Palladium-catalysed direct arylations of heteroaromatics using more eco-compatible solvents pentan-1-ol or 3-methylbutan-1-ol

The palladium-catalysed direct coupling of aryl halides with heteroaromatics in greener solvents than DMF or DMAc, which are often employed for such couplings, would be a considerable advantage for both industrial application and sustainable development. We observed that a range of aryl bromides undergoe coupling via C-H bond activation/functionalisation reaction of thiazoles or imidazoles in moderate to good yields using pentan-1-ol or 3-methylbutan-1-ol as the solvents. Pentan-1-ol and 3-methylbutan-1-ol are less toxic than DMF or DMAc, moreover they are bioresources as they can be obtained by fermentation. Therefore, these reaction conditions are certainly more eco-compatible than those generally employed for such couplings.     

Palladium-catalysed direct 3- or 4-arylation of thiophene derivatives using aryl bromides

The palladium-catalysed direct 3- or 4-arylation of 2,5-disubstituted thiophenes using aryl bromides gives a simple access to a variety of 3- or 4-arylthiophene derivatives. Moderate to good yields of 3-arylated thiophenes were obtained using 2,5-dimethylthiophene. In the presence of unsymmetrically disubstituted, 2-acetyl-5-methylthiophene, a regioselective arylation on carbon 4 of thiophene was observed. This reaction provides only HX associated to the base as by-product and reduces the number of steps to prepare these compounds.     

Sonogashira reaction of aryl halides with propiolaldehyde diethyl acetal catalyzed by a tetraphosphine/palladium complex

All-cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ efficiently catalyzes the Sonogashira reaction of propiolaldehyde diethyl acetal with a variety of aryl bromides and chlorides. A minor electronic effect of the substituents of the aryl bromide was observed. Similar reaction rates were observed in the presence of activated aryl bromides such as 4-trifluoromethylbromobenzene and deactivated aryl bromides such as bromoanisole. Turnover numbers up to 95,000 can be obtained for this reaction. Even aryl chlorides and heteroarylbromides or chlorides have been successfully alkynylated with this catalyst. Moreover, a wide variety of substituents on the aryl halide such as fluoro, trifluoromethyl, acetyl, benzoyl, formyl, nitro, dimethylamino or nitrile are tolerated.     

Direct arylation of benzoxazole C-H bonds with iodobenzene diacetates

A Pd (OAc)₂-catalyzed direct arylation of benzoxazole C-H bonds has been achieved with iodobenzene diacetates as the arylation reagent in moderate to good yields. The procedure tolerates a series of functional groups, such as methoxy, nitro, cyano, chloro, and bromo groups.     

Suzuki-Miyaura cross-coupling of aryl and alkyl halides using palladium/imidazolium salt protocols

A simple new protocol for the high yielding Suzuki-Miyaura cross-couplings of aryl chlorides with aryl boronic acids using a palladium/imidazolium salt catalytic system is presented. The first examples of a palladium/imidazolium salt protocol for sp³-sp³ Suzuki-Miyaura couplings of alkyl halides are also disclosed.     

Direct synthesis of 3-arylpropionic acids by tetraphosphine/palladium catalysed Heck reactions of aryl halides with acrolein ethylene acetal

Through the use of [PdCl(C₃H₅)]₂/Cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst, a range of aryl bromides undergoes Heck reaction with acrolein ethylene acetal. With this acetal, the selective formation of 3-arylpropionic acids/esters was observed. The functional group tolerance on the aryl halide is remarkable; substituents such as fluoro, methyl, methoxy, acetyl, formyl, benzoyl, nitro or nitrile are tolerated. Furthermore, this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides.     

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.     

