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. 2026 May 29;17:6991. doi: 10.1038/s41467-026-73831-5

Mechanochemical Single-Carbon Insertion into (Iso)quinolines

Chunxiu Jing 1,#, Fanchen Huang 1,#, Xiaotong Liang 1, Pan Gao 1, Qing Gao 1, Zhaojing Zheng 1, Hao Wei 1,✉
PMCID: PMC13392005  PMID: 42215502

Abstract

(Iso)quinolines are among the most common heterocycles in US Food and Drug Administration approved drugs, whereas benzoazepines are underrepresented in drug discovery libraries, primarily because of the lack of efficient preparation routes. Therefore, an efficient method of converting (iso)quinolines to benzoazepines by leveraging the chemistries unique to (iso)quinolines to access diverse benzoazepines should be valuable. Herein, we report a mechanochemical skeletal editing protocol for use in carbon-atom insertion into (iso)quinolines to afford the corresponding benzoazepines. This reaction proceeds readily under ambient conditions without the need for metal additives, bulk solvent, or complicated pre-activation processes. Using this user-friendly protocol, we investigate substrate scope, and reaction mechanism. Moreover, benzoazepines undergo light-induced cycloaddition to yield cyclobutene-fused indolines, which can be converted to indoles by selectively removing carbon atoms. The utility of this skeletal transform is further demonstrated through the skeletal editing of pharmaceutically relevant (iso)quinolines.

Subject terms: Synthetic chemistry methodology, Solid-phase synthesis

Benzoazepines are underrepresented in drug discovery libraries, primarily because of the lack of efficient preparation routes. Here, the authors report a mechanochemical skeletal editing protocol for use in carbon-atom insertion into (iso)quinolines to afford the corresponding benzoazepines.

Introduction

Selective modifying of aromatic ring systems via single-atom skeletal editing is a transformative strategy in modern organic synthesis1–7. It involves the selective insertion, deletion, or exchange of atoms at specific sites within the molecular skeleton while preserving the core structure, which is a perfect complement to established peripheral editing techniques, such as C–H bond functionalization (Fig. 1A). Such heterocycle-to-heterocycle transmutation offers efficient strategies to expand structural diversity and provide rapid access to distinct scaffolds with potential biological relevance8–15. However, owing to the current limited methodologies used in skeletally modifying aromatic heterocycles, the development of innovative methodologies is in high demand.

Fig. 1. Mechanochemical single-carbon Insertion into (iso)quinolines.

Fig. 1

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A Skeletal editing by single-atom manipulation. B Synthetic limitations of quinolines and isoquinolines compared to benzodiazepines. C Recent advances in skeletal editing of quinolines and isoquinolines. D This work: Mechanochemically single-atom skeletal editing.

(Iso)quinolines are among the most versatile heterocyclic systems occurring in natural products, pharmaceuticals, agrochemicals, and functional materials16–19, and benzoazepines are seven-membered nitrogen heterocycle motifs. Compared to (iso)quinolines, benzoazepines remain underrepresented in drug discovery libraries, primarily beacuse the lack of efficient, modular synthetic routes20–22. The development of a strategy that can straightforwardly generate underrepresented benzoazepines using readily available (iso)quinolines via skeletal editing may enhance the evaluation of their utilities in drug discovery (Fig. 1B). Owing to their wide availabilities, (iso)quinolones are considered ideal substrates use in advancing skeletal editing reactions (Fig. 1C). Pioneering single-atom skeletal editing, Levin et al. reported elegant carbon-atom deletion from quinolines to generate indole motifs23,24. Wu et al. reported the skeletal editing of quinolines via carbon-atom insertion, affording benzoazepines via [3 + 2] cyclization/[3,5]-sigmatropic rearrangement/ring expansion25. Similarly, research by Levin regarding photoinduced oxidative restructuring facilitated the conversion of carbon atoms within quinoline derivatives to nitrogen atoms26. The research groups of Pandya27, Studer28, Glorius29, Kano30, Leonori31, and Song32, and our group33 realized the N-to-C atomic transmutation of (iso)quinolines, leading to the formation of naphthalene derivatives. Despite these impressive advances, current skeletal editing methods typically require high temperatures and transition-metal catalysts, posing challenges in terms of sustainability and functional group tolerance.

