Suzuki-Miyaura coupling reaction of aryl chlorides using di(2,6-dimethylmorpholino)phenylphosphine as ligand

Suzuki-Miyaura coupling was achieved on a variety of aryl chlorides by using di(2,6-dimethylmorpholino)phenylphosphine (L1) as a bulky electron-rich monoaryl phosphine ligand. We report the couplings of various chlorobenzenes and heteroaryl chlorides.     

Progress in the palladium-catalyzed cyanation of aryl chlorides

The development of new palladium catalysts for the cyanation of various aryl and heteroaryl chlorides is described. The combination of amine co-catalysts with chelating phosphine ligands, for example, 1,4-bis(diphenylphosphino)butane (dppb) or 1,5-bis(diphenylphosphino)pentane (dpppe), allows an efficient cyanation of chloroarenes with simple potassium cyanide. General palladium-catalyzed cyanation of nonactivated and deactivated chloroarenes is possible for the first time. Studies of the oxidative addition of aryl halides to palladium triphenylphosphine complexes in the presence and absence of amines suggest that the co-catalyst is capable of preventing catalyst deactivation caused by the presence of excess cyanide ions in solution.     

Sulfate additives generate robust and highly active palladium catalysts for the cyanation of aryl chlorides

The use of sulfate additives such as H₂SO₄ greatly increases the reactivity of palladium catalysts for the cyanation of aryl and heteroaryl chlorides and renders them more robust toward adventitious air. Using this method, a wide variety of aromatic and heteroaromatic nitriles were prepared in high yield.     

Improving palladium-catalyzed cyanation of aryl halides: development of a state-of-the-art methodology using potassium hexacyanoferrate(II) as cyanating agent

Benzonitriles are easily accessible via palladium-catalyzed cyanation of aryl halides using potassium hexacyanoferrate(II) as cyanide source. This method is applicable on both activated and deactivated aryl and heteroaryl bromides and activated chlorides giving the corresponding benzonitriles in good to excellent yield. Advantageously, the used cyanating agent is non-toxic and cheap. The presented catalyst system is rather simple and it is not necessary to add expensive phosphines, making the novel method also attractive for industrial applications.     

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of potassium aryl- and heteroaryltrifluoroborates

An extended study of the reactivity of potassium aryl- and heteroaryltrifluoroborates in Suzuki-Miyaura cross-coupling reactions is presented. The coupling of aryl- and electron-rich heteroaryltrifluoroborates with aryl and activated heteroaryl bromides proceeds readily under ligandless conditions. When deactivated aryl- and heteroaryltrifluoroborates are coupled with aryl and heteroaryl bromides and chlorides, a low loading (0.5-2%) of PdCl(2)(dppf).CH(2)Cl(2) efficiently catalyzes the reactions. Under either condition, reactions can generally be carried out in an open atmosphere.     

Palladium-phosphinous acid-catalyzed cross-coupling of aryl and acyl halides with aryl-, alkyl-, and vinylzinc reagents

Several palladium-phosphinous acids have been prepared and employed in cross-coupling reactions of aryl or acyl halides with aliphatic and aromatic organozinc reagents. The POPd7-catalyzed reaction of aryl halides, including electron-rich aryl chlorides, and arylzinc reagents was found to afford biaryls exhibiting alkoxy, alkylthio, amino, ketone, cyano, nitro, ester, and heteroaryl groups in 75-93% yield. Excellent results were obtained with sterically hindered substrates which gave di- and tri -ortho-substituted biaryls in up to 92% yield. Aryl halides also undergo POPd7-catalyzed aryl-vinyl and aryl-alkyl bond formation under mild conditions. Styrenes and alkylarenes were prepared in 79-93% yield from aryl halides and vinyl or alkylzinc reagents. The replacement of aryl halides by acyl halides provides access to ketones which were produced in up to 98% yield when POPd was used as catalyst. This approach overcomes the limited substrate scope, reduced regiocontrol, and low functional group tolerance of traditional Friedel-Crafts acylation methods.     

