Facile synthesis of alkynyl‐, aryl‐ and ferrocenyl‐substituted pyrazoles via Sonogashira and Suzuki–Miyaura approaches

A concise and efficient synthesis of densely substituted novel pyrazoles with alkynyl, aryl and ferrocenyl functionalities is reported, providing a platform for biological studies. The general strategy involves Sonogashira and Suzuki–Miyaura cross‐coupling reactions of easily obtainable 5‐ferrocenyl/phenyl‐4‐iodo‐1‐phenylpyrazoles with terminal alkynes and boronic acids, respectively. The starting 4‐iodopyrazoles were synthesized by electrophilic cyclization of α,β‐alkynic hydrazones with molecular iodine. Sonogashira reactions have been achieved by employing 5 mol% PdCl₂(PPh₃)₂, 5 mol% CuI, excess Et₃N and 1.2 equiv. of terminal alkyne, relative to 4‐iodopyrazole, in tetrahydrofuran at 65 °C, while Suzuki–Miyaura reactions have been accomplished using 5 mol% PdCl₂(PPh₃)₂ and 1.4 equiv. of both boronic acid/ester and KHCO₃, with respect to 4‐iodopyrazole, in 4:1 dimethylformamide–H₂O solution at 110 °C. Both Sonogashira and Suzuki–Miyaura coupling reactions have proven effective for the synthesis of alkynyl‐, aryl‐ and ferrocenyl‐substituted pyrazoles and demonstrated good tolerance to a diverse range of substituents, including electron‐donating and electron‐withdrawing groups. These coupling approaches could allow for the rapid construction of a library of functionalized pyrazoles of pharmacological interest. Copyright © 2016 John Wiley & Sons, Ltd.     

Rotation‐Locked 2,6‐Pyrido‐allenophanes: Characterization of all Stereoisomers

New 2,6‐disubstituted pyrido‐allenophanes with locked rotation of aromatic spacers were designed and synthesized. The synthesis was accomplished by Pd‐catalyzed C(sp²)–C(sp) Sonogashira cross‐coupling reaction between 1,3‐diethynylallene (DEA) and 2,6‐dibromopyridine followed by an intermolecular ring closure. Because racemic DEA was employed, pyrido‐allenophanes were obtained as mixtures of stereoisomers that were resolved by preparative HPLC. The conformational space of all these diastereoisomers was explored at the CAM‐B3LYP/6‐31+G*//AM1 level of theory. The isomers were characterized through their symmetry properties revealed in NMR, circular dichroism, and chiral stationary‐phase HPLC experiments. X‐ray diffraction was used to assign and to corroborate the configuration of several diastereoisomers. The unexpected encapsulation of two molecules of CHCl₃ in the crystal structures shows the potential of these conformationally hampered allenophanes as encapsulating hosts.     

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.     

Copper(II)‐Catalyzed Tandem Synthesis of Substituted 3‐Methyleneisoindolin‐1‐ones

An efficient strategy for the synthesis of a variety of 3‐methyleneisoindolin‐1‐ones has been developed. The reaction proceeded from coupling of 2‐iodobenzamides (or 2‐bromobenzamides) and terminal alkynes via Cu(OAc)₂·H₂O/2,2′‐biimidazole catalyzed in DMF at 60°C and subsequent additive cyclization produced substituted 3‐methyleneisoindolin‐1‐ones in good to excellent yields.     

Synthesis,characterization, and preceramic properties of π‐conjugated polymers based on Ni(II) complexes of goedken's macrocycle

Nickel(II) complexes of Goedken's macrocycle bearing alkyne substituents were copolymerized with 2,7‐dibromo‐9,9‐dihexylfluorene, 2,5‐dibromo‐3‐hexylthiophene, and 1,4‐dibromo‐2,5‐bis(hexyloxy)benzene via microwave‐induced Sonogashira cross‐coupling reactions to produce copolymers 6F , 6T , and 6B . The spectroscopic and electrochemical properties of the copolymers were examined and compared to model compounds. Specifically, each polymer exhibited a nickel‐based absorption centered at about 589 nm and two π → π* transitions between 272 and 387 nm. While the copolymers did not exhibit extended π conjugation, the nature of the organic spacer did affect the high energy transitions. Furthermore, each copolymer underwent two ligand‐based one‐electron oxidations at potentials of about 0.24 V and about 0.75 V relative to the ferrocene/ferrocenium redox couple. Postpolymerization functionalization of the alkyne group in 6F with Co₂(CO)₈ afforded a novel heterobimetallic copolymer that yielded amorphous nanomaterials containing Ni/Co when pyrolyzed at 800 °C for 3 h under an atmosphere of N₂/H₂ (95:5). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3257–3266     

