Transition-metal-catalyzed enantioselective C-N cross-coupling.

Chiral amine scaffolds are among the most important building blocks in natural products, drug molecules, and functional materials, which have prompted chemists to focus more on their synthesis. Among the accomplishments in chiral amine synthesis, transition-metal-catalyzed enantioselective C-N cross-coupling is considered one of the most efficient protocols. This approach combines traditional C(sp2)-N cross-coupling methods (such as the Buchwald-Hartwig reaction Ullmann-type reaction, and Chan-Evans-Lam reaction), aryliodonium salt chemistry and radical chemistry, providing an attractive pathway to a wide range of structurally diverse chiral amines with high enantioselectivity. This review summarizes the established protocols and offers a comprehensive outlook on the promising enantioselective C-N cross-coupling reaction.

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis.

ConspectusAtropisomers bearing a rotation-restricted axis are common structural units in natural products, chiral ligands, and drugs; thus, the prevalence of asymmetric synthesis has increased in recent decades. Research into atropisomers featuring an N-containing axis (N-X atropisomers) remains in its infancy compared with the well-developed C-C atropisomer analogue. Notably, N-X atropisomers could offer divergent scaffolds, which are extremely important in bioactive molecules. The asymmetric synthesis of N-X atropisomers is recognized as both appealing and challenging. Recently, we devoted our efforts to the catalytic asymmetric synthesis of N-X atropisomers, benzimidazole-aryl N-C atropisomers, indole-aryl N-C atropisomers, hydrogen-bond-assisted N-C atropisomers, pyrrole-pyrrole N-N atropisomers, pyrrole-indole N-N atropisomers, and indole-indole N-N atropisomers. To obtain the N-C atropisomers, an asymmetric Buchwald-Hartwig reaction of amidines or enamines was employed. Using a Pd(OAc)2/(S)-BINAP or Pd(OAc)2/(S)-Xyl-BINAP catalyst system, benzimidazole-aryl N-C atropisomers and indole-aryl N-C atropisomers were readily obtained. To address the issue of the reduced stability of the diarylamine axis, a six-membered intramolecular N-H-O hydrogen bond was introduced into the N-C atropisomer scaffold. A tandem N-arylation/oxidation process was used for the chiral phosphoric acid (CPA)-catalyzed asymmetric synthesis of N-aryl quinone atropisomers. For N-N atropisomers, a copper-mediated asymmetric Friedel-Crafts alkylation/arylation reaction was developed. The desymmetrization process was completed successfully via a Cu(OTf)2/chiral bisoxazoline or (CuOTf)·Tol/bis(phosphine) dioxide system, thereby achieving the first catalytic asymmetric synthesis of N/N bipyrrole atropisomers. Asymmetric Buchwald-Hartwig amination of enamines was utilized to provide N-N bisindole atropisomers with excellent stereogenic control. This was the first asymmetric synthesis of N-N atropisomers featuring a bisindole structural scaffold using the de novo indole construction strategy. The asymmetric N-N heterobiaryl atropisomer synthesis was substantially facilitated using palladium-catalyzed transient directing group (TDG)-mediated C-H functionalization. Atropisomeric alkenylation, allylation, or alkynylation was accomplished using the Pd(OAc)2/l-tert-leucine system. Herein, we summarize our work on the palladium-, copper-, and CPA-catalyzed asymmetric syntheses of N-C and N-N atropisomers. Furthermore, the application of our work in the synthesis of bioactive molecule analogues and axially chiral ligands is demonstrated. Subsequently, the stability of the chiral N-containing axis is briefly discussed in terms of single crystals and obtained rotational barriers. Finally, an outlook on the asymmetric N-X atropisomer synthesis is provided.

Organocatalytic Enantioselective Synthesis of Seven-Membered Ring with Inherent Chirality.

Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)-catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7-membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee).

Enantioselective Nickel-Catalyzed Denitrogenative Transannulation En Route to N-N Atropisomers.

Nickel-catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, their use in asymmetric synthesis remains challenging because of the difficulty in controlling stereo- and regioselectivity. Herein, we report the first nickel-catalyzed asymmetric synthesis of N-N atropisomers by the denitrogenative transannulation of benzotriazones with alkynes. A broad range of N-N atropisomers was obtained with excellent regio- and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel-catalyzed reaction mechanism and enantioselectivity control.

Palladium-Catalyzed Double N-Arylation to Access Unsymmetric N,N'-Bicarbazole Scaffolds.

