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. 2026 Aug 7;6(5):707–714. doi: 10.1021/acsorginorgau.6c00077

Programmable Leaving Group Controlled Skeletal Editing of Pyrroles into Pyridines via Sulfenylcarbenes

Upasana Chatterjee 1, Prakash Kafle 1, Shuhei Yasuda 1, Indrajeet Sharma 1,*
PMCID: PMC13650952  PMID: 42857519

Abstract

Skeletal editing plays a key role in diversifying nitrogen-containing heterocycles and their remodeling. Herein, we present a programmable, leaving-group-controlled single-carbon insertion into pyrroles using sulfenylcarbene. By tuning the leaving group in these sulfenylcarbenes, precise control over functional-group installation through ring expansion was achieved. This methodology was successfully applied to pyrroles, providing access to privileged meta-functionalized pyridines and establishing a platform for the programmable synthesis of pyridine derivatives.

Keywords: sulfenylcarbene, skeletal editing, thioether, ring expansion, carbene

graphic file with name gg6c00077_0008.webp

graphic file with name gg6c00077_0006.webp

Introduction

The Ciamician-Dennstedt rearrangement is the first carbene-mediated ring expansion of pyrroles into C3-functionalized pyridines, in which dichlorocarbene enables carbon atom insertion (Figure A). , Beyond its synthetic utility, this transformation laid an early conceptual foundation for the direct modification of existing scaffolds. − More than a century later, advances in synthetic chemistry have transformed this concept into the modern field of skeletal editing, where molecular frameworks can be precisely remodeled through the insertion, deletion, or exchange of atoms. − These strategies provide efficient access to structurally diverse analogues and have emerged as powerful tools for exploring structure–activity relationships in drug discovery. ,, At the foundation of these transformations lie the basic concepts of bond-making and bond-breaking. Bond cleavage is often controlled by leaving-group ability and plays a key role in determining both the efficiency and the outcome of a transformation. − Equally important, the site and mechanism of bond cleavage dictate how a molecular framework is remodeled. Thus, controlling bond-breaking events is central to the development of skeletal editing reactions. −

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(A) Ring expansion of pyrrole to pyridine using dichlorocarbene; (B) other reports of skeletal editing of pyrroles to pyridines; (C) different drug candidates having 3-substituted pyridine moieties; (D) scheme showcasing this work.

In the skeletal editing of pyrroles to pyridines, the leaving-group ability of carbene substituents is a key determinant of the functionality installed at the newly formed meta position. , Recent advances in single-carbon insertion strategy have employed a variety of carbene precursors to efficiently convert pyrroles into functionalized pyridines (Figure B). ,− These studies reveal that substituents on the carbene carbon dictate both carbene reactivity and the functionality incorporated during ring expansion, with halogens emerging as particularly effective leaving groups.

Access to substituted pyridines is highly valuable because approximately 80% of FDA-approved drugs contain nitrogen-based heterocycles. Pyridines are among the most prevalent moieties in these N-heterocycles (Figure C). Moreover, they are found in 18% of agrochemicals, serve as key scaffolds for ligands, and form the fundamental building blocks of supramolecular systems. Despite their widespread importance, the synthesis of meta-substituted pyridines has been a longstanding challenge. − These moieties are intrinsically more electrophilic at the 2- and 4-positions, making them more reactive. As a consequence, direct C–H functionalization at the 3-position of a pyridine remains challenging due to this center being comparatively electron-rich. Recent advances in heterocycle remodeling provide an alternative strategy for accessing meta-substituted pyridines from corresponding pyrroles. ,−

Beyond traditional pyridine substitution patterns, sulfur-containing functionalities, such as phenyl sulfonyl (–SO2Ph) and thioether (–SR) groups, have attracted growing interest due to their extensive applications and synthetic utility. − Sulfonyl groups are known to enhance drug properties by improving lipophilicity, metabolic stability, and target-binding affinity, making them advantageous for target optimization. − Whereas thioethers have widespread applications as both a valuable structural motif and a synthetic intermediate for other sulfur-containing functionalities. , Beyond these functions, thioethers have also emerged as a synthetic handle for various metal-catalyzed cross-coupling reactions. − However, the requirement for prefunctionalized substrates and the limitations of conventional functionalization strategies highlight a fundamental challenge in modern synthetic chemistry: the effective functionalization of complex molecular frameworks. −

