In Pd-catalyzed C-N cross-coupling reactions α-branched secondary amines are hard IWR-1-endo coupling partners and the desired products are often produced in low yields. of pharmaceutically relevant compounds and biologically active natural products (Number 1). Although Pd-catalyzed carbon-nitrogen (C-N) cross-coupling would provide an efficient means of accessing this valuable class of chemical substances the use of α-branched secondary amine nucleophiles offers seen only limited success and in many instances low yields of the desired product are acquired. Other methods for preparing tertiary N-aryl α-branched amines rely on the addition of an PLA2B amine to an aryne or nucleophilic aromatic substitution. While effective these methods IWR-1-endo typically have a narrow substrate scope or result in a mixture of regioisomeric products. Copper-catalyzed electrophilic amination has also been utilized  with a recent record by Lalic demonstrating its IWR-1-endo effectiveness for the arylation of sterically hindered secondary O-benzoyl hydroxylamine electrophiles.[5b] Despite these advances there remains no general method for the direct arylation of α-branched secondary amines. Consequently we sought to develop a catalyst system capable of cross-coupling sterically encumbered secondary amines. Number 1 Selected examples of biologically active compounds comprising tertiary N-aryl α-branched amines. The development of a highly effective catalyst system for the arylation of α-branched secondary amines must address the specific challenges presented by these coupling partners. Their poor nucleophilicity as a consequence steric hindrance can lead to slower rates of amine transmetalation resulting in the competitive reaction of the alkoxide foundation and formation of the related aryl tert-butyl ether (ArOtBu) (V Number 2). Additionally β-hydride removal may occur from your intermediate Pd(II)-amido complex[6 7 (IV Number 2) leading to the formation of the reduced arene (VI Number 2). In this IWR-1-endo regard the assisting ligand for the palladium catalyst must be cautiously IWR-1-endo designed in order to facilitate the preferential formation of the desired aryl amine while suppressing part reactions. Number 2 Proposed catalytic cycle and potential difficulties offered by sterically hindered α-branched secondary amine nucleophiles. We began our investigation by examining the effect of the assisting ligands within the efficiency of the catalyst system for the reaction shown in Table 1. RuPhos(L1)-based catalyst systems have been demonstrated to be highly effective for the cross-coupling of secondary amines  including some instances of reactions between sterically demanding coupling partners.[2a 2 However when RuPhos precatalyst P1 was used in the reaction of 2-bromo-p-xylene (1a) and 2-ethylpiperidine (1b) only a 10% yield of the desired product was obtained (Table 1 access 1). Additional biaryl phosphine ligands such as XPhos (L2) and BrettPhos (L3) have also been used for advertising Pd-catalyzed C-N relationship formation. Nevertheless these catalyst systems (P2 and P3 respectively) proved to be inefficient in facilitating the desired transformation (Table 1 entries 2-3). In all instances the major byproduct was the reduced arene which presumably occurs as a result of β-hydride removal. Table 1 Supporting Ligand Evaluation.[a] Specific these results we turned to CPhos (L4 Table 1) which has been demonstrated to suppress β-hydride removal in Pd-catalyzed Negishi cross-coupling reactions. Indeed CPhos precatalyst P4 produced aryl amine 1c in improved yield although the reduced arene remained the major product (Table 1 entry 4). In the proposed catalytic cycle the β-hydride removal pathway competes with reductive removal from your Pd(II)-amido intermediate (IV Number 2). We therefore envisoned that using a less electron-rich biaryl phosphine ligand would increase the rate of C-N reductive removal. A less electron-rich biaryl phosphine ligand could also increase the rate of transmetalation (amine binding and deprotonation Number 2) by rendering the Pd(II) intermediates II and III more electrophilic (Number 2). Based on this IWR-1-endo hypothesis we examined a catalyst system utilizing the ligand L5 (P5 Table 1).[14 15 The use of precatalyst P5 dramatically increased the yield of 1c along while reducing the amount of reduced arene formed (Table 1 access 5). Following these results we changed the phosphorus substituents from phenyl to 3 5 organizations to provide ligand L6 (P6 Table 1); this led to additional improvement in the yield and further diminished the formation of.