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Atropisomers 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 novoindole 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.

Despite the great advancement in atroposelective synthesis in the past decades, the enantioselective synthesis of 2,2′-difluoro-1-biaryls is unprecedented. Herein, a palladium and chiral amino acid catalyzed atroposelective C–H olefination to construct the axially chiral 2,2′-difluoro-1-biaryls is reported. A variety of polyfluoro-substituted biaryls were forged under mild conditions in good yields with excellent enantioselectivity (up to 99% ee). The potential application was demonstrated by a gram-scale synthesis and synthetic transformations.

We report herein that copper(I) catalysis using a bis(phosphine) dioxide ligand can catalyze the desymmetric C–H arylation of prochiral bipyrroles. More than 50 nitrogen–nitrogen atropisomers were achieved in good to excellent yields with excellent enantioselectivities (≤97% yield, ≤98% ee). The reaction proceeds under mild conditions with good functional group compatibility on arenes and diaryliodonium salts. Moreover, this principle enables iterative arylation of the bipyrroles to enantioselectively arylate different positions during the catalysis of copper.

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 4and tetraalkynylate 5.

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.