Scaffold hopping of furans into 3-cyanopyridines

Abstract

Furans are economically accessible bulk chemicals largely derived from lignocellulosic biomass. Although the furan motif is widely found in natural products, it remains underrepresented in FDA-approved therapeutics owing to its metabolic instability. This gap underscores the need for strategies that diversify and functionalize furan scaffolds for drug discovery. Here, we report a scaffold-hopping strategy in which the cyano-sulfenylcarbene selectively cleaves the furan core, generating dienone intermediates bearing an intrinsic thioaryl leaving group. A subsequent reaction with a nitrogen source restores aromaticity and yields pyridines, a privileged and pharmaceutically indispensable heterocycle. This metal-free process exhibits broad functional-group tolerance, enables ¹⁵N-incorporation, and provides a conceptually distinct approach to the controlled remodeling of heterocycles. Mechanistic studies, supported by density functional theory calculations, highlight the critical role of the cyano-group in the ring-opening step of furan and uncover an unusual ring-closing pathway that proceeds via a cyclopropane-fused pyrrole, ultimately yielding an unexpected pyridine regioisomer.

The authors report a scaffold-hopping strategy in which a cyanosulfenylcarbene selectively cleaves furan cores, generating dienone intermediates bearing an intrinsic thioaryl leaving group. A subsequent reaction with a nitrogen source restores aromaticity and yields pyridines, a privileged and pharmaceutically indispensable heterocycle.

Introduction

Furan is a prominent structural motif in many natural products, yet it remains relatively uncommon among FDA-approved drugs^1,2. This discrepancy largely arises from furan’s susceptibility to oxidative ring opening mediated by cytochrome P450 enzymes, particularly CYP2E1 (Fig. 1A)³. The resulting electrophilic endial/enone intermediates can react with and deplete essential cellular nucleophiles, including amino acids, proteins, and DNA, thereby impairing critical biological functions^3–7. This inherent metabolic liability provides a compelling rationale for the limited use of furans in approved pharmaceuticals relative to more stable N-heterocyclic scaffolds^8,9.

Fig. 1. Background and our hypothesis for skeletal editing of furans.

A Furan as a liability in drug design; B Oxidative rearrangement of furans; C Skeletal editing of furan to pyrrole; D Reaction of furans with carbenes; E Our hypothesis. Blue dots represent the carbon-atom mapping.

Furans are valuable and cost-effective bulk chemicals primarily produced from renewable feedstocks, such as lignocellulosic biomass, the most abundant organic material on Earth^10–14. Because of their low cost and abundant availability, furans and their derivatives, such as furfuryl alcohol, furfuryl amine, and methylfuran, serve as attractive feedstocks for the synthesis of diverse C5 building blocks^15,16. Consequently, the rearrangement of furfural and related furan derivatives into functionalized pyrans, piperidines, and pyridines provides a synthetically valuable and sustainable strategy through the Achmatowicz and Aza-Achmatowicz rearrangements (Fig. 1B)^17–20.

Among scaffold-hopping strategies^21–23, skeletal editing has emerged as a transformative approach in drug discovery, enabling the direct reconfiguration of molecular frameworks within complex bioactive compounds^24–36. This strategy allows chemists to convert one core scaffold into another without de novo synthesis, effectively creating new chemical space from existing lead structures^29,37,38. By facilitating the precise modification of molecular skeletons, skeletal editing enhances biological activity, improves pharmacokinetic profiles, and accelerates the optimization of lead compounds in a time- and resource-efficient manner^28,29,38. Notably, substantial advances have been made in the skeletal editing of five-membered heterocycles such as pyrroles, pyrazoles, imidazoles, and thiazoles, which are prevalent motifs in pharmaceuticals^39–46. In contrast, analogous skeletal editing transformations of furans remain largely unexplored, although a few reports have described related transformations in benzofurans^47,48. In a recent study, the Park group reported a photocatalytic approach for late-stage skeletal editing of furans, enabling their conversion into pyrroles (Fig. 1C)⁴⁹. These limited precedents highlight the significant challenges and opportunities in establishing general and selective skeletal editing strategies for furan-containing molecules^50,51.

