Synthesis of Saturated N-Heterocycles via a Catalytic Hydrogenation Cascade.

Saturated N-heterocycles are prominent motifs found in various natural products and pharmaceuticals. Despite the increasing interest in this class of compounds, the synthesis of saturated bicyclic azacycles requires tedious multi-step syntheses. Herein, we present a one-pot protocol for the synthesis of octahydroindoles, decahydroquinolines, and octahydroindolizines through a cascade reaction.

Substituted Dihydropyridine Synthesis by Dearomatization of Pyridines.

Dearomatization is an effective method to transform readily available N-heterocycles into partially saturated motifs. Manipulation of dihydro-derivatives holds great potential and provides access to a variety of semi-saturated N-heterocyclic building blocks. However, current strategies are limited in scope and the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we report the synthesis of a broad variety of N-substituted 1,4- and 1,2-dihydropyridines by very mild and selective reduction with amine borane for the first time.

Catalytic Transfer Hydrogenation of Arenes and Heteroarenes.

Transfer hydrogenation reactions are of great interest to reduce diverse molecules under mild reaction conditions. To date, this type of reaction has only been successfully applied to alkenes, alkynes and polarized unsaturated compounds such as ketones, imines, pyridines, etc. The reduction of benzene derivatives by transfer hydrogenation has never been described, which is likely due to the high energy barrier required to dearomatize these compounds. In this context, we have developed a catalytic transfer hydrogenation reaction for the reduction of benzene derivatives and heteroarenes to form complex 3-dimensional scaffolds bearing various functional groups at room temperature without needing compressed hydrogen gas.

Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes.

Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer-mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities.

trans-Selective and Switchable Arene Hydrogenation of Phenol Derivatives.

A trans-selective arene hydrogenation of abundant phenol derivatives catalyzed by a commercially available heterogeneous palladium catalyst is reported. The described method tolerates a variety of functional groups and provides access to a broad scope of trans-configurated cyclohexanols as potential building blocks for life sciences and beyond in a one-step procedure. The transformation is strategically important because arene hydrogenation preferentially delivers the opposite cis-isomers. The diastereoselectivity of the phenol hydrogenation can be switched to the cis-isomers by employing rhodium-based catalysts. Moreover, a protocol for the chemoselective hydrogenation of phenols to cyclohexanones was developed.

Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation.

Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general synthetic access remains out of reach. Herein, we describe a simple and robust cis-selective hydrogenation of abundant and cheap fluoropyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoropyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated derivatives of important drug compounds are prepared, and a straightforward strategy for the synthesis of enantioenriched fluorinated piperidines is disclosed.

Halogen-Bonding-Induced Conjugate Addition of Thiophenes to Enones and Enals.

Herein, we report the conjugate addition of α,ß-unsaturated carbonyl compounds to thiophene derivatives. We used a 2-iodoimidazolinium triflate salt as a halogen-bonding donor, which afforded moderate-to-excellent yields of the corresponding alkylated thiophenes. Insight into the catalytic process was obtained from 1 H NMR spectroscopy studies and DFT calculations, which indicated a halogen-bonding-supported mechanism with limited Brønsted acid catalysis.