Homologative Alkene Difunctionalization

Homologative Alkene Difunctionalization | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Homologative Alkene Difunctionalization Seung Youn Hong, Morgan Kim, So Yeon Ahn, Seongmin Kim, Junhwan Won, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6070447/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Nature Chemistry → Version 1 posted You are reading this latest preprint version Abstract Systematic evaluation of homologous series plays a pivotal role in synthetic and medicinal chemistry 1 , 2 . Despite their structural resemblance, the preparation of homologs often requires individual synthetic planning tailored to distinct precursors and reactions. Here, we introduce a conceptually new strategy that integrates single-carbon insertion into established methods, specifically redirecting alkene vicinal difunctionalization towards direct routes for 1,3-difunctionalized products. This transformation is enabled by a designer methylene dication reagent, iodomethylthianthrenium salt, which facilitates the photocatalytic conversion of alkenes into linchpin 1,3-dielectrophilic intermediates, allowing seamless incorporation of nucleophiles at distal positions. Mechanistic studies suggest that the reaction proceeds via an α-thianthrenium methyl radical with unusual ambiphilic reactivity governed by multiple stereoelectronic effects. This approach shows high compatibility in pharmaceutical and late-stage settings, providing broad access to diverse 1,3-difunctionalized products, including azetidines, 1,3-diazides, and 1,3-dihalides. This work establishes “homologative alkene difunctionalization” as a powerful platform for repurposing ubiquitous alkenes as meritorious synthetic intermediates to unveil heretofore unknown 1,3-substitution patterns. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Catalysis/Photocatalysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Main Homologous series—compounds sharing identical functionality but differing in the number of repeating methylene (− CH₂−) units—have long been mainstay targets in drug design and discovery 3 . Subtle variations in carbon chain lengths or ring sizes can profoundly alter molecular dynamics and physicochemical behaviors, imparting distinct pharmacological attributes to each member of these chemical families 4 . In particular, one-carbon elongation of lead compounds has been widely recognized for its beneficial impacts on desired activity such as binding affinity and potency and, as a corollary, has become a routine practice in drug discovery campaigns (Fig. 1 a) 4 – 6 . Practically, however, preparing homologs is often non-trivial, as the structural similarity does not necessarily translate into the comparable synthetic accessibility. For instance, aziridines and azetidines are both privileged N -heterocycles that differ only in ring size, while they are synthesized through entirely different synthetic schemes; alkene aziridination 7 – 9 or nucleophilic ring-closure 10 for aziridines versus lactam reduction 11 , strain-release transformations 12 , 13 , or [2 + 2] cycloaddition 14 , 15 for azetidines. Such disparity necessitates orthogonal sets of starting materials and reaction plans, imposing a substantial synthetic burden. One prominent strategy to this challenge is homologation, a process that inserts a methylene component into a preformed bond to generate the next homolog in the series 16 . To implement the carbon elongation sequence, existing methods primarily rely on specific functional handles on substrates, often in conjugation with high-energy C1-delivering reagents 17 . The prevailing exemplars in this regard are the carbon-extension functionalization of carbonyl compounds 18 – 20 and boron-mediated homologation 21 – 24 . On the contrary, further generalization to other compound classes has lagged behind. This substrate specificity of current homologation techniques underscores the clear need for an alternative solution. A conceptually distinct approach to accessing homologs would be incorporating a single-carbon unit during the assembly of building blocks, rather than post-modifying established molecular frameworks. This “homologative synthesis” allows substrates originally primed for parent compound synthesis (easy) to be harnessed for the preparation of one-carbon-extended analogs (difficult), which require lengthy processes or were previously inaccessible (Fig. 1 b). Thus, establishing this shortcut from common starting points effectively bridges the synthetic gap between homologs and