Furans exhibit versatile reactivity, functioning both as arene analogues and as masked alkenes or dienes^52–54. One attractive approach to harnessing their synthetic utility involves reactions with carbenes, which generate intermediates for subsequent functionalization^54,55. The reaction between furans and carbenes was first reported in 1958 and was found to yield unstable cyclopropane intermediates that gradually decompose into a mixture of diene products (Fig. 1D)⁵⁶. Multiple literature report describes the formation of diene–carbonyl mixtures; however, these compounds have limited synthetic utility due to the absence of a suitable leaving group^57–60. In addition, furans are known to undergo intra- and inter-molecular reactions with various metal carbenes to produce products such as pyrroles, cyclopentenes, and dihydropyridines with an alternate rearranged backbone^59,61–65.

Inspired by previous studies on furan reactivity and building on our own work in late-stage skeletal editing using sulfur-based carbenes and nitrenes^39,41,46, we envisioned a strategy employing sulfenylcarbenes bearing a built-in thioaryl leaving group to achieve skeletal editing of furans (Fig. 1E). We hypothesized that such carbenes would react with the electron-rich furan ring to generate dienone intermediates featuring a built-in thioaryl leaving group. These intermediates may subsequently transform upon treatment with an ammonia source to form functionalized pyridines. This two-step sequence exemplifies a deconstruction–reconstruction strategy^66,67: first breaking down the furan framework via selective carbene insertion, and then rebuilding molecular complexity through cyanopyridine formation. Additionally, cyanopyridines are valuable nitrogen-containing heterocycles widely found in pharmaceuticals and bioactive compounds^8,68–71. The cyano group is an important functional group, as it enhances target binding through the lone pair of electrons on the nitrile nitrogen and improves the physicochemical properties of drug molecules^72,73. Notably, cyanopyridines are recognized as bioisosteres of pyrimidines, making them valuable scaffolds in medicinal chemistry⁷³.

Here we report a strategy that represents a conceptually distinct dearomatization–rearomatization approach for scaffold hopping of furans, providing a promising pathway for structural diversification.

Results and discussion

We initiated our study by using commercially available symmetric 2,5-dimethylfuran (1a) as the model substrate (Fig. 2A), with cyano-sulfenylcarbene developed by our group for the skeletal editing of N-heterocycles⁷⁴. Remarkably, 1a resulted in efficient formation of the desired dienone intermediates (2e and 2e’), featuring a thioaryl moiety as a built-in leaving group (Fig. 2A). These intermediates were confirmed by detailed NMR and X-ray crystallography analyses (CCDC 2478590; see supplementary information for details).

Fig. 2. Reaction optimization for skeletal editing of furan to pyridine.

A Initial result on ring opening of furans; B Reaction optimization; C Other sulfenylcarbenes for ring opening; D Phenylcarbene for ring-opening reaction; E Screening of literature-reported carbenes-bearing leaving group. Conditions A. Reactions were carried out on a 0.5−1.0 mmol scale in a sealed vial. 1a (1.0 equiv.), SCP (1.5 equiv.), base (2.0 equiv.), solvent (0.1 M); Conditions B. Reactions were carried out on a 0.5−1.0 mmol scale in a sealed tube 2 (1.0 equiv.), source of ammonia (10 equiv.), solvent (0.1 M). Yields were determined by ¹H-NMR using 1,3,5-trimethoxybenzene as an internal standard. Not detected (n.d). ^*Isolated yield of reaction in 1 mmol scale. ^#1H-NMR yield of reaction under one-pot conditions. Blue dots represent the carbon-atom mapping.