Palladium-catalyzed coupling reactions of aryl chlorides

Collectively, palladium-catalyzed coupling reactions represent some of the most powerful and versatile tools available to synthetic organic chemists. Their widespread popularity stems in part from the fact that they are generally tolerant to a large number of functional groups, which allows them to be employed in a wide range of applications. However, for many years a major limitation of palladium-catalyzed coupling processes has been the poor reactivity of aryl chlorides, which from the standpoints of cost and availability are more attractive substrates than the corresponding bromides, iodides, and triflates. Traditional palladium/triarylphosphane catalysts are only effective for the coupling of certain activated aryl chlorides (for example, heteroaryl chlorides and substrates that bear electron-withdrawing groups), but not for aryl chlorides in general. Since 1998, major advances have been described by a number of research groups addressing this challenge; catalysts based on bulky, electron-rich phosphanes and carbenes have proved to be particularly mild and versatile. This review summarizes both the seminal early work and the exciting recent developments in the area of palladium-catalyzed couplings of aryl chlorides.     

A mild and efficient palladium-catalyzed cyanation of aryl chlorides with K4[Fe(CN)6

An efficient palladium-catalyzed cyanation of aryl chlorides is established. In the presence of a highly effective Pd/CM-phos catalyst, cyanation of aryl chlorides proceeds at 70 °C in general, which is the mildest reaction temperature achieved so far for this process. Common functional groups such as keto, aldehyde, ester, nitrile and -NH(2), and heterocyclic coupling partners including N-H indoles are well tolerated. Moreover, a sterically hindered nonactivated ortho,ortho-disubstituted electrophile is shown to be a feasible coupling partner in cyanation.     

Palladium-catalyzed arylation and heteroarylation of azolopyrimidines

A comparative study of the palladium-catalyzed arylation and heteroarylation of 5-bromoazolopyrimidines shows that aryl and electron-rich heteroaryl boronic acids gave higher yields than those obtained using the corresponding aryl and heteroaryl tributyl stannanes. In contrast, the reaction with electron-poor heteroaryl tributyl stannanes gave better results than the corresponding boronic acids.     

Pd-catalyzed aryl amination mediated by well defined, N-heterocyclic carbene (NHC)-Pd precatalysts, PEPPSI

Pd-N-heterocyclic carbene (NHC)-catalyzed Buchwald-Hartwig amination protocols mediated by Pd-PEPPSI precatalysts is described. These protocols provide access to a range of hindered and functionalized drug-like aryl amines in high yield with both electron-deficient and electron-rich aryl- and heteroaryl chlorides and bromides. Variations in solvent polarity, base and temperature are tolerated, enhancing the scope and utility of this protocol. A mechanistic rationalization for base strength (pKb) requirements is also provided.     

A General Palladium‐Catalyzed Hiyama Cross‐Coupling Reaction of Aryl and Heteroaryl Chlorides

A general palladium‐catalyzed Hiyama cross‐coupling reaction of aryl and heteroaryl chlorides with aryl and heteroaryl trialkoxysilanes by a Pd(OAc)₂/ L2 catalytic system is presented. A newly developed water addition protocol can dramatically improve the product yields. The conjugation of the Pd/ L2 system and the water addition protocol can efficiently catalyze a broad range of electron‐rich, ‐neutral, ‐deficient, and sterically hindered aryl chlorides and heteroaryl chlorides with excellent yields within three hours and the catalyst loading can be down to 0.05 mol % Pd for the first time. Hiyama coupling of heteroaryl chlorides with heteroaryl silanes is also reported for the first time. The reaction can be easily scaled up 200 times (100 mmol) without any degasification and purification of reactants; this facilitates the practical application in routine synthesis.     

Copper-catalyzed conversion of aryl and heteroaryl bromides into the corresponding chlorides

An efficient method for the synthesis of aryl and heteroaryl chlorides is described. The reactions of aryl and heteroaryl bromides with tetramethylammonium chloride proceeded smoothly in the presence of a copper catalyst under mild reaction conditions to produce the corresponding chlorides in satisfactory to excellent yields.     

An efficient and general method for the Heck and Buchwald-Hartwig coupling reactions of aryl chlorides

The β-diketiminatophosphane Pd complex acted as a powerful catalyst for the Heck coupling of aryl chlorides with alkenes. Various aryl and heteroaryl chlorides were coupled efficiently under relatively mild conditions. Furthermore, this catalytic system also proved to be highly active in the Buchwald-Hartwig coupling of deactivated and sterically hindered aryl chlorides at room temperature.     

