1. Introduction

Dearomatization represents a fundamental and powerful strategy in organic synthesis, enabling the transformation of simple aromatic compounds into partially saturated cyclic frameworks characterized by enhanced structural complexity and stereochemical diversity^[1-3]. In particular, catalytic asymmetric dearomatization (CADA) reactions have garnered significant attention, as they offer efficient and streamlined access to chiral molecules bearing multiple stereocenters from readily available aromatic precursors^[4]. Among various aromatic substrates^[5-8], indoles have emerged as exceptionally attractive platforms for dearomatization. Given that polycyclic indole derivatives are prevalent in alkaloid natural products and biologically active compounds^[9-11], their asymmetric synthesis has stimulated sustained interest^[12,13]. From a synthetic perspective, the dearomative functionalization of indole derivatives represents one of the most straightforward and versatile approaches for constructing these privileged molecular scaffolds^[14,15].

Asymmetric dearomatization of indoles via carbene insertion has recently emerged as an effective strategy for the construction of fused indoline frameworks. Although asymmetric carbene-transfer reactions have been extensively investigated over the past decades^[16-21], enantioselective dearomative cyclopropanation of indoles remains relatively underexplored. In 2024, Bi and co-workers^[22] reported a rhodium-catalyzed intermolecular asymmetric dearomative cyclopropanation of indoles using trifluoromethyl N-triftosylhydrazones as carbene precursors, achieving excellent enantioselectivities of up to 99% ee (Figure 1a). The utilization of chiral dirhodium(II) paddlewheel complexes proved crucial, as their unique electronic and coordination properties facilitate the efficient generation and stabilization of metal–carbene intermediates, thereby enhancing both reactivity and stereocontrol^[23,24]. Given the economic advantages and greater availability of copper compared to rhodium, the development of Cu-catalyzed asymmetric carbene-transfer reactions is of substantial practical interest. Boysen^[25] and Pirovano^[26] independently reported Cu-catalyzed intermolecular cyclopropanation of indoles with ethyl diazoacetate. However, these two protocols generally afforded only moderate enantioselectivity or unsatisfactory reaction yields (Figure 1b). In 2017, Zhou and co-workers^[27] developed the first highly enantioselective Cu-catalyzed intramolecular cyclopropanation of indoles using a chiral spiro bisoxazoline ligand (Figure 1b, up to > 99% ee).

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Figure 1. The asymmetric cyclopropanation of indole.

Despite their potential advantages, asymmetric dearomative cyclopropanation of indoles, particularly intermolecular processes, remains largely underexplored. This limitation primarily stems from the relative stability of indoles compared to simple alkenes^[17]. Furthermore, several competing side reactions, such as the ring-opening of strained cyclopropanes to form quinoline derivatives^[28], competitive C₃–H insertion of indoles^[22,29], and dimerization of carbene intermediates^[30], often compromise reaction efficiency and stereochemical control. Consequently, highly efficient asymmetric intermolecular cyclopropanation of indoles based on earth-abundant metals remains rare. A major challenge lies in the scarcity of suitable chiral ligands capable of simultaneously promoting high reactivity and excellent stereocontrol^[31,32].

In recent years, our group has developed a series of chiral N-heterocyclic carbene (NHC) ligands^[33-37]. Characterized by their strong σ-donor ability and bulky, flexible steric profiles, these ligands have consistently delivered high catalytic efficiency and outstanding stereoselectivity across a diverse array of asymmetric transformations^[38-45]. Motivated by these findings, we hypothesized that an NHC/Cu catalyst system could effectively facilitate asymmetric carbene transfer. Furthermore, we postulated that the deep chiral pocket created by our NHC ligand might address the challenging stereocontrol associated with the quasi-linear NHC/Cu(I)–carbenoid intermediate^[46-49]. To the best of our knowledge, enantioselective carbene transfer reactions enabled by chiral NHC/metal catalysis have not been reported^[49-53]. Herein, we report a rare example of enantioselective NHC/Cu-catalyzed intermolecular cyclopropanation of indoles with diazo esters (Figure 1c). This protocol provides efficient access to cyclopropane-fused indolines with broad functional group tolerance.

2. Experimental Section

General Considerations: Chemicals were commercially purchased from Adamas-beta, Bide Pharmatech Ltd., Aladdin, and J & K Chemical Co. Ltd., and were used directly without further purification unless otherwise stated. Copper chloride was purchased from Strem Chemicals Inc. and used as received. All the reactions were conducted under a N₂ atmosphere using a glovebox or vacuum-line techniques, and the glassware was dried in an oven (140 °C) or flame-dried. ¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were recorded at room temperature on an Agilent 400 MHz or 600MHz, Varian 400 MHz, or Bruker 400 MHz spectrometers and were calibrated using residual solvent as an internal reference (CDCl₃: 7.26 ppm for ¹H NMR and 77.16 ppm for ¹³C NMR). Enantiomeric excess was determined by high-performance liquid chromatography (HPLC) analysis using the chiral column described below in detail.