After the initial success with cyano-sulfenylcarbene, we synthesized a series of cyano sulfenylcarbene precursors (SCPs) to understand the influence of thio-functionality on the carbene center (Fig. 2B). We performed a Hammett study by substituting the para-position of aromatic thiol in the cyano-sulfenylcarbene precursors. SCP-1a bearing a nitro substitution (ρ = +0.778), failed to yield a dienone intermediate (entry 1), however, a weaker electron-withdrawing group, CF₃ (ρ = 0.540), on the aryl ring, resulted in intermediates in a low yield (entry 2). Furthermore, our study revealed that halogens such as Br (ρ = +0.232) and F (ρ = +0.062) on the aryl ring provided a moderate yield of the intermediate (entries 3,4). Finally, electron-donating groups on the aryl ring, such as SCP-1e (Me, ρ = –0.170) and SCP-1f (OMe, ρ = –0.268), also provided the intermediate 2 (entry 5,6). To our delight, the corresponding intermediate 2e and 2e’ were formed in 96% yield (entry 5) when the thio-functionality was para-substituted with a methyl group.

Changing the reaction solvent to dioxane resulted in a slightly lower yield (entry 7). We also employed industrially preferred solvents, including acetone, acetonitrile, and tertiary, secondary, and primary alcohols (entries 8–12)⁷⁵. The reaction yielded moderate to good results in all solvents. When secondary alcohol (isopropyl alcohol) was used as the solvent, the reaction worked similarly to tetrahydrofuran (THF) (entry 11). To evaluate the broader applicability of this methodology, the reaction was performed under aqueous conditions and proceeded efficiently in THF/H₂O (entry 13).

To optimize the cyclization–rearomatization step, we treated the dienone intermediates 2e and 2e’ with 10 equivalents of ammonium acetate in acetonitrile (0.1 M) at 120 °C. Under these conditions, the reaction proceeded cleanly to afford the 3-cyanopyridine 3a in quantitative yield. We then evaluated various sources of ammonia (HCOONH₄, NH₄Cl, and (NH₄)₂CO₃); however, none outperformed ammonium acetate under the optimized conditions (entries 2 and 3). These results indicate that ammonium salts (NH₄OAc and HCOONH₄) of weaker organic acids (pKa ~4) are more effective than salts (NH₄Cl) derived from strong acids (e.g., HCl) in facilitating the initial step of reconstruction, which is imine formation. However, (NH₄)₂CO₃ is a salt of a weak acid that may be too weak (pKa ~6) to enable easy formation of imine. When sodium acetate was used as an additive in the presence of NH₄Cl, it produced the desired product, albeit in low yield (entry 4), likely due to in situ formation of NH₄OAc, whereas excess organic acid (AcOH, 10 equiv.) in the presence of ammonium chloride led to substrate decomposition (entry 5).

Lowering the reaction temperature resulted in a significant decrease in yield, indicating that an elevated temperature is crucial for efficient cyclization (entry 6). To determine the optimal amount of ammonia source required, we tested 5 equivalents of ammonium acetate. While the reaction still proceeded, the yield was slightly reduced, suggesting that a higher concentration of ammonia facilitates complete conversion (entry 7). We also examined the effect of additives. The addition of a mild Lewis acid, such as copper(I) iodide, resulted in a diminished yield, whereas the use of cesium carbonate as a base additive led to decomposition of the intermediate, with only trace amounts of the desired product observed (entries 8, 9). When higher-boiling solvents tert-butylnitrile or n-butyl acetate were used, the reaction proceeded in moderate yield, further confirming acetonitrile as the optimal solvent for the reconstruction pathway (entries 10, 11).

We tested a ¹⁵N-labeled ammonia source to demonstrate the applicability of this methodology for isotopic labeling of pyridines, and the reaction proceeded in good yield (entry 12) (see Supplementary Information for additional details). To shorten the reaction time, we carried out the reaction using a microwave reactor, which significantly reduced the reaction time with a slight decrease in yield (entry 13) (see Supplementary Information for additional details on microwave reaction conditions). Collectively, these studies established a robust and reproducible skeletal editing protocol for the efficient conversion of furan-derived dienones into 3-cyanopyridines. Furthermore, the cyano group is a versatile diversification handle that can be readily transformed into a broad range of functional groups⁷⁶.

