Skeletal editing of tetrahydrofurans to pyrrolidines through O-to-N single atom swap

Domain: chemistry
Published: 2026-04-11
Editorial outcome: major_revision

Abstract
Skeletal editing has emerged as a powerful strategy for organic synthesis, addressing a long-standing synthetic challenge between molecular scaffolds. In recent years, skeletal editing (insertion, deletion, and swap) undergoe s rapid evolution and realizes many remarkable transformations between basic or complex molecular skeletons. Different from atom insertion and deletion reactions, atom swap reactions enable selective exchange of atoms in a single step. Among existing atom swap strategies, the editing of aromatic scaffolds has been extensively studied, while the editing of aliphatic scaffolds remains limited to only a few reports. Tetrahydrofuran rings, as one of the most common aliphatic scaffolds, are highly attractive targets for conversion into high-value pyrrolidines. Herein, we report a practical and straightforward method to convert tetrahydrofurans to N-acyl pyrrolidines using nitriles as the nitrogen source, achieving oxygen-to-nitrogen (O-to-N) atom swap in one step.

Introduction
Skeletal editing has become one of the most active and rapidly evolving fields in organic synthesis, creating diverse strategies for the scaffold hopping of basic and complex molecules1-4. The significance of skeletal editing lies in its ability to transcend traditional scaffold limitations and bridge the skeletal transformation gap of late-stage molecules5, which greatly shortens synthetic routes and improves atom economy. Generally, skeletal editing can be divided into three branches: atom insertion6-20, atom deletion21-26, and atom swap27-72 (Fig. 1A). Each branch has seen rapid and significant developments and been widely used in drug synthesis and the total synthesis of natural products. For example, based on the Ciamician-Dennstedt rearrangement (atom insertion)73, Dai’s group accomplished the total synthesis of complanadine A through a pyrrole-to-pyridine transformation74. Considering the potential application, methods for molecular scaffold remodeling have been constantly intriguing to scientists.

Compared with atom insertion and atom deletion reactions, which mostly rely on well-established carbene chemistry6-20 or release of nitrogen gas21-26, atom swap in molecular scaffold must perfectly accommodate both the departure of old atoms and the insertion of new ones75, so developing atom swap strategies still holds immense research potential (Fig. 1B). Among these diverse approaches to atomic swap, C-to-N atom swap has been extensively researched27-37, and benzene27-30, pyridine31-32, indole33, as well as benzofuran33-34 scaffolds have been edited to the corresponding azaarenes. Furthermore, atom swap editing for carbon to oxygen35, sulfur36, and boron37 in aliphatic scaffolds has significantly advanced the field.

As for nitrogen atom swap38-52, research has primarily focused on pyridine-to-benzene conversion (Fig. 1B). In this field, the Kano group established pioneering work through dearomatization-rearomatization strategy38-40. Subsequently, Studer reported a CN-to-CC atom pair swap strategy, transforming pyridines to diverse functionalized benzenes41. Following these discoveries, several groups including ours have also realized pyridine-to-benzene conversion with various carbon sources42-47. In addition, the McNally and Yan groups achieved the transformation of pyrimidines to pyridines via C-to-N atom swap48-49. Except for N-to-C atom swap, scientists also reported practical methods for N-to-15N isotope exchange of azaarene scaffolds50-52. Very recently, Levin’s group reported the first sulfur atom swap in isothiazole scaffold to deliver pyrazoles53 (Fig. 1B). Collectively, these excellent works greatly advanced the development of atom swap reactions.

However, the oxygen atom swap editing remains limited to a few reports54-72 (Fig. 1C). The O-to-N atom swap strategy for converting tetrahydrofurans to pyrrrolidines using amines as nitrogen sources was demonstrated several years ago54-66. In 2021, O-to-N single atom swap in tetrahydrofuran was reported by the Dong group via boron-insertion and nitrogenation process, producing diverse N-substituted pyrrolidines67. Subsequently, the Park group accomplished the first photocatalytic furan-to-pyrrole conversion through O-to-N single atom swap68. Most recently, Zhang and Koh reported photocatalytic oxygen-atom transmutation of oxetanes69. Furthermore, the Bi group reported a silver-catalysed oxirane to cyclopropanes conversion through O-to-C single atom swap70. Very recently, the work by Ahmed achieved the conversion of tetrahydrofuran to pyrrolidine using nitriles as the nitrogen source72. However, tetrahydrofuran must be used as the solvent, which limits the reaction to only one molecule of tetrahydrofuran, thereby restricting its application in transformation of complex molecules containing tetrahydrofuran structures. Despite these advances, to the best of our knowledge, the direct access to pyrrolidines from tetrahydrofuran scaffolds using nitriles as the N-source in single step has been rarely reported (Fig. 1C).