Mechanochemical reactions garner widespread attention due to their operational simplicities and capacities to reveal distinct reaction pathways that are unavailable in solution34–43. Mechanochemistry offers the key advantage of transforming liquid-phase organic synthesis into the solid state44–53, which enables the use of insoluble starting materials, eliminates the need for hazardous organic solvents, reduces operational reaction times, and enhances reaction activity and selectivity54–64. Mechanochemistry uses mechanical forces to break, form, and manipulate chemical bonds to realize functional transformations and syntheses. Notably, empirical evidence indicates that the mechanical force applied during ball milling enhances the cleavage of C–C bonds e.g., mechanical forces can be used to stretch and cleave polymer chains65. Inspired by these findings, we propose the skeletal editing of aromatic heterocycles via mechanochemistry. Mechanical energy aids in overcoming the high energy barrier associated with dearomatization and facilitates the cleavage of C–C bonds, thus enabling skeletal editing to proceed with a higher efficiency and improved sustainability.

Herein, we present an efficient mechanochemical skeletal editing protocol for use in converting (iso)quinolines to the corresponding benzoazepines (Fig. 1D). Although previous methods that utilize transition-metal catalysts successfully realized this transformation via traditional solvent-based systems, they often require high temperatures and prolonged reaction times. Additionally, (iso)quinolines cannot be directly transformed – they must be activated via by conversion to converting them into the corresponding salts to facilitate the subsequent transformation66,67. In contrast, our approach reveals that even low-cost natural clay minerals, such as kaolin, can effectively promote mechanochemical skeletal editing transformations. The reaction occurs in air at room temperature, eliminating the need for the prior activation of the (iso)quinolines and use of metal catalysts. Notably, cyclobutene-fused indolines and indoles can be rapidly synthesized using the carbon-insertion products, and furthermore, this methodology enables the potential late-stage skeletal modification of complex drug compounds and more intricate transformation of the products of skeletal editing.

Results

We began to explore the single-carbon atom insertion reaction between isoquinoline (1a) and TMSCHN2 using ball-milling techniques (Fig. 2A). First, we evaluated whether atomic insertion could be realized solely via mechanical force using ball milling, but this results in low yields (entry 1). Remarkably, using Celite as a milling auxiliary is effective, affording the desired product in a 25% yield (entry 2). Several milling auxiliaries were examined, and kaolin is the most effective, whereas other solids, such as silica, Al2O3, and bentonite, are less effective (entries 3–6). Kaolin, an aluminosilicate mineral and one of the most abundant clay minerals on Earth, may provide a high surface area and a favorable pH for this reaction. Additionally, the roles of different solvents were investigated. Small amounts of solvents are necessary, with CH3CN the most efficient (entries 7–11), and the use of a protic solvent (e.g., MeOH) does not yield the product. Employing a nitrogen atmosphere instead of air does not improve the yield, indicating the insensitivity of the reaction to air (entry 12). Using a lower ball milling frequency (20 Hz) leads to a similar yield (entry 13), whereas a further reducing to 10 Hz leads to a significant loss of activity (entry 14), and decreasing the milling time to 10 min results in a lower yield of 2a (entry 15). The activating reagent generates an isoquinolinium salt in situ, thus activating the isoquinoline ring. We screened various reagents that could form salts with the nitrogen atoms of isoquinolines (Fig. 2B). Only chloroformate salts (AR5–AR7) are effective in providing the desired atom-insertion products, with phenyl chloroformate (AR7) supporting the most efficient transformation.

Fig. 2. Reaction development.

Fig. 2

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A Screening of reaction conditions. Standard conditions: 1a (0.2 mmol), PhCOOCl (1.5 equiv), kaolin (0.05 g) and MeCN (5 equiv) in a stainless-steel milling jar (5.0 mL) with two stainless-steel balls (diameter, 7 mm). Ball milling was conducted under air for 2 min, and then TMSCHN2 (2.5 equiv) was added, followed by ball milling for 20 min. B Effect of activating reagent. aUnder a nitrogen atmosphere. THF, tetrahydrofuran; Ph, phenyl; DCM.

