Suzuki-Miyaura coupling reactions of aryl and heteroaryl halides with aryl-, heteroaryl- and vinylboronic acids proceed in very good to excellent yield with the use of 2-(2',6'-dimethoxybiphenyl)dicyclohexylphosphine, SPhos (1). This ligand confers unprecedented activity for these processes, allowing reactions to be performed at low catalyst levels, to prepare extremely hindered biaryls and to be carried out, in general, for reactions of aryl chlorides at room temperature. Additionally, structural studies of various 1.Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts on Suzuki-Miyaura coupling processes. Moreover, a comparison of the reactions with 1 and with 2-(2',4',6'-triisopropylbiphenyl)diphenylphosphine (2) is presented that is informative in determining the relative importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands of this type. Further, when the aryl bromide becomes too hindered, an interesting C-H bond functionalization-cross-coupling sequence intervenes to provide product in high yield.

Despite advances in the Suzuki-Miyaura cross-coupling process, [1] the need for an operationally simple and general system remains. The minimum criteria for an optimum system that must be met include: 1) a broad substrate scope, 2) the ability to make truly hindered biaryls, 3) the ability to operate at low levels of catalyst for a range of substrates not just with the most simple examples (e.g., other than phenyl boronic acid), [2] and 4) the ability to operate at room temperature. Moreover, it is most desirable to develop protocols that do not necessitate the use of a glovebox. Herein we report a catalyst system based on a new ligand that meets the above four criteria, has unprecedented scope, reactivity, and stability, uses only commercially available, air-stable components, and is experimentally simple to employ.Our previous work on cross-coupling methodology demonstrated that dialkylphosphanylbiphenyls were excellent supporting ligands. We have reported that these can be prepared by the addition of an aryl Grignard reagent to an insitu-generated benzyne intermediate, followed by trapping of the newly formed organomagnesium complex with ClPR 2 .[3]The thought process that led to the design of the new ligand 1 is shown in Scheme 1.Mechanistic studies in our laboratory indicated that the elimination of ortho hydrogens on the bottom ring (that not bearing the dialkylphosphanyl group) was important for catalyst activity and longevity. [4] We believe that this is due to two effects: 1) prevention of cyclometalation [5] (to form a palladacycle), which diminishes catalyst lifetime, and 2) increased steric bulk relative to complexes with two ortho hydrogens. We also feel that it is important that the two methoxy groups are smaller in size than two alkyl groups as in our previously reported ligands. Moreover, the lone pairs of the alkoxy groups might interact with the Pd center and/or add electron density to the ligand backbone. The latter could be important as the interaction of the metal with the bottom ring is well documented [6] and could help stabilize intermediate complexes. [2c, 7] Furthermore, the 1,3-dimethoxybenzene moiety offers the advantage that it can be installed by means[*] Dr.

This paper details the copper-catalyzed N-arylation of pi-excessive nitrogen heterocycles. The coupling of either aryl iodides or aryl bromides with common nitrogen heterocycles (pyrroles, pyrazoles, indazoles, imidazoles, and triazoles) was successfully performed in good yield with catalysts derived from diamine ligands and CuI. General conditions were found that tolerate functional groups such as aldehydes, ketones, alcohols, primary amines, and nitriles on the aryl halide or heterocycle. Hindered aryl halides or heterocycles were also found to be suitable substrates using the conditions reported herein.

