Cobalt-Catalyzed Migratory E-Selective Asymmetric Aza-Nozaki–Hiyama–Kishi Coupling
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Publication Information
Journal: Angewandte Chemie International EditionArticle Type: Hot PaperDOI: 10.1002/anie.8611979Publication Year: 2026Research Group: Prof. Shaolin Zhu & Dr. Yu Wang Group, Nanjing UniversityAuthors: Yi Wang, Yougui Luo, Lifu Wu, Jian Chen, Mei Duan, Asif Rasool, You Wang, Shaolin Zhu
1. English Research Summary
Chiral α-allylic amines are privileged core scaffolds extensively found in pharmaceutical candidates, natural products and nitrogen-containing heterocyclic building blocks. Migratory cross-coupling enables remote activation of inert C–H bonds, representing an ideal synthetic strategy to access this structural motif. Nevertheless, existing catalytic systems are limited to single metal migration pathways, failing to sequentially couple two mechanistically distinct migration modes: intramolecular 1,4-Co/H hydride shift and alkenylmetal E/Z isomerization.
Additionally, cobalt-based earth-abundant metal catalytic systems for migratory C(sp²)–H functionalization remain underdeveloped. Simultaneous precise control over regioselectivity, olefin E/Z stereoselectivity and enantioselectivity constitutes a long-standing bottleneck; conventional ligands cannot balance catalytic activity with triple stereocontrol.
To address these challenges, the research team led by Professor Shaolin Zhu and Dr. Yu Wang at Nanjing University developed a cobalt-catalyzed tandem dual-migratory E-selective asymmetric aza-Nozaki–Hiyama–Kishi (aza-NHK) coupling reaction. The catalytic system relies on two rigid P-chiral bisphosphine ligands, (R,R)-QuinoxP* and (R,R)-BenzP*, combined with an auxiliary chiral phosphoramidite ligand to construct a stereodefined chiral cobalt catalytic complex.
This methodology tolerates ortho-iodostyrenes as starting materials for cascade migratory coupling. Critically, unseparated E/Z mixed alkenyl halides can be directly employed as feedstocks. Via dynamic stereoconvergence modulated by chiral ligands, exclusively E-configured chiral allylic amines are delivered with excellent functional group compatibility. The reaction is scalable to gram scale without loss of selectivity. The obtained chiral α-allylic amine products can undergo diversified orthogonal transformations to furnish amino alcohols, 1,3-diamines, tricyclic heterocycles and other complex nitrogenated molecules.
For the first time within earth-abundant cobalt catalysis, this work achieves ordered tandem operation of two discrete migratory pathways via the unique stereoregulating capacity of chiral bisphosphine ligands. It establishes a brand-new design paradigm for multimodal metal-migratory asymmetric C–H functionalization.
2. Core Highlights
- Realizes highly E-selective and enantioselective olefin C–H functionalization
- Integrates 1,4-Co/H hydride shift and alkenyl E/Z isomerization into one tandem catalytic cycle
- Synchronously controls three critical selectivity metrics: regioselectivity (rr), olefin E/Z geometry, and enantioselectivity (ee)
- Mild reaction conditions, high operational robustness, convenient handling and scalable synthesis
3. Standard Catalytic Reaction System
General Reaction Conditions
Cobalt source: CoCl₂ (10 mol%)Main chiral bisphosphine ligand: (R,R)-QuinoxP* (12 mol%)Auxiliary chiral phosphoramidite ligand: (R)-P1 (8 mol%)Additives: MgBr₂ (1 eq), Mn metal powder (3 eq)Imine substrate loading: 1.5 eqSolvent mixture: EtOH / DMI = 1:1, concentration = 0.2 MTemperature & Time: 35 °C, 24 hGram-scale condition adjustment: 30 °C, 36 h, 5 mmol scale
Key Optimization Results
- Ligand Screening
- (R,R)-QuinoxP*: 85% yield, >20:1 rr, >20:1 E/Z, 99% ee
- (R,R)-BenzP*: 85% yield, >20:1 rr, >20:1 E/Z, 99% ee
- (S,S)-Me-DuPhos: 80% yield, 19:1 rr, >20:1 E/Z, 99% ee
- Ligand absence of auxiliary (R)-P1: yield plummets to 9%, severe E/Z loss (1:4 E/Z ratio)
- Additive & Solvent Screening
- MgBr₂ is irreplaceable; replacement with MgCl₂, NaBr or removal drastically reduces yield
- Mn metal reductant outperforms Zn; single solvent (pure EtOH / pure DMI) causes obvious decline in regioselectivity and yield
- Elevated temperature (60 °C) deteriorates both regiocontrol and enantioselectivity
4. Substrate Scope Performance
A. Ortho-Iodophenylethylene Substrates
Compatible with α-unsubstituted and α-substituted ortho-iodostyrenes bearing electron-withdrawing and electron-donating aromatic substituents: F, Cl, Br, CF₃, CN, CO₂Et, CONMe₂, alkoxy groups. Most substrates afford >75% isolated yield, >20:1 regioselectivity, >20:1 E/Z ratio and 95–99% ee.
