N-substituted 2-aminobiphenylpalladium Methanesulfonate Precatalysts and Their Use in C–c and C–n Cross-couplings Publisher Version Accessed Terms of Use Detailed Terms

A series of phosphine-ligated palladium precatalysts based on N-methyland N-phenyl-2-aminobiphenyl have been developed. Substitution at the nitrogen center prevents the presence of traces of aminobiphenyls that contain a free −NH2 group from contaminating cross-coupling products. These precatalysts produce N-substituted carbazoles upon activation, which cannot consume starting materials. These precatalysts were efficiently generated from 2-aminobiphenyl with minimal purification and found to be highly effective in Suzuki−Miyaura and C−N cross-coupling reactions. W recently reported palladium precatalysts based on a ligated 2-aminobiphenylpalladium methanesulfonate palladacycle (1, Scheme 1). Precatalyst 1 activates through the deprotonation of the palladium-bound amine to give a Pd− amido complex which then reductively eliminates to form carbazole, a methanesulfonate salt, and LPd(0). Precatalysts of type 1 can accommodate a variety of ligands and are applicable to numerous palladium-catalyzed transformations. Despite the advantages of 1, a few drawbacks limit their utility in some applications, including (1) the carbazole byproduct generated through the activation of 1 can be Narylated, consuming valuable starting materials or potentially complicating work-up/purification of the desired product, and (2) there is some concern regarding the presence of trace amounts of residual NH2-aminobiphenyls in pharmaceutical samples due to potential health risks. N-Alkyl and N-aryl analogues of 1 would overcome these concerns and provide a useful alternative to 1. N-Substituted 2-aminobiphenyls could be readily prepared on a 30 mmol scale via N-methylation and N-arylation as shown in Scheme 2. The unpurified products from these reactions can be directly used to prepare the corresponding palladacycles. Treatment of N-methyl-2-aminobiphenyl, 2, and N-phenyl-2-aminobiphenyl, 3, with methanesulfonic acid followed by heating the resulting salt solution with Pd(OAc)2 provided the dimeric palladacycles 4 and 5. These procedures were amenable to scale up, providing the desired palladium dimers in excellent yields at a 30 mmol scale (Scheme 3). These were subsequently treated with phosphines at room temperature in dichloromethane to provide the N-substituted precatalysts (Scheme 4). Precatalysts that incorporated a variety Received: February 13, 2014 Published: April 11, 2014 Scheme 1. Palladium Methanesulfonate Precatalysts and Their Generic Activation Scheme 2. Preparation of N-Methyland N-Phenyl-2aminobiphenyl Derivatives (i) nBuLi, THF, 0 °C, 30 min; (ii) MeI, 0 °C to rt, 30 min, quant conversion. 1 mol % 1·L1, PhCl, NaOtBu, dioxane, 100 °C, 30 min, 99%. Scheme 3. Preparation of N-Substituted μ-OMs Palladium Dimers Note