Next, we also examined a broad range of literature-reported carbene precursors bearing leaving groups, including those previously employed by our group for the skeletal editing of N-heterocycles to introduce diverse substituents at the C-3 position of the resulting heterocycles. When sulfonyl-, sulfonamide-, and phosphonate-derived sulfenylcarbene precursors were tested, they failed to produce the desired ring-opening products, emphasizing the specific role of the cyano group in the ring opening of furans (Fig. 2C).

To elucidate the role of the cyano-substituted carbene in promoting furan ring opening, we next investigated both metal-mediated and metal-free strategies for generating phenyl cyanocarbene to achieve the desired ring-opening products (Fig. 2D). Both approaches produced the corresponding ring-opened intermediate, with the metal-free conditions providing superior yields. As the ring-opened intermediates 2g and 2g’ did not have a leaving group, our optimized conditions (NH₄OAc in acetonitrile) for the reconstruction pathway did not furnish the targeted pyridine. Building upon these results, we next performed a reaction with cyanocarbene bearing a bromo leaving group using the dibromoacetonitrile precursor. However, this precursor was unable to open the furan ring⁷⁷. Next, we investigated other carbene precursors, such as diazirine^40,78 and diazo-based^79–81 precursors commonly used in skeletal editing of N-heterocycles, but none yielded the desired product under literature-reported conditions (Fig. 2E). All these results further highlight the optimal electronic match of the cyano-sulfenylcarbene as a donor/acceptor carbene for the successful scaffold-hopping of furans into 3-cyanopyridines. To further understand the underlying mechanism, we performed density functional theory (DFT) calculations (See supplementary information for additional details).

Computational insights on reaction mechanism and pathways

Density functional theory (DFT) calculations were performed to understand the underlying mechanisms involved in this transformation. Geometry optimizations and frequency calculations were performed using B3LYP-D3(BJ)/6-31G(d), which was selected for its balance of accuracy and efficiency (Fig. 3)^82,83. Single point corrections were then added to the self-consistent field (SCF) energy using ωB97x-D/6-311G(d,p)⁸⁴. Solvent effects were treated using SMD(THF) or SMD(MeCN) and were included in all self-consistent field (SCF) calculations with the exception of some structures along the electrocyclic pathway, which were solvated via single-point calculations due to issues with dissociation in implicit MeCN (see supplementary information for additional details and justification)⁸⁵.

Fig. 3. DFT computational analysis on mechanism and reaction pathway.

A Resonance structures of cyano-sulfenylcarbene; B LUMO of cyano-sulfenylcarbene; C DFT calculations on ring opening; D DFT calculations on ring closing. Blue dots represent the carbon-atom mapping.

As described above (Fig. 2), not all carbenes are capable of achieving furan deconstruction and reconstruction. Specifically, non-cyano-substituted sulfenylcarbenes are not able to ring-open furan. In order to understand this behavior, we computed the equilibrium bond lengths and lowest unoccupied molecular orbital (LUMO) of cyano-sulfenylcarbene and compared these to a variety of other substituted sulfenylcarbenes (Fig. 3A) (see Supplementary Information for details). This showed that the C2-C3 bond of cyano-sulfenylcarbene was significantly contracted compared to an ordinary carbon-carbon bond and that the LUMO displayed a clear π-type interaction involving C2 and C3. This indicates that an allene-like resonance is a reasonable way of viewing this carbene (Fig. 3B). No significant interactions between the R-group and carbenic center were observed in -H, -SO₂Ph, or sulfonamide-substituted sulfenylcarbenes. We suggest that this unique electronic structure allows cyano-sulfenylcarbene to cleanly ring-open furan without the interference of competing pathways (see supplementary information for details).