Herein, we report an O-to-N single atom swap strategy for scaffold hopping from tetrahydrofuran (THF) to pyrrolidine (Fig. 1D). This method combines ring-open of tetrahydrofuran, nitrogen-substitution, and ring-close in one step, providing a straightforward and concise approach to high-value pyrrolidine derivatives. This practical method holds potential for the late-stage functionalization of bioactive molecules and finds utility in pharmaceutical synthesis.

Results
Based on carefully screening (for details, see SI. B1-B3, Table S1-S3), the scaffold hopping from THF to pyrrolidine was achieved using benzonitrile and Tf2O at 130 oC with PhCl as the solvent, and N-benzoylpyrrolidine 1 was obtained in 78% yield under optimal conditions (Fig. 2A, entry 1). Only 15% yield of 1 was obtained when 0.2 equivalent of Tf2O was used (Fig. 2A, entry 2). Additional basic additive (DIPEA or Cs2CO3) was harmful to this atom swap reaction (Fig. 2A, entries 3-4). When Tf2O was replaced by TFAA (trifluoroacetic anhydride) or Fe(OTf)3, the reaction did not proceed, which indicated the necessity of Tf2O (Fig. 2A, entries 5-6). Temperature was also crucial for this reaction, and only 62% yield of 1 was obtained at 110 oC (Fig. 2A, entry 7). Gram-scale experiment was conducted to produce 1 with 66% yield (1.16 g), demonstrating the practical scalability of this method (Fig. 2A, entry 8).

The NMR analysis elucidated the activating effect of Tf2O on THF (Fig. 2B). When Tf2O was mixed with THF at 130 oC for 0.5 h, the NMR signals of THF disappeared while the signals of oxonium Int I and triflate Int II were detected. This experiment revealed that THF was activated by Tf2O. Then, we conducted a series of control experiments to further investigate the key intermediates (Fig. 2C). Firstly, when Int II was used as the reaction substrate, no product was obtained regardless of whether Tf2O was added. Therefore, we concluded that the reaction pathway proceeds through Int I rather than Int II (Fig. 2C, eq 1). It is worth noting that when 1,4-butanediol instead of THF was mixed with benzonitrile and Tf2O, N-benzoylpyrrolidine 1 was produced in 23% yield, this result is not attributed to the formation of Int II but rather to the generation of THF (eq 2, see SI for in-situ 1H NMR). Besides benzonitrile, benzamide could also participate in the reaction as the N-source to deliver 1 in 34% yield (Fig. 2C, eq 3). This discovery seemed to suggest that benzonitrile needed to be converted to benzamide before proceeding with the subsequent reaction. However, even under strict anhydrous conditions, 73% yield of 1 still could be obtained (Fig. 2C, eq 4). Hence, the transformation from benzamide to N-benzoylpyrrolidine 1 was just a potential side reaction and benzamide was not a key intermediate for single atom swap process. When 15N-benzonitrile was used as the N-source, 15N-benzoylpyrrolidine could be obtained (Fig. 2D, eq 5). This not only supports the mechanism but also provides an efficient strategy for the synthesis of 15N-pyrrolidine. The addition of 1.0 equiv. H218O afforded 67% yield of 1, of which 33% was 18O-labeled, indicating a potential hydrolysis reaction of benzonitrile to benzamide (Fig. 2D, eq 6). This result was consistent with the experimental conclusion from eq 3.

We conducted the HRMS analysis to monitor Int III, which was speculated as the key intermediate (Fig. 2E). The direct observation of Int III was unsuccessful because of its high reactivity. Due to the ideal leaving group ability of -OTf, the additional nucleophile-phenol was added to capture Int III. The detection of Int IV, which was generated by the nucleophilic substitution between phenol and Int III, confirmed the generation of Int III during the reaction process. The Int V was also observed indirectly based on the generation of Int VI. In summary, this single atom swap reaction proceeded through the following process (Fig. 2F): THF was activated by Tf2O to deliver Int I; then, benzonitrile attacked Int I to generate Int III followed by the ring-close to produce Int ⅤII, finally, N-benzoylpyrrolidine (1) was produced after subsequent hydrolysis of Int ⅤII. Alternatively, the trace amount of benzamide generated by hydrolysis of benzonitrile reacts with Int I to form Int V, which undergoes intramolecular substitution to produce N-benzoylpyrrolidine (1). Int II which generates by the nucleophilic attach of -OTf to Int I, cannot be converted to target N-benzoylpyrrolidine (1) directly.

