1. Introduction

Chiral benzene-fused indole skeletons represent privileged core structural motifs commonly encountered in natural alkaloids, drug candidates, and agrochemicals^[1-7]. Among these architectures, benzo-fused chiral indoles exhibit distinctive biological activities and broad synthetic utility, making them highly attractive targets for asymmetric catalysis. While numerous methodologies have been developed for C2/C3 C-H functionalization of indole heterocycles^[8-14], precise regio- and enantioselective modification at the remote benzenoid carbocyclic ring remains a formidable synthetic challenge. The inherently low reactivity and unpredictable site selectivity of aromatic C-H bonds on the benzene moiety severely restrict the efficient assembly of fused chiral indole frameworks. Accordingly, advanced catalytic strategies for the asymmetric functionalization of indoles are urgently needed to streamline the synthesis of indole-derived bioactive molecules and fine chemicals.

Friedel-Crafts (F-C) alkylation constitutes one of the most robust and versatile strategies for constructing aromatic C-C bonds^[15-20], enabling efficient derivatization of electron-rich arenes including indoles. Conventionally, asymmetric F-C transformations of indoles rely predominantly on chiral Brønsted or Lewis acid catalysis^[21-25], which typically favor functionalization at the C2 and C3 positions of the pyrrole ring. In sharp contrast, remote C-H functionalization on the benzene ring generally requires pre-installed directing groups; such established catalytic systems frequently suffer from narrow substrate scope and insufficient stereochemical control. Furthermore, nearly all documented protocols rely on hydrogen-bond-driven asymmetric induction, whereas alternative activation modes for enantioselective F-C reactions of indole remain largely underexplored.

As a powerful complement to conventional acid catalysis, N-heterocyclic carbene (NHC) organocatalysis has emerged as a prominent platform in modern asymmetric synthesis^[26-33], owing to its exceptional capacity to achieve umpolung reactivity of carbonyl substrates. Under mild and facile conditions, NHC catalysts efficiently activate α-bromoenal to generate α,β-unsaturated acylazolium intermediates^[34-41]. These versatile electrophilic synthons participate in diverse cascade alkylation and annulation processes, enabling modular construction of structurally complex chiral heterocycles with outstanding stereoselectivity.

Taking advantage of these unique catalytic features, a recent experimental study reported an elegant NHC-catalyzed cascade reaction merging F-C alkylation and lactamization, achieving regio- and enantioselective annulation between 4-aminoindoles and α-bromoenals (Scheme 1)^[42]. This protocol delivers highly selective C5-functionalization of 4-aminoindole and provides facile access to benzene-fused chiral indole derivatives with excellent enantioselectivity. Notably, Li^[43] demonstrated that F-C alkylation of 4-aminoindole can alternatively furnish C7-substituted products with high regio- and enantioselectivity under related organocatalytic conditions. Despite these remarkable experimental advances, the mechanism of this cascade transformation, the origin of C5 regioselectivity, and the key factors governing enantioselective induction have not been systematically elucidated. For computational purposes, the full catalyst structure was modeled throughout the calculations, and the substituent abbreviated as R in the following figures and schemes was truncated for clarity.

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Scheme 1. NHC-catalyzed F-C alkylation/annulation reaction. NHC: N-heterocyclic carbene; F-C: Friedel-Crafts.

Against this backdrop, density functional theory (DFT) calculations have become an indispensable theoretical tool for probing organocatalytic^[44-48] and organometallic reaction mechanisms^[49-52], allowing precise clarification of complex catalytic pathways and identification of the origins of regio- and stereoselectivity. In the present work, we selected a model reaction of NHC-catalyzed F-C alkylation/annulation cascade reaction between α-bromoenal (1a) and 4-aminoindole (2a) to clarify the reaction mechanism and the origins of regio- and stereoselectivity. According to experimental observations, the α,β-unsaturated acylazolium intermediate can undergo C3-, C5-, or C7-addition, yet the reaction regioselectively affords the C5-functionalized product 3a as the major isomer. The reaction exhibits excellent enantioselectivity (97:3 er, Scheme 1), which attracted our attention and warranted theoretical exploration. As a continuation of our ongoing efforts to understand mechanistic aspects of asymmetric catalysis^[53-56], we herein report DFT calculations for this NHC-catalyzed F-C reaction. We map the complete mechanistic pathway and disclose the origins of both regio- and stereoselectivity.