After optimizing the reaction conditions, the scope and functional group compatibility of the process were investigated (Fig. 3). Functional groups, such as nitro (2b), halides (2c–2e), methoxy (2f and 2g), methanesulfonyl (2h), thiomethyl (2i), aryl (2j and 2k), and alky (2l and 2m) substituents are tolerated using this method. Moieties reactive under various transition-metal catalysis conditions, such as alkynes (2n–2o), and strained rings (2p), remain intact and furthermore, isoquinolines containing furan and thiophene derivatives are amenable to this transformation (2q and 2r). Notably, double carbon-atom insertions occur to yield bibenzoazepine 2s in a 32% yield when 5,8’-biisoquinoline 1s is used as the substrate. Fasudil, which is an inhibitor of the Rho-associated coil-containing kinase68, is transformed into the corresponding benzoazepine core structure 2t, indicating the FG tolerance towards sulfonamides and amides.

Fig. 3. Substrate Scope of carbon-atom insertion in term of isoquinoline.

Fig. 3

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Standard conditions: 1 (0.2 mmol), PhCOOCl (1.5 equiv), kaolin, and MeCN (5 or 10 equiv) in a stainless-steel milling jar with two stainless-steel balls. Ball milling was conducted under air for 2 min, and then TMSCHN2 (2.5 equiv) was added, followed by ball milling for 20 min at 30 Hz.

In addition to isoquinolines, quinolines are also effective in this mechanochemical skeletal editing (Fig. 4). Various quinolines bearing electron-donating (methyl, cyclopropyl, methoxy) or -withdrawing (chloro, fluoro, trifluoromethyl, ester) groups at their C4, C5, or C6 positions are successfully subjected to this transmutation, producing the corresponding benzoazepines 4b–4h in moderate yields. Remarkably, quinolines containing bioactive heterocycles, such as furan, benzothiophene, and 2,3-dihydrobenzo[b][1,4]dioxine, are tolerated well (4i–4k). Furthermore, quinolines bearing aryl and alkyne groups are efficiently converted to the corresponding benzoazepines (4l–4n). Finally, Quinoxyfen, a protectant fungicide, is converted to a benzoazepine derivative (4o) in a moderate yield.

Fig. 4. Substrate Scope of carbon-atom insertion in term of quinoline.

Fig. 4

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Standard conditions: 3 (0.2 mmol), PhCOOCl (1.5 equiv), kaolin, and MeCN (7 equiv) in a stainless-steel milling jar with two stainless-steel balls. Ball milling was conducted under air for 2 min, and then TMSCHN2 (2.5 equiv.) was added, followed by ball milling for 20 min at 30 Hz.

Cyclobutene-fused indolines, which are structures that combine fundamental indole cores with the highly strained structure of cyclobutene, are potentially useful in drug design and discovery. Traditionally, they are accessed via the dearomative [2 + 2] cycloaddition of indole derivatives with olefins69. The product of carbon-atom insertion into quinoline can be folded into a rigid cyclobutene-fused indoline via excited-state 4π electrocyclization, and thus, we established a unique modular synthetic strategy to prepare this compound using quinoline. Skeletal editing via one-carbon deletion from quinolines has been reported by Levin23,24. Based on this mechanochemical skeletal editing method, we developed a complementary, mechanistically distinct quinoline carbon-deletion protocol. Gratifyingly, the carbon[4,5]-deletion product indole could also be prepared when cyclobutane-fused indoline was further reacted with diphenyl tetrazine via (4 + 2) and retro (2 + 2) cycloaddition. Other heterocyclic compounds were also investigated, but the results did not improve (see Supporting Information for details). The substrate scope of the carbon-deletion method was examined (Fig. 5). Unsubstituted benzo[b]azepine 4a is successfully converted to cyclobutene-fused indoline 5a (68%) and indole 6a (70%). Reacting alkyl-substituted benzo[b]azepines affords fused indolines 5b and 5c in high yields, and the corresponding indoles 6b and 6c are isolated in good yields. Notably, the cyclopropyl group is tolerated under the photo- and thermochemical conditions. This method exhibits good tolerances toward various FGs, including methoxy (5d and 6d), fluoro (5e and 6e), ester (5f and 6f), and trifluoromethyl (5g and 6g) groups. Aryl substituents are compatible with our two processes, and the targets 5 h, 5i, 6h, and 6i are produced in moderate yields.