Palladium-catalyzed hydrodehalogenation of aryl halides using paraformaldehyde as the hydride source: high-throughput screening by paper-based colorimetric iodide sensor

Paraformaldehyde was employed as a hydride source in the palladium-catalyzed hydrodehalogenation of aryl iodides and bromides. High throughput screening using a paper-based colorimetric iodide sensor (PBCIS) showed that Pd(OAc)₂ and Cs₂CO₃ were the best catalyst and base, respectively. Aryl iodides and bromides were hydrodehalogenated to produce the reduced arenes using Pd(OAc)₂ and Pd(PPh₃)₄ catalyst. This catalytic system showed good functional group tolerance. In addition, it was found that paraformaldehyde is the hydride source and the reducing agent for the formation of palladium nanoparticles.     

A new palladium catalyzed protocol for atom-efficient cross-coupling reactions of triarylbismuths with aryl halides and triflates

A new palladium catalyzed protocol for an atom-efficient cross-coupling reaction of triarylbismuths with aryl halides and triflates has been described. The palladium catalytic system with Cs₂CO₃ base was found to be very efficient in DMA solvent to furnish excellent yields of cross-coupled functionalized biaryls in short reaction times.     

Palladium(II)-catalyzed arylation of unactivated C(sp3)-H bonds by using 2,1,3-benzoselenadiazole-4-amine as directing ligand

A modified bidentate directing ligand derived from 2,1,3-benzoselenadiazole (BSeD) was designed and synthesized. It exhibited high regioselectivity in the catalytic activation of unactivated C(sp³)-H bonds with aryl iodides in the presence of palladium catalyst in yields up to 94%.     

Heck arylations of pent-4-enoates or allylmalonate using a palladium/tetraphosphine catalyst

The Heck reaction of aryl halides with functionalised alk-1-enes should be a powerful method for the synthesis of functionalised (E)-1-arylalk-1-ene derivatives. The major problem of this reaction is the palladium-catalysed migration of the carbon-carbon double bond along the alkyl chain when there are no substituents on the C3 carbon of the alk-1-enes. We observed that for the arylation of ethyl pent-4-enoate, ethyl 2-methylpent-4-enoate or dimethyl allylmalonate this migration could be partially or completely controlled using appropriate reaction conditions. The ramification on the alkyl chain and the substituents on the aryl halide have also an important influence on this migration. Moreover, the cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane/1/2[PdCl(C₃H₅)]₂ system catalyses this reaction with a wide range of aryl bromides using very high ratio substrate/catalyst in good yields.     

Pd-catalyzed reduction of aryl halides using dimethylformamide as the hydride source

The Pd-catalyzed homocoupling of aryl halides in a basic DMF solution is often accompanied by the dehalogenation of the substrate as side reaction. When an inorganic base such as sodium bicarbonate is used, the reducing role of the solvent has been demonstrated using DMF-d₇ and GC/MS analysis.     

Direct 2-Arylation of Thiophene Using Low Loading of a Phosphine-Free Palladium Catalyst

The direct coupling of aryl halides with thiophene would be a considerable advantage for sustainable development because of only HBr associated with a base as by-product is formed and the number of steps to prepare these compounds is less than in more classical coupling reactions. We observed that through the use of only 0.2 mol% Pd(OAc)₂ as the catalyst, a range of aryl bromides undergoes coupling via a C-H bond activation/functionalization reaction with thiophene to give 2-arylated thiophenes in good yields. In most cases, only traces of polyarylated thiophenes were detected when a large excess of thiophene was employed. This air-stable catalyst can be used with a wide variety of aryl bromides.      

Palladium catalyzed-dehalogenation of aryl chlorides and bromides using phosphite ligands

The catalytic system based on Pd-phosphite for the dehalogenation reactions of aryl chlorides and bromides is described. The Pd-phosphite catalyst effectively promoted the dehalogenation of aryl halides to give dehalogenated products in moderate to excellent yields. The aryl chlorides required strong bases such as NaO^tBu for this transformation, whereas the aryl bromides were dehalogenated in the presence of weak bases such as Cs₂CO₃. This catalytic system exhibited tolerance to functional groups such as methoxy, amine, hydroxyl, ether, amide, benzyl and ketone groups. It also demonstrated chemoselectivity in that bromochlorobenzene was converted only to chlorobenzene.     