2. Methods

All quantum-chemical calculations were performed using the Gaussian 09 program package^[57]. Geometry optimizations of all stationary points, including reactants, key intermediates, transition states, and products, were carried out at the M06-2X^[58]/6-31G(d,p)^[59,60] level of theory. The M06-2X density functional was chosen for its well-documented performance for main-group thermochemistry, weak noncovalent interactions, and organocatalytic processes, based on its successful previous applications to related catalytic systems^[61-64]. To reproduce experimental reaction conditions, solvent effects for chloroform were incorporated during geometry optimizations via the solvation model based on density (SMD)^[65]. Frequency calculations were performed at the same computational level to characterize each optimized stationary point. Intrinsic reaction coordinate (IRC) calculations were conducted for representative transition states to confirm connectivity between the corresponding reactant and product species (Figure S1). All minimum-energy intermediates were confirmed to possess zero imaginary frequencies, whereas each transition state exhibited exactly one imaginary frequency corresponding to the relevant elementary reaction coordinate. Thermal corrections to Gibbs free energy were calculated at 298.15 K and 1 atm for all species. To obtain more accurate energetic parameters, high-level single-point energy calculations were performed at the M06-2X/6-311++G(d,p)//SMD(chloroform) level using the optimized geometries. Final Gibbs free energies used for pathway analysis were obtained by combining these single-point energies with thermal corrections derived from frequency calculations. A standard-state correction of RT(c_s/c_g) (1.89 kcal/mol) was added to all species to convert Gibbs free energies from the gas-phase standard state to the solution-phase standard state; here c_s is the standard molar concentration in solution (1 mol/L), c_g is the standard molar concentration in the gas phase (0.0446 mol/L), and R is the gas constant.

To rationalize the origin of stereoselectivity in this asymmetric cascade transformation, the activation strain model (ASM)^[66] and energy decomposition analysis (EDA)^[67] were applied to key stereoselective transition states to identify dominant factors governing stereoselectivity. Furthermore, the projection of orbital coefficient vector (POCV) method^[68] was employed to elucidate the origin of the C5-regioselectivity observed in the F-C alkylation of 4-aminoindole.

To validate the results obtained at the M06-2X/6-31G(d, p)//SMD(chloroform) level, transition states for the stereoselectivity-determining step were reoptimized using the B3LYP^[69], B3PW91^[70], CAM-B3LYP^[71], mPW1PW91^[72], and ωB97X-D^[73] functionals. Computational results are summarized in Table S1 of the Supplementary materials. Compared with the M06-2X results, those obtained with other functionals showed only slight differences while maintaining the same trends. Accordingly, the mechanistic conclusions derived from M06-2X calculations are reliable.

3. Results and Discussion

3.1 Reaction mechanism

On the basis of prior experimental observations, we proposed a mechanism for the NHC-catalyzed F-C alkylation/annulation cascade reaction. In the presence of the carbonate base Na₂CO₃, triazolium pre-NHC undergoes deprotonation to generate the active free NHC catalyst and NaHCO₃. As presented in Scheme 2, the entire catalytic cycle comprises eight elementary steps: (i) nucleophilic addition of NHC to the enal to furnish zwitterionic intermediate Int-A; (ii) intramolecular [1,2]-proton transfer to generate Breslow intermediate Int-B; (iii) C-Br bond cleavage to deliver the key α,β-unsaturated acylazolium intermediate Int-C; (iv) enantioselective electrophilic addition of the α,β-unsaturated acylazolium intermediate at the C5 atom of 4-aminoindole to form intermediate Int-D; (v) α-protonation of Int-D to yield acyl intermediate Int-E; (vi) intramolecular ring closure to produce intermediate Int-F; (vii) deprotonation of Int-F to afford Int-G; and finally, (viii) dissociation of NHC to release the desired product 3a and regenerate the active NHC catalyst for the subsequent catalytic cycle.

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Scheme 2. Proposed reaction mechanism for the NHC-catalyzed F-C alkylation/annulation cascade reaction. NHC: N-heterocyclic carbene; F-C: Friedel-Crafts.

3.1.1 Formation of α,β-unsaturated acylazolium

Our computational investigation began with nucleophilic addition of the NHC catalyst at the carbonyl carbon of substrate 1a. Given the geometry of 1a, NHC can approach either the Re-face or Si-face of the carbonyl group, generating zwitterionic intermediates Re-M1 or Si-M1 via transition states Re-TS1 or Si-TS1, respectively. The relative Gibbs free energy profile describing formation of α,β-unsaturated acylazolium from NHC and 1a is presented in Figure 1. The energy barrier for the Re-face addition via Re-TS1 to form Re-M1 is 10.2 kcal/mol, confirming that this nucleophilic addition step is kinetically accessible under experimental conditions. By contrast, the energy barrier for Si-face addition via Si-TS1 to generate Si-M1 reaches 11.0 kcal/mol (Scheme S1), which is marginally higher than that for the Re-face pathway.