2.1 Typical procedure for asymmetric NHC/Cu catalyzed intermolecular cyclopropanation of indoles with diazo esters

In a nitrogen-filled glovebox, an oven-dried screw-cap reaction tube equipped with a magnetic stir bar was charged with L1-CuCl (8.8 mg, 0.01 mmol, 5 mol%) and KB(C₆F₅)₄ (7.2 mg, 0.01 mmol, 5 mol%), the indole substrate (0.2 mmol, 1.0 equiv.), and dichloromethane (1 mL). The reaction tube was sealed with a screw-cap septum and stirred at -20 °C for 1 hour. The diazo compound (0.4 mmol, 2.0 equiv.) was dissolved in dichloromethane (1 mL) and frozen at -20 °C for 1 hour before being slowly added dropwise to the reaction mixture. The reaction mixture was stirred within the sealed tube at -20 ^oC for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product. The diastereomeric ratio (d.r.) value of the crude products was determined by ¹H NMR. The crude residue was purified via column chromatography to afford the desired product. The enantiomeric excess (ee) value was determined by chiral HPLC analysis of the isolated product.

3. Results and Discussion

Our investigation began by screening various metal catalysts (Rh, Ag, Pd) with L1 for the reaction of N-protected indole 1 and diazo ester 2; however, these systems failed to promote the desired transformation or yielded racemic product 3 (Table 1, entries 1-3). Gratifyingly, employing ANIPE–CuCl afforded product 3 in 90% yield with 19% ee (entry 4). We observed that the steric bulk of the diazo ester significantly influenced enantioselectivity, with ee values improving as steric demand increased (entries 5-8). Notably, tert-butyl 2-diazo-2-phenylacetate provided an enhanced enantioselectivity of 49% ee (entry 8), a finding we attribute to improved enantioface differentiation of the NHC–copper carbenoid intermediate. Further optimization of the N-protecting group identified N-Piv as optimal, delivering the product in 87% yield and 72% ee (entry 11). While other NHC/Cu complexes showed slightly inferior results, common phosphine and bisoxazoline ligands were ineffective (entries 12-16). Lowering the temperature to -20 °C significantly boosted enantioselectivity but reduced the yield to 57% (entry 17), likely due to competitive diazo dimerization. Increasing the diazo ester loading to 2.0 equivalents restored the yield to 89% (entry 18). Finally, replacing NaBArF with KB(C₆F₅)₄ marginally improved both yield and enantioselectivity (entry 19; see Tables S1-S6 for details).

Table 1. Optimization of the reaction conditions.

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Entry	R1	R2	cat.	Yield (%)a	ee (%)a
1	Boc	Et	L1/HCl + Rh2(OAc)4	N.D.	N.D.
2	Boc	Et	L1-AgCl	N.D.	N.D.
3	Boc	Et	L1-Pd(cin)Cl	82	0
4	Boc	Et	L1-CuCl	90	19
5	Boc	Me	L1-CuCl	99	14
6	Boc	Bn	L1-CuCl	99	22
7	Boc	iPr	L1-CuCl	99	33
8	Boc	tBu	L1-CuCl	95	49
9	Ts	tBu	L1-CuCl	32	69
10	Ac	tBu	L1-CuCl	39	61
11	Piv	tBu	L1-CuCl	87	72
12	Piv	tBu	L2-CuCl	82	56
13	Piv	tBu	L3-CuCl	84	41
14	Piv	tBu	L4-CuCl	94	37
15	Piv	tBu	L5-CuCl	N.D	N.D.
16	Piv	tBu	L6-CuCl	N.D	N.D.
17b	Piv	tBu	L1-CuCl	57	85
18b,c	Piv	tBu	L1-CuCl	86	85
19b,c,d	Piv	tBu	L1-CuCl	89	89

Reaction condition: 1 (0.1 mmol), 2 (0.15 mmol), catalyst (5 mol%), NaBArF (5 mol%) and DCM (1.0 mL) under N₂ atmosphere, 12 h. ^a: The yield and d.r. were determined by ¹H NMR spectroscopy of crude sample with C₂H₂Cl₄ as an internal standard; ^b: -20 ℃; ^c: Using 2.0 equiv. diazo ester; ^d: Using KB(C₆F₅)₄ instead of NaBArF. DCM: dichloromethane; NMR: nuclear magnetic resonance.

