Most palladium-catalyzed asymmetric cycloadditions employing aniline derivatives as 1,3-dipoles are limited to [3+2] cyclization to construct chiral indoline skeletons. Asymmetric [3+3] annulation involving aniline-type 1,3-dipoles has remained unprecedented. Meanwhile, palladium-catalyzed asymmetric cyclization of vinyldiazo compounds suffers from multiple challenges, including poor regioselectivity, low chemoselectivity and facile racemization of newly-formed stereocenters.

Very recently, the research team of Prof. Yuanyuan Liu (East China Normal University) and Prof. Junliang Zhang (Fudan University) applied Ming-Phos, a member of the Sadphos ligand family, to realize palladium-catalyzed asymmetric [3+3] cycloaddition between 2-iodoaniline derivatives and vinyldiazoacetates. This catalytic system features broad substrate scope and delivers a variety of chiral dihydroquinoline compounds in moderate-to-good yields with high enantioselectivity (up to 97% ee).

Synthetic practicability is demonstrated via product derivatization. DFT theoretical calculations reveal that the concerted carbene-formation/migratory-insertion step determines enantioselectivity. Stereoinduction is jointly governed by steric repulsion between the DTBM group and ester moiety, as well as π-π stacking interactions within the transition-state assembly.

Common commercial bisphosphines, monophosphines, Phox ligands, together with Sadphos-type Xu-Phos and PC-Phos fail to furnish this transformation. Among all candidates, Ming-Phos ligands uniquely balance catalytic activity and chiral induction. The optimal ligand M7 delivers 72% isolated yield with 94% ee.

A wide array of 2-iodoaniline substrates and vinyldiazoacetate coupling partners are tolerated. Various alkyl, alkoxy, halogen and aryl substituents on aromatic rings are well accommodated, affording enantioenriched dihydroquinoline products with generally high ee values.

DFT computation indicates that concerted denitrogenation‑carbene insertion (TS1‑S / TS1‑R) represents the enantio‑determining step. A notable energy gap of 3.9 kcal/mol exists between the favorable TS1‑S transition state and disfavored TS1‑R, originating from severe steric clash between the bulky DTBM substituent of ligand M7 and the ester group of substrate in TS1‑R. Removal of the DTBM moiety nearly eliminates this energy difference. π‑π stacking interactions inside the chiral pocket further stabilize the preferred transition‑state geometry. Such non‑covalent interactions vanish for aliphatic substrates, accompanied by decreased enantioselectivity. Subsequent base‑assisted cyclization completes the catalytic cycle.

To support related research, Kaitailai Platinum (Anhui) Co., Ltd. stocks more than 100 structurally diverse Ming-Phos ligands of the Sadphos family. Representative ligands are available for immediate delivery. Global inquiries and research cooperation are warmly welcomed.

Dan Zhao, Zhou Luo, Jingyan Luo, Junliang Zhang*, Yuanyuan Liu*. Pd-Catalyzed Enantioselective [3+3] Annulation of Vinyldiazos with 2-Iodoanilines Enabled by Sadphos. J. Am. Chem. Soc. DOI:10.1021/jacs.6c14159