Enantioselective Rh-Catalyzed Azide-Internal-Alkyne Cycloaddition for the Construction of Axially Chiral 1,2,3-Triazoles

Abstract

Significant advances have been achieved for the construction of chiral skeletons containing 1,2,3-triazoles via transition-metal-catalyzed asymmetric azide–alkyne cycloaddition; however, most of them have been limited to terminal alkynes in the synthesis of central chirality via desymmetrization and dynamic/dynamic kinetic resolution. Enantioselective transition-metal-catalyzed azide-internal-alkyne cycloaddition is extremely limited. Moreover, the construction of a challenging five-membered (hetero)­biaryl axially chiral molecule via transition-metal-catalyzed asymmetric azide-internal-alkyne cycloaddition is still underexplored. Herein, we first report an atroposelective and atom-economical synthesis of axially chiral 1,4,5-trisubstituted 1,2,3-triazoles, directly acting as core chiral units of challenging five-membered atropisomers, via the enantioselective Rh-catalyzed azide–alkyne cycloaddition (E-RhAAC) of internal alkynes and azides. The reaction demonstrates excellent functional group tolerance, forging a variety of C–C axially chiral 1,2,3-triazoles under mild conditions with moderate to excellent yields (up to 99% yield) and generally high to excellent enantioselectivities (up to 99% ee) along with specific regiocontrol. The origin of regio- and enantioselectivity control is disclosed by density functional theory (DFT) calculations, providing new guidance for the facile construction of axially chiral compounds.

Versatile Synthetic Platform for 1,2,3-Triazole Chemistry

“…Moses and co-workers 135 136 reported an unprecedented and challenging approach for five-membered atropisomerism of 1,2,3-triazole 272 as chiral units. Axially chiral 1,4,5-substituted 1,2,3-triazole 272 was synthesized from internal alkyne 257 and azides 270 using enantioselective Rh catalyst, ligand (L) 273, and 4 Å MS (molecular sieves) in toluene at 10 °C for 10 h (Scheme 70).…”

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

“…At around the same time, structurally similar axially chiral 1,2,3-triazole derivatives were furnished by Li and Cui utilizing an Rh/chiral phosphoramidite ligand L5 catalyst system through azide-internal-alkyne cycloaddition with high yield (up to 99%) and excellent enantioselectivities (up to 99% ee) ( Scheme 5 ) [ 66 , 67 ]. Combining density functional theory calculations and control experiments, Li and co-workers presumed that the excellent regioselectivity of the catalytic system is closely related to the hydrogen-bond effect between the Cl-atom in [Rh(COD)Cl] and the H-atom in the hydroxyl group of phenol.…”

Construction of Axial Chirality via Click Chemistry: Rh-Catalyzed Enantioselective Synthesis of 1-Triazolyl-2-Naphthylamines

“…21 On the basis of our long-term research interests in click chemistry, 22 we envisioned that the direct click AAC between suitable internal alkynes and azides might bring opportunities to build a type of triazoles bearing the element of axial chirality (Scheme 1c). Very recently, our group, 23 Xu, 24 and Li 25 independently realized this assumption and developed the metal-catalyzed click AAC process for the construction of axial chirality, resulting in atropisomeric ortho-triazolyl phenols/ naphthols. To extend the applications of click chemistry in the area of axial chirality, and enrich the structural diversity of axially chiral triazole-based biaryls, we report herein a Rhcatalyzed enantioselective click chemistry, generating a class of structurally novel atropisomeric 1-triazolyl-2-naphthylamine frameworks (Scheme 1d).…”

“…Subsequently, a survey of various common solvents showed significant differences in outcomes (entries 6−19), among which CH 3 CN was optimized to give 3a in 92% yield with 92.5:7.5 er value (entry 10). Inspired by Li's work, 25 we added 4 Å molecular sieves into the reaction and found the er value could slightly increase to 94:6 in a satisfactory 91% yield (entry 20).…”