With the optimized conditions in hand, we first examined the structural variation of the diazo esters. As presented in Figure 2, this cyclopropanation reaction proceeded smoothly utilizing a variety of (hetero)aromatic diazo esters, providing the corresponding products in good to excellent yields and good enantioselectivities (75-90% ee). Common functional groups, including fluoride (3d), chlorides (3e, 3f, 3g), bromide (3h), iodide (3i), ethers (3j-3l, 3n-3o), trifluoromethyl (3m) and ester (3p), were well tolerated. Heterocyclic substrates such as those derived from thiophene (3r) and benzodioxole (3l) proved compatible, providing fused indolines in synthetically useful yields. Additionally, the diazo ester derived from isoxazole-4-carboxylic acid afforded product 3s in moderate yield and enantioselectivity (58%, 71% ee). We next explored the scope of the indole component. The reaction proceeded in good yields (65-86%) and high enantioselectivity (82-88% ee), accommodating various electron-donating (e.g., methoxy, benzyloxy, silyloxy, piperonyl; 4a-d) and electron-withdrawing groups (e.g., fluorides (3v, 3w), chloride (3x), and bromides (3y, 3z)). Notably, the substitution position on the aromatic ring had no significant impact on enantioselectivity. The absolute configuration of the product was unambiguously confirmed by X-ray diffraction analysis of a single crystal of 3a (CCDC 2429515).

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Figure 2. Substrate scope^a. ^a: Standard conditions unless otherwise noted: 1 (0.2 mmol), 2 (0.4 mmol), L1-CuCl (0.01 mmol), KB(C₆F₅)₄ (0.01 mmol), DCM (1mL), -20 °C, 12 h. Isolated yields are reported. Ee and dr were determined with HPLC and NMR analysis, respectively. DCM: dichloromethane; NMR: nuclear magnetic resonance; HPLC: high-performance liquid chromatography.

The operational robustness of this transformation was demonstrated on a gram-scale reaction. Notably, performing the reaction with 5 mmol of N-Piv indole 1a and 10 mmol of diazo ester 2a in dichloromethane, using just 2 mol% catalyst loading, afforded product 3a in 81% yield and 86% ee (Figure 3a). Further synthetic utility was illustrated by the transformation of 3a. Under acidic catalysis, transesterification of the ester moiety proceeded smoothly to furnish methyl ester 5 with complete retention of enantioselectivity (Figure 3b). Conversely, treatment with base promoted amide hydrolysis and ring-opening, yielding the C3-substituted indole derivative 6 while preserving stereochemical integrity (Figure 3c).

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Figure 3. Gram scale reaction and synthetic applications.

To gain insight into the reaction mechanism, a series of control experiments was conducted. Parallel kinetic isotope effect (KIE) studies using deuterated indoles revealed KIE values of 0.97 at the C₂-position and 0.79 at the C₃-position (Figure 4a). These observations suggest the presence of a secondary kinetic isotope effect, consistent with a change in hybridization from sp² to sp³ at these positions during the reaction^[54]. Subsequent Hammett analysis using para-substituted diazo esters established a linear free-energy relationship with a positive slope (ρ = 0.283, Figure 4b), indicating that the rate-determining step involves a transition state with partial negative charge accumulation^[55]. Based on these experimental results and previous reports^[22,56], a plausible catalytic cycle is proposed (Figure 4c). Initially, the NHC–Cu complex reacts with the diazo compound to extrude N₂, generating a metal carbenoid intermediate. This is followed by nucleophilic attack of the indole at the carbene center to form a zwitterionic intermediate, which undergoes intramolecular cyclization to furnish the desired product. The use of our bulky yet flexible chiral NHC ligand is crucial for achieving effective control over both enantioselectivity and diastereoselectivity.

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Figure 4. Mechanistic experiments and proposed catalytic cycle.

4. Conclusion

In summary, we have developed a highly efficient NHC/Cu-catalyzed asymmetric dearomative cyclopropanation of indoles using diazo esters as carbene precursors. This method provides straightforward access to structurally diverse cyclopropane-fused indolines bearing quaternary stereogenic centers in good yields with high levels of enantio- and diastereocontrol. The use of bulky chiral NHC ligands was found to be crucial for stabilizing the copper–carbenoid intermediate and enabling effective stereoinduction. Featuring broad substrate scope, excellent functional group tolerance, and scalability, this transformation highlights its practical utility in synthetic chemistry. Mechanistic investigations suggest a pathway involving nucleophilic attack of the indole on a copper–carbenoid species followed by intramolecular cyclization. This study demonstrates the substantial potential of chiral NHC ligands in metal-catalyzed asymmetric carbene-transfer chemistry.

Supplementary materials

The supplementary material for this article is available at: Supplementary materials.

Authors contribution

Shi SL, You SL: Conceptualization, supervision, writing-review & editing.

Ruan LX: Writing-original draft, writing-review & editing.

Liu S: Investigation, methodology.

Lu J: Investigation, methodology, writing-original draft.

Conflicts of interest

Shu-Li You is an Editorial Board Member of Chiral Chemistry. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The data reported in this paper are available in the main text or supplementary information, including methods, NMR data, HRMS data, HPLC spectra Crystal data and NMR spectra. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2429515 (3a).

Funding

This work was financially supported by the National Natural Science Foundation of China (22325110 and 22501291), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0610000), and the Shanghai Science and Technology Committee (25ZR1402566).

Copyright

© The Author(s) 2026.