A highly selective synthesis of 1‐substituted (E)‐buta‐1,3‐dienes with 4,4,5,5‐tetramethyl‐2‐vinyl‐1,3,2‐dioxaborolane as building block

Highly selective synthesis of 1‐substituted (E)‐buta‐1,3‐dienes via palladium‐catalyzed Suzuki–Miyaura cross‐coupling of (E)‐alkenyl iodides with 4,4,5,5‐tetramethyl‐2‐vinyl‐1,3,2‐dioxaborolane ( 1 ) is reported. The vinylboronate pinacol ester ( 1 ) acts as a vinyl building block to show high chemoselectivity for the Suzuki–Miyaura pathway versus Heck coupling in the presence of biphasic conditions (Pd(PPh₃)₄, aqueous K₂CO₃, toluene and ethanol). Copyright © 2014 John Wiley & Sons, Ltd.     

2,5‐Bis(2‐(diphenylphosphino)phenyl)‐1,3,4‐oxadiazole ligands and their Cu(I) complexes for Sonogashira coupling reaction

Two diphosphane ligands – 2,5‐bis(2‐(diphenylphosphino)‐5‐R)phenyl)‐1,3,4‐oxadiazole ( L1 , R = H, L2 , R = OMe) and their binuclear complexes, L1Cu and L2Cu , were prepared and characterized. The molecular structures of L1Cu and L2Cu , as perchlorate salts, were established by X‐ray crystallography, which showed them to be binuclear complexes with each Cu atom tetrahedrally coordinated by two P atoms and two N atoms. The ligands and their Cu(I) complexes catalyzed Sonogashira coupling reactions of iodobenzene with phenylacetylene in the presence of K₂CO₃ under Pd‐free conditions. Coupling reactions catalyzed by L1 or L2 with Cu(MeCN)₄ClO₄ in situ exhibited better yields than those by the corresponding Cu(I) complexes L1Cu or L2Cu . Detailed studies showed L1 or L2 with Cu(MeCN)₄ClO₄ to be suitable catalysts for the coupling reaction of terminal alkynes and aryl halides. The coupling reactions of aryl iodides with electron‐withdrawing groups showed better results. Copyright © 2014 John Wiley & Sons, Ltd.     

HAp‐encapsulated γ‐Fe2O3‐supported dual acidic heterogeneous catalyst for highly efficient one‐pot synthesis of benzoxanthenones and 3‐pyranylindoles

A novel method is reported for the synthesis of benzoxanthenone and 3‐pyranylindole derivatives via one‐pot three‐component reactions using a newly synthesized HAp‐encapsulated γ‐Fe₂O₃‐supported dual acidic heterogeneous catalyst, as a reusable and highly efficient nanocatalyst. In this protocol the use of the nanocatalyst provided a green, useful and rapid method to generate products in short reaction times (4–20 min) and in excellent yields (87–96%). The paramagnetic nature of the catalyst provided a simple, trouble‐free and facile approach for the separation of the catalyst by applying an external magnet, and it could be used in eight cycles without significant loss in catalytic efficiency.     

由(E)-β-碘代烯基砜和末端炔合成多取代的1,3-烯炔

通过(E)-b-碘代烯基砜与末端炔的Sonogashira偶联反应,以中等到良好的产率合成了磺酰基取代的1,3-烯炔。在NiCl2(PPh3)2催化下,产物与格氏试剂发生脱磺酰基偶联反应,磺酰基被进一步转化为不同的取代基。     

Mechanistic Insights into Copper‐Catalyzed Sonogashira–Hagihara‐Type Cross‐Coupling Reactions: Sub‐Mol % Catalyst Loadings and Ligand Effects

An efficient catalytic system for Sonogashira–Hagihara‐type reactions displaying ligand acceleration in the copper‐catalyzed formation of C(sp²)? C(sp) bonds is described. The structure of the ligand plays a key role for the coupling efficiency. Various copper sources show excellent catalytic activity, even in sub‐mol % quantities. A wide variety of substituents is tolerated in the substrates. Mechanistic details have been revealed by kinetic measurements and DFT calculations.     

