A catalyst system based on a new biarylmonophosphine ligand (BrettPhos) that shows excellent reactivity for C-N cross-coupling reactions is reported. This catalyst system enables the use of aryl mesylates as a coupling partner in C-N bond-forming reactions. Additionally, the use of BrettPhos permits the highly selective monoarylation of an array of primary aliphatic amines and anilines at low catalyst loadings and with fast reaction times, including the first monoarylation of methylamine. Lastly, oxidative addition complexes of BrettPhos are included, which provide insight into the origin of reactivity for this system. Palladium-catalyzed C-N cross-coupling reactions are an important technology both in industry and academia. 1 Despite considerable advances in the field, 2 notable limitations remain for which improved methods will have an immediate impact on the chemistry community. Herein, we report a catalyst comprised of a new biaryldialkylphosphine ligand that shows excellent reactivity and stability in C-N cross-coupling reactions and overcomes many restrictions that previous catalyst systems have possessed. This improved ligand enables the aminations of aryl mesylates as well as, for the first time, the highly selective monoarylation of primary amines using low catalyst loadings of a monophosphine-based catalyst.sbuchwal@mit.edu. Supporting Information Available: Procedural, spectral, and crystallographic data. This material is available free of charge via http://pubs.acs.org. Similarly, utilization of water-mediated catalyst activation with 1 and Pd(OAc) 2 gave the desired product in 99% yield (Entry 3). 9 In contrast, the use of ligand 2 (XPhos), which has been shown to be efficient in couplings of other aryl sulfonates, 3c but lacks the methoxy groups, provided only trace amounts of product when used either as precatalyst 7 or with the watermediated activation protocol (Table 1, entries 4 and 5). NIH Public AccessBecause these results clearly implicate the importance of substitution in the upper arene in 1, we also examined the use of the tetra-methyl substituted ligand 4, a congener of a ligand which has been shown to be effective in amidation reactions. 6 Unlike reactions employing 1, reactions employing 4 failed to provide even detectable amounts of the desired product (Table 1, entry 7). These results demonstrate that the nature of the arene substituent is critical to the performance of 1. Further, in order to show that the activity of 1 does not only arise from the ortho methoxy substituent dimethoxy ligand 5, was synthesized. As with 4, the use of 5 as the ligand failed to provide detectable product (Table 1, entry 8). These results, taken together, reveal a cooperative effect between the methoxy substituents and the biaryl motiff and demonstrate that both are required for the observed reactivity in catalytic reactions employing ligand 1.Having defined an efficient catalytic system, the scope of aryl mesylate coupling reactions was next explored. Highlighted below (Table 2), a number of e...

A new class of one-component Pd precatalysts bearing biarylphosphine ligands is described. These precatalysts are air-and thermally-stable, are easily activated under normal reaction conditions at or below room temperature, and ensure the formation of the highly active mono-ligated Pd(0) complex necessary for oxidative addition. The use of these precatalysts as a convenient source of LPd(0) in C-N cross-coupling reactions is explored. The reactivity that is demonstrated in this study is unprecedented in palladium chemistry.Although phosphine-ligated Pd(0) complexes constitute the active catalysts in many C-N bond-forming cross-coupling methodologies, 1,2 such complexes are usually difficult to prepare and extremely air-sensitive. Pd 2 (dba) 3 , developed as a stable source of Pd(0), includes coordinating dba ligands that can significantly retard the formation of active catalyst and/or diminish its reactivity. 3 The use of a Pd(II) salt such as Pd(OAc) 2 , which circumvents problems of precatalyst instability, requires in situ reduction in order to generate the active Pd(0) complex. In light of the complications in forming phosphine-ligated Pd(0) complexes, we sought to develop a precatalyst scaffold constituting the source of Pd and phosphine ligand, which could form the active, mono-ligated Pd complex under mild conditions and without the need for exogenous additives. 4 Herein, we report the development of a new class of air-and moisture-stable, one-component, Pd precatalysts that is activated under standard reaction conditions and ensures the formation of the active, L 1 Pd(0) (L = biarylphosphine) complex. We also demonstrate these precatalysts to be convenient Pd sources for facile C-N bondforming reactions. Finally, we show the efficient oxidative addition of PhCl to a LPd(0) complex at −40 °C. Our group has recently reported the isolation of a phosphineligated Pd(II) complex bearing a free amine. 5 Building on this result, we proposed that an intramolecularly coordinated amine complex would provide an stable, mono-ligated Pd precatalyst. Precatalysts bearing ligands 1 ,6a 2 ,6b and 3 ,6c (4, 5 and 6, respectively) were prepared in excellent yields via the route illustrated in Figure 1. Yields of >85% were obtained for each step of this sequence without the need for a glovebox and using only recrystallization for purification. The X-ray crystal structure of 5 is shown in Figure 2. Calorimetric analysis (Figure 2) shows that activation of 4-6 is complete after ca. 3 minutes when the complexes are treated with NaOt-Am in dioxane at rt. In general, this activation process occurs readily with weak bases (e.g., K 2 CO 3 ) at 80 °C , with alkoxide bases at room temperature, and with HMDS bases at −20 °C, as judged by 31 P NMR. Because of their low nucleophilicity, electron-deficient anilines are typically difficult substrates to employ in C-N cross-coupling reactions. Using 4, numerous highly electrondeficient anilines were successfully coupled with unactivated aryl chlorides in excellent yields (Table 1)...

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.

Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of stereochemistry in these reactions remain poorly understood. Herein we report a mechanistic and synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine ligands, we could apply predictive statistical models to select or design distinct ligands that respectively promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and a general model for the mechanism of alkylboron transmetallation was proposed.