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Figure 1. Relative Gibbs free energy profile for the formation of key α,β-unsaturated acylazolium intermediate.

Subsequently, intermediates Re-M1 and Si-M1 undergo [1,2]-proton transfer to furnish Breslow intermediates (E,Z)-M2 and (Z,Z)-M2 via transition states Re-TS2 or Si-TS2, respectively. Two distinct proton-transfer pathways mediated by different proton sources (i.e., NaHCO₃, HCO₃^-) were calculated and systematically compared. As shown in Scheme 3, the energy barriers for HCO₃^- and NaHCO₃-assisted proton transfer along the Re-face pathway are 12.2 and 5.0 kcal/mol via transition states Re-TS2^C and Re-TS2, respectively. For the Si-face addition pathway, the corresponding barriers associated with transition states Si-TS2^C and Si-TS2 are 20.0 and 8.6 kcal/mol (Scheme S1 of the Supplementary materials). Comparative calculations unambiguously demonstrate that the NaHCO₃-assisted proton transfer pathway is kinetically favored.

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Scheme 3. Comparative energy barriers for HCO₃^- and NaHCO₃-assisted proton transfer pathways.

With the assistance of NaHCO₃, Breslow intermediates (E,Z)-M2 and (Z,Z)-Si-M2 are readily generated with energy barriers of 5.0 and 8.6 kcal/mol via the transition states Re-TS2 and Si-TS2, respectively. These data confirm that the Re-face addition pathway is more energetically favorable; accordingly, only the Re-face pathway is discussed in the following steps. The Breslow intermediate (E,Z)-M2 rapidly undergoes C-Br bond cleavage via transition state (E,Z)-TS3 to form allenol intermediate M3. Subsequent α-protonation proceeds through TS4 with an energy barrier of 17.5 kcal/mol to yield the key electrophilic α,β-unsaturated acylazolium intermediate M4, representing a feasible transformation under experimental conditions.

3.1.2 Transformation of α,β-unsaturated acylazolium intermediate

Electrophilic intermediate M4 reacts with substrate 2a to deliver the desired F-C product 3a-S via selective C5-addition; the corresponding relative Gibbs free energy profile is presented in Figure 2. Computational results reveal that electrophilic addition of M4 to 4-aminoindole 2a proceeds through transition state TS5S to form the S-configured intermediate M5S with an energy barrier of 14.3 kcal/mol. In contrast, formation of the enantiomeric R-configured intermediate M5R via transition state TS5R exhibits a higher energy barrier of 16.4 kcal/mol (Figure S2). This energetic difference establishes that the S-configured pathway is kinetically favored; therefore, subsequent mechanistic discussion focuses on the S-configured pathway. Moreover, we further performed conformational searches for transition states of the stereoselectivity-determining step to confirm the reliability of the calculated results. Starting from the original TS5R and TS5S, the dihedral angle Φ1(C1-C2-C3-C4) was rotated in 90° increments over 0 ~ 360° to generate eight initial transition structures; the 3D structures are presented in Figure S3 of the revised manuscript. As an important note, the initial structures by rotating the dihedral Φ1 with 90° would lead to the same conformations of those with Φ1(C1-C2-C3-C4) = 0°/360° after the structural optimizations. The relative Gibbs free energies depicted in Table S2 of the Supplementary materials confirm that the original transition state conformers possess the lowest energies among all conformers, justifying our focus on TS5R and TS5S in the main text.

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Figure 2. Relative Gibbs free energy profile for the transformation of α,β-acylazolium intermediate. NHC: N-heterocyclic carbene.

Intermediate M5S undergoes α-protonation to generate acylazolium species M6S. Three possible pathways were evaluated (Figure S4), among which bicarbonate anion-promoted proton transfer exhibits the lowest energy barrier. Intermediate M6S is formed via transition state TS6S with an energy barrier of 14.6 kcal/mol. Next, M6S undergoes intramolecular ring closure via transition state TS7S to furnish intermediate M7S, with an energy barrier of 13.4 kcal/mol, indicating that the process is feasible under the experimental conditions. The intermediate rapidly rearranges via transition state TS8S to afford thermodynamically stabilized intermediate M8S with a relative Gibbs free energy of -44.6 kcal/mol. Finally, dissociation of the NHC catalyst occurs via transition state TS9S to release the desired product 3a-S. The energy barrier for catalyst dissociation is only 5.4 kcal/mol, indicating efficient catalyst turnover and facile regeneration of the active NHC throughout the catalytic cycle.

