Water-promoted deconstructive amination of alkenes through single-carbon deletion: access to fully substituted pyrroles

Abstract

Developing efficient methods for the deconstructive nitrogenation of alkenes remains challenging because carbon–carbon double bonds are generally resistant to cleavage under mild conditions. Here we report a catalyst-free, water-promoted deconstructive amination of electron-deficient dienes that proceeds through an unprecedented single-carbon deletion pathway. The transformation operates smoothly in water without photoirradiation, oxidants, or radical precursors, providing diverse fully substituted pyrroles. Mechanistic studies indicate a sequence involving initial aziridination followed by water-assisted C–C and C–N bond cleavage of a transient aziridine intermediate. Water plays a key role in enabling single-carbon extrusion and guiding selective skeletal reorganization. This approach offers high atom- and step-economy and complements existing oxidative and radical-based strategies. The mild conditions, broad substrate scope, and straightforward access to bioactive pyrrole analogs highlight the practical utility of this method. Overall, this work provides a mechanistically distinct route to carbon–carbon double bond deconstructive nitrogenation and expands the toolkit for heterocycle synthesis.

---

Green foundation

1. This work advances green chemistry by enabling deconstructive amination of alkenes in water under catalyst-free, oxidant-free, and organic-solvent-free conditions, providing a rare single-carbon deletion pathway to fully substituted pyrroles—valuable heterocycles with broad pharmaceutical relevance.

2. The reaction exhibits excellent step-economy, with diaryl sulfide recovered as a recyclable byproduct. The pyrrole products precipitate directly from water, allowing isolation by simple filtration and reducing solvent use, waste generation, and energy input.

3. Greenness could be further enhanced by adapting the process to continuous-flow aqueous operation. Extending this water-promoted single-carbon deletion strategy to other deconstructive amination and cascade transformations may broaden its synthetic and environmental impact

Introduction

Selective cleavage and skeletal remodeling of carbon–carbon double (C=C) bonds has emerged as a frontier in modern synthetic chemistry, enabling access to complex molecular architectures that fuel advances in synthesis and drug discovery.¹ Classic methods, such as ozonolysis² and alkene metathesis,³ exemplify the versatility of C=C bond activation (Scheme 1A, left). These transformations either generate carbonyl functionalities or reorganize unsaturated frameworks, thus expanding retrosynthetic options and enhancing molecular diversity.⁴

Scheme 1 (A) Conventional cleavage and deconstructive nitrogenation of C=C bond. (B) Recent achievements in deconstructive nitrogenation of C=C bond. (C) This work: water-promoted deconstructive amination via single-carbon deletion.

Despite these advances, the direct conversion of alkenes into nitrogen-containing frameworks through concurrent C=C bond cleavage and C–N bond formation remains a formidable challenge (Scheme 1A, right). The inherent stability of the C(sp²)–C(sp²) bond often necessitates harsh conditions incompatible with sensitive nitrogen functionalities.⁵ Additionally, achieving precise control over both chemoselectivity and regioselectivity during concurrent bond scission and formation events poses significant difficulties. Unlike conventional alkene amination reactions—such as aziridination, aza-Michael addition, or hydroamination—that introduce nitrogen functionality onto the existing framework,⁶ deconstructive nitrogenation enables fundamental skeletal editing.⁷ This strategy unlocks distinct molecular scaffolds from alkene materials and offers a direct route to valuable nitrogen heterocycles that are inaccessible through traditional methods.