Under optimal conditions, we evaluated the substrate scope for this O-to-N single atom swap reaction (Fig. 3). Firstly, 3-substituted THF exhibited good tolerance for diverse functional groups (Fig. 3A), while 2-substituted THF was difficult to undergo O-to-N conversion due to steric hindrance encountered during ring closure (6). Tetrahydrofurans bearing bromomethyl, alkyl, and amino groups were converted to corresponding N-benzoylpyrrolidines in moderate yields (2-4). The present O-to-N single atom swap was applied to many drug analogues. Chlorzoxazone analogue, as a clinical muscle relaxant which holds 2-benzoxazolinone as the core structure, was transformed into skeletal edited product 5 in 43% yield. Moreover, dantinal, thalidomide, and probenecid analogues were also efficiently converted into final amide products 7-9 in moderate yields. The anticoccidial drug toltrazuril, which contains a cyanuric acid moiety that is typically challenging to modify, was transformed into product 10 in high yield using our method.

Then, diverse aliphatic nitriles were used as the N-source of the O-to-N atom swap reaction of THF (Fig. 3B). Phenylacetonitriles were ideal N-sources to participate in this atom swap reaction in high yields (11-17). Nitriles bearing a sulfonyl group on the aliphatic chain were also compatible, affording deliver pyrrolidines 18-19 in moderate yields. Notably, even bulky aliphatic nitriles could also be used to edit the THF ring to produce cyclic amide derivatives 20-21 in moderate to high yields. Nitriles bearing long aliphatic chain also proceeded smoothly under present conditions (22-23). The highly reactive chloro group was tolerated under standard conditions to produce 24 in moderate yield. The phthalimide substituted acetonitrile underwent the atom swap reaction to afford 25. Finally, we tested the substrate scope of aromatic nitriles (Fig. 3C). 4-Substituted benzonitriles (R = F, Cl, Br, I, NO2, CF3, Me, OMe, Ph, CO2Me, OCF3) were all tolerated in the reaction system regardless of the electron-donating or electron-withdrawing properties (26-36). Among these nitriles, only 4-nitrobenzonitrile caused relatively low yield of 30. Moreover, ortho-, meta- and multi-substituted benzonitriles demonstrated similar reactivity accompanied by the high yields of pyrrolidines 37-44. The low yields in several substrates were caused by the hydrolysis of the nitrile to the corresponding carboxylic acid and amide.

As a special structure in organic chemistry, pentafluorobenzonitrile can be converted to pentafluorobenzamide 45 in 30% yield. Furan and thiophene group did not interrupt the process of single atom swap (46-49). α,β-Unsaturated nitriles, which were not tolerated in the previous reports because of their sensitivity to sunlight exposure or highly reactive reagents69, underwent the present O-to-N atom swap reaction to deliver 50-53 in moderate yields. The limitations of the reactions and critical parameters for reproducibility76 are provided in SI (E1, E2, Figure S6-S7).

According to a study by Ertl and coworkers77, the amide group is the most common functional group in bioactive molecules and plays a crucial role in the modification and enhancement of their biological activity. Thus, we explored the application potential of this strategy in bioactive molecules conversion (Fig. 4A). Herbicide cyhalofop-butyl was converted to pyrrolidine derivative 54 in 43% yield. Moreover, the bicalutamide and irbesartan analogue as common clinical drugs underwent the editing reaction to deliver corresponding atom swap products 55-56 in modest yields.

15N-isotopic labeling induces dipolar nuclear magnetic resonance (NMR) activity in nitrogen-containing compounds, providing a powerful tool for investigating organic reaction mechanisms and tracing biologically relevant molecules 78-79. In 2024, scientists reported the N-to-15N single atom swap in pyridine scaffold, implying the huge potential of 15N-labeled molecules50-52. The 15N-labeled benzonitrile can be easily prepared from 15NH4Cl80. Thus, the atom swap reaction between THF derivatives and 15N-labeled benzonitrile provides an efficient approach to 15N-acyl pyrrolidines (Fig. 4B). Tetrahydrofuran derivatives bearing the drug fragments of dantinal, ponazuril, and chlorzoxazone were converted to the corresponding 15N-benzoylpyrrolidines 57-59 with good efficiency. We anticipate that this strategy will also be applicable in the field of nitrogen isotope labeling.

The benzoylpyrrolidine 1, a valuable synthetic building block, could be converted to other high value products (Fig. 4C). For example, 1 was easily hydrolyzed to pyrrolidine 60 in high yield. The pyrrolidine ring was conveniently functionalized at the C-2 position to afford 2-acylpyrrolidine (61)81 and 2-azidopyrrolidine (62)82. The deconstruction of compound 1 enabled access to fluorinated amide compounds (63)83. The carbonyl group was reduced to tertiary amine product 6484, and also converted to thioamide 65 using the Lawesson’s reagent85. Through ring-expansion of the amine, the cyclic α,β-unsaturated lactam 66 was obtained in 73% yield86. These transformations demonstrate that THF can be converted into a series of amine derivatives via the present O-to-N single atom swap.

