Tandem Dearomatization/Enantioselective Allylic Alkylation of Pyridines.

Herein, we report a multistep one-pot reaction of substituted pyridines leading to N-protected tetrahydropyridines with outstanding enantioselectivity (up to 97% ee). An iridium(I)-catalyzed dearomative 1,2-hydrosilylation of pyridines enables the use of N-silyl enamines as a new type of nucleophile in a subsequent palladium-catalyzed asymmetric allylic alkylation. This telescoped process overcomes the intrinsic nucleophilic selectivity of pyridines to synthesize enantioenriched, C-3-substituted tetrahydropyridine products that have been otherwise challenging to access.

A negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites.

Metabolic distribution of fatty acid to organelles is an essential biological process for energy homeostasis as well as for the maintenance of membrane integrity, and the metabolic pathways are strictly regulated in response to environmental stimuli. Herein, we report a fluorescent fatty acid probe, which bears an azapyrene dye that changes its absorption and emission features depending on the microenvironment polarity of the organelle into which it is transported. Owing to the environmental sensitivity of this dye, the distribution of the metabolically incorporated probe in non-polar lipid droplets, medium-polarity membranes, and the polar aqueous regions, can be visualized in different colors. Based on density scatter plots of the fluorophore, we demonstrate that the degradation of triacylglycerols in lipid droplets occurs predominantly via lipolysis rather than lipophagy in nutrition-starved hepatocytes. This tool can thus be expected to significantly advance our understanding of the lipid metabolism in living organisms.

Silver-Catalysed Hydroarylation of Highly Substituted Styrenes.

Hydroarylation is an effective strategy to rapidly increase the complexity of organic structures by transforming flat alkene moieties into three-dimensional frameworks. Many strategies have already been developed to achieve the hydroarylation of styrenes, however most of these reports examine the hydroarylation of unpolar, ß-mono- or ß-unsubstituted styrenes, while exploring mainly electron-rich benzene nucleophiles. Herein, we report a mild and general catalytic system for the selective hydroheteroarylation of multiply substituted styrenes and heteroaromatic styrenes. Mechanistic analysis of the reaction led to the discovery of commercially available 2,2':5',2''-terthiophene as a key reagent.

Twofold C-H Activation Enables Synthesis of a Diazacoronene-Type Fluorophore with Near Infrared Emission Through Isosteric Replacement.

The synthesis and photophysical properties of a soluble amide-embedded coronene is reported. The key step in this synthesis is the twofold C-H activation of diazaperylene by a rhodium(III)Cp* catalyst. This unprecedented structural motif shows intense fluorescence in the near infrared region with a small Stokes shift and a distinct vibronic structure, which exhibits a slight extent of negative solvatochromism. Comparison of this compound with some relevant compounds revealed the importance of the amide incorporation in the peripheral concave region including an angular position to retain high aromaticity reflecting that of parent coronene. Treatment of this compound with Lewis acid B(C6 F5 )3 formed a bis-adduct, which exhibited enhanced aromaticity as a consequence of the increased double bond character of the amide C-N bonds.

Site-selective C-H activation and regiospecific annulation using propargylic carbonates.

Herein we describe an unprecedented RuII-catalyzed site-selective and regiospecific annulation of benzoic acids with propargylic carbonates. The weakly coordinating carboxylic acid moiety outperformed other typically used directing groups in C-H activation, including ketone, nitrile, sulfonamide, amide and strongly coordinating nitrogen heterocycles. This is an important step towards the application of C-H activation reactions in complex (functional) real-world molecules.

Ligand-Enabled Enantioselective Csp3 -H Activation of Tetrahydroquinolines and Saturated Aza-Heterocycles by RhI.

The first rhodium(I)-catalyzed enantioselective intermolecular Csp3 -H activation of various saturated aza-heterocycles including tetrahydroquinolines, piperidines, piperazines, azetidines, pyrrolidines, and azepanes is presented. The combination of a rhodium(I) precatalyst and a chiral monodentate phosphonite ligand is shown to be a powerful catalytic system to access a variety of important enantio-enriched heterocycles from simple starting materials. Notably, the Csp3 -H activation of tetrahydroquinolines is especially challenging due to the adjacent Csp2 -H bond. This redox-neutral methodology provides a new synthetic route to α-N-arylated heterocycles with high chemoselectivity and enantioselectivity up to 97 % ee.

Manganese(I)-Catalyzed C-H (2-Indolyl)methylation: Expedient Access to Diheteroarylmethanes.

An unprecedented MnI -catalyzed (2-indolyl)methylation of heteroarenes is reported. This method makes use of an aromatizing cascade strategy to install a (2-indolyl)methyl group into target molecules, thereby leading to the expedient synthesis of previously challenging and important unsymmetrical diheteroarylmethanes, in particular bis(2-indolyl)methanes. The proposed cascade process comprises the reorganization of multiple bonds with controlled regioselectivity and high atom economy and can be performed on a gram-scale. Furthermore, a metal-free C-H propargylation is observed. The diverse application of this method is also demonstrated.

Highly Selective Manganese(I)/Lewis Acid Cocatalyzed Direct C-H Propargylation Using Bromoallenes.

A manganese(I)/Lewis acid cocatalyzed direct C-H propargylation with high selectivity has been developed. BPh3 was discovered to not only promote the reactivity, but also enhance the selectivity. Secondary, tertiary, and even quaternary carbon centers at the propargylic position could be directly constructed. Both internal and terminal alkynes are easily accessible. The chirality was successfully transferred from an axially chiral allene to central chirality. The reactivity of the manganese catalyst in this reaction was found to be unique among transition metal catalysts.

Redox-Neutral Manganese(I)-Catalyzed C-H Activation: Traceless Directing Group Enabled Regioselective Annulation.

A strategy is reported in which traceless directing groups (TDGs) are used to promote the redox-neutral MnI -catalyzed regioselective synthesis of N-heterocycles. Alkyne coupling partners bearing a traceless directing group, which serves as both the chelator and internal oxidant, were used to control the regioselectivity of the annulation reactions. This operationally simple approach is highly effective with previously challenging unsymmetrical alkyne systems, including unbiased dialkyl alkynes, with perfect regioselectivity. The simple conditions and the ability to carry out synthesis on a gram scale underscore the usefulness of this method. The application of this strategy in the concise synthesis of the bioactive compound PK11209 and the pharmaceutical moxaverine is also described.

Manganese(I)-Catalyzed Regioselective C-H Allenylation: Direct Access to 2-Allenylindoles.

A MnI -catalyzed regioselective C-H allenylation is reported that allows a broad range of 2-allenylindoles to be synthesized regioselectively on a gram scale under simple conditions. Notably, a highly efficient chirality transfer was observed (up to 93 % ee) in this transformation. This procedure was further found to allow, for the first time, the direct preparation of ketones by MnI -catalyzed C-H activation. Mechanistic investigations revealed that the precoordination of the oxygen atom to the manganese center as well as the congested tertiary carbon atom in the propargylic carbonates play a crucial role.

Cooperative Lewis Acid/Cp*Co(III) Catalyzed C-H Bond Activation for the Synthesis of Isoquinolin-3-ones.

A facile route toward the synthesis of isoquinolin-3-ones through a cooperative B(C6 F5 )3 - and Cp*Co(III) -catalyzed C-H bond activation of imines with diazo compounds is presented. The inclusion of a catalytic amount of B(C6 F5 )3 results in a highly efficient reaction, thus enabling unstable NH imines to serve as substrates.