinum complex 5 showed good catalytic activity towards regio- and stereoselective hydroboration of terminal alkynes. Both the catalytic reactions were performed under mild reaction conditions with a very low catalyst loading.

Synthesis of [6,5,5]Ring‐Fused Tricyclic Triazoles by Copper‐Promoted Double Cyclization

AbstractRing‐fused 1,2,3‐triazoles are important biologically active compounds and synthetic intermediates. Known methods for their synthesis are limited mostly to triazoles fused to six‐membered or larger rings. Herein we disclose a synthetic approach to triazoles fused to five‐membered rings based on copper(I)‐promoted double cyclization consisting of azide‐alkyne cycloaddition, followed by cross coupling to aryl iodides.

Mapping Reaction Pathways by In Situ Step Sweep Voltammetry Flow Electrochemical Mass Spectrometry.

A step sweep voltammetry (SSV) flow electrochemical (EC) mass spectrometry (MS) platform was developed for real-time and in situ mapping of EC reaction pathways. By integrating a flow EC cell into the pneumatic spray nozzle followed by atmospheric chemical ionization, this setup was capable of in situ MS monitoring of short-lived EC intermediates with enhanced sensitivity. This setup also realized precise measurement and control of the electrode potential during in situ EC-MS analysis, which can provide detailed information on the interplay of reaction pathways under different electrode potentials. Taking the EC reductive cross coupling of nitroarenes with arylboronic acids as an example, SSV-MS had identified 13 compounds among four reaction pathways. Among these, the electrode potential of active nitrene and cross coupling intermediates were measured for the first time and the structure of the nitroso coupling complex was also confirmed by MS. With the systematic measurement of electrode potential of the intermediates and products, SSV-MS had clearly mapped out the synergies and competitions between different reaction pathways, offering key insights for optimizing reaction conditions and investigating reaction mechanisms for EC research.

Non-Ionic Peterson-Type Olefination Reactivity and its Use in a Silicon-Promoted Carbonyl-Carbonyl Cross Coupling Reaction.

The [2+2] cycloaddition reaction between the Si=C double bond of adamantylsilene and the carbonyl group of aliphatic, aromatic or acetylenic ketones and aldehydes is demonstrated. The product of this reaction that is central to a non-ionic version of the Peterson olefination is an unusual four-membered 1,2-silaoxetane heterocycle that was characterized spectroscopically and crystallographically. In the presence of SiO2, the silaoxetane undergoes retro-cycloaddition with the formation of alkene products. As the [2+2] cycloaddition proceeds without the necessity of any base, enolizable ketones can be converted into olefins. In addition, it is shown that the adamantylsilene can be produced in situ by a sila-Peterson reaction, providing valuable input for the development of a new one-pot silicon-based reductive carbonyl-carbonyl cross coupling methodology.

Synthesis, Structures, and Reactivity of Organostannanides and Organogermanides of Copper(I).

Organogermane and organostannane compounds are valuable reagents in cross coupling reactions, and copper(I) germanide and stannanide complexes can provide convenient access to these compounds. This review presents the chemistry of copper(I) germanide and stannanide complexes, with a particular focus on systems at the frontier of organic and inorganic chemistry where structural characterisation of coordination complexes facilitates rationalisation of organic mechanisms. These species show both similarities to, and significant divergences from their lighter silanide congeners. For example, they are all viable sources of the relevant organotetranide anion, but in the cases of both germanium and tin, the tetranides can be accessed via direct deprotonation of the corresponding tetranes, a reaction unknown for silicon. Further divergences between copper(I) germanides and stannanides are highlighted; whilst both can be used in productive organic transformations to access organotetranes, catalytic reactions are only reported for germanium. The rather striking ability of triphenylstannanides to acts as sources of the phenyl anion are discussed; the mechanism of this reaction is still subject to discussion, but its absence in the chemistry of germanium and silicon is now well-rationalised. We conclude this review by considering potential research directions in the synthesis and exploitation of copper(I) germanides and stannanides.