Recent advances in this area can be categorized into two principal mechanistic classes (Scheme 1B). The first involves oxidative N-atom insertion,⁸ particularly utilizing an in situ generated iodonitrene-like species,⁹ as elegantly demonstrated by the Morandi and Ball/Kürti groups.¹⁰ Ball and Kürti achieved the oxidative nitrogen insertion into silyl enol ether C=C bonds.^10a Morandi reported nitrogen insertion into unactivated alkenes to form aza-allenium intermediates, which could be further transformed into nitriles or amidines.^10b

The second class encompasses radical-mediated pathways.¹¹ Jiao's copper-catalyzed aerobic oxidative cleavage of C=C bonds affords carbonyl and nitrile functionalities,^12a whereas Studer achieved radical oxidative scission of C=C bonds to form oximes using N-nitrosomorpholine, followed by diversification into benzimidazoles or indazoles.^12b Although these pioneering studies highlight the power of oxidative and radical-mediated deconstructive nitrogenation strategies, approaches that proceed via different mechanism—particularly those operating under mild and operationally simple conditions—still remain highly desirable.

Here, we report a water-promoted deconstructive amination of 2-allylidenemalononitriles that proceeds through an unprecedented single-carbon deletion pathway,¹³ employing sulfilimines as nitrogen sources (Scheme 1C).¹⁴ The reaction operates under green, catalyst-free conditions, using water as the sole solvent without photoirradiation, oxidants, or radical precursors. It features high atom- and step-economy through selective single-carbon deletion, with diaryl sulfide recovered as a recyclable byproduct, and displays a broad substrate scope encompassing diverse functionalized dienes and alkyl- or aryl-substituted sulfilimines. In line with our ongoing efforts toward the construction of pharmaceutically relevant heterocyclic scaffolds,¹⁵ this method grants direct access to fully substituted pyrroles, privileged motifs with wide pharmaceutical relevance. The pyrrole products can be readily diversified into analogs of known bioactive molecules, underscoring the practical value of this strategy. Mechanistic investigations, integrating experimental observations with DFT calculations, reveal a crucial role of water in mediating sequential C–C and C–N bond cleavage of a transient aziridine intermediate. Collectively, this work expands the mechanistic repertoire of single-carbon deletion and deconstructive amination of C=C bonds, offering a sustainable platform for the efficient construction of valuable pyrrole scaffolds.

Results and discussion

We initiated our investigation by examining the model reaction between readily accessible electron-deficient diene 1a (2-allylidenemalononitrile)^15g and the cost-effective nitrene transfer reagent 2a (S,S-diphenyl sulfilimine). Initial attempts in organic solvents produced a mixture of products (Table 1). To gain more detailed insight into the product distribution, we carried out the reactions in deuterated solvents. In CDCl₃ or CD₂Cl₂ at 60 °C for 4 h, the reaction mainly furnished the expected aziridination product 4a together with a small amount of the ring-expanded adduct 5a, while the (4 + 1) cyclization product 6a was not observed (entries 1 and 2). Intriguingly, however, a minor amount of the unconventional single-carbon-deletion pyrrole 3a was also detected. This unexpected outcome suggested a previously unrecognized deconstructive amination pathway and prompted us to explore the reaction further. Using more polar solvents such as CD₃CN or DMSO-d₆ did not enhance the yield of 3a (entries 3 and 4). To probe the fate of the extruded carbon atom, we analyzed the byproducts and detected only diphenyl sulfide (Ph₂S), excluding the group possibility of C–S bond formation. This suggested that trace amounts of water in the medium might facilitate the single-carbon deletion.

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Additive	Yield of 3a (%)	Yield of 4a (%)	Yield of 5a (%)
a Reaction conditions: 1a (0.12 mmol), 2a (0.10 mmol), and additive (50 μL) in solvent (1.0 mL) under Ar at 60 °C for 4 h; NMR yield. b Isolated yield.
1	CDCl3	—	7	61	22
2	CD2Cl2	—	10	63	15
3	CD3CN	—	12	47	23
4	DMSO-d6	—	10	58	18
5	CDCl3	H2O	42	39	14
6^b	EtOH	—	68	—	8
7^b	EtOH	H2O	78	—	—
8^b	H2O	—	81	—	—

