Scope and limitations of Pd2(dba)3/P(i-BuNCH2CH2)3N-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides

Proazaphosphatrane ligands in combination with Pd(2)(dba)(3) generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides. In particular, commercially available P(i-BuNCH(2)CH(2))(3)N is a highly general and efficient ligand, allowing the coupling of an electronically diverse set of aryl chlorides, including chloropyridines, with a wide variety of amines using 1 mol % of Pd at 100 degrees C. Either a 1:1 or 2:1 ratio of ligand to Pd was found to be effective. This catalyst system performs exceptionally well for sterically hindered substrates, even with only 0.25 mol % of Pd. It is shown that NaOH can also be used as the base (instead of NaO-t-Bu) allowing functionalized substrates to participate in these reactions.     

Aminoarenethiolate-copper(I)-catalyzed amination of aryl bromides

[reaction, structure: see text] Aminoarenethiolate-copper(I) complexes are known to be efficient catalysts for carbon-carbon bond formation. Here, we show the first examples that these thiolate-copper(I) complexes are efficient for carbon-nitrogen bond formation reactions as well. N-Arylation of benzylamine and imidazole with bromobenzene was achieved either in NMP as solvent or under solvent-free conditions in the presence of 2.5 mol % of aminoarenethiolate-copper(I) complex only.     

Mild and efficient copper-catalyzed amination of aryl bromides with primary alkylamines

[reaction: see text] An efficient copper-catalyzed amination of aryl bromides with primary alkylamines was developed that uses commercially available diethylsalicylamide as the ligand. This amination reaction can be performed at 90 degrees C in good yield. A variety of functional groups are compatible with these reaction conditions. Preliminary results show that this reaction can be carried out under solvent-free conditions with comparable yields.     

Recyclable polymer-supported Pd catalysts for aryl amination reactions

Polymer-supported palladium catalysts were prepared from three commercially available phosphine-functionalised polymers (PS-PR₂), Pd₂(dba)₃ and P(t-Bu)₃. Catalyst stability was investigated using VT ³¹P NMR spectroscopy. One of the catalysts can be reused in the amination of bromobenzene and chlorotoluene, up to three times, without loss in yield. Recyclability of the catalysts is dependent on the method of preparation and the nature of the polymer-bound phosphine.     

Mechanistic insights into the Pd(BINAP)-catalyzed amination of aryl bromides: kinetic studies under synthetically relevant conditions

Kinetic studies using reaction calorimetry were carried out under synthetically relevant conditions to study the mechanism of the amination of bromobenzene with primary and secondary amines using Pd(2)(dba)(3)/BINAP mixtures as well as preformed (dba)Pd(BINAP), (p-tolyl)(Br)Pd(BINAP), and Pd(BINAP)(2) complexes. The presence of a significant induction period in the reaction was attributed to the slow activation of the catalytic precursor, resulting in an increase in the concentration of active species within the catalytic cycle. The induction period can mask the true kinetics of the reaction, which exhibits positive order dependences on aryl bromide and amine and zero-order dependence on base. It is also determined that the bis-ligand complex Pd(BINAP)(2) does not play a role directly on the catalytic cycle. In addition to the conventionally accepted pathway involving oxidative addition of the aryl halide to (BINAP)Pd as the first step, a pathway initiated by addition of the amine to the catalyst is proposed and supported by kinetic modeling of sequential reaction experiments. A subtle dependence of the reaction mechanism on the relative concentrations of substrates is revealed in these studies. The dependence of the catalyst resting state on reaction conditions is also discussed. This work suggests that conclusions from kinetic studies may be meaningful only for the conditions under which they are carried out, calling into question the use of conventional kinetic methods in this system.     

Palladium-catalyzed amination of aryl bromides and aryl triflates using diphosphane ligands: a kinetic study

[Pd(P-O-P)(Ar)]+ complexes with ligands that have wide bite angles are active catalysts for the coupling of aniline derivatives with aryl triflates. Kinetic studies show that for these systems a fast equilibrium that involves coordination of the amine precedes the deprotonation, which is the rate-limiting step of the reaction. This reaction is faster for compounds with a smaller P-Pd-P angle. When halide salts are present, the base sodium tert-butoxide is activated and adds to the palladium complex. This rate-limiting step is preceded by a fast equilibrium that involves decoordination of the halide. The initial reaction rate is faster for compounds with a larger P-Pd-P angle. This is due to the closer proximity of the oxygen to the Pd center, and this assists in the dissociation of the halide.     

