Palladium‐Catalyzed Regioselective γ‐Mono‐ and Diarylation of Acrylamide Derivatives with Aryl Halides

Palladium‐catalyzed direct mono‐ and diarylations involving C(sp³) H cleavage at the γ‐position of acrylamides are described. The monoarylation products can be obtained with ortho‐substituted aryl halides. Single crystal X‐ray diffraction has shown that the double bond has shifted towards the introduced aryl group to afford the γ‐arylated β,γ‐unsaturated amide products. A second arylation occurs when less sterically hindered aryl halides are employed. This chemistry offers a novel disconnection for the synthesis of γ‐arylated compounds.     

Palladium‐Catalyzed Direct Arylations of 1,2,3‐Triazoles with Aryl Chlorides using Conventional Heating

Generally applicable, palladium‐catalyzed direct arylations of 1,2,3‐triazoles with aryl chlorides were accomplished through conventional heating at reaction temperatures of 105–120 °C. Thereby, intra‐ and intermolecular C H bond functionalizations were achieved with a variety of differently substituted chlorides as electrophiles, bearing numerous valuable functional groups.     

Reversed‐Polarity Synthesis of Diaryl Ketones through Palladium‐Catalyzed Direct Arylation of 2‐Aryl‐1,3‐dithianes

An umpolung approach to the synthesis of diaryl ketones has been developed based on in situ generation of acyl anion equivalents and their catalytic arylation. This method entails the base‐promoted, palladium‐catalyzed direct C‐H arylation of 2‐aryl‐1,3‐dithianes with aryl bromides. Use of MN(SiMe₃)₂ (M=Li, Na) base results in reversible deprotonation of the weakly acidic dithiane. In the presence of a Pd(NiXantphos)‐based catalyst and aryl bromide, cross‐coupling of the metallated 2‐aryl‐1,3‐dithiane takes place under mild conditions (2 h at rt) with yields as high as 96 %. The resulting 2,2‐diaryl‐1,3‐dithianes were converted into diaryl ketones by either molecular iodine, N‐bromo succinimide (NBS) or Selectfluor in the presence of water. The dithiane arylation/hydrolysis can be performed in a one‐pot procedure to yield a variety of diaryl ketones in good to excellent yields. This method is suitable for rapid and large‐scale synthesis of diaryl ketones. A one‐pot preparation of anti‐cholesterol drug fenofibrate (TriCor®) has been achieved on 10.0 mmol scale in 86 % yield.

     

Palladium‐Catalysed Regioselective Sequential C‐5 and C‐2 Direct Arylations of 3‐Acetylpyrroles with Aryl Bromides

The PdCl(C₃H₅)(dppb)/KOAc system was found to be effective for the direct regioselective C‐5 arylation of 3‐acetylpyrroles with ortho‐substituted aryl bromides. This procedure has been found to be tolerant to a variety of functional groups at C‐2 of the aryl bromide such as methyl, formyl, nitrile, nitro, hydroxymethyl, chloro, fluoro or trifluoromethyl. The sequential direct C‐5 arylation followed by C‐2 arylation of such 3‐substituted pyrroles allows the synthesis of 2,5‐diaryl‐3‐acetylpyrroles in high yields.     

Intermolecular versus Intramolecular Palladium‐Catalyzed Direct Arylations between 1‐(2‐Bromobenzyl)imidazoles and Aryl Bromides

Herein, we report on the sequential palladium‐catalyzed intermolecular followed by intramolecular direct arylations of 1‐(2‐bromobenzyl)imidazoles. We found that, in the presence of 1 mol% palladium acetate and potassium acetate as base, the intermolecular reaction between 1‐(2‐bromobenzyl)imidazole derivatives and electron‐deficient aryl bromides proceeded faster than the intramolecular reaction, allowing us to prepare medium‐size polycyclic imidazoles after a second Pd‐catalyzed intramolecular arylation. These iterative direct arylations allowed the synthesis of fused nitrogen‐containing heterocycles with a 5‐ or 7‐membered‐ring in only two steps. Some reactions have also been performed as a one‐pot procedure using 2 mol% of palladium acetate in the presence of a larger amount of base (3 equiv.).