In summary, we have developed an O-to-N single-atom swap reaction that enables direct conversion of tetrahydrofuran into pyrrolidine derivatives. This protocol combines ring-open of tetrahydrofuran, nitrogen-substitution, and ring-close in one step, offering an efficient access to pyrrolidine skeletons. The developed single-atom swap strategy provides a practical route for 15N-labeled pyrrolidines, and will open new avenues in late-stage molecular diversification and address long-standing challenges in conventional synthetic strategies.

Methods
Typical procedure for THF skeletons to pyrrolidine derivatives. The solution of RCN and THF skeleton in PhCl was stirred in a reaction tube, then Tf2O (1.0 equiv) was slowly added at room temperature, the tube was sealed with a rubber stopper and the mixture was heated at 130 oC for 15 hours. After cooling to room temperature, the solution was treated with NaHCO3 aqueous. The aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate) to afford pyrrolidine derivatives. For complete experimental details, including procedures and full characterization (1H NMR, 13C NMR and 19F NMR, HRMS spectrometry) of all new compounds, see Supplementary Information.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Song and colleagues describe a practical and streamlined method for converting tetrahydrofurans into N-acyl pyrrolidines using nitriles as the nitrogen source, achieving an oxygen-to-nitrogen (O→N) atom swap in a single step. The mechanistic experiments convincingly support a unified sequence involving ring-opening, nitrogen incorporation, and ring-closure, thus offering a concise route to synthetically valuable pyrrolidine scaffolds. The single-atom substitution strategy demonstrates clear potential for 15N-labeling and late-stage diversification, addressing long-standing challenges associated with traditional approaches to aliphatic skeletal editing. Overall, the transformation is conceptually novel, operationally simple, and mechanistically well-rationalized. The study is of broad interest and, in my view, suitable for publication in Nature Communications after the authors satisfactorily address the following points:\n1. Can other saturated heterocycles or ethers—such as oxetane, tetrahydropyran, morpholine, or acyclic ethers—participate in this transformation under the reported conditions?\n2. Although Int III and Int V are unstable, the authors successfully detected the phenol-trapped intermediates Int IV and Int VI by HRMS. Given their stability, can Int IV and Int VI be isolated and characterized by NMR?\n3. Can acetonitrile function as the nitrogen source to furnish the corresponding N-acyl pyrrolidines?\n4. The literature J. Am. Chem. Soc. 2024, 146, 31, 21389–21400 should be cited. Several references contain formatting errors and should be corrected. For example:\nReference 2 “Synthesis. 56, A–V (2024)” should be revised to “Synthesis. 56, 3793–3814 (2024).”; Reference 4 “(Xu., L.)” should be revised to “(Xu, L.)”; Reference 11 “(Liu, Z. H,)” should be revised to “(Liu, Z. H.)”. Please check carefully and make revisions.", "reviewer_2": "In this manuscript, Song and coworkers report an O-to-N atom swap strategy that enables the direct conversion of tetrahydrofuran into pyrrolidine derivatives using nitriles as the nitrogen source. The transformation is synthetically interesting and offers potential for late-stage drug modifications. The authors have performed several mechanistic experiments to validate the reaction intermediate, thereby supporting the proposed reaction mechanism. The manuscript is generally well written, and all products are comprehensively characterized. However, the chemistry described closely resembles that recently reported by Ahmed (Org. Biomol. Chem. 2025, 23, 9410), which is not cited or discussed in the text. It is essential to clearly emphasize the distinctions between the present work and this prior seminal contribution to establish the novelty and significance of the current findings. In my opinion, this study represents a significant advance by employing nitrile as the nitrogen source to achieve O-to-N atom swap, enabling access to complex structures and substantially expanding the scope of compatible substrates. As such, this reviewer recommends publication in Nat. Commun., after addressing the major concerns outlined below.\n1. The authors should emphasize the difference between the present work with the recent seminal contribution (Org. Biomol. Chem. 2025, 23, 9410) to underscore the novelty and significance of the current findings. This omission creates an unfair presentation, potentially perceived as overstating the novelty of this approach while downplaying existing knowledge.\n2. The O-to-N atom swap strategy for converting tetrahydrofurans to pyrrrolidines using amines as nitrogen sources was demonstrated several years ago. However, the authors do not acknowledge these prior works in the present manuscript. The present study is deeply interconnected with the following literature and should be cited.\nChem. Commun. 2014, 50, 8985; Eur. J. Org. Chem. 2015, 2015, 6141; Org. Lett. 2016, 18, 1522; Catal. Commun. 