3.2 Origins of Selectivities

3.2.1 Origin of Stereoselectivity

Based on the computational results, the highest point on the R-configured pathway is TS6R with an energy barrier of 16.8 kcal/mol. The highest energy barrier along the S-configured pathway is 14.6 kcal/mol, which is 2.2 kcal/mol lower than that of the R-configured pathway. Consequently, formation of the S-configured isomer is more energetically favorable, in agreement with the experimental results. Thus, the C-C bond formation and α-protonation steps are likely the stereoselectivity-determining processes. Furthermore, the nucleophilic addition of 4-aminoindole to the Re or Si faces of the α,β-unsaturated acylazolium intermediate would lead to the formation of two enantiomers, and the chirality at the β-carbon is preserved during the subsequent transformations. Therefore, the transition states involved in the C-C bond formation step are analyzed to elucidate the key factors that control the stereoselectivity. The 2.1 kcal/mol energy gap between the major and minor transition states predicts an enantioselective ratio (e.r.) of 97.25:2.75, which closely matches the experimentally measured er value of 97:3. To quantitatively rationalize the stereoselective outcome, ASM and EDA were performed for the stereoselective transition states TS5R and TS5S.

ASM was first employed to dissect the energetic differences between stereodivergent transition states. As summarized in Table 1, TS5S has a lower activation energy (E_Act = 2.6 kcal/mol) relative to TS5R (E_Act = 3.4 kcal/mol), rendering the S-configured pathway kinetically favorable. The distortion energy (E_Dist) indicates that the strain discrepancy between the two transition states mainly originates from the α,β-unsaturated acylazolium moiety M4. Formation of TS5S requires substantial geometric distortion of the α,β-unsaturated acylazolium moiety (21.0 kcal/mol), which is larger than the corresponding distortion for TS5R (17.2 kcal/mol). Nevertheless, the interaction energy (E_Int) term provides a strong stabilizing effect within TS5S, which effectively counterbalances its larger distortion penalty. Collectively, stereoselectivity in this reaction is governed by the magnitude of intermolecular interaction energy between the two reacting fragments.

EDA was further employed to identify the dominant energetic contributions to the interaction energy. Total interaction energy (E_int) is decomposed into electrostatic interaction (E_elstat), orbital interaction (E_orb), Coulomb correlation (E_C), and exchange-Pauli repulsion (E_ex-Pauli) components. As shown in Figure 3, TS5S delivers a more favorable interaction energy, reflecting stronger stabilizing effects in the S-configured transition state. Although TS5R features more favorable electrostatic and orbital interactions, with energies of -65.6 and -68.6 kcal/mol, these values provide considerably stronger stabilization than the corresponding values of -51.7 and -63.3 kcal/mol calculated for TS5S. The Coulomb correlation (E_C) term also contributes appreciable stabilization (-43.4 kcal/mol for TS5R vs -37.7 kcal/mol for TS5S, Figure 3). The exchange-Pauli repulsion term E_Pauli describes destabilizing steric repulsion originating from filled-orbital overlap; this repulsive term reaches 145.0 kcal/mol for TS5R but decreases to 129.4 kcal/mol for TS5S. Therefore, the R-configured transition state suffers from severe steric congestion and larger filled-orbital repulsion, whereas the S-configuration effectively alleviates intermolecular Pauli repulsion. In summary, transition state stability arises from a delicate balance between attractive interactions and exchange-Pauli repulsion, making the S-configured transition state geometry kinetically preferred.

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Figure 3. EDA analysis for stereoselective and regioselective transition states. EDA: energy decomposition analysis.

3.2.2 Origin of regioselectivity

Experimentally, preferential C5 F-C functionalization is observed under NHC catalysis. To elucidate the regioselectivity, we calculated and compared the energy barriers for acylazolium addition at the C3, C5, C6, and C7 positions of 4-aminoindole. As shown in Table 2, the energy barriers for addition of M4 to N-methyl 4-aminoindole 2a at C3, C5, C6, and C7 were 23.6, 14.3, 34.5, and 21.2 kcal/mol, respectively. These values confirm that the C5-addition pathway is kinetically most favorable under the experimental conditions. To gain deeper insight into regioselective trends, we also examined the reaction between M4 and unprotected 4-aminoindole 2b. For the reaction between 2b and M4, computed barriers for C3-, C5-, C6-, and C7-addition pathways are 25.4, 18.6, 36.0, and 20.5 kcal/mol, respectively, again identifying C5-addition as the lowest-energy pathway. The computational trends are consistent with the experimental regioselectivity, implying that the intrinsic reactivity of aromatic carbon atoms is one of the key factors governing regioselectivity.

