Pd-mBDPP-catalyzed regioselective internal arylation of electron-rich olefins by aryl halides

meso-2,4-Bis(diphenylphosphino)pentane (mBDPP) has proved to be an effective regiocontrolling ligand for palladium-catalyzed internal arylation by aryl bromides of electron-rich olefins in a common solvent DMSO with no need for any halide scavengers. The arylation of the benchmark electron-rich olefin butyl vinyl ether took place smoothly to afford exclusively alpha-arylated product with high isolated yields. The better performance of mBDPP, compared with that of the commonly used DPPP [1,3-bis(diphenylphosphino)propane], highlights the important but subtle effect of ligand on the regioselectivity of the Heck arylation reactions.     

Palladium-catalyzed highly regioselective Heck reaction of aryl nonaflates with electron-rich olefins

Highly efficient palladium-catalyzed Heck coupling of aryl nonaflates with electron-rich vinyl ethers, and enamides is described. These reactions afforded exclusively the branched products in good yields. The results indicated that aryl nonaflates are effective alternative to the frequently employed aryl triflates.     

A general method for regioselective Heck arylation of electron-rich N-acyl-N-vinylamine with aryl halides

A highly efficient protocol for the Pd-catalyzed regioselective Heck arylation of the electron-rich olefin N-acyl-N-vinylamine with aryl halides has been developed. In the presence of hydrogen-bond donor [H₂NiPr₂][BF₄] as an additive, this proceeds smoothly in isopropanol to afford exclusively the branched products in high yields.     

Palladium-catalyzed regioselective Heck arylation of electron-rich olefins in a molecular solvent-ionic liquid cocktail

We have recently established that highly regioselective Heck arylation of electron-rich olefins can be accomplished with aryl halides without using any halide scavengers in imidazolium ionic liquid solvents. The results presented in this paper show that the benchmark electron-rich olefins vinyl ethers can be readily arylated by aryl bromides in a molecular solvent-ionic liquid cocktail with no compromise on regioselectivity. By introducing a small amount of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF₄]) to DMSO, the arylation reactions of the vinyl ethers 1a-d by the bromides 2a-j took place to afford essentially only the α arylated products. The enamide 1e underwent similar regioselective arylation in the solvent cocktail. In the absence of the ionic liquid, lower regioselectivities were observed. In comparison with the chemistry we have reported so far, the current method reduces considerably the reliance on the volume of ionic liquids used, providing a simpler and more practical synthetic pathway for preparing arylated vinyl ethers and aryl methyl ketones.     

Hydrogen-bond-directed catalysis: faster, regioselective and cleaner Heck arylation of electron-rich olefins in alcohols

A general method for the regioselective Heck reaction of electron-rich olefins is presented. Fast, highly regioselective Pd-catalysed alpha-arylation of electron-rich olefins, vinyl ethers (1 a-d), hydroxyl vinyl ethers (1 e, f), enamides (1 g, h) and a substituted vinyl ether (1i) has been accomplished with a diverse range of aryl bromides (2 a-r), for the first time, in cheap, green and easily available alcohols with no need for any halide scavengers or salt additives. The reaction proceeds with high efficiency, leading exclusively to the alpha-products, in 2-propanol and particularly in ethylene glycol. In the latter, the arylation can be catalysed at a palladium loading of 0.1 mol% and finish in as short a time as 0.5 h. The remarkable performance of the alcohol solvents in promoting alpha regiocontrol is attributed to their hydrogen-bond-donating capability, which is believed to facilitate the dissociation of halide anions from PdII, and hence, the generation of a key ionic PdII-olefin intermediate responsible for the alpha product. This belief is further strengthened by the study of a benchmark arylation reaction in 21 different solvents. The study revealed that exclusive alpha-regioselective arylation takes place in almost all of the protic solvents, and there is a rough correlation between the alpha-arylation rates and the solvent parameter E(T)N. The method is simpler, cleaner and more general than those established thus far.     

Highly regioselective Heck reactions of heteroaryl halides with electron-rich olefins in ionic liquid

Palladium-catalyzed Heck reactions of the heteroaryl halides, halopyridines, bromoquinoline and bromothiophenes, with the electron-rich olefins vinyl ethers and allyl alcohol were shown to give essentially only the branched olefins in an imidazolium ionic liquid, whereas in molecular solvents a mixture of regioisomers was formed. The method obviates the need for aryl triflates and stoichiometric inorganic salt additives, providing an easy entry to functionalized heteroaromatics incorporating acetyl and 2-allyl alcohol functionalities.     

