Nitrogen-containing compounds are the most common structural architectures in drug candidates, natural and biological products, and small-molecule therapeutics. Within the body of work of transition-metal-catalyzed direct C−H amination reactions, palladium remains in the forefront and has been established as one of the most useful transition metals for C−N bond formation. The fundamental organometallic reactivity of palladium in its 0, I, II, III, and IV oxidation states make it special and useful in challenging carbon−heteroatom bond-formation reactions. Palladium undergoes facile formation of chelation-assisted palladacycle and palladiumnitrenoid intermediates that open an avenue for new bond formation. It has been utilized in various new synthetic approaches toward both intermolecular and intramolecular C−N bond formation reactions that employ nitrogen sources ranging from free, unprotected amines to electrophilic nitrogen sources. Palladium's compatibility with various functional groups and oxidants as well as the mild reaction conditions (temperature and air atmosphere) used with this metal have attracted many scientists to the area and will continue to advance new mechanistic insights and opportunities to explore palladium catalysis for C−N bond synthesis. Here, we summarize the progress of Pd-catalyzed C−N bond advances involving both the reaction development and mechanisms in numerous synthetically useful intra-and intermolecular C−H catalytic aminations.

Excellent selectivity with complexes of DIOP, BDPP and Josiphos with E-1,3-dienes reacting faster than the Z-isomers at low temperatures.

In reaction discovery, the search space of discrete reaction parameters such as catalyst structure is often not explored systematically. We have developed a tool set to aid the search of optimal catalysts in the context of phosphine ligands. A virtual library, kraken, which is representative of the monodentate P­(III)-ligand chemical space, was utilized as the basis to represent the discrete ligands as continuous variables. Using dimensionality reduction and clustering techniques, we suggested a Phosphine Optimization Screening Set (PHOSS) of 32 commercially available ligands that samples this chemical space completely and evenly. We present the application of this screening set in the identification of active catalysts for various cross-coupling reactions and show how well-distributed sampling of the chemical space facilitates identification of active catalysts. Furthermore, we demonstrate how proximity in ligand space can be a useful guide to further explore ligands when very few active catalysts are known.

reviewed by Ezequiel Perez-Inestrosa and Donald A. Tomalia) 2,2-Bis(azidomethyl)propionic acid was prepared in four steps and 85% yield from the commercially available 2,2-bis(hydroxymethyl) propionic acid and used as the starting building block for the divergent, convergent, and double-stage convergent-divergent iterative methods for the synthesis of dendrimers and dendrons containing ethylenediamine (EDA), piperazine (PPZ), and methyl 2,2-bis(aminomethyl)propionate (COOMe) cores. These cores have the same multiplicity but different conformations. A diversity of synthetic methods were used for the synthesis of dendrimers and dendrons. Regardless of the method used, a self-interruption of the synthesis was observed at generation 4 for the dendrimer with an EDA core and at generation 5 for the one with a PPZ core, whereas for the COOMe core, self-interruption was observed at generation 6 dendron, which is equivalent to generation 5 dendrimer. Molecular modeling and molecular-dynamics simulations demonstrated that the observed self-interruption is determined by the backfolding of the azide groups at the periphery of the dendrimer. The latter conformation inhibits completely the heterogeneous hydrogenation of the azide groups catalyzed by 10% Pd/carbon as well as homogeneous hydrogenation by the Staudinger method. These self-terminated polyamide dendrimers are enzymatically and hydrolytically stable and also exhibit antimicrobial activity. Thus, these nanoscale constructs open avenues for biomedical applications.dendrons | ethylenediamine core | piperazine core | antimicrobials | nanomedicine