---

Indeed, the deliberate addition of 50 μL of H₂O to the reaction in CDCl₃ dramatically shifted the product distribution, making 3a the major product (42% yield) together with 39% of 4a (entry 5). Encouraged by this result, we examined protic solvents and found ethanol to be particularly effective, affording 3a in 68% isolated yield with 8% of the (4 + 1) adduct 5a, while 4a was no longer detected (entry 6). Adding 50 μL of water to the ethanol medium further improved chemoselectivity, raising the yield of 3a to 78% (entry 7). Remarkably, using water alone as the solvent provided 3a in 81% yield after 4 h (entry 8). The pyrrole product precipitated directly from the aqueous phase, allowing isolation by simple filtration. Further screening showed slower conversion at room temperature and no further improvement at higher temperature (see Table S1 in SI for optimization details). Ultimately, we identified water at 60 °C as the optimal, simple, and sustainable conditions.

With the optimal conditions in hand, we next explored the generality of this water-promoted deconstructive amination cascade (Scheme 2). The protocol proved highly versatile toward both reaction partners, enabling straightforward access to a wide range of fully substituted pyrroles. We first examined the electronic and steric influence of N-aryl substituents on sulfilimine 2. Gratifyingly, a broad variety of N-aryl sulfilimines were well tolerated irrespective of electronic character. Electron-rich substrates (tolyl, 3b, 80%; tBu, 3c, 75%; Ph, 3d, 76%) and electron-deficient ones (NO₂, 3e, 77%; COOMe, 3f, 79%) all reacted efficiently. Halogenated derivatives (F, Cl, Br; 3g–3i, 67–80%) were similarly effective, while CF₃ substitution reduced reactivity (3j, 45%). Substrates bearing meta-substitution or para, meta-disubstitution displayed good reactivity (3k, 82%; 3l, 75%), whereas ortho-substitution significantly suppressed efficiency due to steric hindrance (3m, 49%). The structure of 3a was confirmed unambiguously by X-ray crystallography (CCDC 2466191; see SI for details).

Scheme 2 Substrate scope of the water-promoted deconstructive amination cascade reaction. Reaction conditions: 1 (0.12 mmol) and 2 (0.1 mmol) in 1.0 mL of H₂O at 60 °C for 4 h; isolated yield.

The methodology also accommodated a variety of functional handles. A vinyl-bearing sulfilimine furnished 3n in 87% yield, providing a valuable synthetic vector for further elaboration. Remarkably, 2-formyl-substituted diphenyl sulfilimines (2o–2q) delivered pharmaceutically relevant pyrrolo[1,2-a]quinazoline scaffolds 3o–3q in a single step. Beyond diaryl sulfilimines, cyclic dibenzothiophene analogs (2r–2t)^14e also participated effectively, affording structurally distinct pyrroles (3r–3t). For instance, N-pyridyl 3r was obtained in 57% yield, hydroxyl-substituted 2s furnished 3s in 85% yield, and a protected amine substrate (NHCbz) provided 3t in 67% yield, underscoring excellent functional group tolerance.

We next investigated the scope of the diene component. A diverse range of aryl substituents at the R position were compatible, including para-substituted electron-donating and electron-withdrawing groups (CH₃, NO₂, COOMe, CN, OCH₃, halogens, OCF₃, SCH₃), delivering products 3u–3af in good to excellent yields. Internal and terminal alkynes were also tolerated (3ag, 94%; 3ah, 84%). meta-Substituted arenes (3ai–3am) gave consistently high yields (83–90%), while sterically hindered ortho-substituted derivatives (3an–3aq) remained effective; notably, the ortho-fluoro analogue 3ao reached 92% yield. Furthermore, naphthyl (3ar, 73%) and heteroaryl dienes (3as–3au) consistently observed, with no detectable (4 + 1) or aziridination adducts (products 4–6). The breadth of substrate scope, combined with the operational simplicity of using water as the sole solvent, highlights the utility of this protocol for efficient access to diverse fully substituted pyrroles.