Herein, the palladium-catalyzed double C-N coupling of 9H-carbazol-9-amines and 2,2'-dibromo-1,1'-biphenyl is reported. This protocol offers access to N,N'-bicarbazole scaffolds, which have frequently been used as linkers in the construction of functional covalent organic frameworks (COFs). A variety of substituted N,N'-bicarbazoles were synthesized in moderate to high yields based on this chemistry, and the potential application of this method was showcased by the synthesis of COF monomers like tetrabromide 4 and tetraalkynylate 5.

Atroposelective Synthesis of C-N Vinylindole Atropisomers by Palladium-Catalyzed Asymmetric Hydroarylation of 1-Alkynylindoles.

Transition-metal-catalyzed hydroarylation of unsymmetrical internal alkynes remains challenging because of the difficulty in controlling regioselectivity and stereoselectivity. Moreover, the enantioselective hydroarylation of alkynes using organoboron reagents has not been reported. Herein, we report for the first time that palladium compounds can catalyze the hydroarylation of 1-alkynylindoles with organoborons for the synthesis of chiral C-N atropisomers. A series of rarely reported vinylindole atropisomers was synthesized with excellent regio-, stereo- (Z-selectivity), and enantioselectivity under mild reaction conditions. The ready availability of organoborons and alkynes and the simplicity, high stereoselectivity, and good functional group tolerance of this catalytic system make it highly attractive.

The Asymmetric Buchwald-Hartwig Amination Reaction.

Over the past few decades, the Buchwald-Hartwig reaction has emerged as a powerful tool for forging C-N bonds, and has been vital to the pharmaceuticals, materials, and catalysis fields. However, asymmetric Buchwald-Hartwig amination reactions for constructing centered chirality, planar chirality, and axial chirality remain in their infancy owing to limited substrate scope and laggard ligand design. The recent surge in interest in the synthesis of C-N/N-N atropisomers, has witnessed a renaissance in asymmetric Buchwald-Hartwig amination chemistry as the first practical protocol for the preparation of C-N atropisomers. This review highlights reported asymmetric Buchwald-Hartwig amination protocols and provides a brief overview of their chemical practicality.

Enantioselective Synthesis of N-N Atropisomers by Palladium-Catalyzed C-H Functionalization of Pyrroles.

The catalytic asymmetric construction of N-N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon-carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium-catalyzed enantioselective C-H activation of pyrroles for the synthesis of N-N atropisomers is presented. Structurally diverse indole-pyrrole atropisomers possessing a chiral N-N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N-N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C-H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N-N atropisomers.

Enantioselective Synthesis of N-N Bisindole Atropisomers.

N-N Atropisomers are a common motif in natural products and represent a significant dimension for exploration in modern pharmaceutical and medicinal chemistry. However, the catalytic atroposelective synthesis of such molecules remains challenging, hampering meaningful development. In particular, an enantioselective synthesis of N-N bisindole atropisomers is unprecedented. Herein, the first enantioselective synthesis of N-N bisindole atropisomers via the palladium-catalyzed de novo construction of one indole skeleton is presented. A wide variety of N-N axially chiral bisindoles were generated in good yields with excellent enantioselectivities via a cascade condensation/N-arylation reaction. Structurally diverse indole-pyrrole, indole-carbazole, and non-biaryl-indole atropisomers possessing a chiral N-N axis were accessed using this protocol. Moreover, investigations using density functional theory (DFT) calculations provided insight into the reaction mechanism and enantiocontrol.

Atroposelective Synthesis of N-Arylated Quinoids by Organocatalytic Tandem N-Arylation/Oxidation.

Diarylamines and related scaffolds are ubiquitous atropisomeric chemotypes in biologically active natural products. However, the catalytic asymmetric synthesis of these axially chiral compounds remains largely unexplored. Herein, we report that a BINOL-derived chiral phosphoric acid (CPA) successfully catalyzed the atroposelective coupling of quinone esters and anilines through direct C-N bond formation to afford N-aryl quinone atropisomers with an unprecedented intramolecular N-H-O hydrogen bond within a six-membered ring in good yields and enantioselectivities with the quinone ester as both the electrophile and the oxidant. A gram-scale experiment demonstrated the utility of this synthetic protocol. Moreover, this methodology provides a platform for the synthesis of structurally diverse secondary amine atropisomers by nucleophilic addition.