Transition Metal-Catalyzed C(sp3)-C(sp3) Coupling to Construct All-Carbon Quaternary Carbon Centers

Transition metal-catalyzed C(sp³)-C(sp³) coupling reactions represent a powerful strategy for constructing all-carbon quaternary centers. However, these reactions remain challenging due to significant steric hindrance effects and the propensity for side reactions such as elimination and isomerization. This review provides a comprehensive summary of the progress made over the past few decades in the construction of all-carbon quaternary centers, with a focus on coupling reactions involving tertiary C(sp³) and primary/secondary C(sp³) centers (as the cross coupling of two tertiary C(sp³) centers remains unsuccessful). The discussion is organized around reaction conditions, substrate scope, and reaction mechanisms, and a brief overview of transformations based on these coupling reactions is also presented.

Paired Electrocatalysis-Enabled Cross Coupling of Sulfinamides with Olefins toward the Synthesis of Vinyl Sulfoximines.

We present here a novel paired electrocatalysis-enabled convenient synthesis of the (E)-vinyl sulfoximines through the cross-coupling reaction of sulfinamides and olefins. This protocol showed a broad substrate scope and excellent E selectivity of products under metal- and oxidant-free conditions. A preliminary mechanistic study suggested that fluorinated sulfoximine generated from anodic oxidation of sulfinamide was the key intermediate that was then converted into the sulfonimidoyl radical at the cathode with the help of DBU in this reaction.

A convenient bottom up route to covalently anchor Pd(II)-PEPPSI on layered zirconium(IV) phosphonate: Efficient catalyst for Suzuki-Miyaura cross coupling of aryl chlorides

A rational and bottom-up route for assembling layered Zr(IV) phosphonate framework decorated with covalently anchored N-heterocyclic carbene NHC-Pd(II) fragment has been developed. Reaction of phosphonic acid functionalized Pd(II)-NHC precursor complex with ZrOCl2·8H2O provides easy access to a layered material with covalently anchored catalytically active Pd(II)-NHC sites. The Pd(II)-NHC functionalized Zr(IV) phosphonate showed enhanced catalytic activity in Suzuki-Miyaura cross coupling reaction of both aryl bromides and chlorides with aryl boronic acid, as compared to their homogeneous counterparts. The Zr(IV) phosphonate framework imparts remarkable robustness to the Pd(II)-NHC catalyst and allowed recycling of the catalyst up to nine catalytic cycles without any major loss of catalytic activity.

Regioselective C(sp2)-H nitrosation and nitration of (Hetero)arenes with Fe(NO3)3·9H2O as promoter, nitroso and nitro source

A regioselective C(sp2)-H nitrosation and nitration protocol has been successfully developed for the modification of various undirected bioactive molecules by using the economical and nontoxic Fe(NO3)3.9H2O as nitroso/nitro source. This method is conducted under acid-free and ease of handling conditions and is featured with good regioselectivity as well as a broad substrate scope (38 examples; yields up to 90 %). This reaction could be conducted on a gram scale with good efficiency, demonstrating high utility for the synthesis and modification of drug and material molecules. Detailed mechanistic studies indicate that the formation of the nitroso or nitro products might be proceeded via the radical cross coupling of aryl radical cation intermediates with nitroso or nitro radical.

Manganese(III) Triacetate-Mediated Cross Coupling of Organoboron Compounds with Trichloroethylene (TCE): Synthesis of 1,1-Dichloroalkenes.

Herein, we report an efficient method for the synthesis of 1,1-dichloroalkenes from organoboron compounds. This reaction proceeds in the presence of manganese(III) triacetate using trichloroethylene (TCE) as the vinylation reagent. This reaction can tolerate various types of organoboron compounds and various functional groups. The yields are moderate to good. Surprisingly, this transformation could even be achieved in the presence of manganese(II) acetate. Furthermore, this synthetic strategy could be applied to the synthesis of 1,1,2-trichloro-, 1-chloro-, and 2-chloroalkenes.

