The Heck-Matsuda arylation of 2-hetero-substituted acrylates

The Heck-Matsuda arylation of 2-aza and 2-oxo-substituted acrylates is described. Several reaction conditions were evaluated including the influence of solvents, temperature, catalysts, and stoichiometry. While the oxygenated system was successfully arylated in benzonitrile with Pd₂(dba)₃ as catalyst, the aza-acrylate furnished methoxylated products. The methoxylated products were subjected to an elimination/reduction protocol to obtain the corresponding N,O-protected phenylalanine derivatives. A one-pot procedure for the preparation of phenylalanine derivatives from 2-aza-substituted acrylates is presented.     

Gold(I)-catalyzed direct C-H arylation of pyrazine and pyridine with aryl bromides

An efficient procedure for the direct C-H arylation of electron-poor aromatics such as pyrazine and pyridine with aryl bomides is described. In the presence of catalytic amount of Cy₃PAuCl and with the use of t-BuOK as base, pyrazine undergoes the direct C-H arylation with aryl bromides at 100 °C, and the yields of the arylated products depend on the nature of aryl bromides. In the cases of electron-rich aryl bromides used, the arylated pyrazines can be obtained in good to high yields. For electron-poor aryl bromides, the addition of AgBF₄ is the crucial point to accelerate the coupling reaction to give the arylated products in moderate yields. Pyridine also reacts with electron-rich aryl bromides catalyzed by Cy₃PAuCl to give a mixture of arylated regioisomers in moderate yield. However, in order to realize the direct C-H arylation of pyridine with electron-poor aryl bromides, the addition of silver salt as additive and a milder reaction temperature (60 °C) are required.     

Palladium-catalysed direct arylations of NH-free pyrrole and N-tosylpyrrole with aryl bromides

The palladium-catalysed direct coupling of aryl halides with pyrroles provides a greener access to arylated pyrroles than more classical couplings such as Suzuki, Stille or Negishi reactions. However, so far, NH-free pyrrole and N-tosylpyrrole gave disappointing results for such couplings either in terms of regioselectivity of the arylation, catalyst loading or substrate scope. The reactivity of both NH-free pyrrole and N-tosylpyrrole was studied, and the tosylated pyrrole led to higher yields of coupling products due to better conversions of the aryl bromides. A range of aryl bromides undergo regioselective coupling at C2 of N-tosylpyrrole in moderate to good yields using 1 mol % [Pd(Cl(C₃H₅)]₂ as the catalyst, KOAc as the base in DMAc.     

N‐Arylation of Heterocycles with Chloro‐ and Fluoroarenes using Resin‐Supported Sulfonato‐Cu(salen) Complex

Sulfonato‐Cu(salen) complex immobilized onto a Merrifield's resin was found to be an efficient catalyst for the N‐arylation of heterocycles with electron‐withdrawing hloro‐ and fluoroarenes. The reactions were carried out in the presence of an inexpensive mild base, K₂CO₃, and N‐arylated compounds were obtained in good to excellent yields. The catalyst was recovered by simple filtration and reused for three cycles with almost consistent activity.     

Native amine-directed site-selective C(sp3)-H arylation of primary aliphatic amines with aryl iodides

Direct C(sp³)-H functionalization of N-unprotected aliphatic amines represents one of the most efficient and straightforward strategies for amine synthesis. Despite some recent progress in this field, the NH₂-directed γ-C(sp³)-H arylation of primary aliphatic amines except α-amino esters remained an unmet challenge. In this report, we established a simple and efficient method for site-selective C(sp³)-H arylation of primary aliphatic amines by aryl iodides. In the presence of only 5 mol% Pd(OAc)₂, a wide range of aliphatic amines including O-benzyl and O-silyl amino alcohols were arylated at γ- or δ-positions by aryl iodides containing a broad scope of functional groups. The synthetic application of this method had also been demonstrated by large-scale synthesis, the synthesis of a fingolimod analogue, and the conjugation with natural d-menthol and fluorescent 1,8-naphthalimide.     

Palladium‐catalyzed selective decarboxylative coupling reaction versus direct C―H arylation for arylation of heteroaromatics

Conditions for selective palladium‐catalyzed decarboxylative 2‐arylation of 3‐substituted thiophene and furan derivatives bearing an ester at C2 position have been established. By using 2 mol% phosphine‐free Pd(OAc)₂ as the catalyst and a mixture of KOH and K₂CO₃ as the bases, in dimethylacetamide, moderate to good yields of the desired 2‐arylated products were obtained. A range of functional groups such as nitrile, nitro, formyl or acetyl on the aryl bromides was tolerated. This method allows us to employ in some cases more convenient reactants in terms of cost or physical properties (boiling point) for arylations. Copyright © 2013 John Wiley & Sons, Ltd.     