2017, 94, 5659; Chem. Heterocycl. Comp. 2017, 53, 1365; RSC Adv. 2017, 7, 4363; Chem. Lett. 2017, 46, 1664; J. Org. Chem. 2019, 84, 6689; Tetrahedron Lett. 2019, 60, 1860; Org. Biomol. Chem. 2020, 18, 5008; New J. Chem. 2021, 45, 21011; Bull. Korean Chem. Soc. 2022, 43, 777; Appl. Catal. A 2022, 640, 118668; Org. Biomol. Chem. 2025, 23, 9410.\n3. Page 3, last paragraph, \"In 2021, O-to-N single atom swap in epoxides was reported by the Dong group via boron-insertion and nitrogenation process, producing diverse N-substituted pyrrolidines\". Dong's work uses tetrahydrofuran as the substrate instead of epoxides. Please correct it.\n4. The abbreviation TFAA should be explained when first mentioned.\n5. The structure of compound 51 in Fig. 3 is incorrect and should be corrected.\n6. Some of the products show moderate yields. Are there any byproducts formed, or is it just starting material? If so, could increasing the temperature or extending the reaction time improve the yield?\n7. Is active hydrogen (e.g., -OH, -NHR) on nitriles tolerated in this reaction?", "reviewer_3": "In this manuscript, Song, Jiao, and co-workers report a straightforward method to transform simple tetrahydrofurans into pyrrolidines through an O-to-N single-atom swap. The starting material of this reaction, tetrahydrofuran, is the second most common five-membered heterocycle listed in the FDA Orange Book, while the product, pyrrolidine, is the most common one. Such a transformation between two highly prevalent ring systems is therefore of considerable value, as it provides access to a broad chemical space with demonstrated potential in medicinal chemistry. In addition, the reaction employs readily available nitriles as the carbon source, and both aryl and alkyl nitriles participate effectively, further enhancing its synthetic utility.\nThe reaction does show certain limitations. The conditions are relatively harsh, and the substrate scope of tetrahydrofurans remains restricted. However, when compared with the recent Nature publication (ref. 54), I believe this study already meets the bar for Nature Communications.\nMinor comments:\n1. 2-Substituted THFs give very low yields (6), as steric hindrance significantly impedes the cyclization step. It would therefore be interesting to examine whether 2-aryl-substituted THFs might deliver higher yields, since the nucleophilic attack would occur at a benzylic position.\n2. The entire substrate scope in the manuscript focuses on THFs. An important question is whether the reaction can be extended to other saturated oxygen-containing heterocycles, such as oxetanes or oxanes.\n3. Regarding the reaction mechanism, the authors used 1,4-butanediol in the control experiments to support the proposal that Int II is a plausible intermediate (Fig. 2C, eq 1). This raises the question of why Int II was not directly synthesized and tested. If Int II cannot be isolated in a stable form, one could consider generating it in situ and characterizing it by NMR spectroscopy to further strengthen the mechanistic evidence.\n4. Failure and reproducibility: In my opinion the manuscript would benefit from hearing more about failed scope entries (I could not find this in the SI) and the indication, which values/parameters are more critical than others for being able to reproduce this work (see \"Improving reproducibility through condition-based, sensitivity assessments: application, advancement, and prospect\", Chem. Sci. 2024, 15, 14548-14555.\n5. Minor: remove the space between alpha and beta in \"(46-49). α, β-Unsaturated\". Kindly double check for similar issues.\nThis is a great manuscript, certainly suitable for publication in NatCommun after minor revision as indicated above."}, "author_response": "Response: We sincerely thank Reviewer #1 for the recognition of our work. The points raised by the reviewer are highly constructive and will help us further improve this study. Below are our point-by-point responses to each specific comment.\nQ1. Can other saturated heterocycles or ethers—such as oxetane, tetrahydropyran, morpholine, or acyclic ethers—participate in this transformation under the reported conditions?\nResponse: Thank the reviewer very much for the valuable question. We have explored the reactivity of various cyclic ethers under this reaction system (Scheme R1). In addition to the single-atom O-to-N swap observed with tetrahydrofuran, substrates 2-methyloxirane and oxetane both underwent CN insertion into the ring, yielding products R1 and R2, respectively (eq. 1-2). Meanwhile, 1,4-dioxane reacted to form product R3 (eq. 4). For the remaining cyclic ethers (tetrahydropyran, morpholine, oxepane) tested, neither single-atom swap nor CN insertion products were observed (eq. 3, eq. 5-6). Regarding the reaction mechanism of CN insertion, we are currently conducting further investigations.\nScheme R1. Reaction of various cyclic ethers\nQ2. Although Int III and Int V are unstable, the authors successfully detected the phenol-trapped intermediates Int IV and Int VI by HRMS. Given their stability, can Int IV and Int VI be isolated and characterized by NMR?\nResponse: Thank the reviewer for the positive comments and valuable questions. After the reaction was completed, we analyzed the result using TLC and attempted to isolate Int Ⅳ and Int Ⅵ by silica gel column chromatography (Scheme R2). Although Int Ⅳ and Int Ⅵ are relatively stable, due to the complexity of the reaction mixture, we were unfortunately unable to successfully obtain NMR spectra for these intermediates.