To evaluate the scalability of this water-promoted process, we performed the reaction on a 2.0 mmol scale (Scheme 3A). The scaled-up reaction maintained excellent practicality and efficiency, yielding 521 mg of deconstructive amination cascade product 3a (79% yield). Subsequent synthetic transformations demonstrated the versatility of this green approach in producing a diverse array of biologically active analogs of polysubstituted pyrroles and fused pyrrolic derivatives (Scheme 3B).^16a Treatment of 3a with polyphosphoric acid (PPA) furnished the decarboxylated and hydrolyzed product 7 in 85% yield, while simple acetylation gave compound 8, an analogue of a metallo-β-lactamase inhibitor.^16b [4 + 2] cycloaddition of 3a with isothiocyanatobenzene or 1,2-diphenylethyne smoothly provided the fused heterocycles 9 and 10, respectively. Condensation of 3b with formic acid afforded pyrrolo[2,3-d]pyrimidin-4-ol 11, which upon chlorination yielded the metallo-β-lactamase inhibitor analogue 12.^16c Further diversification of 12 through thiourea incorporation introduced a mercapto group (13, 85%), while substitution with m-chloroaniline delivered EGFR tyrosine kinase inhibitor analogue 14 in 77% yield.^16d In addition, the terminal alkyne-functionalized pyrrole 3ah underwent a copper-catalyzed click reaction with Zidovudine, efficiently appending a nucleoside fragment to the pyrrole scaffold and affording conjugate 15 in 91% yield.

Scheme 3 (A) Scale-up reactions with diphenyl sulfide recovery. (B) Derivatization of fully substituted pyrrole products.

To elucidate the transformation mechanism, we combined experimental and computational investigations. HRMS of the standard reaction mixture detected ions consistent with the 1a–2a adduct (Scheme 4A, top left). To probe the fate of the extruded carbon, a diene 1x (from dimethyl acetylenedicarboxylate) was subjected to the standard water-mediated reaction with sulfilimine 2a (Scheme 4A, top right), smoothly delivering pyrrole 16. HRMS further revealed methyl glyoxylate, indicative of C=C bond scission. Collectively, these results suggest that, in water, the excised single-carbon unit is released as an aldehyde species (or its hydrate).

Scheme 4 (A) Experimental investigations on the reaction mechanism. (B) DFT calculation of the water-promoted pyrrole synthesis through deconstructive amination.

Given the transient nature of the reaction intermediates, we turned to in situ NMR monitoring of the model reaction in EtOH between 1a and 2a to gain further insight (Scheme 4A, bottom). These results revealed the rapid accumulation of aziridine intermediate 4a, whose concentration peaked quickly before being gradually consumed to form the final pyrrole product 3a. This observation provides direct evidence for a kinetically competent, semi-stable intermediate and confirms that 4a is a key on-pathway precursor for the deconstructive amination.

With these experimental insights, we performed DFT calculations (M06-2X functional)¹⁷ to map the detailed energy profile (Scheme 4B, see Fig. S1–S3 in SI for more calculation details). The computational studies revealed that the reaction initiates with addition of sulfilimine 2a to diene 1avia transition state TS1 (ΔG^‡ = 16.2 kcal mol⁻¹) to afford adduct IM1. From this point, two competing pathways emerge: (i) intramolecular cyclopropanation leads to aziridine 4a with concomitant release of diphenyl sulfide (Ph₂S), placing 4a in a deep energy well (ΔG = −28.9 kcal mol⁻¹) consistent with its observed accumulation; (ii) alternatively, IM1 can undergo intramolecular cyclization to form the more stable (4 + 1) cycloadduct 6a. However, this latter pathway features a significantly higher activation barrier (ΔΔG^‡ = 8.2 kcal mol⁻¹), explaining why the reaction selectively proceeds through aziridination to form 3a rather than 6a under aqueous conditions.