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).     

Iridium(I)‐catalyzed C−H Borylation of α,β‐Unsaturated Esters with Bis(pinacolato)diboron

A new process has been developed for the iridium(I)‐catalyzed vinylic C?H borylation of α,β‐unsaturated esters with bis(pinacolato)diboron (B₂pin₂). These reactions proceeded in octane at temperatures in the range of 80–120 °C to afford the corresponding alkenylboronic compounds in high yields with excellent regio‐ and stereoselectivities. The presence of an aryl ester led to significant improvements in the yields of the acyclic alkenylboronates. Crossover experiments involving deuterated substrates as well as a mixture of stereoisomers confirmed that this reaction proceeds via a 1,4‐addition/β‐hydride elimination mechanism. Notably, this reaction was also used to develop a one‐pot borylation/Suzuki–Miyaura cross‐coupling procedure.     

Highly stable magnetically separable copper nanocatalyst as an efficient catalyst for C(sp2)–C(sp) and C(sp2)–C(sp2) cross‐coupling reactions

A copper catalyst has been explored as an efficient and recyclable catalyst to effect Sonogashira and Suzuki cross‐coupling reactions. After modification of 2‐(((piperazin‐1‐ylmethyl)imino)methyl)phenol (PP) on the surface of amorphous silica‐coated iron oxide (Fe₃O₄@SiO₂@Cl) magnetic core–shell nanocomposite, copper(II) chloride was employed to synthesize the Fe₃O₄@SiO₂@PP‐Cu catalyst, affording a copper loading of 1.52 mmol g⁻¹. High yield, low reaction times, non‐toxicity and recyclability of the catalyst are the main merits of this protocol. The catalyst was characterized using Fourier transform infrared, X‐ray photoelectron, energy‐dispersive X‐ray and inductively coupled plasma optical emission spectroscopies, X‐ray diffraction, scanning and transmission electron microscopies, and vibrating sample magnetometry.     

Supramolecular photocatalyst of Palladium (II) Encapsulated within Dendrimer on TiO2 nanoparticles for Photo‐induced Suzuki‐Miyaura and Sonogashira Cross‐Coupling reactions

In this study, synthesis, characterization and catalytic performance of a novel supramolecular photocatalytic system including palladium (II) encapsulated within amine‐terminated poly (triazine‐triamine) dendrimer modified TiO₂ nanoparticles (Pd (II) [PTATAD] @ TiO₂) is presented. The obtained nanodendritic catalyst was characterized by FT‐IR, ICP‐AES, XPS, EDS, TEM, TGA and UV‐DRS. The as‐prepared nanodendritic catalyst was shown to be highly active, selective, and recyclable for the Suzuki–Miyaura and Sonogashira cross‐coupling of a wide range of aryl halides including electron‐rich and electron‐poor and even aryl chlorides, affording the corresponding biaryl compounds in good to excellent yields under visible light irradiation. This study shows that visible light irradiation can drive the cross‐coupling reactions on the Pd (II) [PTATAD] @ TiO₂ under mild reaction conditions (27–30 °C) and no additional additives such as cocatalysts or phosphine ligands. So, we propose that the improved photoactivity predominantly benefits from the synergistic effects of Pd (II) amine‐terminated poly (triazine‐triamine) dendrimer on TiO₂ nanoparticles that cause efficient separation and photogenerated electron–hole pairs and photoredox capability of nanocatalyst which all of these advantages due to the tuning of band gap of catalyst in the visible light region.     

Hiyama cross‐coupling reaction using Pd(II) nanocatalyst immobilized on the surface of Fe3O4@SiO2

We report a simple process for the synthesis of Fe₃O₄@SiO₂/APTMS (APTMS = 3‐aminopropyltrimethoxysilane) core–shell nanocatalyst support. The new nanocatalyst was prepared by stabilization of Pd(cdha)₂ (cdha = bis(2‐chloro‐3,4‐dihydroxyacetophenone)) on the surface of the Fe₃O₄@SiO₂/APTMS support. The structure and composition of this catalyst were characterized using various techniques. An efficient method was developed for the synthesis of a wide variety of biaryl compounds via fluoride‐free Hiyama cross‐coupling reactions of aryl halides with arylsiloxane, with Fe₃O₄@SiO₂/APTMS/Pd(cdha)₂ as the catalyst under reaction conditions. This methodology can be performed at 100°C through a simple one‐pot operation using in situ generated palladium nanoparticles. High catalytic activity, quick separation of catalyst from products using an external magnetic field and use of water as green solvent are attributes of this protocol.     