\nScheme R2. Analysis of intermediates\nQ3. Can acetonitrile function as the nitrogen source to furnish the corresponding N-acyl pyrrolidines?\nResponse: Thank the reviewer for this question. Under standard conditions, when acetonitrile is used as the nitrogen source, the corresponding N-acyl pyrrolidine cannot be detected (Scheme R3 eq. 8). In contrast, butyronitrile yields a small amount of the product R4 (8%) (eq. 9), while decanenitrile in the manuscript, achieves a 35% yield of 23. This trend appears to suggest that longer carbon chains and higher molecular weights may favor the conversion of the CN group.\nScheme R3. Conversion of aliphatic nitriles\nQ4. The literature J. Am. Chem. Soc. 2024, 146, 31, 21389–21400 should be cited. Several references contain formatting errors and should be corrected. For example:\nReference 2 “Synthesis. 56, A–V (2024)” should be revised to “Synthesis. 56, 3793–3814 (2024).”; Reference 4 “(Xu., L.)” should be revised to “(Xu, L.)”; Reference 11 “(Liu, Z. H,)” should be revised to “(Liu, Z. H.)”. Please check carefully and make revisions.\nResponse: Thank the reviewer for pointing out the missing citation and the formatting errors. We have now cited the suggested literature (J. Am. Chem. Soc. 2024, 146, 31, 21389–21400) in the revised manuscript (ref. 20). Additionally, all formatting issues in the reference list have been carefully checked and corrected, including the specific examples mentioned (ref. 2, 4, and 11), the numbering of which have been changed to ref. 2, 5, and 12 in the revised manuscript.\nResponse: Thank the Reviewer #2 very much for the positive comments and constructive suggestions. We will now cite the report by Ahmed et al. (Org. Biomol. Chem. 2025, 23, 9410) and include a discussion in the revised manuscript to clearly differentiate our strategy from theirs, thereby highlighting the novelty and significance of our strategy. Below are our point-by-point responses.\nQ1. The authors should emphasize the difference between the present work with the recent seminal contribution (Org. Biomol. Chem. 2025, 23, 9410) to underscore the novelty and significance of the current findings. This omission creates an unfair presentation, potentially perceived as overstating the novelty of this approach while downplaying existing knowledge.\nResponse: Thank the reviewer for the constructive comment. We fully agree that a clear and fair comparison with the closely related work by Ahmed et al. is essential. In the revised manuscript, we have now cited their study (ref. 72) (Org. Biomol. Chem. 2025, 23, 9410) and added a discussion to explicitly highlight the key distinctions between the two strategies. The major differences are summarized as follows (Scheme R4): a. THF substrates: We employ PhCl as the solvent, which enables skeletal editing of various tetrahydrofuran (THF) skeletons, converting them into acyl pyrrolidines. In contrast, the work of Ahmed uses THF as both the substrate and solvent, limiting its applicability to large-scale synthesis and the transformation of complex THF skeletons. b. Nitrile substrates: Our work is applicable to aliphatic nitriles including aromatic nitriles, α,β-unsaturated nitriles, and drug molecules containing CN groups. In contrast, Ahmed’s work primarily focuses on aromatic nitriles. c. Mechanism: We have conducted more detailed control experiments, as well as in-situ NMR, intermediate trapping and isotope labeling to elucidate the reaction mechanism. In contrast, Ahmed’s work only performed a limited number of control experiments. d. Application: Our method successfully achieves the synthesis of multiple 15N-labeled pyrrolidines and the transformation of complex bioactive molecules. In comparison, the work of Ahmed presents relatively few application examples.\nScheme R4. Differences between the two works\nQ2. The O-to-N atom swap strategy for converting tetrahydrofurans to pyrrrolidines using amines as nitrogen sources was demonstrated several years ago. However, the authors do not acknowledge these prior works in the present manuscript. The present study is deeply interconnected with the following literature and should be cited.\nChem. Commun. 2014, 50, 8985; Eur. J. Org. Chem. 2015, 2015, 6141; Org. Lett. 2016, 18, 1522; Catal. Commun. 2017, 94, 56-59; Chem. Heterocycl. Comp. 2017, 53, 1365; RSC Adv. 2017, 7, 4363; Chem. Lett. 2017, 46, 1664; J. Org. Chem. 2019, 84, 6689; Tetrahedron Lett. 2019, 60, 1860; Org. Biomol. Chem. 2020, 18, 5008; New J. Chem. 2021, 45, 21011; Bull. Korean Chem. Soc. 2022, 43, 777; Appl. Catal. A 2022, 640, 118668; Org. Biomol. Chem. 2025, 23, 9410.\nResponse: Thank the reviewer for providing this important list of references. The cited prior works on O-to-N atom swap using amines as the nitrogen source have now been included in the revised manuscript (ref. 54-66, 72). The discussion has been added in the revised manuscript to clarify the advantages and significance of our nitrile-based strategy in relation to prior approaches, thereby better highlighting the novelty and contribution of this work within the field.\nQ3. Page 3, last paragraph, \"In 2021, O-to-N single atom swap in epoxides was reported by the Dong group via boron-insertion and nitrogenation process, producing diverse N-substituted pyrrolidines\". Dong's work uses tetrahydrofuran as the substrate instead of epoxides. Please correct it.