The subsequent transformations account for the single-carbon deletion process. Water-promoted ring opening of aziridine 4avia C–C bond cleavage completes the scission of the alkene unit and furnishes hemiaminal IM2. This intermediate then undergoes C–N bond cleavage with elimination of formaldehyde to complete the deconstructive amination process, yielding intermediate IM3. Water-assisted intramolecular cyclization of IM4 delivers IM5, which undergoes stepwise proton transfers and aromatization to afford the fully substituted pyrrole 3a as the thermodynamically favored product. These experimental and computational findings define a unique water-promoted single-carbon deletion mechanism for the deconstructive amination and pyrrole synthesis.

Conclusions

In summary, we have developed a water-promoted deconstructive amination of alkenes via a single-carbon deletion mechanism, enabling the direct synthesis of fully substituted pyrroles from readily available dienes and sulfilimines. This protocol features green and operationally simple conditions—using water as the sole solvent, with no catalysts, oxidants, or radical precursor required. The reaction exhibits broad substrate scope and exceptional functional group tolerance, delivering privileged N-heterocyclic scaffolds with high step- and atom-economy. Mechanistic investigations, combining detailed experimental studies and DFT calculations, reveal the critical role of water, the involvement of a transient aziridine intermediate, and provide a comprehensive rationale for the observed chemoselectivity. This work expands the mechanistic landscape of deconstructive nitrogenation of C=C bonds, providing a sustainable and general strategy for constructing valuable nitrogen-containing frameworks.

Author contributions

B. H. and G. Z. designed and guided this project. X. F., X. Z., and K. X. conducted the experimental investigation and data analysis. Q. T. and J. L. performed DFT calculations. X. F., X. Z., and Q. T. prepared the supplementary materials. B. H. and G. Z. contributed to writing, supervision, and project administration. W. H., C. P., B. H., and G. Z. provided resources. All authors discussed the results, reviewed the manuscript, and approved its final version.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data that support the findings of this study are available in the supplementary information (SI). Supplementary information: detailed experimental procedures, characterization data (NMR spectra, mass spectrometry data), and synthetic methods for relevant compounds. See DOI: https://doi.org/10.1039/d5gc06491k.

CCDC 2466191 (3a) contains the supplementary crystallographic data for this paper.¹⁸

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 82374020 and 22371021); Sichuan Science and Technology Program (grant numbers 2023ZYD0054, 2024NSFSC0282 and 2024NSFTD0023).

