The stable Pd(0) species [(1,5-cyclooctadiene)(L•Pd) 2 ] (L = AdBrettPhos) has been prepared and successfully evaluated as a precatalyst for the fluorination of aryl triflates derived from biologically active and heteroaryl phenols, challenging substrates for our previously reported catalyst system. Additionally, this precatalyst activates at room temperature under neutral conditions, generates 1,5-cyclooctadiene as the only byproduct, and leads to overall cleaner reaction profiles.Fluorination of aromatic rings is a widely used strategy for modifying the biological activities of potential pharmaceutical and agrochemical agents. 1 In addition, 18 F-substituted compounds are important radiotracers for positron emission tomography (PET). 2 Aryl fluorides are typically installed early in a target molecule's synthesis using the harsh BalzSchiemann reaction, making the synthesis of 18 F-radiotracers and highly functionalized fluorinated materials difficult. Although a number of methods for electrophilic aryl fluorination with Ag, 3 Pd, 4 and Cu 5 catalysts, and without added transition metals, 6 have been developed to address this need, these reactions typically do not tolerate easily oxidizable functional groups such as tertiary amines and electron-rich heterocycles, result in 5-50% reduction of the starting material, and/or require the synthesis of unstable or toxic organometallic reagents. The direct transformation of aryl (pseudo)halides to aryl fluorides using a metal fluoride salt is a promising alternative to electrophilic fluorination in terms of generality and practicality 7 that has received less attention than electrophilic fluorination methods. 8 To this end, we reported the successful coupling of aryl triflates with CsF using a Pd catalyst based on the bulkyl biaryl phosphine ligand tBuBrettPhos (1) (Figure 1). 9,10 However, there remains a strong need for the further development of simple methods for aryl fluorination that demonstrate broad substrate scope and clean reaction profiles.Our original catalyst system of [(cinnamyl)PdCl] 2 /1 facilitates the catalytic fluorination of a variety of aryl triflates with minimal formation (<5%) of the corresponding reduction product. 9b However, this method suffers from poor reactivity with highly electron-rich and * sbuchwal@mit.edu. Supporting Information AvailableProcedural and spectroscopic data for all compounds are provided. This data is provided free of charge at http://pubs.acs.org. (Figure 1) was found to be more capable in the fluorination of these substrates (Table 1, Entry 2), though formation of two regioisomeric aryl fluorides was observed in the case of estrone triflate. 9b The effectiveness of a catalyst based on 2 is likely due to the faster rate of reductive elimination from Pd-F intermediates bearing 2 compared to those bearing 1. 11 However, the use of [(cinnamyl)PdCl] 2 as the source of active Pd requires 1.5 equiv of 2 relative to Pd to be added and results in generation of one equivalent of "Cl − ", which participates in a compe...

We describe an efficient and mild method for the synthesis of macrocyclic peptides via nitrogen arylation from unprotected precursors. Various electro-philes and lysine-based nucleophiles were investigated and showed high-yielding product formation, even for a macrocyclization scan with 14 variants. We found that nitrogen-linked aryl products were more stable to base and oxidation when compared to thiol arylated species, thereby highlighting the utility of this methodology. Finally, N-aryl macrocyclization was performed on a p53 peptide inhibitor of MDM2 and resulted in identification of a nanomolar binder with improved proteolytic stability and cell permeability.

A mild method for the arylation of lysine in an unprotected peptide is presented. In the presence of a preformed biarylphosphine-supported Pd(II)-aryl complex and weak base, lysine amino groups underwent C–N bond formation at room temperature. The process generally exhibited high selectivity for lysine over other amino acids containing nucleophilic side chains and was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, with an array of peptides. Lastly, this method was also successfully applied to the formation of cyclic peptides via macrocyclization.

On the basis of mechanism-driven reaction design, a Pd-catalyzed nucleophilic fluorination of aryl bromides and iodides has been developed. The method exhibits a broad substrate scope, especially with respect to nitrogen-containing heteroaryl bromides, and proceeds with minimal formation of the corresponding reduction products. A facilitated ligand modification process was shown to be critical to the success of the reaction.

A new radiosynthetic protocol for the preparation of [11C]aryl nitriles has been developed. This process is based on the direct reaction of in situ prepared L•Pd(Ar)X complexes (L=biaryl phosphine) with [11C]HCN. The strategy is operationally simple, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of [11C]nitrile-containing pharmaceuticals were prepared with high radiochemical efficiency.