Palladium-catalyzed highly regioselective and stereoselective arylation of electron-rich allylamines with aryl bromides

A palladium-catalyzed, highly efficient Heck arylation of electron-rich N,N-diprotected allylamine derivatives with a wide range of aryl bromides under ligand-free conditions has been developed. In the presence of Pd(OAc)₂ and an appropriate additive, the reaction proceeds with excellent regioselectivity and stereoselectivity, leading exclusively to the γ-arylated (E)-allylamine products in good to excellent yields. It was found that the choice of solvent, olefin, additive and temperature has an important influence on the reaction. Worthy of note is that good results were observed only when using N,N-diprotected allylamines containing carbamate moiety, and the steric properties of allylamines also have important impacts on the regiocontrol. The use of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or HQ (hydroquinone) as the additive is also crucial for securing a faster reaction rate. This method provides a straightforward approach for the efficient synthesis of various γ-arylated, linear (E)-allylamines.     

Palladium-catalyzed highly regioselective and stereoselective decarboxylative arylation of unactivated olefins with aryl carboxylic acids

Palladium(II)-catalyzed highly regioselective and stereoselective decarboxylative arylation of unactivated olefins with aryl carboxylic acids has been developed. This method is applicable to a variety of unactivated olefins, including allylamides, long chain functionalized olefins and purely aliphatic olefins, leads to the formation of linear E-configured products in high yields. Both electron-rich and electron-deficient aryl carboxylic acids are suitable arylation reagents. It was found that the choice of solvent, catalyst precursor and oxidant had an important influence on reaction efficiency. As a co-solvent and ligand, DMSO is critical to catalysis. This chemistry expands the scope of decarboxylative arylation of olefins with aryl carboxylic acids, and provides a rapid access to useful linear arylation products of unactivated olefins.     

Transition-metal-free highly chemo- and regioselective arylation of unactivated arenes with aryl halides over recyclable heterogeneous catalysts

A novel heterogeneous catalysis system using metal-organic frameworks as catalyst demonstrated excellent chemo- and regioselectivity for the direct arylation of unactivated arenes with aryl iodides/bromides without the assistance of any transition metals.     

Hydrogen-bonding-promoted oxidative addition and regioselective arylation of olefins with aryl chlorides

The first, general, and highly efficient catalytic system that allows a wide range of activated and unactivated aryl chlorides to couple regioselectively with olefins has been developed. The Heck arylation reaction is likely to be controlled by the oxidative addition of ArCl to Pd(0). Hence, an electron-rich diphosphine, 4-MeO-dppp, was introduced to facilitate the catalysis. Solvent choice is critical, however; only sluggish arylation is observed in DMF or DMSO, whereas the reaction proceeds well in ethylene glycol at 0.1-1 mol % catalyst loadings, displaying excellent regioselectivity. Mechanistic evidence supports that the arylation is turnover-limited by the oxidative addition step and, most importantly, that the oxidative addition is accelerated by ethylene glycol, most likely via hydrogen bonding to the chloride at the transition state as shown by DFT calculations. Ethylene glycol thus plays a double role in the arylation, facilitating oxidative addition and promoting the subsequent dissociation of chloride from Pd(II) to give a cationic Pd(II)-olefin species, which is key to the regioselectivity observed.     

Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water

Highly regioselective and fast Pd(0)-catalyzed internal alpha-arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water without the need for any halide scavengers or ionic liquid additives. This presents, to our knowledge, the first case of water being utilized in the selective arylation of electron-rich olefins. Resulting alpha-products were hydrolyzed and isolated as corresponding acetophenones in good to excellent yields when using aryl bromides and with good to moderate yields in the case of aryl iodides. Microwave irradiation was shown to be beneficial in activation of aryl chlorides toward the internal Heck arylation. The scope of the protocol was further increased to include different hydroxyalkyl vinyl ethers, these all giving selectively only branched alpha-products. Finally, the active role of the hydroxy group in directing the regioselectivity toward internal arylation of electron-rich olefins, even in nonpolar toluene, was revealed.     

The first MCM-41-supported thioether palladium(0) complex: A highly active and stereoselective catalyst for Heck arylation of olefins with aryl halides

The first MCM-41-supported thioether palladium(0) complex has been synthesized from 3-(2-cyanoethylsulfanyl)propyltriethoxysilane via immobilization on MCM-41, followed by reacting with palladium chloride, and then the reduction with hydrazine hydrate. It was found that this complex has not only high activity and stereoselectivity for arylation reaction of conjugated alkenes with aryl iodides or activated aryl bromides, but also can efficiently catalyze the arylation reaction of conjugated alkenes with unactivated bromoarenes. This polymeric palladium catalyst can be easily recovered from the products and reused at least 10 times without loss of activity.     

Palladium-catalyzed arylation of electron-rich heterocycles with aryl chlorides

[reaction: see text] Palladium-catalyzed C-H activation: cheap aryl chlorides can now be used for the arylation of a wide variety of electron-rich heterocycles. The key to the success of this reaction is the use of a bulky, electron-rich phosphine ligand. No copper additives are needed.     