B. Cyclic N-Sulfonyl Imine Electrophiles
Broad functional group tolerance for aryl-substituted cyclic N-sulfonyl imines, including halogen, trifluoromethoxy, alkoxy substitution. Target products maintain exclusive E-olefin geometry and high enantiomeric excess (92–99% ee).
5. Mechanism Investigation & Product Derivatization
Mechanism Experiments
- Competition reaction verifies the preferential reactivity of ortho-iodophenylethylene over simple aromatic aldehydes.
- Isotope labeling experiments confirm the occurrence of 1,4-Co/H hydride migration.
- Key catalytic intermediate is isolated and structurally characterized by single-crystal X-ray diffraction (CCDC No. 2532464, 2527979, 2527978), validating the cascade migration-isomerization-aza-NHK coupling catalytic cycle.
- Control experiments confirm the sequential order: 1,4-Co/H shift → alkenyl E/Z isomerization → asymmetric aza-NHK bond formation.
Diversified Synthetic Transformations of Chiral (E)-Allylic Amines
The chiral α-allylic amine products serve as versatile synthetic building blocks for downstream derivatization:
- Hydrogenation to generate chiral 1,3-diamines
- Epoxidation/oxidation to construct chiral amino alcohols
- Intramolecular hydroamination to form nitrogen heterocycles
- Olefin metathesis, Mitsunobu reaction, N-alkylation to access complex polycyclic nitrogen-containing scaffolds
6. Synergistic Catalysis Mechanism of Dual Ligand System ((R,R)-QuinoxP* + Chiral Phosphoramidite)
- Hierarchical Stereocontrol
The rigid chiral cavity constructed by bisphosphine master ligand governs enantioselectivity and E/Z olefin selectivity; the auxiliary phosphoramidite fine-tunes the cobalt metal coordination microenvironment to boost regioselectivity, realizing triple high-selectivity control simultaneously.
- Intermediate Stabilization
Weak coordination of phosphoramidite stabilizes low-reactivity aryl-Co(II) intermediates, while strong chelation of bisphosphine inhibits cobalt metal deactivation, significantly elevating reaction yields.
- Tandem Dual-Migration Cycle Adaptation
The combination of rigid bisphosphine and flexible phosphoramidite fixes the cobalt center while reserving structural distortion space for 1,4-Co/H migration and alkenyl E/Z isomerization, ensuring smooth progression of cascade dual-migratory pathways.
- Electronic Matching for Broad Substrate Compatibility
Electron-rich bisphosphine and electron-withdrawing amide groups of phosphoramidite synergistically balance electron density on cobalt center, enabling compatibility with various aromatic substrates and crude E/Z mixed alkenyl halide feedstocks.
- Industrial Synthetic Value
Mild reaction conditions, gram-scale reproducibility, and stereoconvergent synthesis from E/Z mixed olefins eliminate tedious olefin separation steps, greatly improving synthetic efficiency for chiral amine intermediates in drug manufacturing.
7. Commercial Supply Information
Kaitailai Platinum (Anhui) Co., Ltd. provides commercial supply of chiral QuinoxP* ligands and chiral phosphoramidite ligands described in this work. Customized ligand synthesis service is available for academic and industrial research groups worldwide. Global cooperation & inquiry are warmly welcomed.