References

1. (a) Y.-F. Liang, M. Bilal, L.-Y. Tang, T.-Z. Wang, Y.-Q. Guan, Z. Cheng, M. Zhu, J. Wei and N. Jiao, Chem. Rev., 2023, 123, 12313–12370; (b) F. Chen, T. Wang and N. Jiao, Chem. Rev., 2014, 114, 8613–8661; (c) Z. Amara, J. F. B. Bellamy, R. Horvath, S. J. Miller, A. Beeby, A. Burgard, K. Rossen, M. Poliakoff and M. W. George, Nat. Chem., 2015, 7, 489–495; (d) A. Ruffoni, C. Hampton, M. Simonetti and D. Leonori, Nature, 2022, 610, 81–86; (e) Z. Huang, R. Guan, M. Shanmugam, E. L. Bennett, C. M. Robertson, A. Brookfield, E. J. L. McInnes and J. Xiao, J. Am. Chem. Soc., 2021, 143, 10005–10013; (f) S. Hu, T. Shima and Z. Hou, Nature, 2014, 512, 413–415.
2. T. J. Fisher and P. H. Dussault, Tetrahedron, 2017, 73, 4233–4258.
3. G. C. Vougioukalakis and R. H. Grubbs, Chem. Rev., 2010, 110, 1746–1787.
4. (a) F.-P. Wu, J. L. Tyler and F. Glorius, Acc. Chem. Res., 2025, 58, 893–906; (b) M. Šimek, J. H. Dworkin and O. Kwon, Acc. Chem. Res., 2025, 58, 1547–1561; (c) D. E. Wise, E. S. Gogarnoiu, A. D. Duke, J. M. Paolillo, T. L. Vacala, W. A. Hussain and M. Parasram, J. Am. Chem. Soc., 2022, 144, 15437–15442; (d) B. D. Dherange, P. Q. Kelly, J. P. Liles, M. S. Sigman and M. D. Levin, J. Am. Chem. Soc., 2021, 143, 11337–11344; (e) H. Wang, H. Shao, A. Das, S. Dutta, H. T. Chan, C. Daniliuc, K. N. Houk and F. Glorius, Science, 2023, 381, 75–81; (f) K.-G. Cao, T.-Y. Gao, L.-L. Liao, C.-K. Ran, Y.-X. Jiang, W. Zhang, Q. Zhou, J.-H. Ye, Y. Lan and D.-G. Yu, Chin. J. Catal., 2024, 56, 74–80.
5. (a) S. N. Brown, J. Am. Chem. Soc., 1999, 121, 9752–9753; (b) A. G. Maestri, S. D. Taylor, S. M. Schuck and S. N. Brown, Organometallics, 2004, 23, 1932–1946; (c) P. G. Gassman and D. K. Dygos, J. Am. Chem. Soc., 1969, 91, 1543–1544; (d) P. Q. Kelly, A. S. Filatov and M. D. Levin, Angew. Chem., Int. Ed., 2022, 61, e202213041; (e) H. Guo, S. Qiu and P. Xu, Angew. Chem., Int. Ed., 2024, 63, e202317104.
6. (a) R. Y. Liu and S. L. Buchwald, Acc. Chem. Res., 2020, 53, 1229–1243; (b) J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin, D. Devarajan, D. H. Ess, L. Kürti and J. R. Falck, Science, 2014, 343, 61–65; (c) S. Ma and J. F. Hartwig, Acc. Chem. Res., 2023, 56, 1565–1577; (d) D. G. Kohler, S. N. Gockel, J. L. Kennemur, P. J. Waller and K. L. Hull, Nat. Chem., 2018, 10, 333–340; (e) A. J. Musacchio, B. C. Lainhart, X. Zhang, S. G. Naguib, T. C. Sherwood and R. R. Knowles, Science, 2017, 355, 727–730; (f) Q.-Q. Cheng, Z. Zhou, H. Jiang, J. H. Siitonen, D. H. Ess, X. Zhang and L. Kürti, Nat. Catal., 2020, 3, 386–392; (g) T. Shima, Q. Zhuo, X. Zhou, P. Wu, R. Owada, G. Luo and Z. Hou, Nature, 2024, 632, 307–312; (h) Y. Jin, Y. Jing, C. Li, M. Li, W. Wu, Z. Ke and H. Jiang, Nat. Chem., 2022, 14, 1118–1125; (i) S. Wang, Y. Gao, Z. Liu, D. Ren, H. Sun, L. Niu, D. Yang, D. Zhang, X. a. Liang, R. Shi, X. Qi and A. Lei, Nat. Catal., 2022, 5, 642–651; (j) F.-L. Wang, X.-Y. Dong, J.-S. Lin, Y. Zeng, G.-Y. Jiao, Q.-S. Gu, X.-Q. Guo, C.-L. Ma and X.-Y. Liu, Chem, 2017, 3, 979–990; (k) H.-L. Teng, Y. Luo, B. Wang, L. Zhang, M. Nishiura and Z. Hou, Angew. Chem., Int. Ed., 2016, 55, 15406–15410.
