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.
A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.
A practical procedure for 11CN-labeling of native peptides has been developed. The process involves two sequential Pd-mediated cross-coupling reactions at the cysteine residue of a peptide and operates under mild conditions. The method was shown to be highly chemoselective for cysteine over other potentially nucleophilic residues and the radiolabelled products were synthesized and purified in less than 15 minutes. Appropriate for biomedical applications, the method could be used on extremely small scale (20 nmol) with high radiochemical yield. The success of the protocol stems from the use of a Pd-reagent based on a dihaloarene, which enables direct “nucleophile-nucleophile” coupling of the peptide and [11C]-cyanide by temporal separation of nucleophile addition.
Contemporary organic chemists employ a broad range of catalytic and stoichiometric methods to construct molecules for applications in many fields, including material sciences1, pharmaceuticals2–5, agrochemicals, and sensors6. The potential utility of a synthetic method can be greatly reduced if it relies on the use of air- and/or moisture-sensitive reagents or catalysts. Furthermore, many synthetic chemistry laboratories have numerous containers of partially used reagents that have been spoiled by exposure to the ambient atmosphere. This is exceptionally wasteful from both an environmental and a cost perspective. In this manuscript, we report an encapsulation method through which air- and moisture-sensitive sensitive compounds can be rendered stable and stored on a laboratory bench top. We demonstrate this approach in three contexts, by describing single use capsules that contain all of the reagents (i.e., catalysts, ligands, and bases) necessary for palladium-catalyzed carbon–fluorine7–9, carbon–nitrogen10,11, and carbon–carbon12 bond forming reactions. The strategy described in this paper should be broadly applicable to a wide range of reagents and catalysts and should have the power to be transformative in preparative organic chemistry, particularly for inexperienced chemists. In addition, this approach will reduce the amount of tedious and time-consuming weighing procedures for the synthetic chemist performing these techniques on a large number of substrate combinations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.