In Pd-catalyzed C-N cross-coupling reactions α-branched secondary amines are hard

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).[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.[2] Other methods for preparing tertiary N-aryl α-branched amines rely on the addition of an PLA2B amine to an aryne[3] or nucleophilic aromatic substitution.[4] While effective these methods IWR-1-endo typically have a narrow substrate scope or result in a mixture of regioisomeric products.[3] Copper-catalyzed electrophilic amination has also been utilized [5] 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.[1] 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.[8] RuPhos(L1)-based catalyst systems have been demonstrated to be highly effective for the cross-coupling of secondary amines [9] 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.[9] 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.[10] 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.[11] 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.[12] 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).[13] 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.