Aqueous hydroxide as a base for palladium-catalyzed amination of aryl chlorides and bromides

The amination of aryl halides in the presence of inexpensive and air-stable alkali metal hydroxide bases and Pd[P(t-Bu)3]2 as catalyst gave arylamines in high yields. The reactions were conducted with a catalytic amount of cetyltrimethylammonium bromide as phase-transfer agent and either aqueous hydroxide or solid hydroxide in the presence of water. This combination of alkali metal hydroxide base, H2O, and the ammonium salt performed as well as NaO-t-Bu in the amination of p-chlorotoluene with dibutylamine. Hydroxide base was suitable for reactions of a wide range of aryl chlorides and bromides with aliphatic and aromatic amines. Some functional groups that were intolerant of tert-butoxide base, such as esters, enolizable ketones, nitriles, and nitro groups, were tolerated by the combination of hydroxide base, H2O, and cetyltrimethylammonium bromide in toluene solvent.     

Bulky alkylphosphines with neopentyl substituents as ligands in the amination of aryl bromides and chlorides

Di(tert-butyl)neopentylphosphine (DTBNpP) in combination with palladium sources provided catalysts with comparable or better activity for the Hartwig-Buchwald amination of aryl bromides than tri(tert-butyl)phosphine (TTBP) under mild conditions. DTBNpP also provided effective catalysts for amination reactions of aryl chlorides at elevated temperatures. Further replacement of tert-butyl groups with neopentyl substituents resulted in less effective ligands for amination reactions. Computationally derived cone angles showed that replacement of a tert-butyl group with a neopentyl group significantly increased the cone angle of the phosphine. The larger cone angle of DTBNpP than TTBP appears to correlate with the higher activity of catalysts derived from DTBNpP in the amination of aryl bromides. TTBP is a stronger electron donor than DTBNpP, which may explain the higher activity for TTBP-derived catalysts toward aryl chlorides.     

A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl bromides employing heterogeneous Pd/C

An industrially viable cyanation of aryl bromides with Zn(CN)₂ was accomplished in the presence of inexpensive and readily accessible Pd/C, Zn dust, ZnBr₂, and PPh₃ in DMA to provide functionalized aryl nitriles in moderate to high yields.     

An inexpensive cyclodiphosphazane as an efficient ligand for the palladium-catalyzed amination of aryl bromides and chlorides

An economic and novel ligand, cyclodiphosphazane [ClPN(t-Bu)]₂ (1), was introduced in the palladium-catalyzed amination of unactivated aryl halides. The catalyst allows for the amination of aryl chlorides and bromides with secondary cyclic amines and anilines in good yields.     

Simple, efficient catalyst system for the palladium-catalyzed amination of aryl chlorides, bromides, and triflates

Palladium complexes supported by (o-biphenyl)P(t-Bu)(2) (3) or (o-biphenyl)PCy(2) (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 degrees C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination.     

Investigation of the catalytic activity of a Pd/biphenyl-based phosphine system in the Ullmann homocoupling of aryl bromides

We described Ullmann homocoupling promoted by a Pd/biphenyl-based phosphine system using DMF as solvent. Using Hammett equation it is found that the rate determining step of the reaction depends on the electronic nature of substituents of aryl bromides. Increase the rate of reaction with decreasing the electron donating of the substituent from NH₂ to H suggesting an oxidative addition step as the rate determining step. Decrease the rate of reaction with increasing the electron-withdrawing ability of the substituent from H to NO₂ indicating a reductive elimination step as the rate determining step.     