Scans of the potential energy surface (PES) suggest that the ring-opening of dimethylfuran by cyano-sulfenylcarbene is taking place through an ambimodal transition state (Fig. 3C). A similar mechanism has also been invoked in the ring-opening of cyclopropene by dichlorocarbene^86–88. A two-dimensional PES scan varying the C2–carbene and C3–carbene bond distances revealed two perpendicular reaction coordinates that converge at a single transition state connecting the starting materials, the furan–cyclopropane intermediate, and the open-chain dienone product (an interpolated potential energy surface is shown with further details and structures in the SI).

Next, this dienone is converted in situ to an imine-diene. This intermediate will exist in a thermal equilibrium with its trans isomer at 120 °C. From here, the imine-diene is capable of either a disrotatory 6π-electrocyclization to form the 1,2-dihydropyridine analogue (not observed) or a 5-exo-trig cyclization to form a zwitterionic pyrrole derivative (Fig. 3D). Although both pathways are formally allowed, the presence of the cyano group facilitates the intramolecular Michael reaction, making this 5-exo-trig cyclization significantly faster. This is supported by the relative energies of TS-1 and TS-1’ as well as the values of Fukui functions at C5 and C6 within SM-cis. This zwitterionic intermediate (INT-1) closes via TS-2 to form pyrrole-cyclopropane (INT-2), which is relatively stable. Internal ring-opening of this cyclopropane through the loss of the thioaryl subunit proceeds through TS-3 and affords the observed pyridine product. Calculations revealed that although the internal ring opening of the two possible cyclopropane diastereomers is somewhat torquoselective, both isomers can readily open at the reaction’s operating temperature (see supplementary information for details).

Scope and regioselectivity of furans

With these optimized conditions, we investigated the scope and regioselectivity of furans (Figs. 4 and 5). We began by investigating an unsymmetrical furan substrates (Fig. 4). The reaction proceeded efficiently with the 2,5-dialkyl-substituted furan 1b, affording a mixture of regioisomeric pyridines (3b and 3b’) due to the ring opening from the C2 and C5 positions of the furan. Next, furans bearing a methyl group at the 2-position and various functionalized alkyl substituents such as free hydroxyl groups and esters at the 5-position (1c, 1d, and 1e) afforded the corresponding pyridines as a mixture of regioisomers in good yields, underscoring the broad functional group tolerance of this transformation. Several trisubstituted furans (1f to 1h) were subjected to the reaction conditions, and carbene insertion took place on both sides of furan, showing no regioselectivity. We found that different para-substitution in phenyl rings at the C3-position of the furan (1f and 1h) did not influence the regioselectivity. In contrast, a trisubstituted furan with a carbonyl group directly attached at the C3-position (1i) influenced the site of carbene insertion, slightly favoring the more substituted side, forming the corresponding tetrasubstituted pyridines (3i and 3i’) with moderate regioselectivity.

Fig. 4. Scope and regioselectivity of furans.

All the reported yields are isolated, and the regioisomeric ratio was determined by ¹H NMR using 1,3,5-trimethoxybenzene as an internal standard. Blue dots represent the carbon-atom mapping.

Fig. 5. Scaffold hopping of furans into a single regioisomer of 3-cyanopyridines.

^*Isopropyl alcohol (ⁱPrOH) was used as a reaction solvent. Blue dots represent the carbon-atom mapping.

Rosefuran is a naturally occurring furan derivative found in the essential oils of certain roses, valued for its distinct floral aroma and importance in fragrance chemistry⁸⁹. Application of our protocol enabled the selective conversion of regioisomer 1j to the pyridine product 3j′ with high regioselectivity, demonstrating full compatibility with the sensitive prenyl substituent. Although the exclusive formation of a single regioisomer was not anticipated, we propose that the dienone intermediate arising from the alternative ring-opening pathway decomposes preferentially. This decomposition likely accounts for the observed regioselectivity and the modest yield in the deconstruction step.