     

Base‐Mediated Direct Arylation of Pyrrole Derivatives

It appears that transition metal catalysts are not necessary to perform the direct arylation of electron‐rich heterocycles with aryl iodides and bromides. Lithium tert‐butoxide in DMF promotes this reaction for a variety of N‐alkyl‐ and N‐arylpyrroles as well as for benzofuran and some other electron‐rich aromatic compounds and provides the desired products in moderate to high yields. In contrast to all previous reports on the Pd‐catalyzed direct arylation of indolizine, the reaction mediated by lithium tert‐butoxide proceeds selectively at position 5.     

Cyanides‐Free Cyanation of Aryl Halides using Formamide

A novel method for cyanation of aryl halides using formamide as a non‐toxic cyanide source is reported. It is a single‐step, solvent‐free method wherein formamide itself acts as solvent as well as source of cyanide in the presence of phosphorus oxychloride and palladium acetate/xantphos catalyst. Aryl iodides as well as aryl bromides provided moderate to excellent yields of up to 93%.     

Mechanistic Studies on the Palladium‐Catalyzed Direct C‐5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium

An in‐depth mechanistic study on the palladium‐catalyzed direct arylation of imidazoles at the C‐5 position is presented. The interactions of triphenylphosphine (PPh₃)‐ligated aryl‐Pd species with 1,2‐dimethyl‐1H‐imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine‐ligated organo‐Pd species are not active and the reaction proceeds through imidazole‐ligated organo‐Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim‐ligated Pd(0) species have been characterized in a Pd(dba)₂/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)₂X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)₃]⁺ is also reported. The ability of these species to effect the C H arylation of dmim at room temperature in the presence of acetate is also demonstrated.

     

Palladium‐Catalyzed Aryl Amination Reactions of 6‐Bromo‐ and 6‐Chloropurine Nucleosides

Palladium‐catalyzed C N bond forming reactions of 6‐bromo‐ as well as 6‐chloropurine ribonucleosides and the 2′‐deoxy analogues with arylamines are described. Efficient conversions were observed with palladium(II) acetate/Xantphos/cesium carbonate, in toluene at 100 °C. Reactions of the bromonucleoside derivatives could be conducted at a lowered catalytic loading [5 mol% Pd(OAc)₂/7.5 mol% Xantphos], whereas good product yields were obtained with a higher catalyst load [10 mol% Pd(OAc)₂/15 mol% Xantphos] when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxy groups appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of arylamines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6‐chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates.     

A Further Decrease in the Catalyst Loading for the Palladium‐Catalyzed Direct Intramolecular Arylation of Amides and Sulfonamides

The direct arylation of N‐substituted o‐bromobenzanilides and benzenesulfonamides via C H bond functionalization has been developed using very low catalyst loadings. This novel cost‐effective and more sustainable method relies on a PCN‐type palladium pincer complex as a highly active palladium source, providing a general and efficient access to phenanthridinones, biaryl sultams and related heterocyclic systems. The beneficial effect of water as cosolvent has been observed in this process, which is not seriously influenced by electronic effects at the arene moieties or sterically demanding substituents at the amide or sulfonamide nitrogen. In addition, a number of experiments (kinetic plot, poisoning assays, TEM, ESI) have been performed in order to understand the role of the employed palladium complex in this reaction.

     

Palladium‐Catalysed Intramolecular Direct Arylation of 2‐Bromobenzenesulfonic Acid Derivatives

A palladium‐catalysed intramolecular direct arylation of 2‐bromobenzenesulfonic acid derivatives was found to proceed using 1 mol% of palladium acetate as the catalyst. The influence of the substituents on the phenol moiety of 2‐bromobenzenesulfonic acid phenyl esters reveals that electron‐donating substituents favour the reaction while electron‐withdrawing ones are unfavourable. The reactivity of sulfonamides was also studied and, in all cases, a selective activation at sp² C H vs. sp³ C H was observed. A sulfonamide bearing both phenyl and benzyl substituents on nitrogen gave selectively the six‐membered ring product.     