augments the technical capacity to explore structure-activity relationships. Despite its readily conceivable potential, such transformations that ideally leverage abundant substructures remain largely untapped. Alkenes are among the most widely used building blocks in synthesis 25 , readily undergoing 1,2-difunctionalization via classical dihalogenations as well as transition-metal-catalysed 26 , 27 , photochemical 28 , and electrochemical addition reactions 29 (Fig. 1 c, left). Consequently, vicinal motifs frequently appear in a myriad of important organic commodities. By contrast, their homologs with 1,3-disubstitution patterns are significantly underrepresented due to the lack of reliable methods for introducing two functional groups at distal positions. While a handful of 1,3-difunctionalizations have been disclosed based on chain-walking process, they invariably require specialized alkenes to achieve regioselectivity 30 – 32 . Very recently, Maulide and coworkers further advanced this nascent field by utilizing charge relocation in a Friedel–Crafts-type reaction of unactivated alkenes 33 . However, this methodology is inherently limited to acylation. Herein, we present a distinct strategy of homologative synthesis, in which the synthetic scheme of alkene difunctionalization is redirected towards 1,3-difunctionalization with a one-carbon elongation (Fig. 1 c, right). We have identified a new class of a methylene dication (CH₂²⁺) reagent capable of transforming alkenes into a 1,3-dication synthon, which serve as points for nucleophilic entrapment with complete regiochemical fidelity under operationally simple, one-pot conditions. While the majority of the reported methods for alkene difunctionalization furnish vicinal compounds, our approach enables the formal insertion of a single carbon unit between two reactive sites on alkenes, granting unified access to their underexplored homologs such as azetidines, 1,3-diazides, and 1,3-dihalides from various alkene/nucleophile substrate pairs. Reaction development In pursuing the proposed homologative alkene difunctionalization, two key components must be addressed: (i) the identification of an appropriate CH₂²⁺ equivalent and (ii) the development of an efficient transfer method. We hypothesized that halomethylsulfonium salts ( 1 ) could be ideally suited for grafting functional handles (halogen and sulfonium motifs) at 1,3-positions via photocatalytic atom transfer radical addition 34 . As shown in Fig. 2 a right, the designed process is believed to proceed through α-sulfonium methyl radicals. Compared to the extensive body of electrophilic C-centered radicals bearing multiple electron-withdrawing groups, the sulfonium substituent alone may impart the requisite polarity. Despite their virtually unknown synthetic use, these putative species could, in principle, be generated from halomethylsulfonium salts (1) through mesolytic cleavage of C–X bonds (X = halogens). However, a fundamental challenge in this seemingly simple approach lies in the propensity of C–S bonds for facile fragmentation, which has been noted under nucleophilic 35 , photolytic 36 – 38 , and transition-metal catalytic conditions 39 – 41 (Fig. 2 a, left). As a result, the general consensus is that C–S bond in sulfonium salts is a notional strategic site for retrosynthetic disconnection 42 . Moreover, as the targeting incipient product itself contains a fragile C–S linkage, product degradation through conventional pathways poses an additional challenge in reaction design. With these considerations in mind, we commenced our investigation by evaluating a series of halomethylsulfonium salts 1 in the model reaction with 4-phenyl-1-butene 2 under photocatalytic conditions (Fig. 2 b). This class of compounds can be readily prepared in a single step and isolated as bench-stable solids 43 (Fig. S2 ). After thorough optimization, iodomethylthianthrenium salt ( 1a ) was identified to be most promising, affording the desired 1,3-dielectrophile 3a in nearly quantitative yield (95%, Entry 1). The catalytic system comprised of 5 mol% of carbazole-based photocatalyst (4CzIPN) in acetonitrile solvent at 5°C was optimal and operated efficiently without the need for external additive, highlighting the mild and redox-neutral nature of the process. The identity of the CH₂²⁺ donors was found to be crucial for the success of the reaction; brominated ( 1b , Entry 2) and chlorinated analogs ( 1c , Entry 3) were unproductive. Replacing thianthrene with other sulfide moieties resulted in either no reaction (dibenzothiophene 1d , