Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Iron‐catalyzed cross‐coupling reaction: Heterogeneous palladium and copper‐free Heck and Sonogashira cross‐coupling reactions catalyzed by a reusable Fe(III) complex

An interesting silica‐supported iron catalyst was successfully prepared and demonstrated as an efficient heterogeneous catalyst for cross‐coupling reactions of aryl halides. The as‐prepared nanocatalyst was well characterized and found to be highly efficient in Heck reaction under mild and sustainable conditions (water as solvent at 80 °C in short reaction time). Furthermore, the obtained catalyst was used as an efficient, inexpensive and green heterogeneous catalyst for Sonogashira cross‐coupling reactions of various aryl iodides and provided the corresponding products with moderate to good yields. This phosphine, copper and palladium‐free catalyst was simply recovered from the reaction mixture and recycled five times without substantial decrease in its catalytic activity.     

Mesoporous Silica MCM‐41 Supported N‐Heterocyclic Carbene‐Pd Complex for Heck and Sonogashira Coupling Reactions

Heterocyclic carbene‐Pd complex was anchored onto the mesoporous silica MCM‐41 which exhibits high catalytic activity in Heck reaction under phosphine free reaction conditions for the reaction of iodo/bromoarenes with olefinic compounds such as butyl acrylate, isopropyl acrylate and styrene. This catalytic system also showed high activity for Sonogashira coupling reaction of various aryl halides under copper, phosphine and solvent‐free reaction conditions. The air and thermally stable catalyst were reused several times without significant loss of its activity. High efficiency of the catalyst along with its recycling ability and the rather low Pd‐loading demonstrated in both Heck and Sonogashira coupling reactions are the merits of the presented catalyst system.     

Dimeric ortho‐palladated homoveratrylamine as an efficient homogeneous catalyst for copper‐free Sonogashira cross‐coupling reaction

The catalytic activity of ortho‐palladated [Pd{C6H2(CH2CH2NH2)‐(OMe)2,3,4}(m‐Br)]2, a complex of homoveratrylamine in the copper‐free Sonogashira coupling reaction has been investigated. This complex is a catalyst that is efficient, stable and non‐sensitive to air and moisture in the Sonogashira reaction. In this homogeneous catalytic system, various aryl halides were efficiently coupled with phenylacetylene in mostly moderate to good yields in N‐methylpyrrolidone at 100 °C under copper‐free conditions. Copyright © 2012 John Wiley & Sons, Ltd.     

Copper‐ and phosphine‐free Sonogashira coupling reaction catalyzed by silica–(acac)‐supported palladium nanoparticles in water

A palladium‐based catalyst supported on acac‐functionalized silica was used as a heterogeneous catalyst for the Sonogashira cross‐coupling reaction of various aryl halides and phenylacetylene under copper‐ and phosphine‐free conditions. This catalytic system serves as an efficient and stable catalyst for this cross‐coupling reaction and allows easy separation and recycling of the catalyst. The catalyst could be recycled for five runs without appreciable loss of its catalytic activity. In addition, the reaction was carried out in water as a green solvent. Copyright © 2014 John Wiley & Sons, Ltd.     

Cu‐free Sonogashira Type Cross‐Coupling of 6‐Halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl) Quinazolin‐4(3H)‐ones as Potential Antimicrobial Agents

C(sp)–C(sp2) bond formation via Sonogashira cross‐coupling reactions on 6‐halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl)quinazolin‐4(3H )‐ones with appropriate alkynes was explored. Optimization of reaction conditions with various catalysts, ligands, bases, and solvents was conducted. The combination of PdCl₂(MeCN)₂ with X‐Phos proved to be the best metal–ligand system for this conversion in the presence of triethylamine (Et₃N) in tetrahydrofuran at room temperature for iodosubstrates, at 80°C for the bromosubstrates in 8 h, and also for the chlorosubstrates in 16 h. We also demonstrated synthesis of a successful diversity‐oriented synthesis library of highly functionalized quinazolinones via Cu‐free Sonogashira coupling of diverse aryl halides and azido‐alkyne (“click”) ligation reactions with substituted azides. The library exhibited significant antimicrobial activity when screened against several microorganisms.     