Fig. 5. Derivatizations of the products of carbon-atom insertion into quinolines.

Fig. 5

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Step 1: 4 (0.1 mmol) in tetrahydrofuran (THF, 0.5 mL) under LEDs (λ = 430 nm, 10 W) at room temperature (r.t.) for 12 h. Isolated yields are given. Step 2: 5 (0.1 mmol) in dichloromethane (DCM, 1.0 mL) at 60 °C for 12 h. a) In preparing 5c: The reaction time of step 1 is extended to 16 h. b) In preparing 6 g and 6 h: The reaction time of step 2 is extended to 24 h.

The scope of this ring expansion protocol in terms of the carbon source was successfully extended to ethyl diazoacetate, enabling the regioselective insertion of a carbon atom bearing an ester, which is a flexible FG handle (Fig. 6A). However, the benzoazepine products are not obtained, with compounds 7a and 8a isolated instead. The structure of 7a was identified using X-ray crystallography. The tetrahydrobenzoazepine ring system occurs within several marketed drugs, such as tolvaptan and benazepril, and the hydrogenation of the products of carbon-atom insertion provides a two-step entry towards tetrahydrobenzoazepines using (iso)quinolines (Fig. 6B). Benzoazepine 2a is converted to tetrahydrobenzoazepine 9a in a 77% yield using Pd/carbon (5 mol%) under 1 atm H2 at room temperature, and benzoazepine 4a is similarly hydrogenated to afford tetrahydrobenzoazepine 10a in a 71% yield. Recycling studies were conducted to determine whether kaolin could be reused over several cycles (Fig. 6C). After each reaction, the solids were centrifuged, washed with HCl (2 M) followed by water, and dried. Kaolin can be reused five times without a significant loss of efficiency. Scanning electron microscopy (SEM) of kaolin was conducted before and after the reaction to investigate the mechanical effects of ball milling (Fig. 6D). The observed decrease in particle size and extensive fragmentation are primarily attributed to the mechanical forces applied during milling. These alterations not only enhance the specific surface area but also induce surface disorder within the kaolin structure. The elemental composition of kaolin was analyzed using energy-dispersive X-ray (EDX) microanalysis to investigate the possible natures of its active sites. The previously reported elements within kaolin are predominantly consistent with those in our sample, with O, Si, and Al representing the major fractions and Fe, Ti, Zn, Ca, and Cu representing the minor fractions70. Based on the results of EDX, the individual metal oxides were evaluated for use in mechanoactivated carbon-atom insertion (Fig. 6E). SiO2 results in almost no improvement in the reaction yield, whereas Al2O3 generates the product in a 54% yield, which is lower than that produced using kaolin. Iron and copper oxide afford comparable yields, suggesting that the metal oxides within kaolin may be the main causes of its activity in this reaction. TMSCDN2 was used as the carbon source to label the carbon atoms inserted in the reaction (Fig. 6F). The experimental results for isoquinoline 1a clearly indicate that the inserted carbon atom is located at the C-1 position of the benzo[d]azepine ring (d-2a). Conversely, the carbon atom inserted into quinoline 3a is located at the C-3 position of the benzo[b]azepine product (d-4a). Subsequently, experiments were conducted to compare the results to those obtained using the traditional solution-based method (Fig. 6G). Control experiments using CH3CN as the solvent were performed in a conventional glassware setup. Kinetic monitoring reveals that peak yields of 76% (isoquinoline 1a as the substrate) and 49% (quinoline 3a as the substrate) are reached within 20 min at a milling frequency of 30 Hz. Remarkably, approximately 50% of the starting material is transformed within the first 5 min. Notably, regardless of kaolin presence, the yield and reaction rate decrease significantly in the glassware setup, highlighting the pivotal role of mechanochemical activation in enhancing the reaction.

Fig. 6. Mechanistic studies.

Fig. 6

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A Ethyl diazoacetate used as the carbon source. B Hydrogenation of the products of carbon-atom insertion. C Kaolin recycling studies. D SEM images of kaolin before and after ball milling. E Testing of additives. F Deuterium labeling studies. G Comparison with solution systems. H Proposed mechanism.