The furan ring bound in N-protected indole-3-acetic acid (1k) was selectively converted to the corresponding pyridines (3k and 3k’), while the N-methylindole moiety remained untouched. The furan moiety bound to ciprofibrate (1l), was also successfully converted, demonstrating the compatibility of our methodology with cyclopropane functionality. When our standard reaction conditions were applied to the ketoprofen-bound furan 1m, the furan moiety was efficiently converted into the corresponding pyridines (3m and 3m’) in good yield, demonstrating the compatibility of the methodology with ketone functionality.

Difuran-containing compounds, which incorporate two furan rings within a single molecular framework, have attracted considerable interest due to their distinctive structural and reactive features^90,91. This methodology enables the efficient transformation of difuran compound 1n into all its possible dipyridine-containing products with moderate yield, demonstrating the synthetic utility of this platform for complex heterocycle construction. Together, these results suggest that the regioselectivity of the pyridine products is established at the initial carbene-induced ring-opening step. Multiple factors, including electronic effects, steric constraints, and conformational preferences, dictate the ring-opening step and determine which C–O bond is cleaved, thereby dictating the substitution pattern in the final pyridine products.

Next, we investigated 2-methyl-5-aryl-substituted furans (1o and 1p), which furnish the corresponding pyridine derivatives (3o and 3p) as single regioisomers (Fig. 5). In these cases, ring opening occurs preferentially on the sterically less-hindered and electron-rich methyl-substituted side, in line with the established behavior of unsymmetrical substituted furans^92,93.

Motivated by this precedent, we next examined unsymmetrical furans with systematically varied electronic properties with similar steric constrain. 2,5-aryl-substituted unsymmetrical furan (1q) was subjected to the reaction conditions, and a single regioisomer of the corresponding pyridine (3q) was obtained. The observed regioselectivity can be rationalized by electronic differences between the C-2 and C-5 positions where carbene insertion preferentially occurs at C-5 due to the presence of an electron-donating aryl substituent at C-2, consistent with the known reactivity of five-membered heterocycles toward electrophilic species like nitrene⁹⁴. The molecular structure of 3q was confirmed by single-crystal X-ray diffraction analysis (CCDC 2471490). Similarly, the furan bearing a phenyl group at the 2-position and functionalized alkyl substituents at the 5-position (1r) provided a single regioisomer.

Furan fatty acids (F-acids) and their derivatives (esters, amides) are a rare type of minor fatty acids present in sources such as fish, milk fat, soybeans, and various green plants⁹⁵. They are recognized for their potent antioxidant properties and play a crucial role in protecting polyunsaturated fatty acids from oxidative damage⁹⁶. Our scaffold-hopping methodology enables the regioselective conversion of rare non-methylated furan fatty acid ethyl esters (1s and 1t) and benzylamide (1u) into their corresponding pyridine derivatives. Using our optimized conditions, the amino acid L-methionine bound to furan 1v was successfully transformed into the corresponding pyridine, demonstrating its compatibility with both amide and thioether linkages. The reason behind the stark change in regioselectivity in these substrates as compared to substrate (1e) is unclear, but may be a result of a number of different stereoelectronic effects (see Supplementary Information for details).

Furan-containing macrocycles are important scaffolds, valued for their electronic properties, flexibility, and molecular recognition capacity in host–guest systems and in material design⁹⁷. We expanded the scope of our methodology to selectively edit the furan-containing macrocycle 1w, thereby accessing the synthetically challenging pyridine-containing macrocycle 3w, which also exhibits anisotropic effects during NMR analyses (see Supplementary Information for additional details).

As a synthetic application, we regioselectively transformed the trisubstituted furan (1x) into a substituted 3-cyanopyridine (3x). The product 3x is a valuable synthon, serving as an intermediate in the synthesis of cytokine biosynthesis inhibitors shown in Fig. 6A⁹⁸. Next, we also exploited the versatility of the cyano group by transforming it into representative functional groups, including amide, carboxylic acid, aldehyde, and ketone (Fig. 6B).

Fig. 6. Synthetic applications, post-modifications, and limitation of the scope.

A Synthetic applications; B Post-modifications; C Limitation of the scope. Blue dots represent the carbon-atom mapping.