Aryl boronic acids and esters are versatile reagents for organic synthesis that are utilized in the preparation of various carbon-oxygen, carbon-nitrogen, and carbon-carbon bonds. [1] In addition, the use of organoboranes for crosscoupling processes is particularly attractive owing to their high stability and low toxicity. However, boronic acids and esters usually are prepared via intermediate alkyl and aryllithium compounds or Grignard reagents, processes that are not compatible with numerous functional groups. [2] Furthermore, the use of aryl iodides or bromides is often necessary, while the more readily available aryl chlorides [3] are often unsuitable precursors.In recent years, the development of a variety of transitionmetal-catalyzed processes has allowed for the preparation of aryl boronate esters under milder conditions.[4] In particular, numerous palladium-catalyzed methods have emerged for the conversion of aryl iodides, bromides, and triflates to the corresponding pinacol or catechol boronate esters.[5] However, only two reports [6] can be found in which unactivated aryl chlorides are suitable coupling partners, and these methods have several disadvantages: 1) High quantities of palladium catalysts (5-6 mol %) are required for many substrates. 2) Long reaction times (24-48 h) are necessary. 3) Limited substrate scope and functional-group tolerance (e.g. few or no examples with ortho substituents, phenols, and anilines) is exhibited. Herein, we report an active catalyst composed of Pd and dialkylphosphinobiphenyl ligands 1 or 2 that efficiently converts aryl chlorides to pinacol boronate esters and allows, for the first time, the direct "one-pot" synthesis of symmetrical and unsymmetrical biaryl compounds from two aryl chlorides. In addition, computational studies are presented that provide insight into the efficacy of biaryl monophosphine ligands in the palladium-catalyzed borylation process.We began by optimizing the reaction parameters. We found that a variety of dialkylphosphinobiphenyl ligands could be employed to afford highly active catalysts for the borylation of 4-n-butylchlorobenzene (Table 1). In each instance, the desired aryl boronate ester was obtained in good or excellent yield. The optimum system, based upon [Pd 2 dba 3 ] and XPhos (1), allowed for the use of relatively low quantities of catalyst and provided a quantitative yield of product in just two hours (Table 1, entry 6). We found KOAc to be the optimum base, although a variety of inorganic bases could be utilized. However, the use of K 3 PO 4 or fluoride bases, despite resulting in full conversion of the aryl chloride, also led to the formation of approximately 15-20 % of the homocoupling product 4,4'-n-butylbiphenyl.To illustrate the activity of the catalyst, the borylation of an electron-rich aryl chloride, 4-chloroanisole, was examined (Scheme 1). The best previous result for the transformation of this substrate combination required 5 mol % [Pd(dba) 2 ] and a 24-h reaction time to obtain a 86 % yield of the pinacol boronate est...

A variety of diaryl ethers were synthesized by the Pd‐catalyzed reaction of (hetero)aryl halides and phenols. These reactions were achieved through the use of two new di‐tert‐butylphosphino biaryl ligands that overcome several limitations of previously described methods.

A method for the Pd-catalyzed carbonylation of aryl bromides has been developed using Xantphos as the ligand. This method is effective for the direct synthesis of Weinreb amides, 1° and 2°b enzamides and methyl esters from the corresponding aryl bromides at atmospheric pressure. In addition, a putative catalytic intermediate, (Xanphos)Pd(Br)benzoyl, was prepared and an X-ray crystal structure was obtained revealing an unusual cis-coordination mode of Xantphos in this palladium-acyl complex.

We present results on the structure of monoligated active catalysts based upon 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 1) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 2) with Pd(0). Additionally, the reaction of SPhos‚Pd with chlorobenzene has been explored via all-atom density functional theory (DFT) and these results are supported by NMR studies. The same reaction, but with a catalyst based on a larger ligand, XPhos‚Pd, is also analyzed. Finally, it has been determined that inclusion of the entire ligand structure in these types of calculations is of importance for obtaining accurate and significant results.

We present results on the amidation of aryl halides and sulfonates utilizing a monodentate biaryl phosphine-Pd catalyst. Our results are in accord with a previous report that suggests that the formation of kappa(2)-amidate complexes is deleterious to the effectiveness of a catalyst for this transformation and that their formation can be prevented by the use of appropriate bidentate ligands. We now provide data that suggest that the use of certain monodentate ligands can also prevent the formation of the kappa(2)-amidate complexes and thereby generate more stable catalysts for the amination of aryl chlorides. Furthermore, computational studies shed light on the importance of the key feature(s) of the biaryl phosphines (a methyl group ortho to the phosphorus center) that enable the coupling to occur. The use of ligands that possess a methyl group ortho to the phosphorus center allows a variety of aryl and heteroaryl chlorides with various amides to be coupled in high yield.