Novel pyridine‐bis(ferrocene‐isoxazole) ligand: synthesis and application to palladium‐catalyzed Sonogashira cross‐coupling reactions under copper‐ and phosphine‐free conditions

We present here the first synthesis and application to Sonogashira reaction of pyridine‐bis(ferrocene‐isoxazole) Pd(II) complex 5 , prepared from 2,6‐bis‐(5‐ferrocenylisoxazole‐3‐yl)pyridine. Under copper‐ and phosphine‐free conditions, the stable complex 5 efficiently catalyzed the cross‐coupling of aryl halides with terminal alkynes in DMF–H₂O with TBAB as an additive, hexahydropyridine as base and affording internal arylated alkynes in moderate to excellent yields. Copyright © 2008 John Wiley & Sons, Ltd.     

Ferrocenyl bisoxazoline as an efficient non‐phosphorus ligand for palladium‐catalyzed copper‐free Sonogashira reaction in aqueous solution

Pd(OAc)₂‐catalyzed Sonogashira coupling reactions of alkynes and a variety of aryl halides with 1,3‐bis(5‐ferrocenylisoxazoline‐3‐yl)benzene as an efficient non‐phosphorus ligand under copper‐free conditions are presented. The main advantages over previous methodologies include low catalyst loading (0.2 mol% Pd(OAc)₂ and 0.4 mol% ferrocenyl bisoxazoline ligand are sufficient for these coupling reactions), less problematic reaction medium (water–dimethylformamide) and more convenient operation (no requirement for nitrogen protection).     

有机-无机杂化材料负载的钯催化剂: 一种新型有效而可循环的无铜Sonogashira偶联反应

本文报道了有机-无机杂化材料固载的钯催化的无铜Sonogashira偶联反应。在3-[N,N-双（二苯基膦）氨基）]丙基功能化的硅胶固载的钯催化下,末端炔烃和碘代芳烃、溴代芳烃的偶联反应生成高产率相应的偶联产物。反应条件包括使用乙二醇为溶剂,三乙胺为碱。而且硅胶负载的膦钯催化剂和溶剂乙二醇经简单处理,可循环使用6次不降低活性。     

A novel imidazolium‐supported palladium–chloroglycine complex: copper‐ and solvent‐free high‐turnover catalysts for the Sonogashira coupling reaction

A novel, effective 1‐glycyl‐3‐methyl imidazolium chloride–palladium(II) complex ([Gmim]Cl–Pd(II)) was synthesized and studied as an organocatalyst for the Sonogashira coupling reaction under solvent‐free conditions at 25 °C. The hydrophobic group on amino acid favors reagent diffusion toward the chloroglycine moiety, increasing the catalytic activity of supported palladium complex. By this protocol, different aryl halides (Cl, Br and I) were reacted with phenylacetylene in good to excellent yields with turnover number 8.0 × 10² to 9.6 × 10². The catalyst was recycled for the reaction of bromobenzene with phenylacetylene for eight runs without appreciable loss of its catalytic activity and negligible metal leaching. Copyright © 2012 John Wiley & Sons, Ltd.     

Well‐Defined N‐Heterocyclic Carbene‐Palladium Complexes as Efficient Catalysts for Domino Sonogashira Coupling/Cyclization Reaction and C‐H bond Arylation of Benzothiazole