POCV analysis was applied to test whether regioselectivity is governed by intrinsic reactivity at different carbon sites. Within the POCV framework, the local atomic reactivity is quantified by the magnitude of the atomic reactivity vector $(\overrightarrow{F})$; larger magnitude $\overrightarrow{F}$ values correspond to higher intrinsic reactivity and lower addition barriers. As displayed in Figure S5, the atomic reactivity vectors of the carbonyl carbon and β-carbon within M4 are 1.08 and 1.24, confirming that the β-carbon of the acylazolium species constitutes the dominant electrophilic site for reaction with 4-aminoindole. As presented in Table 2, the atomic reactivity vectors of the C3, C5, C6, and C7 positions are 1.16, 1.21, 1.15, and 1.20 for substrate 2a, respectively. The corresponding values in unprotected 4-aminoindole 2b are 1.16, 1.21, 1.14, and 1.20, respectively. The atomic reactivity vector values correlate directly with the computed energy barriers for both substrates: higher intrinsic reactivity corresponds to lower energy barriers. This correlation demonstrates that regioselectivity in this cascade reaction is intrinsically controlled by site-specific atomic reactivity, which can be reliably predicted via POCV calculations. This work establishes a straightforward theoretical protocol to forecast regioselective outcomes by evaluating the intrinsic reactivity of all plausible reactive sites in advance. In addition, the ASM and EDA results presented in Table 1 and Figure 3 further confirm that the preferred transition state TS5S has a more negative interaction energy, indicating that this transition state is stabilized by stronger stabilizing effects. These results verify that the intrinsic reactivity vector, together with stronger stabilizing effects, jointly determines regioselectivity. Furthermore, the reaction between 4-hydroxyindole and the α,β-unsaturated acylazolium intermediate was also calculated, and the computational results (Figure S6) show that the C5-addition pathway is the most energetically favorable, with the largest atomic reactivity vector $(\overrightarrow{F_{C5}}=1.23)$, which further validates the POCV calculations.

4. Conclusion

Systematic DFT calculations have fully deciphered the mechanism and origins of regio- and stereoselectivity for the NHC-catalyzed F-C alkylation/annulation cascade reaction between 4-aminoindole and α-bromoenal. The entire catalytic cycle consists of eight elementary steps, in which carbonate base-assisted proton transfer facilitates efficient construction of the key α,β-unsaturated acylazolium intermediate. The electrophilic addition of the α,β-unsaturated acylazolium intermediate to 4-aminoindole is unambiguously identified as the stereoselectivity-determining step, and the computed energy difference between the two stereoselective transition states quantitatively reproduces the experimentally observed high enantioselectivity. Combined ASM and EDA analyses quantitatively demonstrate that electrostatic interactions and dispersion forces constitute the dominant stabilizing factors for the energetically favorable S-configured transition state, alleviating Pauli steric repulsion and driving stereochemical differentiation. From a regioselective perspective, the POCV method directly correlates with the intrinsic atomic reactivity of indole, offering a clear explanation for the predominant C5-site selectivity. This study validates the combined use of ASM, EDA, and POCV as robust theoretical tools to dissect stereo- and regioselectivity in organocatalytic asymmetric transformations. Overall, this study provides in-depth mechanistic insights into NHC-catalyzed asymmetric F-C functionalization of indole and offers reliable theoretical guidance for the rational design of stereoselective organocatalytic systems.

Supplementary materials

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

Acknowledgements

The authors declare that Doubao was used solely for language polishing during the manuscript preparation process. All research content, including study design, data analysis, interpretations, figures, and tables, is original and was not generated using AI tools. The authors reviewed, revised, and approved the final manuscript and take full responsibility for its content.

Authors contribution

Wang YN: Data curation, formal analysis.

Wang Y: Conceptualization, writing-review & editing.

Wei D: Software, writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The data and materials could be obtained from the corresponding author.

Funding

We acknowledge financial support from the Outstanding Youth Science Foundation Project of Henan Province (Grant No. 252300421039), the Key Project of the Joint Fund for Science and Technology Research and Development in Henan Province (Grant No. 232301420008), the National Natural Science Fund of China (Grant Nos. 22473100 and 21903072), the Key Scientific Research Projects of Higher Education Institutions in Henan Province (Grant No. 25A310007), and Zhengzhou University’s Key Faculty Development Program (Grant No. 2023ZDGGJS033).

Copyright

© The Author(s) 2026.