Based on these results and those of previous studies, a plausible mechanistic pathway is proposed (Fig. 6H). Under ball-milling conditions, the in situ acylation of the isoquinoline nitrogen atom produces isoquinoline salt A. The nucleophilic reaction of TMSCHN2 with salt A generates intermediate B, which undergoes carbon-atom migration with the concomitant release of nitrogen, generating intermediate C. The subsequent rearrangement and release of TMS+ result in the formation of the benzoazepine product. A similar reaction mechanism is proposed for quinoline.

In conclusion, we developed a mechanochemical method for use in the single-atom skeletal editing of (iso)quinolines to access the corresponding benzoazepines. Kaolin, which is a natural clay material, exhibited the capacity to promote efficient mechanochemical skeletal editing. In addition, a complementary carbon-deletion strategy was developed to convert benzoazepines to indole derivatives. These reactions did not require the use of metal catalysts or substrate preactivation; they were insensitive to air and moisture, and they could accommodate a wide range of substrates with adequate complexities. The practicality of this strategy was demonstrated via its successful late-stage application in drug modification. This study highlights the potential of mechanochemistry as a powerful tool for use in the sustainable, versatile skeletal editing of aromatic heterocycles.

Methods

General condition for conversion of (iso)quinolines to benzoazepines

(Iso)quinoline substrate (1.0 equiv, 0.2 mmol), phenyl chloroformate (1.5 equiv, 0.3 mmol, 38 μL), kaolin (0.05 g – 0.1 g), and MeCN (5.0 equiv or 10.0 equiv) were added to a 5.0 mL stainless-steel milling jar containing two stainless steel balls (7.0 mm diameter) in air. The sealed jar was placed in a Gladman GT300 vibratory ball mill and operated at 30 Hz. After 2 minutes, TMSCHN₂ (2.5 equiv, 0.25 mL, 2.0 M in hexanes) was added, and milling was continued for an additional 20 minutes. Upon completion, the reaction mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the pure product.

Supplementary information

Supplementary Information (9.9MB, pdf)
Transparent Peer Review file (1MB, pdf)

Acknowledgements

We thank Wei Sun for his assistance with the NMR experiments. We also thank Tianyang Yu for his support with data analysis.

Author contributions

H.W. conceived and designed the project and composed the manuscript. C.J., F.H., X.L., P.G., and Q.G. conducted the experiments and analyzed the data. C.J. and Z.Z. discussed the experimental results and commented on the manuscript. H.W. conducted general guidance, project directing, and manuscript revisions.

Peer review

Peer review information

Nature Communications thanks Asish Das, and the other, anonymous, reviewer for their contribution to the peer review of this work. A peer review file is available.

Funding

H.W. discloses support for the research of this work from the National Natural Science Foundation of China (22271231), and the Natural Science Basic Research Plan in Shaanxi Province of China (2024SF-YBXM-419). Z. Z. discloses support for the research of this work from Shaanxi Fundamental Science Research Project for Chemistry and Biology (22JHO005).

Data availability

The crystallographic data generated in this study have been deposited in the Cambridge Crystallographic Data Centre (CCDC) under accession codes [CCDC 2502065 (2a), 2502066 (2 s), and 2502068 (7a)]. The data are available free of charge via [https://www.ccdc.cam.ac.uk/structures]. Data relating to the optimization studies, mechanistic studies, and general methods are provided in the Supplementary Information. Data supporting the findings of this manuscript are also available from the corresponding author upon request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Chunxiu Jing, Fanchen Huang.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-026-73831-5.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information (9.9MB, pdf)
Transparent Peer Review file (1MB, pdf)

Data Availability Statement

The crystallographic data generated in this study have been deposited in the Cambridge Crystallographic Data Centre (CCDC) under accession codes [CCDC 2502065 (2a), 2502066 (2 s), and 2502068 (7a)]. The data are available free of charge via [https://www.ccdc.cam.ac.uk/structures]. Data relating to the optimization studies, mechanistic studies, and general methods are provided in the Supplementary Information. Data supporting the findings of this manuscript are also available from the corresponding author upon request.

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