Well‐defined and air‐stable PEPPSI (Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) themed palladium bis‐N‐heterocyclic carbene complexes have been developed for the domino Sonogashira coupling/cyclization reaction of 2‐iodophenol with a variety of terminal alkynes and C‐H bond arylation of benzothiazole with aryl iodides. The PEPPSI themed palladium complexes, 2a and 2b were synthesized in good yields from the reaction of corresponding imidazolium salts with PdCl₂ and K₂CO₃ in pyridine. The new air‐stable palladium‐NHC complexes were characterized by NMR spectroscopy, X‐ray crystallography, elemental analysis, and mass spectroscopy studies. The PEPPSI themed palladium(II) bis‐N‐heterocyclic carbene complexes 2a and 2b exhibited excellent catalytic activities for domino Sonogashira coupling/cyclization reaction of 2‐iodophenol with terminal alkynes yielding benzofuran derivatives. In addition, the palladium complexes, 2a and 2b successfully catalyzed the direct C‐H bond arylation of benzothiazole with aryl iodides as coupling partners in presence of CuI as co‐catalyst.     

Nano tetraimine Pd(0) complex as an efficient catalyst for phosphine‐free Suzuki reaction in water and copper‐free Sonogashira reaction under aerobic conditions

A nano tetraimine Pd(0) complex catalyst was successfully used as an efficient heterogeneous catalyst for the phosphine‐free palladium‐catalysed Suzuki coupling reaction in water at 80 °C. This nano tetraimine Pd(0) complex was also used for copper‐free Sonogashira reaction in dimethylformamide at 100 °C. The catalyst was easily recovered from the reaction mixture by centrifugation and reused for at least six cycles without any significant loss in its catalytic activity. Analysis of the reaction mixture using inductively coupled plasma analysis showed that leaching of palladium from the catalyst was negligible. The reactions can be performed efficiently for aryl iodides, bromides and also chlorides. Copyright © 2016 John Wiley & Sons, Ltd.     

Nano palladium supported on high‐surface‐area metal–organic framework MIL‐101: an efficient catalyst for Sonogashira coupling of aryl and heteroaryl bromides with alkynes

Palladium nanoparticle‐incorporated metal–organic framework MIL‐101 (Pd/MIL‐101) was successfully synthesized and characterized using X‐ray diffraction, nitrogen physisorption, X‐ray photoelectron, UV–visible and infrared spectroscopies, and transmission electron microscopy. The characterization techniques confirmed high porosity and high surface area of MIL‐101 and high stability of nano‐size palladium particles. Pd/MIL‐101 nanocomposite was investigated for the Sonogashira cross‐coupling reaction of aryl and heteroaryl bromides with various alkynes under copper‐free conditions. The reusability of the catalyst was tested for up to four cycles without any significant loss in catalytic activity. Copyright © 2015 John Wiley & Sons, Ltd.     

Dppc+PF6−–PdCl2–[bmim][PF6]–a copper‐free recyclable catalytic system for Sonogashira coupling reaction

An air‐stable, copper‐free and highly efficient Dppc⁺PF₆^?–PdCl₂–[bmim][PF₆] catalytic system has been developed for the Sonogashira coupling reaction of aryl iodides with various aryl‐ and alkylacetylenes. The catalytic system allows for facile separation and can be recycled at least eight times with minimal loss of activity. Copyright © 2007 John Wiley & Sons, Ltd.     

Palladium nanoparticles immobilized on EDTA‐modified Fe3O4@SiO2 nanospheres as an efficient and magnetically separable catalyst for Suzuki and Sonogashira cross‐coupling reactions

In this study, a novel heterogeneous palladium catalyst was synthesized by anchoring palladium onto ethylenediaminetetraacetic acid (EDTA)‐coated Fe₃O₄@SiO₂ magnetic nanocomposite and used for the Suzuki and Sonogashira cross‐coupling reactions. The properties of the magnetic catalyst were characterized by FT‐IR, XRD, TEM, FE‐SEM, DLS EDX, XPS, N₂ adsorption‐desorption isotherm analysis, TGA, VSM, elemental analysis and the loading level of Pd in catalyst was measured to be 0.51 mmol/g by ICP. The catalyst was used in Suzuki cross‐coupling reactions of various aryl halides, including less reactive chlorobenzenes with phenylboronic acid without any additive or ligand under green conditions. Furthermore, we have reported this recyclable catalytic system for Sonogashira cross‐coupling reactions of various aryl halides (I, Br, Cl) under copper and ligand‐free conditions in the presence of DMF/H₂O (1:2/v:v) as a solvent. The magnetic catalyst could also be separated by an external magnet and reused six times without any significant loss of activity.     