Enantioselective Synthesis of Nitrogen-Nitrogen Biaryl Atropisomers via Copper-Catalyzed Friedel-Crafts Alkylation Reaction.

Nitrogen-nitrogen bonds containing motifs are ubiquitous in natural products and bioactive compounds. However, the atropisomerism arising from a restricted rotation around an N-N bond is largely overlooked. Here, we describe a method to access the first enantioselective synthesis of N-N biaryl atropisomers via a Cu-bisoxazoline-catalyzed Friedel-Crafts alkylation reaction. A wide range of axially chiral N-N bisazaheterocycle compounds were efficiently prepared in high yields with excellent enantioselectivities via desymmetrization and kinetic resolution. Heating experiments showed that the axially chiral bisazaheterocycle products have high rotational barriers.

Palladium-catalyzed dearomative allylation of indoles with cyclopropyl acetylenes: access to indolenine derivatives.

A palladium-catalyzed redox-neutral allylic alkylation of indoles with cyclopropyl acetylenes has been disclosed. Various 1,3-diene indolenine framework bearing a quaternary stereocenter at the C3 position were synthesized straightforwardly in good to excellent yields with high regio- and stereoselectivities. The reaction could be further expanded to the dearomatization of naphthols to synthesize functionalized cyclohexadienones with 1,3-diene motifs. The reaction exhibited high atom economy and good functional group tolerance.

Enantioselective Synthesis of Atropisomeric Biaryls by Pd-Catalyzed Asymmetric Buchwald-Hartwig Amination.

N-C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the enantioselective synthesis of N-C biaryl atropisomers by stereoselective metal-catalyzed aryl amination remains unprecedented. Herein, a Pd-catalyzed cross-coupling strategy is presented for the synthesis of N-C axially chiral biaryl molecules. A broad spectrum of N-C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 % ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules.

Palladium-catalyzed allylation of aminophenol with alkynes to construct C-N bonds.

A method for the allylic alkylation of aminophenol with alkynes was developed using a palladium-catalysed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted allylamines were synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions.

Palladium-catalyzed allylation of tautomerizable heterocycles with alkynes.

A method for the allylic amidation of tautomerizable heterocycles was developed by a palladium catalyzed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted heterocycles can be synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions.

Palladium-catalyzed allylation of sulfonyl hydrazides with alkynes to synthesize allylic arylsulfones.

A novel method for the construction of allyl arylsulfone derivatives was developed by palladium catalyzed allylation of sulfonyl hydrazides with alkynes. A series of structurally diverse allyl arylsulfones can be regioselectively synthesized in high yields under mild conditions.

Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) as effective inhibitor of metal-induced Aß aggregation and antioxidant.

A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer's disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aß1-42 aggregation, rapid H2O2 scavenging and glutathione peroxidise (GPx)-like catalytic activity. Among these molecules, compound 9a is the most potent peroxide scavenger that possesses the ability to scavenge most H2O2 within 200-220min and possesses GPx-like activity (v0=106.0µM·min(-1)), enabling modulation of metal-induced Aß aggregation.

Palladium-catalyzed three-component cascade reaction: facial access to densely functionalized indolizines.

A palladium-catalyzed three-component cascade reaction of 2-(2-enynyl)pyridines with nucleophiles and allyl halides has been developed, enabling the synthesis of densely functionalized indolizines in moderate to good yields. The newly developed methodology offers several practical advantages, including operational simplicity, ready availability of starting materials, and mild reaction conditions.

Au-catalyzed ring-opening reactions of 2-(1-alkynyl-cyclopropyl)pyridines with nucleophiles.

A novel method for the C-C bond cleavage of cyclopropanes was developed by gold-catalyzed cycloisomerization of 2-(1-alkynyl-cyclopropyl)pyridine with nucleophiles, which provides efficient access to structurally diverse indolizines under mild conditions. A series of N-, C- and O-based nucleophiles were involved in this reaction to afford the corresponding indolizines in modest to excellent yields.

Dual catalysis for the redox annulation of nitroalkynes with indoles: enantioselective construction of indolin-3-ones bearing quaternary stereocenters.

The enantioselective redox annulation of nitroalkynes with indoles is enabled by gold/chiral phosphoric acid dual catalysis. A range of indolin-3-one derivatives bearing quaternary stereocenters at the C2 position were afforded in good yields and excellent enantioselectivities (up to 96 % ee) from readily available starting materials.