Recent developments for intermolecular enantioselective amination of non-acidic C(sp3)-H bonds.

Enantioenriched chiral amines are of exceptional importance in the pharmaceutical industry. Recently, several new methods for the installation of these functional groups directly from non-acidic C(sp3)-H bonds by catalytic intermolecular enantioselective amination have been reported. These methods represent significant advances of the field and most of them display high levels of enantioselectivity, utilize the C(sp3)-H substrate as the limiting reagent, feature good functional group tolerance, and show compatibility with late-stage C(sp3)-H amination of advanced substrates. This perspective provides an overview of the recent developments in this rapidly advancing field and outlines possibilities and limitations, which will help identify unsolved challenges and guide future research efforts.

Mechanochemical Synthesis of Aryl Fluorides by Using Ball Milling and a Piezoelectric Material as the Redox Catalyst.

Aryl fluorides are important structural motifs in many pharmaceuticals. Although the Balz-Schiemann reaction provides an entry to aryl fluorides from aryldiazonium tetrafluoroborates, it suffers from drawbacks such as long reaction time, high temperature, toxic solvent, toxic gas release, and low functional group tolerance. Here, we describe a general method for the synthesis of aryl fluorides from aryldiazonium tetrafluoroborates using a piezoelectric material as redox catalyst under ball milling conditions in the presence of Selectfluor. This approach effectively addresses the aforementioned limitations. Furthermore, the piezoelectric material can be recycled multiple times. Mechanistic investigations indicate that this fluorination reaction may proceed via a radical pathway, and Selectfluor plays a dual role as both a source of fluorine and a terminal reductant.

Enantioselective Intermolecular Radical Amidation and Amination of Benzylic C-H Bonds via Dual Copper and Photocatalysis.

A method for direct access to enantioenriched benzylic amides and carbamate-protected primary benzylamines by C-H functionalization is reported. The C-H substrate is used as limiting reagent with only a small excess of the unactivated amide or carbamate nucleophile. The enantioselective intermolecular dehydrogenative C-N bond formation is enabled by a combination of a chiral copper catalyst, a photocatalyst, and an oxidant, and it takes place under mild conditions, which allow for a broad substrate scope. The method is compatible with late-stage C-H functionalization, and it provides easy access to 15 N-labeled amides and amines starting from cheap 15 NH4 Cl.

Photo-induced metal-free dehydrogenative N-N homo-coupling.

We report a photo-induced dehydrogenative N-N coupling of diarylimines, diarylamines, carbazoles, and anilines. These homo-coupling reactions require only the combination of readily available di-tert-butyl peroxide (DTBP) and light irradition. The operationally simple protocol works under catalyst- and metal-free conditions and exhibits a good substrate scope. Preliminary mechanistic studies indicate that the reaction proceeds via photo-induced homolytic cleavage of the peroxide followed by hydrogen atom transfer leading to the formation of N-centered radicals.

Design and Applications of a SO2 Surrogate in Palladium-Catalyzed Direct Aminosulfonylation between Aryl Iodides and Amines.

A new SO2 surrogate is reported that is cheap, bench-stable, and can be accessed in just two steps from bulk chemicals. Essentially complete SO2 release is achieved in 5 minutes. Eight established sulfonylation reactions proceeded smoothly by ex situ formation of SO2 by utilizing a two-chamber system in combination with the SO2 surrogate. Furthermore, we report the first direct aminosulfonylation between aryl iodides and amines. Broad functional group tolerance is demonstrated, and the method is applicable to pharmaceutically relevant substrates, including heterocyclic substrates.

Dual Nickel-/Palladium-Catalyzed Reductive Cross-Coupling Reactions between Two Phenol Derivatives.