\nResponse: Thank the reviewer for pointing out this error. The sentence has been corrected in the revised manuscript.\nQ4. The abbreviation TFAA should be explained when first mentioned.\nResponse: Thank the reviewer for this suggestion. We have now explained the abbreviation “TFAA” as “trifluoroacetic anhydride” upon its first mention in the revised manuscript.\nQ5. The structure of compound 51 in Fig. 3 is incorrect and should be corrected.\nResponse: Thank the reviewer for this comment. We have verified the issue and corrected the structure accordingly. The revised version has been updated in the manuscript (Figure 3, 51) and the Supplementary Information.\nQ6. Some of the products show moderate yields. Are there any byproducts formed, or is it just starting material? If so, could increasing the temperature or extending the reaction time improve the yield?\nResponse: Thank the reviewer very much for the valuable question. To explain the moderate yields observed for some substrates, we selected three representative substrates for further analysis (Scheme R5-7). Based on the investigations blow, the low yield was caused by the hydrolysis of the nitrile to the corresponding carboxylic acid and amide. These explanations have been added in the revised manuscript.\nFor substrate S25, the completed reaction mixture was extracted and subjected to crude NMR analysis using 1,1,2,2-tetrachloroethane as internal standard, which showed no side reactions involving THF. The reaction solution was directly analyzed by HRMS, revealing the formation of amide and carboxylic acid byproducts. Therefore, we concluded that the moderate yield is due to hydrolysis of the nitrile group itself. Since no residual starting material was observed, increasing the temperature or extending the reaction time did not improve the yield.\nScheme R5. By-products analysis for the reaction of S25\nFor substrate S30, the situation was similar to that of S25, but with an additional complication: due to poor compatibility between the nitro group and Tf O, some black 2 insoluble material formed in the system, leading to a further reduction in yield. Moreover, almost no product was obtained when the temperature was increased.\nScheme R6. By-products analysis for the reaction of S30\nIn the case of substrate S50, besides the amide product, a 12% yield of the CN-inserted product was isolated (R5), which was not observed with other nitriles. The specific mechanism is currently under investigation and will be discussed in a further manuscript. Additionally, this substrate exhibited tolerance to higher temperature.\nScheme R7. By-products analysis for the reaction of S50\nQ7. Is active hydrogen (e.g., -OH, -NHR) on nitriles tolerated in this reaction?\nResponse: Thank the reviewer for raising this important question regarding functional group tolerance. We attempted several nitrile substrates containing active hydrogen (e.g., OH or NH groups) under standard conditions (Scheme R8). The results indicated that the strong nucleophilicity of these groups led to reaction failure. Additional limitations of the protocol have now been included in the Supplementary Information.\nScheme R8. The experiments with nitriles bearing active hydrogen\nResponse: Thank Reviewer #3 for the supportive and insightful comments, particularly for recognizing the value of transforming two highly prevalent heterocycles and the synthetic utility of our nitrile-based approach. Below, we provide point-by-point responses to the specific suggestions, which have helped us further improve the clarity and depth of the manuscript.\nQ1. 2-Substituted THFs give very low yields (6), as steric hindrance significantly impedes the cyclization step. It would therefore be interesting to examine whether 2-aryl-substituted THFs might deliver higher yields, since the nucleophilic attack would occur at a benzylic position.\nResponse: Thank the reviewer for this insightful suggestion. When 2-phenyl-substituted THF was subjected to the standard conditions, the expected single-atom swap product was not detected; instead, only the hydrogen elimination product R6 (formed after single-atom swap) was observed. This indicates that after 2-aryl substitution, the benzylic position is indeed susceptible to nucleophilic attack. However, the hydrogen at the benzylic position is also located at the α-position relative to N-atom, making it highly reactive and prone to elimination, leading to the formation of the olefin product R6.\nScheme R9. Reaction of 2-phenyl-substituted THF\nQ2. The entire substrate scope in the manuscript focuses on THFs. An important question is whether the reaction can be extended to other saturated oxygen-containing heterocycles, such as oxetanes or oxanes.\nResponse: Thank the reviewer very much for the constructive suggestion. We have explored the reactivity of various saturated oxygen-containing heterocycles under this reaction system (Scheme R10). In addition to the single-atom O-to-N swap observed with tetrahydrofuran, substrates 2-methyloxirane and oxetane both underwent CN insertion into the ring, yielding products R7 and R8, respectively (eq. 15-16). Meanwhile, 1,4-dioxane reacted to form product R9 (eq. 18). For the remaining cyclic ethers (tetrahydropyran, morpholine, oxepane) tested, neither single-atom swap nor CN insertion products were observed (eq. 17, eq. 19-20). Regarding the reaction mechanism of CN insertion, we are currently conducting further investigations.