Palladium‐Catalyzed Direct Denitrogenative C‐3‐Arylation of 1H‐Indoles with Arylhydrazines using Air as the Oxidant

A novel palladium‐catalyzed approach to direct C‐3‐arylation of 1H‐indoles with arylhydrazines using air as the oxidant via C N bond cleavage has been developed. Various substituents are tolerated in this system in moderate to good yields. This reaction could also be compatible with a larger scale. Thus, this strategy using arylhydrazines as arylating reagents provides a powerful method for constructing substituted 3‐aryl‐1H‐indoles.     

Thioethers as Directing Group for the Palladium‐Catalyzed Direct Arylation of Arenes

Thioethers have proven to be efficient directing groups for the arylation of arenes under palladium catalysis. The thioether group can be readily removed or converted to other functional groups. Kinetic isotopic effect studies reveal that the C H cleavage of arenes might be the turnover‐limiting step.     

Palladium‐Catalyzed Dienylation of Haloalkynes using 2,3‐Butadienyl Acetates: A Facile Access to (1Z)‐1,2‐Dihalo‐ 3‐vinyl‐1,3‐dienes

A highly efficient and stereoselective method for the synthesis of (1Z)‐1,2‐dihalo‐3‐vinyl‐1,3‐dienes featuring palladium‐catalyzed coupling of haloalkynes and 2,3‐butadienyl acetates was developed. The resulting products were smoothly converted into cis‐1,2‐dihalostyrene derivatives using the Diels–Alder/aromatization sequence.     

One‐Pot Palladium‐Catalyzed Synthesis of Selectively Substituted Phenanthridines by Sequential Aryl‐Aryl and Heck Couplings,Aza‐Michael and Retro‐Mannich Reactions

A catalytic synthesis of selectively substituted phenanthridines is achieved through a reaction sequence involving palladium/norbornene‐catalyzed unsymmetrical aryl‐aryl and Heck couplings followed by aza‐Michael and retro‐Mannich reactions. In spite of the many steps involved the method is very simple and allows the formation of selectively substituted phenanthridines under mild conditions in a straightforward one‐pot reaction starting from readily available aryl iodides and bromides.     

Recent Applications of Palladium‐Catalyzed Coupling Reactions in the Pharmaceutical,Agrochemical, and Fine Chemical Industries

Palladium‐catalyzed coupling reactions have become a central tool for the synthesis of biologically active compounds both in academia and industry. Most of these transformations make use of easily available substrates and allow for a shorter and more selective preparation of substituted arenes and heteroarenes compared to non‐catalytic pathways. Notably, molecular‐defined palladium catalysts offer high chemoselectivity and broad functional group tolerance. Considering these advantages, it is not surprising that several palladium‐catalyzed coupling reactions have been implemented in the last decade into the industrial manufacture of pharmaceuticals and fine chemicals. In this review different examples from 2001–2008 are highlighted, which have been performed at least on a kilogram scale in the chemical and pharmaceutical industries.     

Zheda‐Phos for General α‐Monoarylation of Acetone with Aryl Chlorides

A new, readily available, and air‐stable monophosphine ligand, i.e., Zheda‐Phos , has been developed for the general and highly effective palladium‐catalyzed monoarylation of acetone with aryl chlorides. The reaction rate is of first‐order dependence with the aryl chloride.     

Nickel‐Catalyzed Highly Selective Hydrovinylation of α‐Ketals of Vinylarenes

A nickel‐catalyzed hydrovinylation of α‐ketal derivatives of vinylarenes has been developed, providing a new method for preparing functional olefins with a quarternary carbon center in high yields and selectivities.