Cross-coupling between substrates that can be easily derived from phenols is highly attractive due to the abundance of phenols. Here, we report a dual nickel-/palladium-catalyzed reductive cross-coupling between aryl tosylates and aryl triflates; both substrates can be accessed in just one step from readily available phenols. The reaction has a broad functional group tolerance and substrate scope (>60 examples). Furthermore, it displays low sensitivity to steric effects demonstrated by the synthesis of a 2,2'-disubstituted biaryl and a fully substituted aryl product. The widespread presence of phenols in natural products and pharmaceuticals allows for straightforward late-stage functionalization, illustrated with examples such as ezetimibe and tyrosine.

Nickel-Catalyzed Intramolecular Desulfitative C-N Coupling: A Synthesis of Aromatic Amines.

A nickel-catalyzed intramolecular C-N coupling reaction via SO2 extrusion is presented. The use of a catalytic amount of BPh3 allows the transformation to take place under much milder conditions (60 °C) than previously reported C-N coupling reactions by CO or CO2 extrusion (160-180 °C). In addition, this method displays good functional group tolerance and versatility, as it can be applied to the synthesis of dialkyl aryl amines, alkyl diaryl amines, and triaryl amines. The robustness of the desulfitative C-N coupling is demonstrated by three high-yielding gram-scale reactions.

Enantioselective aryl-aryl coupling facilitated by chiral binuclear gold complexes.

Herein, we report stoichiometric investigations embodying the first highly enantioselective aryl-aryl coupling facilitated by a gold complex. With up to 91% ee, this is the first demonstration of a transmetalation and C(sp2)-C(sp2) reductive elimination sequence with high enantioselectivity using a gold complex. The results offer a basis for development of enantioselective gold-catalyzed aryl-aryl coupling reactions.

Synthesis of α-Substituted Primary Benzylamines through Copper-Catalyzed Cross-Dehydrogenative Coupling.

A copper-catalyzed route to α-substituted, primary benzylamines by C-H functionalization of alkylarenes is described. The method directly affords the amine hydrochloride salt. Catalyst loadings down to 0.1 mol % in combination with scalability, insensitivity to air and moisture, and no need for column chromatography makes the procedure highly practical. The facile synthesis of the racemate of a blockbuster drug highlights the relevance for the development of pharmaceuticals. Preliminary mechanistic data are also included.

Asymmetric Synthesis of Chiral Spiroketal Bisphosphine Ligands and Their Application in Enantioselective Olefin Hydrogenation.

A series of chiral spiroketal bisphosphine ligands containing 1,1'-spirobi(3 H,3' H)isobenzofuran backbones was accessed through asymmetric synthesis and subsequently tested in enantioselective Rh-catalyzed hydrogenation of α-dehydroamino acid esters. The ligand providing the highest enantioselectivity (up to 99.5%) was obtained in seven steps in an overall 38% yield. The synthesis could be performed on a gram scale, and no kinetic resolution of enantiomers is required. Overall, the developed ligand provides an easily accessible alternative to SDP ligands as well as other chiral bisphosphine ligands.

Asymmetric Organocatalytic [4 + 1] Annulations: Enantioselective Construction of Multifunctionalized Spirocyclopentane Oxindoles Bearing α,α-Disubstituted α-Amino-ß-keto Esters.

The highly enantioselective preparation of spirooxindoles bearing α,α-disubstituted α-amino-ß-keto esters was achieved through [4 + 1] annulation of oxindoles and α-imine-ß-oxo-γ,δ-unsaturated esters under mild conditions in good yields (up to 82%) and stereoselectivities (up to >20:1 dr, 96% ee). The reaction is amenable to gram scale synthesis using catalyst loading as low as 1 mol %. The corresponding chiral α,α-disubstituted α-amino-ß-keto esters could be easily transformed into cyclopenta[ b]indole derivatives without erosion of enantiopurity.

Asymmetric Total Syntheses of (-)-α-Lycorane, (-)-Zephyranthine, and Formal Synthesis of (+)-Clivonine.

An asymmetric route to (-)-α-lycorane and (-)-zephyranthine, and a formal total synthesis of (+)-clivonine were achieved. A pivotal intermediate, which serves as a potent precursor for the divergent syntheses of these natural products, was accessed by a diastereoselective Pd-catalyzed cinnamylation of an N-tert-butanesulfinyl imine.