A novel and convenient synthesis of benzonitriles: electrophilic cyanation of aryl and heteroaryl bromides

N-Cyano-N-phenyl-p-methylbenzenesulfonamide has been used as a more benign electrophilic cyanation reagent for the synthesis of various benzonitriles from (hetero)aryl bromides via formation of Grignard reagents. Electronically different and sterically demanding aryl bromides including functionalized substrates and heteroaryl bromides are successfully cyanated in good to excellent yields. The efficiency of the present methodology is shown by the expeditious syntheses of interesting pharmaceutical intermediates. Notably, chemoselective monocyanation of dibromoarenes is also achieved.     

The palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides and sodium sulfinates

A palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides and sodium sulfinates has been developed, providing aryl nitriles in moderate to excellent yields. It represents a facile procedure to access aryl nitriles.     

Palladium-catalyzed Stille cross-couplings of sulfonyl chlorides and organostannanes

Arene and phenylmethanesulfonyl chlorides can be cross-coupled with aryl, heteroaryl, and alkenylstannanes with desulfitation in the presence of 10 mol % CuBr.Me2S, 1.5 mol % Pd2dba3, and 5 mol % tri-2-furylphosphine in tetrahydrofuran or toluene under reflux. This extension of the Stille cross-coupling reaction realizes a new and economical method for the generation of C-C bonds. The palladium-catalyzed carbonylative Stille cross-coupling reactions of arenesulfonyl chlorides and organostannanes in the presence of CO (60 bar) at 110 degrees C in toluene generate the corresponding ketones. Arenesulfonyl chlorides are more reactive than aryl chlorides and aryl bromides in their Stille cross-coupling with organostannanes but less reactive than aryl iodides. The new methods disclosed for the generation of C-C bonds open new possibilities for medicinal chemistry and material sciences.     

Cross-coupling of cyclopropyl- and cyclobutyltrifluoroborates with aryl and heteroaryl chlorides

Suitable conditions were found for the Suzuki-Miyaura cross-coupling reaction of potassium cyclopropyl- and cyclobutyltrifluoroborates with aryl chlorides. Both of these secondary alkyl trifluoroborates coupled in moderate to excellent yield with electron-rich, electron-poor, and hindered aryl chlorides to give a variety of substituted aryl cyclopropanes and cyclobutanes.     

Cross‐Coupling of Sodium Sulfinates with Aryl,Heteroaryl, and Vinyl Halides by Nickel/Photoredox Dual Catalysis

An efficient photoredox/nickel catalyzed sulfonylation reaction of aryl, heteroaryl, and vinyl halides has been achieved for the first time. This newly developed sulfonylation protocol provides a versatile method for the synthesis of diverse aromatic sulfones at room temperature and shows excellent functional group tolerance. The electrophilic coupling partners are not limited to aryl, heteroaryl, and vinyl bromides and iodides, but also includes less reactive aryl chlorides as suitable substrates for this transformation.     

Cross‐Coupling of Sodium Sulfinates with Aryl,Heteroaryl, and Vinyl Halides by Nickel/Photoredox Dual Catalysis

An efficient photoredox/nickel catalyzed sulfonylation reaction of aryl, heteroaryl, and vinyl halides has been achieved for the first time. This newly developed sulfonylation protocol provides a versatile method for the synthesis of diverse aromatic sulfones at room temperature and shows excellent functional group tolerance. The electrophilic coupling partners are not limited to aryl, heteroaryl, and vinyl bromides and iodides, but also includes less reactive aryl chlorides as suitable substrates for this transformation.     

Palladium-Catalyzed Cross-Coupling Reactions of Potassium N-Methyltrifluoroborate Isoindolin-1-one with Aryl and Heteroaryl Chlorides

Potassium N-methyltrifluoroborate isoindolin-1-one was synthesized and used in Suzuki–Miyaura palladium-catalyzed cross-coupling reactions with aryl and heteroaryl chlorides to prepare 29 examples of substituted N-benzyl isoindolin-1-ones. The new approach benefits from mild reaction conditions that tolerate a variety of functional groups. In addition, because of the large number of commercially available aryl and heteroaryl chlorides that can serve as coupling partners, the approach readily provides access to libraries of substituted N-benzyl isoindolin-1-ones.