Conversion of Amides into Esters by the Nickel-Catalyzed Activation of Amide C-N Bonds

The amide function is ubiquitous in natural compounds as well as in man-made molecules and materials. It is generally very stable and poorly reactive owing to its resonance-stabilized C–N group that imparts a planar geometry to amides. In contrast, carboxylic esters are generally reactive under a variety of mild conditions; therefore, it is not surprising that a number of direct methods are available to the chemist for converting esters into amides (amino-de-alkoxylation reaction) but very few for achieving the opposite transformation. Recently, Professors Neil Garg and Ken Houk from the University of California, Los Angeles (UCLA, USA) reported in Nature a groundbreaking method for converting amides into esters with a high degree of efficiency

Nickel-Catalyzed Amination of Aryl Carbamates and Sulfamates Using an Air-Stable Precatalyst

This study describes a facile nickel-catalyzed method to achieve the synthetically useful amination of aryl sulfamates and carbamates. This approach uses an air-stable Ni(II) precatalyst, which, when employed with a mild reducing agent, efficiently delivers aminated products in good yields. The scope of the method is broad with respect to both coupling partners. For instance, substrates with electron-donating and electron-withdrawing groups are tolerated, as well as those that possess ortho and para substituents. Furthermore, heteroaryl substrates may also be employed as coupling partners

Development of Nickel-Catalyzed Cross-Coupling Reactions

Transition metal-catalyzed cross-couplings provide a powerful means to assemble carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds. Although Pd catalysis is most commonly used in these transformations, Ni catalysis offers a valuable alternative due to the low cost and high reactivity of Ni. More importantly, Ni catalysis has proven effective for the activation of traditionally inert carbon–heteroatom bonds and therefore provides exciting opportunities with regard to chemical reactivity and synthetic applications.Chapter one, two, and three describe the development of practical cross-coupling methodologies. Chapter one explains the amination of aryl sulfamates and carbamates that relies on an air-stable Ni(II) precatalyst. Chapter two introduces the development of green cross-couplings of phenolic derivatives and aryl halides to form biaryls. Subsequently, the couplings of heterocycles, which are commonly encountered in natural product synthesis and in the pharmaceutical sector, are described. Chapter three describes the development of green cross-couplings of aryl sulfamates and chlorides to form aryl amines.Chapter four and seven concern the utility of amides as electrophilic cross-coupling partners. These traditionally unreactive moieties are activated by nickel and coupled to alcohols to form acyl C–O bonds. This study suggests that amides may serve as useful building blocks to construct carbon–carbon and carbon–heteroatom bonds. Chapter four describes the development of nickel-catalyzed activation of benzamides and chapter seven introduces the development of nickel-catalyzed activation of aliphatic amide derivatives. Chapter five describes the nickel-catalyzed activation of the acyl carbon–oxygen bonds of methyl esters through an oxidative addition process. The oxidative addition adducts, formed using nickel catalysis, undergo in situ trapping to provide anilide products. DFT calculations are used to support the proposed reaction mechanism, understand why decarbonylation does not occur competitively, and to elucidate the beneficial role of the substrate structure and Al(OtBu)3 additive on the kinetics and thermodynamics of the reaction.Chapter six focus on the nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in bioactive molecules

Nickel-Catalyzed Amination of Aryl Chlorides and Sulfamates in 2-Methyl-THF.

The nickel-catalyzed amination of aryl O-sulfamates and chlorides using the green solvent 2-methyl-THF is reported. This methodology employs the commercially available and air-stable precatalyst NiCl2(DME), is broad in scope, and provides access to aryl amines in synthetically useful yields. The utility of this methodology is underscored by examples of gram-scale couplings conducted with catalyst loadings as low as 1 mol % nickel. Moreover, the nickel-catalyzed amination described is tolerant of heterocycles and should prove useful in the synthesis of pharmaceutical candidates and other heteroatom-containing compounds

Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH)2, proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O-glycosylated peptides in water