Ruthenium‐Catalyzed α‐(Hetero)Arylation of Saturated Cyclic Amines: Reaction Scope and Mechanism

Transition‐metal‐catalyzed sp³ C? H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1‐(Pyridin‐2‐yl)piperidine could be smoothly α‐arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru₃(CO)₁₂] and one equivalent of 3‐ethyl‐3‐pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α‐arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru^II? H species.     

Ruthenium-catalyzed arylation of fluorinated aromatic ketones via ortho-selective carbon-fluorine bond cleavage

We report here ruthenium-catalyzed arylation of fluorinated aromatic ketones via ortho-selective carbon-fluorine bond cleavage. In the presence of trimethylvinylsilane and cesium fluoride, ortho carbon-fluoride bonds of aromatic ketones were phenylated by 5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane using RuH₂(CO)(PPh₃)₃ as a catalyst. Tandem C-F phenylation/C-H alkylation was observed for substrates bearing both one ortho hydrogen and one ortho fluorine atoms.     

Palladium‐catalyzed direct arylation of polyfluoroarene and facile synthesis of liquid crystal compounds

A convenient approach has been developed to prepare polyfluorobiphenyl by Pd(OAc)₂/PCy₃‐catalyzed direct arylation of polyfluoroarenes with aromatic halides in the presence of Cs₂CO₃ as base and toluene as solvent. In most cases, the desired arylated products of aromatic bromides were obtained in good to excellent yield at 80°C, and aryl chlorides also gave modest to good yields of arylated products at 110°C. According to this efficient C―C bondforming method, polyfluorobiphenyl liquid crystal compounds were prepared by Pd‐catalyzed direct arylation reactions of polyfluoroarenes with long alkyl chain substituted aryl bromides in 62–96% yield. Copyright © 2014 John Wiley & Sons, Ltd.     

Arenediazonium o-benzenedisulfonimides as efficient reagents for Heck-type arylation reactions

Arenediazonium o-benzenedisulfonimides can be used as new and efficient reagents for Heck-type arylation reactions of some common substrates containing C-C multiple bonds, namely ethyl acrylate, acrylic acid, acroleyne, styrene and cyclopentene. The reactions were carried out in an organic solvent, in the presence of Pd(OAc)₂ as pre-catalyst, and gave rise to arylated products, for example, ethyl cinnamates, cinnamic acids, cinnamic aldehydes and stilbenes, possessing an (E)-configuration, and 1-arylcyclopentenes, in good to excellent yields. It is noteworthy that all the reactions led to the recovery, in greater than 80% yield, of o-benzenedisulfonimide, recyclable for the preparation of other diazonium salts.     

One-pot,solvent-free Pd(II)-catalyzed direct β-C-H arylation of carboxamides involving anhydrides as substrates via in situ installation of directing group

A one-pot, multicomponent-type, solvent-free Pd(II)-catalyzed direct β-C-H activation/arylation of carboxamides involving anhydrides as substrates via in situ installation of directing group (DG) is reported. Typically, the DG-assisted β-C-H activation/arylation of carboxamides is a two-step process comprising the installation of DG and Pd(II)-catalyzed CH arylation. We attempted a multicomponent-type reaction comprising an anhydride, a DG (e.g. 8-aminoquinoline), an aryl iodide in the presence of the Pd(II) catalyst and an appropriate additive. Different anhydrides, DGs, aryl iodides, catalysts and additives were screened to reveal the scope of this multicomponent-type CH arylation reaction process and various β-C-H arylated carboxamides were obtained in satisfactory to good yields.     