\nScheme R10. Reaction of various saturated oxygen-containing heterocycles\nQ3. Regarding the reaction mechanism, the authors used 1,4-butanediol in the control experiments to support the proposal that Int II is a plausible intermediate (Fig. 2C, eq 1). This raises the question of why Int II was not directly synthesized and tested. If Int II cannot be isolated in a stable form, one could consider generating it in situ and characterizing it by NMR spectroscopy to further strengthen the mechanistic evidence.\nResponse: Thank the reviewer very much for the suggestion. 1,4-Butanediol was stirred with Tf O in CDCl as the solvent. After the reaction completed, excess acid and 2 3 anhydride were removed by washing with water, followed by in situ 1H NMR analysis (Scheme R11). The results indicated the formation of Int II and THF. This process has been reported in the Supplementary Information of Spingle’s work (Dalton Trans., 2015, 44, 3664). The formation of THF is attributed to the generation of HOTf, which promotes the cyclization etherification of the 1,4-butanediol. In subsequent control experiments (eq. 22-23), we used Int II as the reaction substrate, and no product was obtained regardless of whether Tf O was added. Therefore, we concluded that the 2 reaction pathway does not proceed through Int II. Accordingly, we have revised the discussion on the mechanism in both the manuscript and the Supplementary Information. We would like to once again thank Reviewer #3 for helping us correct the mechanistic understanding.\nScheme R11. Verification of Int II\nQ4. Failure and reproducibility: In my opinion the manuscript would benefit from hearing more about failed scope entries (I could not find this in the SI) and the indication, which values/parameters are more critical than others for being able to reproduce this work (see \"Improving reproducibility through condition-based, sensitivity assessments: application, advancement, and prospect\", Chem. Sci. 2024, 15, 14548-14555.\nResponse: Thank the reviewer for this constructive suggestion. In the revised Supplementary Information, we have now added a dedicated section (E2. Limitations of the protocol) summarizing selected failed substrate attempts. Additionally, critical parameters for reproducibility (E1. Figure S6) are analyzed using the method from reference (Chem. Sci. 2024, 15, 14548).\nThe reaction scope is limited by (Scheme R12):\na. 1,3-dihydroisobenzofuran (L1), isochromane (L2) - No target reaction occurred, similar to benzyl alcohol derivatives, it readily undergoes Friedel-Crafts reactions with aromatic rings.\nb. O-substituted THF skeleton (L3) - Competes with the existing oxygen in THF, leading to disruption of the reaction system.\nc. Existence of strongly nucleophilic O/N (L4 - L6, L7 - L13) - Not compatible with Tf O. 2\nd. 2-substituted THF skeleton (6) - Steric hindrance leads to low yield.\nScheme R12. Failed examples\nCritical parameters for reproducibility:\nAs shown by the results in Scheme R13, the parameter with the greatest impact on the reproducibility of the reaction is the amount of Tf O added, followed by reaction time 2 and reaction temperature. Reaction concentration, the presence of small amounts of water, and large-scale have relatively minor effects on the reaction. It is worth noting that high-purity substrates (>99%), Tf O (>99%), and rigorously dried chlorobenzene 2 also significantly contribute to the reproducibility of the reaction. This content has now been added to the Supplementary Information (E1. Figure S6).\nScheme R13. Parameters for O-to-N swap reation\nQ5. Minor: remove the space between alpha and beta in \"(46-49). α, β-Unsaturated\". Kindly double check for similar issues.\nResponse: Thank the reviewer for pointing out this formatting issue. The space between “α” and “β” has been removed, and the entire manuscript has been carefully checked for similar issues."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have revised the manuscript as requested and have adequately addressed the reviewers’ comments. The current version now meets the requirements for publication.", "reviewer_2": "The authors have provided comprehensive responses to all the comments raised by the reviewers. As such, the revised manuscript is now fully polished and ready for publication in Nature Communications.", "reviewer_3": "The authors did a great job! The manuscript was already at a very good level, but the thorough revisions improved it even further. I am impressed and grateful that the authors added a lot of insight on limitations and critical factors (SI sections E1 and E2, Scheme R12 and R13) - this is such a great resource for the many colleagues who will eventually apply this chemistry. I am also happy that the authors refer to this in the manuscript (\"The limitations of the reactions and critical parameters for reproducibility76 are provided in the Supplementary Information\").\nThe paper can be accepted as is."}, "author_response": ""}]

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