Modular synthesis of α-branched secondary alkylamines visible-light-mediated carbonyl alkylative amination.

The development of methods for the assembly of secondary α-alkyl amines remains a central challenge to chemical synthesis because of their critical importance in modulating the physical properties of biologically active molecules. Despite decades of intensive research, chemists still rely on selective N-alkylation and carbonyl reductive amination to make most amine products. Here we report the further evolution of a carbonyl alkylative amination process that, for the first time, brings together primary amines, aldehydes and alkyl iodides in a visible-light-mediated multicomponent coupling reaction for the synthesis of a wide range of α-branched secondary alkylamines.

Modular Synthesis of Heterobenzylic Amines via Carbonyl Azinylative Amination.

Transformations enabling the synthesis of α-alkyl, α'-2-azinyl amines by addition of 2-heteroaryl-based nucleophiles to in situ-generated and non-activated alkyl-substituted iminium ions are extremely rare. Approaches involving classical 2-azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2-azinyl indium nucleophile, generated in situ from the corresponding 2-iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction.

Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction.

Methods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite the development of many methods for amine preparation, C(sp)-rich nitrogen-containing compounds continue to pose challenges for synthesis. While carbonyl reductive amination (CRA) between ketones and alkylamines is the cornerstone method for α-branched alkylamine synthesis, it is sometimes limited by the sterically demanding condensation step between dialkyl ketones and amines and the more restricted availability of ketones compared to aldehydes.

C(sp)-C(sp) coupling of non-activated alkyl-iodides with electron-deficient alkenes visible-light/silane-mediated alkyl-radical formation.

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides. An interaction between a silane and an alkyl iodide is excited by irradiation with visible light to trigger carbon-iodide bond homolysis and form the alkyl radical. We show how this method can be developed into an operationally simple and general Giese addition reaction that can tolerate a range of sensitive functionalities not normally explored in established approaches to this strategically important transformation.

Visible light-mediated radical fluoromethylation halogen atom transfer activation of fluoroiodomethane.

Incorporation of the fluoromethyl group can profoundly influence the physicochemical properties of organic molecules, offering a promising strategy for the discovery of novel pharmaceutical agents. Direct fluoromethylation of unfunctionalized C(sp) centres can be achieved using fluoromethyl radicals, but current methods for their generation usually rely on the activation of non-commercial or expensive radical precursors inefficient single electron transfer pathways, which limits their synthetic application. Here we report the development of a fluoromethylation strategy based on the generation of fluoromethyl radicals from commercially available fluoroiodomethane halogen atom transfer.

Visible-light mediated carbonyl trifluoromethylative amination as a practical method for the synthesis of β-trifluoromethyl tertiary alkylamines.

We report the development of an operationally straigtforward, visible-light-mediated multicomponent strategy for the construction of β-trifluoromethylated tertiary alkylamines from feedstock aldehydes, secondary amines and a convenient source of trifluoromethyl iodide. The new process does not require a photocatalyst, is metal-free, displays a broad functional group tolerance and offers rapid, one-pot access to trifluoromethylated drug-like compounds that will be of interest in medicinal chemistry.

Visible-Light-Mediated Carbonyl Alkylative Amination to All-Alkyl α-Tertiary Amino Acid Derivatives.

The all-alkyl α-tertiary amino acid scaffold represents an important structural feature in many biologically and pharmaceutically relevant molecules. Syntheses of this class of molecule, however, often involve multiple steps and require activating auxiliary groups on the nitrogen atom or tailored building blocks. Here, we report a straightforward, single-step, and modular methodology for the synthesis of all-alkyl α-tertiary amino esters.

Phosphorescent κ -(N^C^C)-Gold(III) Complexes: Synthesis, Photophysics, Computational Studies and Application to Solution-Processable OLEDs.

Efficient OLED devices have been fabricated using organometallic complexes of platinum group metals. Still, the high material cost and low stability represent central challenges for their application in commercial display technologies. Based on its innate stability, gold(III) complexes are emerging as promising candidates for high-performance OLEDs.

A general carbonyl alkylative amination for tertiary amine synthesis.

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes has stimulated efforts towards their streamlined synthesis. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ.

The LANCA three-component reaction to highly substituted β-ketoenamides - versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives.

The LANCA three-component reaction of lithiated alkoxyallenes , nitriles and carboxylic acids leads to β-ketoenamides in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions.

The First Gold(III) Formate: Evidence for β-Hydride Elimination.

The first stable gold(III) formate and experimental evidence for its β-hydride elimination are described. A catalytic dehydrogenation of formic acid together with mechanistic studies shed light on potential pathways operating in fundamental gold-catalyzed transformations.

Gold-Catalyzed Direct Oxidative Arylation with Boron Coupling Partners.

An efficient synthesis of biaryls through a gold-catalyzed oxidative cross-coupling of arenes with strong electron-deprived aryl boronates is presented herein. Regio- and chemocontrol are achieved by the selective activation of these coupling partners by gold at different oxidation states. Under reaction conditions devoid of basic additives or directing groups, the role of acetato ligand as an internal base has been revealed as a key parameter for expanding the reaction scope in these transformations.

Cyclometalated Gold(III) Complexes: Synthesis, Reactivity, and Physicochemical Properties.

This Review showcases the ability of bi- and tridentate ligands to stabilize gold in high oxidation states through the formation of mono- and biscyclometalated gold(III) complexes. In-depth studies on the synthesis, intrinsic reactivity, catalytic relevance, and photophysical properties of stabilized gold(III) species have been carried out, setting the stage for exciting developments in various research areas, such as catalysis, inorganic and bioinorganic chemistry, ligand design, and materials science.

Evidence for Direct Transmetalation of Au-F with Boronic Acids.

The underlying reactivity of Au-F species with aryl boronic acids has been studied in detail taking advantage of four novel, stable difluoro-[(C^N)AuF], arylmonofluoro-[(C^N)AuArF], and alkylmonofluoro-[(C^N)AuAlkF] gold(III) complexes, prepared and isolated in monomeric form. We provide the first experimental evidence for a direct Au-F/B transmetalation preceding the Csp-Csp or Csp-Csp bond formation.

Luminescent (N^C^C) Gold(III) Complexes: Stabilized Gold(III) Fluorides.

We report the design, synthesis, and application of a (N^C^C)-ligand framework able to stabilize highly electron-deprived gold(III) species. This novel platform enabled the preparation of C(sp(2))-gold(III) fluorides for the first time in monomeric, easy-to-handle, bench-stable form by a Cl/F ligand-exchange reaction. Devoid of oxidative conditions or stoichiometric use of toxic Hg salts, this method was applied to the preparation of multiple [C(sp(2))-Au(III)-F] complexes, which were used as mechanistic probes for the study of the unique properties and intrinsic reactivity of Au-F bonds.

A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction.

A practical approach to highly functionalized 4-hydroxypyridine derivatives with stereogenic side chains in the 2- and 6-positions is described. The presented two-step process utilizes a multicomponent reaction of alkoxyallenes, nitriles and carboxylic acids to provide β-methoxy-β-ketoenamides which are transformed into 4-hydroxypyridines in a subsequent cyclocondensation. The process shows broad substrate scope and leads to differentially substituted enantiopure pyridines in good to moderate yields.