Recent Advances in Gold-Catalyzed Intermolecular Aryl C-H Functionalization.

The direct and selective functionalization of C-H bonds offers a powerful opportunity for greener and shorter routes to valuable chemicals. While still in its infancy, research exploiting the unique features of gold catalysis for the functionalization of aryl C-H bonds has demonstrated great potential for facile regioselective decoration of (hetero)arenes. Particularly within the last five years, a more general strategy for utilizing oxidative gold catalysis has emanated including an improved understanding of the underlying mechanistic pathways. To encourage and facilitate further research in intermolecular C-H functionalization of arenes with homogeneous gold catalysis, this Minireview critically presents the transformations and mechanistic data available within this field.

Use of a new spirophosphine to achieve catalytic enantioselective [4 + 1] annulations of amines with allenes to generate dihydropyrroles.

Due in part to the common occurrence of five-membered nitrogen heterocycles in bioactive molecules, the discovery of methods for the enantioselective synthesis of such structures is a useful endeavor. Building on a single example by Tong of a phosphine-catalyzed [4 + 1] annulation of an amine with an allene that furnished an achiral dihydropyrrole in 22% yield, we have developed, with the aid of a new chiral spirophosphine catalyst, a method with increased utility, specifically, improved yield, enhanced scope (the use of γ-substituted allenes), and good ee. The enantioenriched dihydropyrrole products can be transformed into other interesting families of compounds with very good stereoselectivity.

Access to 1,2-dihydroisoquinolines through gold-catalyzed formal [4+2] cycloaddition.

A new synthetic route to the privileged 1,2-dihydroisoquinolines is reported. This method, which relies on a gold-catalyzed formal [4+2] cycloaddition between ynamides and imines, provides a new retrosynthetic disconnection of the 1,2-dihydroisoquinoline core by installing the 1,8a C-C and 2,3 C-N bonds in one step. Both aldimines and ketimines can be used as substrates. In addition, one example of dihydrofuropyridine synthesis is also demonstrated.

Divergent product selectivity in gold- versus silver-catalyzed reaction of 2-propynyloxy-6-fluoropyridines with arylamines.

A study of the reaction of easily accessible 2-propynyloxy-6-fluoropyridines with arylamines under gold or silver catalysis is described. It has been shown that two types of isomeric oxazolopyridine imine derivatives, which represent unusual heterocyclic motifs, can be selectively obtained in moderate to excellent yields depending on the nature of the metal employed.

Generation of stoichiometric ethylene and isotopic derivatives and application in transition-metal-catalyzed vinylation and enyne metathesis.

Ethylene is one of the most important building blocks in industry for the production of polymers and commodity chemicals. (13)C- and D-isotope-labeled ethylenes are also valuable reagents with applications ranging from polymer-structure determination, reaction-mechanism elucidation to the preparation of more complex isotopically labeled compounds. However, these isotopic derivatives are expensive, and are flammable gases, which are difficult to handle. We have developed a method for the controlled generation of ethylene and its isotopic variants including, for the first time, fully isotopically labeled ethylene, from simple alkene precursors by using Ru catalysis. Applying a two-chamber reactor allows both the synthesis of ethylene and its immediate consumption in a chemical transformation permitting reactions to be performed with only stoichiometric amounts of this two carbon olefin. This was demonstrated in the Ni-catalyzed Heck reaction with aryl triflates and benzyl chlorides, as well as Ru-mediated enyne metathesis.

Cu(I)-catalyzed oxidative cyclization of alkynyl oxiranes and oxetanes.

In the presence of a Cu(I) catalyst and a pyridine oxide, alkynyl oxiranes and oxetanes can be converted into functionalized five- or six-membered α,ß-unsaturated lactones or dihydrofuranaldehydes. This new oxidative cyclization is proposed to proceed via an unusual allenyloxypyridinium intermediate.