This problem has led to the emergence of skeletal editing of pyrroles to pyridines as a powerful technique, achieved by single-carbon-atom insertion using a carbene. The advantages of this technique include a streamlined synthetic approach, single-atom manipulation, and its use for late-stage functionalization of drug candidates. − In 2025, Sharma and co-workers developed a strategy for single-carbon insertion into unprotected pyrroles using sulfur-based carbenes, namely sulfenylcarbenes. These versatile carbenes were able to install a variety of functionalities, including cyano, phosphonate, alkyne, sulfonamide, and sulfonyl groups (Figure B). Despite the broad functional-group compatibility of this sulfenylcarbene work, it could not install a thioaryl or thioalkyl moiety; thus, the present study addresses this limitation and serves as a meaningful continuation.

Mechanistically, sulfenylcarbenes primarily exist as ground-state singlets and exhibit partial double-bond character in the C–S bond. These carbenes also showed chemoselectivity, offering diverse functional group tolerance and enabling late-stage applications. In this study, the thioaryl group attached to the carbenic carbon was found to serve a dual role: modulating carbene reactivity and acting as a leaving group, thereby enabling the incorporation of a broad range of functional groups (Figure D). These findings suggest that the leaving-group ability of substituents attached to the carbenic carbon can be strategically exploited to control both carbene reactivity and the installation of new functionality. , Guided by these reactivity trends, we began investigating the synthesis of a carbene that can incorporate a functional group (e.g., a thioether or sulfonyl group) by leveraging the leaving-group ability of substituents at the carbenic carbon. To explore this, we started the synthesis of a sulfur-based carbene precursor bearing a thioalkyl and a phenylsulfonyl group at the carbene carbon. These carbene precursors were prepared using a previously reported method (Figure A) that employed DMSO and the aryl-sulfinate salt under acidic conditions and at elevated temperatures, yielding the methylthio methyl sulfonyl compound. This, upon further monochlorination, delivered the final sulfenylcarbene precursors (SCPs) bearing the thioether (alkyl) functionality (Figure B).

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Synthesis of SCPs and optimization for ring expansion. (A) The synthesis of SCPs using DMSO; (B) versatile SCPs synthesized; (C) reaction optimization. Reaction conditions: 2 (1.0 equiv., 0.05 mmol), SCPs (1.5 equiv), Cs2CO3 (3.0 equiv), and solvent (0.1 M) at room temperature for 12 h.

Results and Discussion

Our investigations into this reaction began with 2,3-diphenyl pyrrole (2) as the model substrate (Figure C). For the optimization study, we used 1.5 equiv of the SCPs, 3.0 equiv of Cs2CO3 as the base and tetrahydrofuran as a solvent. We preferred SCP-1 as the original precursor for this study in accordance with our previous work to obtain the product 2a in 65%, along with the byproduct 2a ’ in 12% yield (entry 1). To probe the electronic effect at the carbon center, we performed a Hammett study by substituting the para position of the phenyl ring of the sulfinate salt with various groups, ranging from electron donors to electron acceptors (entries 1–5). SCP bearing pyridine ring (SCP-6), also afforded single-carbon insertion in moderate yield (entry 6). Overall, substituting the para position of the phenyl ring on the SCP with a -cyano (SCP-4), an electron-withdrawing group, gave an excellent yield (entry 4).

This observation is complementary to our previous work, in which the presence of an electron-donating group on the phenyl ring of the thioaryl moiety was found to be the most optimized precursor for installing cyano, phosphonate, alkyne, sulfonamide, and sulfonyl functionalities. Changing the solvent from THF to i PrOH or DMF yielded no product, whereas t BuOH gave a lower yield of the expanded product (entries 7–9). Since we highlighted the role of cesium carbonate in our previous study, we used it as the optimized base for this reaction.