7. (a) J. Woo, A. H. Christian, S. A. Burgess, Y. Jiang, U. F. Mansoor and M. D. Levin, Science, 2022, 376, 527–532; (b) J. Jurczyk, J. Woo, S. F. Kim, B. D. Dherange, R. Sarpong and M. D. Levin, Nat. Synth., 2022, 1, 352–364; (c) J. Woo, T. Zeqiri, A. H. Christian, M. C. Ryan and M. D. Levin, J. Am. Chem. Soc., 2025, 147, 20120–20131; (d) G. L. Bartholomew, F. Carpaneto and R. Sarpong, J. Am. Chem. Soc., 2022, 144, 22309–22315.
8. (a) H. Yu, L. Xu, L. Li and C. Min, J. Am. Chem. Soc., 2025, 147, 26584–26594; (b) M. A. Pasha, J. Jang, Y. Bae and S. Shin, Angew. Chem., Int. Ed., 2025, 64, e202505341; (c) S. Liu and X. Cheng, Nat. Commun., 2022, 13, 425; (d) Y. Zhang, J. Wang, Y. Tao, A. Wang, G. Shen, Z. Li, M. Zhang, B. Yu, X. Zhang and X. Huang, Nat. Commun., 2025, 16, 6660; (e) F.-T. Meng, Y.-N. Wang, X.-Y. Qin, S.-J. Li, J. Li, W.-J. Hao, S.-J. Tu, Y. Lan and B. Jiang, Nat. Commun., 2022, 13, 7393; (f) T. Lin, D. Shang, R. Hu and W. Rao, Org. Lett., 2025, 27, 2958–2963.
9. (a) M. Zenzola, R. Doran, L. Degennaro, R. Luisi and J. A. Bull, Angew. Chem., Int. Ed., 2016, 55, 7203–7207; (b) C. Hui and A. P. Antonchick, Org. Chem. Front., 2022, 9, 3897–3907.
10. (a) A. Lin, A. Ghosh, S. Yellen, Z. T. Ball and L. Kürti, J. Am. Chem. Soc., 2024, 146, 21129–21136; (b) Y. Brägger, A.-S. K. Paschke, N. Nasiri, B. B. Botlik, F. Felician and B. Morandi, Science, 2025, 387, 1108–1114; (c) P. Finkelstein, J. C. Reisenbauer, B. B. Botlik, O. Green, A. Florin and B. Morandi, Chem. Sci., 2023, 14, 2954–2959; (d) B. B. Botlik, M. Weber, F. Ruepp, K. Kawanaka, P. Finkelstein and B. Morandi, Angew. Chem., Int. Ed., 2024, 63, e202408230.
11. (a) H. Lu, J. Chang and H. Wei, Acc. Chem. Res., 2025, 58, 933–946; (b) T. Wang and N. Jiao, J. Am. Chem. Soc., 2013, 135, 11692–11695; (c) J. Wang, H. Lu, Y. He, C. Jing and H. Wei, J. Am. Chem. Soc., 2022, 144, 22433–22439.
12. (a) Z. Wang, P. Xu, S.-M. Guo, C. G. Daniliuc and A. Studer, Nature, 2025, 642, 92–98; (b) Z. Cheng, K. Huang, C. Wang, L. Chen, X. Li, Z. Hu, X. Shan, P.-F. Cao, H. Sun, W. Chen, C. Li, Z. Zhang, H. Tan, X. Jiang, G. Zhang, Z. Zhang, M. Lin, L. Wang, A. Zheng, C. Xia, T. Wang, S. Song, X. Shu and N. Jiao, Science, 2025, 387, 1083–1090.