Mizoroki-Heck reaction, catalysis by nitrogen ligand Pd complexes and activation of aryl bromides

Nitrogen ligands are an excellent alternative for the traditional P-ligands in the Pd catalyzed Mizoroki-Heck reaction. Pd complexes of dimethyl glyoxime, 8-hydroxyquinoline, salen, picolinic acid, DAB ligands gave high yields of the E-cinnamates and E-stilbenes. Acetophenone oxime N,N-dimethybenzyl amine and ferrocenyl oxime palladacycle were better catalysts and comparable yields, TON (95,000) and TOF's (2500 h⁻¹) to P-ligand catalysts, were obtained. Aryl iodides, aryl bromides and in a few cases, aryl chlorides could be also be activated by these complexes by the use of Lewis acid and (C₄H₉)₄NI as additive. DAB ligands gave good yields with electron rich aryl bromides and the use of ionic liquid improved the yield. These metal complexes can be readily synthesized and the N-ligands possess the advantage of easy functional group modifications and convenient synthetic methods compared to P-ligands. The degradation reactions associated with P-ligands is not observed in the N-ligands, with comparable high thermal, moisture and air stability and insensitivity.     

Pd/P(t-Bu)(3): a mild and general catalyst for Stille reactions of aryl chlorides and aryl bromides

Pd/P(t-Bu)(3) serves as an unusually reactive catalyst for Stille reactions of aryl chlorides and bromides, providing solutions to a number of long-standing challenges. An unprecedented array of aryl chlorides can be cross-coupled with a range of organotin reagents, including SnBu(4). Very hindered biaryls (e.g., tetra-ortho-substituted) can be synthesized, and aryl chlorides can be coupled in the presence of aryl triflates. The method is user-friendly, since a commercially available complex, Pd(P(t-Bu)(3))(2), is effective. Pd/P(t-Bu)(3) also functions as an active catalyst for Stille reactions of aryl bromides, furnishing the first general method for room-temperature cross-couplings.     

New binuclear Pd(II) thioamide complexes for the Heck reaction of aryl bromides

The reaction of binucleating thioamide ligands (L₁-L₃) with [PdCl₂(PPh₃)₂] in 1:2 molar ratio in methanol medium afforded a series of binuclear palladium(II) complexes. The synthesized complexes were characterized by elemental analysis and ¹H NMR. The molecular structure of one of the complexes was established by X-ray diffraction method. The binuclear palladium(II) thioamide complex has been shown to be an active catalyst for the Heck reaction of aryl bromides with alkenes.     

Convenient copper- and solvent-free Sonogashira-type alkynylation of aryl iodides and bromides using Pd EnCat™

A straightforward methodology is described for the copper- and solvent-free alkynylations of aryl iodides and bromides using 0.1-0.01 mol % of Pd as Pd EnCat™ 40 or TPP30. High yielding reactions can be achieved under aerobic conditions for a variety of activated and deactivated aryl iodides; a few examples with aryl bromides are also described. Microwave irradiation is able to enhance yields and rates of these reactions.     

Photolysis of aryl bromides and aryl chlorides in benzene

Conclusions As a result of photolysis of aromatic bromo- and chlorohydrocarbons in benzene solution, products of replacement of the halogen atoms by a phenyl group were obtained.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 456–457, February, 1967.     

Studies on Pd/imidazolium salt protocols for aminations of aryl bromides and iodides using lithium hexamethyldisilazide (LHMDS)

The reactions of a range of secondary amines with aryl bromides and iodides have been performed using an in situ protocol involving palladium and imidazolium salts. Many of these reactions proceed at room temperature, providing a mild protocol for aminations of aryl iodides and bromides. Key to the success of this procedure is the use of lithium hexamethyldisilazide (LHMDS) as base.     

Pd PEPPSI-IPr-mediated reactions in metal-coated capillaries under MACOS: the synthesis of indoles by sequential aryl amination/Heck coupling

A method has been devised for the microwave-assisted, continuous-flow preparation of indole alkaloids by a two-step aryl amination/cross-coupling sequence of bromoalkenes and 2-bromoanilines. This process requires both the presence of a metal-lined flow tube (a 1180 micron capillary) and the Pd PEPPSI-IPr catalyst; without either, the catalyst or the film, there is zero turnover of this catalytic process. A silver film has been shown to provide some conversion (48-62 %), but optimal results (quantitative) across a variety of bromoalkenes and bromoanilines were achieved by using a highly porous palladium film. Possible roles for the Pd film are considered, as is the interplay of the catalyst and the film.