Application of C-Atom Insertion and Thioalkyl (–SMe) Installation to Pyrroles

Having identified the optimized conditions, we turned our attention to investigating the scope of single-carbon insertion in 2,3-disubstituted pyrroles using SCP-4 as the optimized precursor to obtain the meta thioether-functionalized pyridines (Figure A). In our previous study, these sulfenylcarbene precursors reacted with 2,3-diphenylpyrrole on the sterically less hindered side, resulting in 3-substituted pyridines. We also observed a similar regioselectivity outcome in this study. Then, we began screening various substitutions on the phenyl ring attached to the 2-position of the pyrrole. We screened different groups, including methoxy, methyl, chloro, bromo, and trifluoromethyl (3a, 5a-8a). All these substrates gave moderate to excellent yields. We used a bulky substituent at the 4-position of the phenyl ring, a tert-butyl group (4). This also gave the substituted pyridine in moderate yield. Next, we substituted the phenyl ring at the 3- and 4-positions with two fluoro groups, yielding 9a in a good yield.

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Substrate scope of pyrroles and deuterated precursor. (A) Substrate scope of pyrroles for–SMe installation; (B) synthesis of deuterated precursor; (C) scope of pyrroles for–SCD3 installation.

Thereafter, we tried replacing the phenyl ring at the 2-position of the pyrrole with another heterocycle, such as thiophene, and obtained 73% yield of the meta-substituted pyridine (11a). Thioether- and thiophene-bearing pyridine resembles the core of a helicase inhibitor. We then investigated the pyrrole bearing an alkyl substituent at the 2-position using SCP-4. To achieve this transformation, we installed an ester group at the 2-position of the pyrrole and subjected it to the optimized reaction conditions. Notably, we obtained the corresponding pyridine product 10a in 45% yield. Encouraged by our findings, we sought to explore the reactivity of SCP-4 with complex substrates, such as C-glycosides. Under the optimized conditions, this reaction successfully afforded 12a, the desired pyridine-bearing thioether functionality, in 63% yield. To demonstrate the scalability of the reaction, the reaction was performed on a 1.0 mmol scale under the optimized conditions using pyrrole 2 as the substrate, affording the product in good yield (0.238 g, 86%). Monosubstituted pyrroles, such as 2-phenyl pyrrole and 2-methyl pyrrole, were found to be a limitation of the methodology. Presumably, the necessity of C3-substitution may be explained by the stabilization of the formal positive charge at C3 in the zwitterionic intermediate preceding cyclopropanation.

Deuterated drug candidates are often considered as the bioisosteres of their parent counterparts. − Not only do they impart greater stability to bioactive molecules, but they also help alter properties such as metabolic fate, reduce toxicity, and modulate drug–target interactions. − To illustrate the applicability of single-carbon insertions using SCPs, we synthesized the deuterated sulfenylcarbene precursor from commercially available deuterated DMSO (Figure B). Based on our optimized precursor SCP-4, we synthesized the deuterated precursor bearing a para-cyano substituent on the sodium sulfinate moiety. Following the synthesis of SCP-4D, we began investigating the substrate scope. To our pleasure, different substituted pyrroles underwent single-carbon expansion with SCP-4D under optimized conditions (Figure C). Substrates having para-halo substitution on the phenyl ring (6aa) gave a moderate yield of 64%, whereas the pyrrole ring having a thiophene substitution yielded the expanded pyridine with a–SCD3 moiety at the meta position (11aa) in 89% yield.

Leveraging the Leaving Group Ability of Different SCPs

Building on the successful single-carbon insertion with 2,3-disubstituted pyrroles, we began probing the reactivity of our SCPs with respect to the leaving-group abilities of the substituents at the carbenic carbon center. Under the optimized conditions, we began to leverage the effects of different leaving groups attached to the sulfenylcarbene precursors, which dictate the outcome of single-carbon expansion. To explore this, we synthesized a range of sulfenylcarbene precursors incorporating thioaryl, thioalkyl, phenylsulfonyl, and cyano substituents. To determine the leaving-group tendencies of these substitutions at the carbene carbon, we synthesized a combination of these precursors.