Synthesis of 1‐Aryl‐1H‐indazoles via a Ligand‐Free Copper‐ Catalyzed Intramolecular Amination Reaction

A general synthesis of 1‐aryl‐1‐H‐indazoles from o‐halogenated aryl aldehydes or ketones and aryl hydrazines was described. This protocol included an intermolecular condensation and a ligand‐free copper‐catalyzed intramolecular Ullmann‐type coupling reaction. This method was applied to a wide range of substrates to produce the indazole products in good yields.     

Highly modulated bisindoles: ligands for copper‐catalyzed Sonogashira reaction

Bisindoles (BIMs) were modulated as powerful N,N′ donor ligands for the copper‐catalyzed Sonogashira reaction. Ligand screening experiments on 11 BIM compounds found that 3,3′‐(4‐chlorophenyl)methylenebis(1‐methyl‐1H‐indole) (10%) efficiently accelerated CuCl (5%)‐catalyzed cross‐coupling of aryl iodides with terminal alkynes. A wide range of substituted aryl iodides and/or alkyl‐ and aryl‐substituted terminal alkynes were examined, leading to the corresponding coupling products with yields up to 99%. An efficient and scalable protocol for the synthesis of BIM ligands on a gram scale, with extremely low catalyst loading of o‐ClC₆H₄NH₃⁺Cl^?, was also developed with a reaction time of 20 min with yields up to 93%. This novel N,N′ ligand was air‐stable, easily available and highly modulated with low copper loading. Copyright © 2016 John Wiley & Sons, Ltd.     

Palladium‐mediated synthesis of novel nimesulide derivatives

Synthesis of a series of compounds structurally related to the anti‐inflammatory agent nimesulide has been accomplished via Pd‐catalyzed C? C bond forming reactions. Thus 4‐iodo derivative, prepared from nimesulide, participated in Sonogashira (copper‐free), Heck and Suzuki coupling reactions to afford the corresponding alkynyl, alkenyl and aryl substituted products. Some of the compounds synthesized were tested for anti‐inflammatory activities in vivo. Copyright © 2010 John Wiley & Sons, Ltd.     

Cobalt‐Catalyzed Intermolecular C(sp2)O Cross‐Coupling

Cobalt(II)‐catalyzed C(sp²)?O cross‐coupling between aryl/heteroaryl alcohols and vinyl/aryl halides in the presence of Cu^I has been achieved under ligand‐free conditions. In this reaction, copper plays a significant role in transmetalation rather than being directly involved in the C?O coupling. This unique Co/Cu‐dual catalyst system provides an easy access to a library of aryl–vinyl, heteroaryl–styryl, aryl–aryl, and heteroaryl–heteroaryl ethers in the absence of any ligand or additive.     

Efficient Synthesis of Substituted 3‐Azabicyclo[3.1.0]hexan‐2‐ones from 2‐Iodocyclopropanecarboxamides Using a Copper‐Free Sonogashira Coupling

The copper‐free Sonogashira coupling between N‐substituted cis‐ 2‐iodocyclopropanecarboxamides and terminal aryl‐, heteroaryl‐alkynes or enynes, followed by 5‐exo‐dig cyclization of the nitrogen amide onto the carbon–carbon triple bond, provides a remarkably efficient access to a variety of substituted 4‐methylene‐3‐azabicyclo[3.1.0]hexan‐2‐ones in excellent yields. Protonation of these latter enamides generates bicyclic N‐acyliminium ions that can be involved in Pictet–Spengler cyclizations leading to new 3‐azabicyclo[3.1.0]hexan‐2‐ones, possessing a quaternary stereocenter at C4, with high diastereoselectivities. This strategy constitutes an attractive complementary alternative to the classical route that relies on the addition of organometallic reagents to cyclopropyl imides.