13. (a) F.-P. Wu, J. L. Tyler, C. G. Daniliuc and F. Glorius, ACS Catal., 2024, 14, 13343–13351; (b) S. C. Patel and N. Z. Burns, J. Am. Chem. Soc., 2022, 144, 17797–17802; (c) J. Woo, C. Stein, A. H. Christian and M. D. Levin, Nature, 2023, 623, 77–82; (d) H. Fujimoto, T. Nishioka, K. Imachi, S. Ogawa, R. Nishimura and M. Tobisu, J. Am. Chem. Soc., 2025, 147, 8138–8144.
14. (a) X. Tian, L. Song, M. Rudolph, F. Rominger, T. Oeser and A. S. K. Hashmi, Angew. Chem., Int. Ed., 2019, 58, 3589–3593; (b) T. L. Gilchrist and C. J. Moody, Chem. Rev., 1977, 77, 409–435; (c) X. Tian, L. Song and A. S. K. Hashmi, Angew. Chem., Int. Ed., 2020, 59, 12342–12346; (d) Q. Cheng, J. Chen, S. Lin and T. Ritter, J. Am. Chem. Soc., 2020, 142, 17287–17293; (e) Q. Cheng, Z. Bai, S. Tewari and T. Ritter, Nat. Chem., 2022, 14, 898–904; (f) L. Song, X. Tian, K. Farshadfar, F. Shiri, F. Rominger, A. Ariafard and A. S. K. Hashmi, Nat. Commun., 2023, 14, 831; (g) K. O. Marichev, K. Wang, K. Dong, N. Greco, L. A. Massey, Y. Deng, H. Arman and M. P. Doyle, Angew. Chem., Int. Ed., 2019, 58, 16188–16192.
15. (a) B. Han, X.-H. He, Y.-Q. Liu, G. He, C. Peng and J.-L. Li, Chem. Soc. Rev., 2021, 50, 1522–1586; (b) Q. Hou, C. Cai, S.-J. Liu, W. Huang, C. Peng, G. Zhan and B. Han, Sci. Adv., 2025, 11, eadt5997; (c) Q.-Q. Yang, C. Chen, D. Yao, W. Liu, B. Liu, J. Zhou, D. Pan, C. Peng, G. Zhan and B. Han, Angew. Chem., Int. Ed., 2024, 63, e202312663; (d) K. Ma, T. Qi, L. Hu, C. Chen, W. Wang, J.-L. Li, C. Peng, G. Zhan and B. Han, Adv. Sci., 2024, 11, 2405743; (e) J. Jiang, J. Zhou, Y. Li, C. Peng, G. He, W. Huang, G. Zhan and B. Han, Commun. Chem., 2023, 6, 128; (f) J. Wang, T. Qi, S. He, W. Huang, C. Peng, G. Zhan and B. Han, ACS Catal., 2023, 13, 10694–10704; (g) X. Zhang, Q.-F. Huang, W.-L. Zou, Q.-Z. Li, X. Feng, Z.-Q. Jia, Y. Liu, J.-L. Li and Q.-W. Wang, Org. Chem. Front., 2019, 6, 3321–3326.
16. (a) J. S. Scott, S. L. Degorce, R. Anjum, J. Culshaw, R. D. M. Davies, N. L. Davies, K. S. Dillman, J. E. Dowling, L. Drew, A. D. Ferguson, S. D. Groombridge, C. T. Halsall, J. A. Hudson, S. Lamont, N. A. Lindsay, S. K. Marden, M. F. Mayo, J. E. Pease, D. R. Perkins, J. H. Pink, G. R. Robb, A. Rosen, M. Shen, C. McWhirter and D. Wu, J. Med. Chem., 2017, 60, 10071–10091; (b) R. P. McGeary, D. T. C. Tan, C. Selleck, M. M. Pedroso, H. E. Sidjabat and G. Schenk, Eur. J. Med. Chem., 2017, 137, 351–364; (c) M. S. Mohamed, W. M. Hussein, R. P. McGeary, P. Vella, G. Schenk and R. H. Abd El-hameed, Eur. J. Med. Chem., 2011, 46, 6075–6082; (d) P. M. Traxler, P. Furet, H. Mett, E. Buchdunger, T. Meyer and N. Lydon, J. Med. Chem., 1996, 39, 2285–2292.
17. (a) Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2008, 120, 215–241; (b) Y. Zhao and D. G. Truhlar, Acc. Chem. Res., 2008, 41, 157–167.
18. CCDC 2466191: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2ns8k9.

---

Footnote

† These authors contributed equally to this work.

---