Mild and efficient nickel-catalyzed Heck reactions with electron-rich olefins

A new efficient protocol for the nickel-catalyzed Heck reaction of aryl triflates with vinyl ethers is presented. Mild reaction conditions that equal those of the corresponding palladium-catalyzed Heck reaction are applied, representing a practical and more sustainable alternative to the conventional regioselective arylation of vinyl ethers. A catalytic system comprised of Ni(COD)(2) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) in combination with the tertiary amine Cy(2)NMe proved effective in the olefination of a wide range of aryl triflates. Both electron-deficient and electron-rich arenes proved compatible, and the corresponding aryl methyl ketone could be secured after hydrolysis in yields approaching quantitative. Good functional group tolerance was observed matching the characteristics of the analogous Pd-catalyzed Heck reaction. The high levels of catalytic activity were explained by the intermediacy of a cationic nickel(II) complex potentially responsible for the successive β-hydride elimination and base promoted catalyst regeneration. Although these elementary reactions are normally considered challenging, DFT calculations suggested this pathway to be favorable under the applied reaction conditions.     

Efficient and highly regioselective direct C-2 arylation of azoles, including free (NH)-imidazole, -benzimidazole and -indole, with aryl halides

The Pd- and Cu-mediated reaction of a large variety of π-electron sufficient heteroarenes, which include free (NH)-imidazoles, -benzimidazole and -indole, with aryl iodides under ligandless and base-free conditions provides regioselectively the required 2-arylheterocycle derivatives in high yields. 2-Aryl-1-phenyl-1H-imidazoles can also be prepared by a one-pot domino HALEX and Pd- and Cu-mediated arylation reactions of 1-phenyl-1H-imidazole with activated and unactivated aryl bromides under base-free and ligandless conditions. The protocol for the synthesis of 2-arylazoles involving the use of aryl iodides has been found to be suitable for the efficient preparation of three bioactive compounds and a key intermediate in the synthesis of a heparanase inhibitor.     

Regioselective Heck couplings of alpha,beta-unsaturated tosylates and mesylates with electron-rich olefins

[chemical reaction: see text]. Highly regioselective Heck couplings of alpha,beta-unsaturated tosylate and mesylate derivatives with N-acyl N-vinylamines and vinyl ethers were achieved. Several 2-alkoxy-1,3-dienes and 2-acylamino-1,3-butadienes were synthesized in good yields using 1.5 mol % of Pd2(dba)3, 3 mol % of DPPF, and diisopropylethylamine in dioxane. When working with alpha,beta-unsaturated ketones and esters, this method provides a less costly alternative to similar couplings using a triflate electrophile.     

Palladium-catalyzed regiocontrolled internal heteroarylation of electron-rich olefins with heteroaryl halides

A highly efficient palladium-catalyzed Heck coupling reaction of heteroaryl halides with electron-rich vinyl ether and hydroxyalkyl vinyl ethers is described. It was found that the choice of solvent, ligand, and reaction temperature had a fundamental influence on the regioselectivity and reactivity of the reaction, and the combination of Pd(OAc)₂ and DPPF in ethylene glycol led to the most effective catalytic system. Under these conditions, a variety of heteroaryl halides reacted very quickly with electron-rich olefins to afford exclusively the branched products in good to excellent yields without employing triflates, halide scavengers, or ionic liquids.     

Dioxygen-promoted regioselective oxidative heck arylations of electron-rich olefins with arylboronic acids

Arylations of electron-rich heteroatom-substituted olefins were performed with arylboronic acids. This appears to constitute the first example of palladium(II)-catalyzed internal Heck arylations. The novel protocol exploits oxygen gas for environmentally benign reoxidation and a stable 1,10-phenanthroline bidentate ligand to promote the palladium(II) regeneration and to control the regioselectivity. Internal arylation is strongly favored with electron-rich arylboronic acids. DFT calculations support a charge-driven selectivity rationale, where phenyls substituted with electron-donating groups prefer the electron-poor alpha-carbon of the olefin. Experiments, verified by calculations, confirm the cationic nature of the catalytic route. This Heck methodology provides a facile and mild access to functionalized enamides. Controlled microwave heating and increased oxygen pressure were used to further reduce the reaction time to 1 h.     

Palladium-catalyzed direct arylation of nitro-substituted aromatics with aryl halides

Direct arylation reactions of nitrobenzenes and aryl halides occur in good yield and high ortho regioselectivity. These reactions can be performed on gram scale with as few as 3 equiv of the nitro arene relative to the aryl halide. The synthetic utility of this method is demonstrated via rapid synthesis of a Boscalid intermediate.