Palladium‐Catalyzed Annulation of 1,2‐Diborylalkenes and ‐Arenes with 1‐Bromo‐2‐[(Z)‐2‐bromoethenyl]arenes: A Modular Approach to Multisubstituted Naphthalenes and Fused Phenanthrenes

(Z)‐1,2‐Diaryl‐1,2‐bis(pinacolatoboryl)ethenes underwent double‐cross‐coupling reactions with 1‐bromo‐2‐[(Z)‐2‐bromoethenyl]arenes in the presence of [Pd(PPh₃)₄] as a catalyst and 3 M aqueous Cs₂CO₃ as a base in THF at 80 °C. The double‐coupling reaction gave multisubstituted naphthalenes in good to high yields. Annulation of 1,2‐bis(pinacolatoboryl)arenes with bromo(bromoethenyl)arenes in the presence of a catalyst system that consisted of [Pd₂(dba)₃] (dba=dibenzylideneacetone) and 2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl (SPhos) under the same conditions produced fused phenanthrenes in good to high yields. The first annulation coupling occurred regiospecifically at the bromoethenyl moiety. This procedure is applicable to the facile synthesis of polysubstituted anthracenes, benzothiophenes, and dibenzoanthracenes through a double annulation pathway by using the corresponding dibromobis[(Z)‐2‐bromoethenyl]benzenes as diboryl coupling partners.     

Synthesis of α‐(Fluorophenyl)pyridine by Palladium‐Catalyzed Cross‐Coupling Reaction

A series of α‐(fluoro‐substituted phenyl)pyridines have been synthesized by means of a palladium‐catalyzed cross‐coupling reaction between fluoro‐substituted phenylboronic acid and 2‐bromopyridine or its derivatives. The reactivities of the phenylboronic acids containing di‐ and tri‐fluoro substituents with α‐pyridyl bromide were investigated in different catalyst systems. Unsuccessful results were observed in the Pd/C and PPh₃ catalyst system due to phenylboronic acid containing electron‐withdrawing F atom(s). For the catalyst system of Pd(OAc)₂/PPh₃, the reactions gave moderate yields of 55% –80%, meanwhile, affording 10% –20% of dimerisation (self‐coupling) by‐products, but trace products were obtained in coupling with 2,4‐difluorophenylboronic acids because of steric hinderance. Pd(PPh₃)₄ was more reactive for boronic acids with sterically hindering F atom(s), and the coupling reactions gave good yields of 90% and 91% without any self‐coupling by‐product.     

Synthesis of Potentially Biologically Active 6‐(1,3‐Butadiynyl)purines

1,3‐Alkadiynyl(trimethyl)silanes were prepared by the Negishi or Sonogashira reactions of bromoethynyl(trimethyl)silane with several terminal alkynes in 34–75% yield. However, the direct Hiyama coupling of these compounds with 6‐iodopurine derivatives has not been successful. Therefore, a modified Sonogashira reaction using TBAF or CsF for in situ removal of the trimethylsilyl group has been utilized. This methodology afforded the desired 6‐(1,3‐butadiynyl)purines in 47–87% yield.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Reactions of rac‐(ebthi)M(η2‐Me3SiC2SiMe3) (M=Ti,Zr) with Aryl Nitriles

The reactions of the Group 4 metallocene alkyne complexes rac‐(ebthi)M(η²‐Me₃SiC₂SiMe₃) ( 1 a : M=Ti, 1 b : M=Zr; rac‐(ebthi)=rac‐1,2‐ethylene‐1,1′‐bis(η⁵‐tetrahydroindenyl)) with Ph?C?N were investigated. For 1 a , an unusual nitrile–nitrile coupling to 1‐titana‐2,5‐diazacyclopenta‐2,4‐diene ( 2 ) at ambient temperature was observed. At higher temperature, the C?C coupling of two nitriles resulted in the formation of a dinuclear complex with a four‐membered diimine bridge ( 3 ). The reaction of 1 b with Ph?C?N afforded dinuclear compound 4 and 2,4,6‐triphenyltriazine. Additionally, the reactivity of 1 b towards other nitriles was investigated.