Palladium-Catalyzed C–H Amination of C(sp²) and C(sp³)–H Bonds: Mechanism and Scope for N-Based Molecule Synthesis

Abstract

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.

Weinreb Amides as Directing Groups for Transition Metal-Catalyzed C-H Functionalizations

“…Palladium is perhaps the most firmly established metal for coupling chemistry [ 58 , 59 , 60 , 61 , 62 ], and this has translated to its high level of popularity for C-H functionalization reactions [ 16 , 63 , 64 , 65 , 66 ]. Many Pd-based catalysts are well-defined [ 67 , 68 ], permitting systematic tuning of their properties, and are understood, most usually, to work via Pd(0)/Pd(II) or Pd(II)/Pd(IV) manifolds [ 62 , 64 , 66 ].…”

“…The discovery of general and efficient methods that allow selective substitution of C(sp 3 )-H at transition metal centers is a long-standing challenge. For Pd, progress has been notably rapid in in the past few years [ 63 , 81 , 82 , 83 ], and its various aspects have been reviewed recently [ 65 , 84 , 85 ].…”

Preparation, Characterization, and Reactivity of Aliphatic Amino Iodane(III) Reagents

“…Furthermore, electrophilic nitrogen sources are an increasingly popular class of reagents for the formation of CÀ N bonds. [12] Although the aforementioned nitrogen-containing hypervalent iodane reagents have been well-explored, the N-atom is commonly required to be protected, such as phenyl, acyl, p-toluenesulfonyl and Phthaloyl. To the best of our knowledge, the preparation, structure and reactivity of the aliphatic aminobenziodoxole has never been documented to date.…”

Conformationally Driven Ru(II)-Catalyzed Multiple ortho-C–H Bond Activation in Diphenylpyrazine Derivatives in Water: Where Is the Limit?

“…Heteroarylation via C-H bond activation has been largely applied to material science, for example, the synthesis of conjugated dyes [8] and polymers [9]. Although Pd [10][11][12][13][14] and Rh [15][16][17][18] catalysts are very efficient in enabling the selective functionalization of C-H bonds, the use of easy-to-prepare, air-stable, often stable in water and functional groups tolerant Ru(II) complexes have attracted much interest in the development of efficient catalytic systems for these processes [19][20][21][22][23][24][25][26]. Despite the ubiquity of C-H bonds in organic molecules, the regioselectivity of C-H bond functionalization can elegantly be controlled by chelation assistance of directing groups [27][28][29][30][31][32].…”