First, we examined replacing the thioalkyl group (–SMe) of our standard precursor (SCP-4) with a thioaryl group, which motivated us to synthesize the precursor, SCP-7 (Figure A). On successfully synthesizing this precursor, we reacted it with our parent substrate, 2,3-diphenylpyrrole. We observed the expanded pyridine 13 exclusively in the reaction mixture, indicating that the–SAr (Ar = p-Tol) group preferentially departed as a leaving group, installing the phenylsulfonyl group at the meta position of the pyridine. Inspired by this reactivity result, we sought to design a carbene that would be useful for installing a thioaryl group onto pyrroles. Keeping this outcome in mind, we replaced the sulfonyl group with a chlorine atom at the carbene carbon center. As a result, we synthesized the previously known sulfenylcarbene , precursor SCP-10 from the commercially available alpha-chlorothioanisole.

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Leaving group tendencies of different SCPs. (A) Leaving group tendency of thioaryl vs phenylsulfonyl; thioalkyl and thioaryl vs cyano; (B) applications of SCP-10 for installing thioether functionality.

After extensive optimization of conditions for successful single-carbon insertion in pyrroles, we found that at 0 °C, with t BuOK as the optimized base and THF as the optimized solvent, the carbene precursor SCP-10 achieved single-carbon insertion, converting a 2,5-diphenyl-substituted symmetrical pyrrole to pyridine in 49% yield while incorporating a thioaryl (–SPh) group into the product scaffold. We explored the scope of this transformation by synthesizing two other 2,5-diphenylpyrrole moieties having para-methyl and para-bromo substituents. Both these pyrroles gave moderate yields of around 50–55%. Following this, we designed a sulfenylcarbene precursor, SCP-8, using dodecanethiol to probe which functional group would be installed under the optimized conditions, thioalkyl or cyano (Figure A). This was consistent with the previously published result (using SCP-9 with a thioaryl substituent bearing a methyl group), showing that, irrespective of any other group at the carbene carbon, the–CN group is always installed to give 3-cyano-functionalized pyridine (14). This observation is consistent with the recent report in which dimethyl sulfide acts as a leaving group, enabling the installation of the trifluoromethyl moiety via a single-carbon expansion strategy. By leveraging the leaving-group properties of our SCPs and literature precedents, ,,− we found that chloride is the best leaving group (Figure B).

Conclusion

In conclusion, we synthesized a versatile range of sulfenylcarbene precursors that efficiently perform single-carbon insertion on substituted pyrroles. Through systematic modulation, we probed a skeletal editing platform in which functional group installations can be tuned by varying the substituents on the carbene C-atom through subtle structural modifications. Mechanistic investigations revealed distinct leaving-group preferences at the carbene center, including thioether, thioaryl, sulfonyl, and cyano, as shown in Figure . Furthermore, the synthetic utility of this method is highlighted by its application to different substituted pyrroles, which, under optimized conditions, afforded the desired pyridines bearing thioether functionality. In summary, these findings demonstrate SCPs as tunable reagents for the future design of carbene-mediated single-atom insertion strategies.

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Showcasing the leaving group and function group of different SCPs.

Materials and Experimental Methods

Further information on the reagents, experimental procedures, reaction optimization, and characterization data are provided in the Supporting Information.

General Procedure for C-Atom Insertion

To a solution of pyrrole (0.09 mmol, 1.0 equiv) in THF (0.1 M), 1.5 equiv of sulfenylcarbene precursor (SCPs) was added in one portion at room temperature, followed by the addition of 3.0 equiv of Cs2CO3 and the resulting mixture was stirred for the next 12 h. The reaction mixture was diluted with ethyl acetate, filtered through a pad of silica gel, and all the volatiles were removed under reduced pressure. The product was purified by silica gel column chromatography.

Supplementary Material

gg6c00077_si_001.pdf (3.7MB, pdf)

Acknowledgments

We thank Dr. Novruz Akhmedov from the NMR facility, Research Support Services, University of Oklahoma. We sincerely acknowledge Deacon Herndon for his valuable suggestions. Finally, we thank the Graduate College for the Nancy L. Mergler Dissertation Completion Fellowship to PK.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.6c00077.

  • Experimental procedures, NMR spectroscopic, and analytical data for all compounds (PDF) (PDF)

The manuscript was prepared by UC, PK, and IS. All authors participated in research discussions and approved the final version.

This work was supported by the American Chemical Society Petroleum Research Fund (ACS-PRF) New Directions grant (PRF no. 69051-ND1) for financial support.

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

gg6c00077_si_001.pdf (3.7MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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