Immobilization of laccase on mesoporous metal organic frameworks for efficient cross-coupling of ethyl ferulate.

Laccases act as green catalysts for oxidative cross-coupling of phenolic antioxidnt compounds, but low stability and non-recyclability limit its application. To address that, metal-organic frameworks Cu-BTC and Cr-MOF were synthesized as supports to immobilize the efficient laccase from Cerrena sp. HYB07. The Brunauer-Emmett-Teller surface area of Cu-BTC and Cr-MOF were 1213.2 and 907.1m2/g, respectively. The two carriers respectively presented pore diameters of 1.2-10nm and 1.4-12nm as octahedron, indicating nano-scale mesoporosity. These Cu-BTC and Cr-MOF carriers could adsorb laccase with enzyme loading of 1933.2 and 1564.4U/g carrier, respectively. The stability and organic solvent tolerance of Cu-BTC-laccase and Cr-MOF-laccase were both obviously improved compared to free laccase. Thermal inactivation kinetics showed that both the two immobilized laccases displayed lower thermal inactivation rate constants. Importantly, the Cu-BTC-laccase and Cr-MOF-laccase both showed much higher activity for cross-coupling of ethyl ferulate than free laccase, which had 2.5-fold higher cross-coupling efficiency than that by free laccase. The ethyl ferulate coupling product was also analyzed by mass spectroscopy and the synthesis pathway of ethyl ferulate dimer was proposed. The cross coupling of ethyl ferulate required the formation of radical intermediates of ethyl ferulate generated by laccase mediated oxidation. This work paved the way for MOFs immobilized laccase for cross coupling of antioxidant phenols.

Copper-Catalyzed Intramolecular Decarboxylative C(sp2)-Heteroatom Cross-Couplings: Mechanism Insights and Synthetic Applications.

Decarboxylative C(sp2)-heteroatom cross-coupling reactions hold extraordinary potential for the sustainable preparation of biologically active scaffolds. Herein, we report a copper sulfate/1,10-phenathroline catalytic system for the decarboxylative intramolecular C(sp2)-O, C(sp2)-S, and C(sp2)-N coupling reactions leading to the construction of a series of benzo[b]furans, benzo[b]thiophenes, and indole derivatives from the corresponding coumarins, thiocoumarins, or quinolones, respectively. Our mechanistic study based on benzo[b]furan formation suggests a three-step process of the transformations, which consists of (i) base-mediated hydrolytic ring opening of coumarin, (ii) copper-oxygen co-initiated radical decarboxylation, and (iii) copper-catalyzed C-heteroatom cross coupling. Application of this method in the total synthesis of egonol, a bioactive natural product, was demonstrated successfully, with an overall yield of 51.7%.

Perfect Partners: Biocatalytic Halogenation and Metal Catalysis for Protein Bioconjugation.

Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH2 in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.

Aggregation-induced C–C bond formation on an electrode driven by the surface tension of water

Electrochemical organic synthesis is typically conducted in organic media. The solvent and related supporting electrolytes negatively affect the greenness of electrosynthesis. In this work, with 100% water used as the solvent, we realize aggregation-driven electrochemical radical cross coupling of unsaturated compounds driven by water tension. A key finding is that aggregation of the substrate at the electrode confined the radical intermediate and prevented side reactions, thus providing a way to regulate radical reactions in addition to their native properties. The reaction provides up to 90% yields with almost quantitative chemoselectivity. The pure water system readily yields the products via cold filtration, and the solvent is recycled repeatedly. In particular, the life span of the radical species generated in the reaction increase significantly because of the confined environment in the aggregation state. The greenness of this protocol is further enhanced with readily separation of product from media using cooling and filtration.

C1‐4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow

The homologous series of gaseous C1‐4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C–H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp2)–C(sp3) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel‐catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate‐determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.