Isatin N-protected ketimines with nitromethane catalyzed by chiral binol linked monomeric macrocyclic Cu(II)–salen complex

Chiral Cu-1B generated in situ was used as an efficient catalyst for the synthesis of β-nitroamines in high yield (88%) with excellent enantioselectivity (ee up to 99%) at RT in absence of co-catalyst via asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with nitromethane. This catalytic system did not work well with other nitroalkanes under the above optimized reaction conditions. To examine this catalytic behaviour, quantum chemical DFT calculations were performed with the nucleophiles (CH₂NO₂^? and CH₃CHNO₂^?) for the conversion of 1a to 2a using macrocyclic Cu-1B complex. The DFT calculated results have shown that the reaction with CH₂NO₂^? is more favourable than the corresponding CH₃CHNO₂^?. The calculated activation barriers suggest that the reaction with CH₂NO₂^? is ～8.0?kcal/mol energetically favoured than CH₃CHNO₂^?. This catalytic protocol was further used to obtain chiral β-diamines (a building block for pharmaceuticals) at gram scale. In order to elucidate the reaction mechanism of asymmetric aza Henry reaction kinetic experiments were performed with different concentrations of the catalyst Cu-1B, nitromethane and 1g as the representative substrate. The reaction of isatin N-Boc ketimine was first order with respect to the concentration of the catalyst and the nitromethane but did not depend on the initial concentration of the substrate. A possible mechanism for the aza Henry reaction was proposed.     

Pd/C as a Catalyst for Completely Regioselective CH Functionalization of Thiophenes under Mild Conditions

The completely C3‐selective arylation of thiophenes and benzo[b]thiophenes was achieved by using Pd/C as a heterogeneous catalyst without ligands or additives under mild reaction conditions. The practicability of this transformation is demonstrated by notable functional group tolerance and the insensitivity of the reaction to H₂O and air. This method is also applicable to nitrogen‐ and oxygen‐containing heterocycles, yielding the corresponding C2‐arylated products. Three‐phase tests along with Hg‐poisoning and hot‐filtration tests suggest that the catalytically active species is heterogeneous in nature.     

Catalytic activity of Pd(II) and Pd(II)/DAB-R systems for the Heck arylation of olefins

Palladium-catalyzed reactions of aryl bromides with various olefins involving Pd(II)/diazabutadiene (DAB-R) systems have been investigated. The scope of a coupling process using Pd(II) sources and an α-diimine as ligand in the presence of Cs₂CO₃ as base was tested using various substrates. The Pd(OAc)₂/DAB-Cy (1, DAB-Cy=1,4-dicyclohexyl-diazabutadiene) system presents the highest activity with respect to electron-neutral and electron-deficient aryl bromides in coupling with electron rich olefins. The synthesis and X-ray characterization of a Pd(II)-diazabutadiene ligand is reported. Extensive optimization experiments showed that another Pd(II) source, Pd(acac)₂ (acac=acetylacetonate), proved to activate aryl bromides at high temperatures, low catalyst loadings when the appropriate concentration of ⁿBu₄NBr additive was employed. The effect of the DAB-Cy ligand is important at very low catalyst loadings and high temperatures. Pd(acac)₂ and Pd(acac)₂/DAB-Cy precatalysts were very effective for the arylation of various olefins with aryl bromides with respect to reaction rate, catalyst loadings, and functional group tolerance.     

Substituent effects and stereochemical mechanisms for substitution reactions of 18F for halogen atoms in CF3X, (CH3)3−n CHnX,and CH3X

No thermal substitutions of ¹⁸F for X (X  halogen atom) are observed with CF₃X and (CH₃)_3?nCH_nX substrates in excess SF₆. The absence of thermal yield increasing with weaker CX bond energies, as found with CH₃X substrates, is attributed to the much larger mass versus H of F and CH₃ substituents. The thermal substitution of ¹⁸F/X in CH₃X molecules probably occurs by an inversion mechanism.     

Ligand‐Enabled Auxiliary‐Free meta‐C−H Arylation of Phenylacetic Acids

The meta ‐C−H arylation of free phenylacetic acid was realized using 2‐carbomethoxynorbornene (NBE‐CO₂Me) as a transient mediator. Both the modified norbornene and the mono‐protected 3‐amino‐2‐hydroxypyridine type ligand are crucial for this auxiliary‐free meta ‐C−H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta ‐arylated products in high yields.     

Palladium-catalyzed direct 5-arylation of formyl- or acetyl-halothiophene derivatives

Pd(OAc)₂ was found to catalyze the direct arylation of some functionalized halothiophene derivatives allowing the synthesis in only one step of polyfunctionalized arylated thiophenes. In the presence of 2-acetyl-3-chlorothiophene, 2-acetyl-4-chlorothiophene, 2-acetyl-3-bromothiophene diethylacetal or 2-(4-bromothiophen-2-yl)-[1,3]dioxolane, and a variety of aryl bromides, the 5-arylation products were obtained in moderate to high yields employing only 0.5 mol% catalyst. On the other hand, the use of 2-formyl-3-chlorothiophene, 2-acetyl-3-bromothiophene or 2-formyl-3-bromothiophene gave disappointing results.     