We evaluated a C-2 monosubstituted furan (1y) to achieve regioselective ring opening from the sterically less hindered unsubstituted C-5 position; however, the subsequent reconstruction step proceeded in poor yield (Fig. 6C). This outcome highlights a limitation of the methodology, which appears to require 2,5-disubstituted furans for efficient product formation. We then utilize DFT calculations to understand why not all substrates that cyano-sulfenylcarbene is capable of opening readily close to afford the pyridine product. We suggest that the reconstruction process is dominated by the stability of the pyrrole-cyclopropane intermediate (INT-2) and interactions within the rate determining transition state (TS-3) (Fig. 3D) (see supplementary information for details).

The deconstruction of substituted furfuryl alcohol (1z) afforded the corresponding substituted dihydropyrans (2z and 2z’), which are presumably produced in a manner similar to an Achmatowicz-type rearrangement via an intramolecular condensation of the ring-opened intermediates generated by regioselective ring opening of the furan from its electron-rich side. This methodology is ineffective for the ring-opening of C-2- and C-3 -substituted furans bearing electron-withdrawing groups. Additionally, furan derivatives such as benzofurans and dibenzofurans did not undergo the desired transformation.

In summary, we have developed a selective, deconstructive ring-opening strategy for furans using cyano-sulfenylcarbenes, enabling the formation of reactive intermediates equipped with an intrinsic thioaryl leaving group. Building on this transformation, we established a streamlined approach for converting these intermediates into pharmaceutically relevant pyridines, thereby demonstrating the skeletal editing of furans into substituted 3-cyanopyridines. Notable features of this methodology include the use of metal-free, bench-stable sulfenylcarbene precursors, broad substrate scope, excellent functional-group tolerance, and comprehensive mechanistic elucidation through both experimental and computational studies. Overall, this work provides an efficient platform for dearomatization–rearomatization that transforms simple feedstock molecules into complex heterocycles, offering a sustainable, conceptually innovative strategy for skeletal editing.

Methods

Deconstruction to furans

To a mixture of an appropriate furan (1 equiv.) and sulfenylcarbene precursors (SCPs) (1.5 equiv.) in THF or ⁱPrOH (0.1 M), was added cesium carbonate (2 equiv.) and the reaction mixture was stirred at 25 °C for 10 h. After completion of reaction as indicated by TLC, the reaction mixture was diluted with ethyl acetate, passed over a pad of silica, and concentrated under reduced pressure. Major impurities were removed by passing through a short pad of silica before conducting the next step.

Reconstruction to pyridine

An oven-dried sealed tube was charged with a corresponding mixture of dienones (1.0 equiv.), 10 equiv. of ammonium acetate (NH₄OAc), and MeCN (0.1 M). The reaction mixture was placed into a 120 °C pre-heated sand bath and stirred at the same temperature for 5 h. The resulting black mixture was passed over a pad of silica while eluting with EtOAc and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography to obtain the pyridines.

Author contributions

PK and I.S. conceptualized the idea, and I.S. supervised the research. ^†P.K. and S.Y contributed equally in designing and conducting synthetic experiments, including purification and characterization. D.H. conducted computational studies. D.N. and R.F. contributed in starting materials synthesis. N.A. contributed in NMR analyses. P.K. and I.S. prepared the manuscript with input from all authors. All authors participated in research discussions and approved the final version of the manuscript.

Peer review

Peer review information

Nature Communications thanks Zhanhui Yang, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.

Funding

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

Data availability

All data supporting the findings of this study, including experimental details, spectroscopic characterization data for all compounds are available in the text and the Supplementary Information section. Crystallographic data for the structure reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2478590 (for 2e’) and 2471490 (for 3q). Copies of the data can be obtained free of charge via https://www.ccdccam.ac.uk/structures/. All data are available from the corresponding author upon request. Details of DFT calculation have been provided in Source Data accompanying this paper. Source data are provided with this paper.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41467-026-77185-w.