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

Reaction Discovery Using Nickel Catalysis and Total Syntheses of Indolactam Alkaloids

Transition metal-catalyzed cross-coupling reactions are useful tools to assemble carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds. Traditionally, electrophilic halides and pseudohalides have been cross-coupled to their nucleophilic counterparts with palladium. Recently, however, the implementation of nickel as a catalyst for cross-coupling reactions has enabled the use of less reactive cross-coupling partners, such as carbamates, sulfamates, and amides. This dissertation describes the development of nickel-catalyzed cross-couplings of untraditional electrophiles to forge carbon–heteroatom (C–X) bonds. Additionally, the total syntheses of four indolactam alkaloids, indolactam V, pendolmycin, lyngbyatoxin A, and teleocidin A-2, using both a key distortion-controlled indolyne reaction and palladium-catalyzed sp2–sp3 C–C bond construction, are described.Chapters one and two describe the development of nickel-catalyzed amination reactions of aryl electrophiles to form carbon–nitrogen (C–N) bonds. The amination reaction of aryl carbamates to form aryl amines is discussed. Subsequently, the development of green cross-couplings of aryl sulfamates and chlorides to similarly form aryl amines is reported.Chapter three introduces a means to accomplish a controlled cine substitution. This two-step process is comprised of a carbamate-directed ortho-lithiation/functionalization of an arene, followed by a nickel-catalyzed reductive deoxygenation of the directing group. This sequence provides a new strategy for synthesis and complements the more commonly employed ipso substitution in arene functionalization.Chapter four concerns 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 C–X and C–C bonds.Chapter five describes the total syntheses of (–)-indolactam V and its C7-substituted natural product derivatives, (–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The C4–N linkage is constructed with a distortion-controlled indolyne functionalization. The total synthesis of (–)-indolactam V provides a platform for the divergent syntheses of the other three natural products via a palladium-catalyzed cross-coupling to functionalize C7 and introduce a quaternary center

Reaction Discovery Using Nickel Catalysis and Total Syntheses of Indolactam Alkaloids

Transition metal-catalyzed cross-coupling reactions are useful tools to assemble carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds. Traditionally, electrophilic halides and pseudohalides have been cross-coupled to their nucleophilic counterparts with palladium. Recently, however, the implementation of nickel as a catalyst for cross-coupling reactions has enabled the use of less reactive cross-coupling partners, such as carbamates, sulfamates, and amides. This dissertation describes the development of nickel-catalyzed cross-couplings of untraditional electrophiles to forge carbon–heteroatom (C–X) bonds. Additionally, the total syntheses of four indolactam alkaloids, indolactam V, pendolmycin, lyngbyatoxin A, and teleocidin A-2, using both a key distortion-controlled indolyne reaction and palladium-catalyzed sp2–sp3 C–C bond construction, are described.Chapters one and two describe the development of nickel-catalyzed amination reactions of aryl electrophiles to form carbon–nitrogen (C–N) bonds. The amination reaction of aryl carbamates to form aryl amines is discussed. Subsequently, the development of green cross-couplings of aryl sulfamates and chlorides to similarly form aryl amines is reported.Chapter three introduces a means to accomplish a controlled cine substitution. This two-step process is comprised of a carbamate-directed ortho-lithiation/functionalization of an arene, followed by a nickel-catalyzed reductive deoxygenation of the directing group. This sequence provides a new strategy for synthesis and complements the more commonly employed ipso substitution in arene functionalization.Chapter four concerns 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 C–X and C–C bonds.Chapter five describes the total syntheses of (–)-indolactam V and its C7-substituted natural product derivatives, (–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The C4–N linkage is constructed with a distortion-controlled indolyne functionalization. The total synthesis of (–)-indolactam V provides a platform for the divergent syntheses of the other three natural products via a palladium-catalyzed cross-coupling to functionalize C7 and introduce a quaternary center

Cine Substitution of Arenes Using the Aryl Carbamate as a Removable Directing Group

An efficient and controlled means to achieve a rare cine substitution of arenes is reported. The methodology relies on the strategic use of aryl <i>O</i>-carbamates as readily removable directing groups for arene functionalization. The removal of aryl carbamates is achieved by employing an air-stable Ni(II) precatalyst, along with an inexpensive reducing agent, to give synthetically useful yields across a range of substrates. The net cine substitution process offers a new strategy for analogue synthesis, which complements the well-established logic for achieving arene functionalization by ipso substitution

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

Total syntheses of indolactam alkaloids (−)-indolactam V, (−)-pendolmycin, (−)-lyngbyatoxin A, and (−)-teleocidin A-2

We report the total syntheses of (-)-indolactam V and the C7-substituted indolactam alkaloids (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2. The strategy for preparing indolactam V relies on a distortion-controlled indolyne functionalization reaction to establish the C4-N linkage, in addition to an intramolecular conjugate addition to build the conformationally-flexible nine-membered ring. The total synthesis of indolactam V then sets the stage for the divergent synthesis of the other targeted alkaloids. Specifically, late-stage sp2-sp3 cross-couplings on an indolactam V derivative are used to introduce the key C7 substituents and the necessary quaternary carbons. These challenging couplings, in addition to other delicate manipulations, all proceed in the presence of a basic tertiary amine, an unprotected secondary amide, and an unprotected indole. Thus, our approach not only enables the enantiospecific total syntheses of four indolactam alkaloids, but also serves as a platform for probing complexity-generating and chemoselective transformations in the context of alkaloid total synthesis

Quantification of the Electrophilicity of Benzyne and Related Intermediates

The determination of reactivity parameters for short-lived intermediates provides an indispensable tool for synthetic design. Despite that electrophilicity parameters have now been established for more than 250 reactive species, the corresponding parameters for benzyne and related intermediates have not been uncovered. We report a study that has allowed for the quantification of benzyne’s electrophilicity parameter. Our approach relies on the strategic use of the diffusion-clock method and also provides electrophilicity parameters <i>E</i> for other substituted arynes

Nickel‐Catalyzed Activation of Acyl C−O Bonds of Methyl Esters

We report the first catalytic method for activating the acyl C–O 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