Reactivity of 4‐phenylthiazoles in ruthenium catalyzed direct arylations

The reactivity of the phenyl substituent of 4‐phenylthiazoles in Ru‐catalyzed direct arylation was studied. 4‐Phenylthiazole was found to be unreactive; whereas, the introduction of an aryl unit at C5‐position of 4‐phenylthiazole enhances its reactivity, allowing the selective mono‐arylation of the phenyl unit of 4‐phenylthiazoles in moderate to high yields using 5 mol% of [Ru(p‐cymene)Cl₂]₂ catalyst precursor associated to KOPiv as base. These results reveal that the conformation and electronic properties of 4‐phenylthiazoles are crucial to allow the formation of suitable intermediates in the course of the catalytic cycle. The reaction tolerated both electron‐rich and electron‐poor aryl bromides allowing the straightforward tuning of the electronic properties of the arylated 2‐methyl‐4‐phenyl‐5‐arylthiazoles.     

Recyclable Palladium Catalysts for the Heck/Sonogashira Reaction under Microwave‐assisted Thermomorphic Conditions

The reaction of allyl palladium(II) chloride dimer and 4,4′‐bis(R_fCH₂OCH₂)‐2,2′‐bpy, 1a–b , in the presence of AgOT_f resulted in the synthesis of cationic palladium complex, [Pd(η³‐allyl)(4,4′‐bis‐(R_fCH₂OCH₂)‐2,2′‐bpy)](OT_f), 2a–b where R_f = C₉F₁₉ ( a ), C₁₀F₂₁ ( b ), respectively. The reaction of [PdCl₂(CH₃CN)] or K₂PdCl₄ with 1b , gave rise to the synthesis of [PdCl₂(4,4′‐bis‐(C₁₀F₂₁CH₂OCH₂)‐2,2′‐bpy)], 3b . The quantitatively determined solubility curves of 2a–b and 3b in DMF indicated dramatic increase of solubility for 2a – b and 3b from ?40 to 90 °C. The catalyst‐recoverable Pd‐catalyzed Heck/Sonogashira reactions were successfully achieved in DMF with microwave‐assistance. The cationic Pd‐catalyzed Heck arylation of methyl acrylate was selected to demonstrate the feasibility of recycling 2a–b using DMF as a solvent under microwave‐assisted thermomorphic conditions. At the end of each cycle, the product mixtures were cooled, and then the catalysts were recovered by decantation. The Heck arylation catalyzed by 2b under microwave‐assisted mode exhibited good recycling results favoring the trans product. To our knowledge, this is the first example of cationic Pd‐catalyzed Heck arylation under microwave‐assisted thermomorphic conditions. Additionally, recoverable 3b ‐catalyzed Sonogashira reactions were also achieved successfully in DMF. The reactions under microwave‐assistance gave much better results in yield and in efficiency than that under conventional thermal heating.     

Real-time mid-IR monitoring of metathesis reactions by fiber optic FTIR spectroscopy

The real-time monitoring of metathesis reactions using a recently developed fiber optic transmission FTIR technique is reported in this paper. The ring-opening metathesis polymerization (ROMP) of 1,5-cyclooctadiene, the ring-closing metathesis (RCM) of 1,7-octadiene and the polymerization of phenylacetylene were investigated. The Schrock carbyne complex, Cl₃(dme)WCCMe₃, was used as the catalyst for these reactions. The phenylacetylene polymerization was also studied with WCl₆ as the catalyst. In the ROMP of 1,5-cyclooctadiene, monomer consumption was followed by monitoring the disappearance of the 1486 cm⁻¹ absorbance, characteristic of the CH₂ deformation vibration (δ_s CH₂) in the monomer. In the RCM of 1,7-octadiene, conversion data was obtained by monitoring the 1832 cm⁻¹ signal, which is an overtone of the wagging absorbance at 910 cm⁻¹ of the CH₂ end group in the monomer. Phenylacetylene polymerization was monitored by the disappearance of the ν -CCH stretch signal at 2110 cm⁻¹. Polymerization was much faster with the Schrock catalyst than with WCl₆, but similar conversions were reached in both reactions. Conversion data obtained by the IR technique agreed well with gravimetric product yields.