Efficient Synthesis of Eight‐Membered Nitrogen Heterocycles from O‐Propargylic Oximes by Rhodium‐Catalyzed Cascade Reactions

Azocine derivatives were successfully synthesized from O‐propargylic oximes by means of a Rh‐catalyzed 2,3‐rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines.     

Regio‐ and Enantioselective Synthesis of N‐Substituted Pyrazoles by Rhodium‐Catalyzed Asymmetric Addition to Allenes

The rhodium‐catalyzed asymmetric N‐selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)‐ruxolitinib.     

Direct Asymmetric Dearomatization of Pyridines and Pyrazines by Iridium‐Catalyzed Allylic Amination Reactions

The first iridium‐catalyzed intramolecular asymmetric allylic dearomatization reaction of pyridines and pyrazines has been realized. 2,3‐Dihydroindolizine and 6,7‐dihydropyrrolo[1,2‐a]pyrazine derivatives were obtained with excellent yields and enantioselectivity. This methodology features dearomatization by direct N‐allylic alkylation of pyridines or pyrazines under mild reaction conditions.     

Highly Regio‐ and Enantioselective Synthesis of N‐Substituted 2‐Pyridones: Iridium‐Catalyzed Intermolecular Asymmetric Allylic Amination

The first iridium‐catalyzed intermolecular asymmetric allylic amination reaction with 2‐hydroxypyridines has been developed, thus providing a highly efficient synthesis of enantioenriched N‐substituted 2‐pyridone derivatives from readily available starting materials. This protocol features a good tolerance of functional groups in both the allylic carbonates and 2‐hydroxypyridines, thereby delivering multifunctionalized heterocyclic products with up to 98 % yield and 99 % ee.     

Regioconvergent and Enantioselective Rhodium‐Catalyzed Hydroamination of Internal and Terminal Alkynes: A Highly Flexible Access to Chiral Pyrazoles

The rhodium‐catalyzed asymmetric N‐selective coupling of pyrazole derivatives with internal and terminal alkynes features an utmost chemo‐, regio‐, and enantioselective access to enantiopure allylic pyrazoles, readily available for incorporation in small‐molecule pharmaceuticals. This methodology is distinguished by a broad substrate scope, resulting in a remarkable compatability with a variety of different functional groups. It furthermore exhibits an intriguing case of regio‐, position‐, and enantioselectivity in just one step, underscoring the sole synthesis of just one out of up to six possible products in a highly flexible approach to allylated pyrazoles by emanating from various internal and terminal alkynes.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

Immobilized Catalysts for Iridium‐Catalyzed Allylic Amination: Rate Enhancement by Immobilization

The first immobilized catalyst for Ir‐catalyzed asymmetric allylic aminations is described. The catalyst is a cationic (π‐allyl)Ir complex bound by cation exchange to an anionic silica gel support. Preparation of the catalyst is facile, and the supported catalyst displayed considerably enhanced activity compared with the parent homogeneous catalyst. Up to 43 consecutive amination runs were possible in recycling experiments.     

Phosphine‐Catalyzed Enantioselective Synthesis of Oxygen Heterocycles

Chiral phosphepine 1 catalyzes the transformation of an array of hydroxy‐2‐alkynoates into saturated oxygen heterocycles with good enantioselectivity. Phenols are also shown to participate in such phosphine‐catalyzed cyclizations, including an asymmetric variant. This method provides a new approach to the enantioselective synthesis of tetrahydrofurans, tetrahydropyrans, and dihydrobenzopyrans.

     

Rhodium‐Catalyzed Highly Regio‐ and Enantioselective Hydrogenation of Tetrasubstituted Allenyl Sulfones: An Efficient Access to Chiral Allylic Sulfones

A highly regio‐ and enantioselective hydrogenation of challenging tetrasubstituted allenyl sulfones has been developed, affording chiral allylic sulfones in good yields with excellent regio‐ and enantioselectivities (up to 99 % yield and 99 % ee). This method provides an efficient and concise route to chiral allylic sulfones, thus offering an atom‐economic process with a wide range of potential applications in organic synthesis and medicinal chemistry.     

Substrate‐Directed Hydroacylation: Rhodium‐Catalyzed Coupling of Vinylphenols and Nonchelating Aldehydes

We report a protocol for the hydroacylation of vinylphenols with aryl, alkenyl, and alkyl aldehydes to form branched products with high selectivity. This cross‐coupling yields α‐aryl ketones that can be cyclized to benzofurans, and it enables access to eupomatenoid natural products in four steps or less from eugenol. Excellent reactivity and high levels of regioselectivity for the formation of the branched products were observed. We propose that aldehyde decarbonylation is avoided by the use of an anionic directing group on the alkene and a diphosphine ligand with a small bite angle.     

Synthesis of Heterocycles through Transition‐Metal‐Catalyzed Isomerization Reactions

Metal‐catalyzed isomerization of N‐ and O‐allylic systems is emerging as an effective method to form synthetically useful iminium and oxocarbenium intermediates. In the presence of tethered nucleophiles, several recent examples illuminate this approach as a powerful strategy for the synthesis of structurally complex and diverse heterocycles. In this Concept article, we attempt to cover this area of research through a selection of recent versatile examples.     

Construction of Quaternary Stereogenic Carbon Centers through Copper‐Catalyzed Enantioselective Allylic Alkylation of Azoles

Copper‐catalyzed enantioselective allylic alkylation of azoles with γ,γ‐disubstituted primary allylic phosphates was achieved using a new chiral N‐heterocyclic carbene ligand bearing a naphtholic hydroxy group. This reaction occurred with excellent branch regioselectivity and high enantioselectivity, thus forming a controlled all‐carbon quaternary stereogenic center at the position α to the heteroaromatic ring.     

Enantioselective Rhodium‐Catalyzed Atom‐Economical Macrolactonization

A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom‐economical rhodium‐catalyzed coupling of ω‐allenyl‐substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM‐diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β‐unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio‐ and diastereoselectivity.     

Rhodium‐Catalyzed Enantioselective Intermolecular Hydroalkoxylation of Allenes and Alkynes with Alcohols: Synthesis of Branched Allylic Ethers

Regio‐ and enantioselective additions of alcohols to either terminal allenes or internal alkynes provides access to allylic ethers by using a Rh^I/diphenyl phosphate catalytic system. This method provides an atom‐economic way to obtain chiral aliphatic and aryl allylic ethers in moderate to good yield with good to excellent enantioselectivities.