Reaction of aryl di-, tri-, or tetrabromides with arylboronic acids or alkenes in the presence of a palladium-tetraphosphine catalyst

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ system catalyses the Suzuki and Heck reactions of aryl di-, tri-, or tetrabromides with a range of arylboronic acids or alkenes with moderate to high ratio substrate/catalyst in good yields. Aryl polybromides such as dibromobenzenes, 1,3,5-tribromobenzene, 1,2,4,5-tetrabromobenzene, dibromopyridines or a dibromothiophene have been successfully used. Convenient synthesis of a variety of di- and triarylated or vinylated compounds and even a 1,2,4,5-tetraarylated compound were prepared by use of this reaction.     

Sonogashira cross-coupling reactions with heteroaryl halides in the presence of a tetraphosphine-palladium catalyst

Heteroaryl halides undergoes cross-couplings with alkynes in good yields in the presence of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as catalyst. A variety of heteroaryl halides such as pyridines, quinolines, a pyrimidine, an indole, a thiophene, or a thiazole have been used successfully. The reaction also tolerates several alkynes such as phenylacetylene and a range of alk-1-ynols. Furthermore, this catalyst can be used at low loading with some substrates.     

Palladium-catalyzed cross-coupling of trimethoxysilylbenzene with aryl bromides and chlorides using phosphite ligands

Phosphites were employed as ligands in palladium-catalyzed Hiyama coupling reactions. The optimized reaction conditions were equimolar amounts (5 mol % each) of Pd(acac)₂ and phosphite 1 in p-xylene at 80 °C with TBAF as an additive. This catalyst system exhibited high activities in the reactions with trimethoxysilylbenzene and aryl bromides that have electron-donating or electron-withdrawing groups. In the case of aryl chlorides, substrates possessing electron-withdrawing groups gave the coupled products in high yields.     

Microwave-assisted Pd(OH)2-catalyzed direct C−H arylation of free-(NH2) adenines with aryl halides

A direct C−H arylation of free-(NH₂) adenines using Pd(OH)₂/C (Pearlman’s catalyst) and stoichiometric amount of copper iodide under ligandless microwave activation is described. This new protocol proved to be highly effective to synthesize a variety of 8-aryladenine derivatives 3 without prior protection of the amino substituent. The arylation reaction takes place rapidly within few minutes and allows the coupling to proceed regioselectively at the 8-position with a wide range of aryl halides including aryl iodides, bromides and the less reactive aryl chlorides.     

Tetraphosphine/palladium catalysed Suzuki cross-coupling reactions of aryl halides with alkylboronic acids

Through the use of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst, a range of aryl bromides and chlorides undergoes Suzuki cross-coupling with alkylboronic acids in good yields. Several alkyl substituents such as ethyl, n-butyl, n-octyl, isobutyl or 2,2-dimethylpropyl on the alkylboronic acids have been successfully used. The functional group tolerance on the aryl halide is remarkable; substituents such as fluoro, methyl, methoxy, acetyl, formyl, benzoyl, nitro or nitrile are tolerated. Furthermore, this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides.     

Palladium-catalyzed direct heteroarylation of chloropyridines and chloroquinolines

The direct coupling of aryl chlorides with heteroarenes would be a considerable advantage for sustainable development due to their lower cost, lower mass, the wider diversity of available compounds and also because of the formation of only HCl associated to a base as by-product and the reduction of the number of steps to prepare these compounds. We observed that through the use of PdCl(dppb)(C₃H₅) as a catalyst, a range of heteroaryl derivatives undergoes coupling via C-H bond activation/functionalization reaction with chloropyridines or chloroquinolines in low to high yields. This air-stable catalyst can be used with a wide variety of substrates. The position of the chloro substituent on pyridines has a minor influence on the yields. On the other hand, the nature on the heteroaryl derivative has a large influence. The highest yields were obtained using benzoxazole, thiophene or thiazole derivatives. The coupling of chloropyridines with furans also gave the expected products, but in low to moderate yields.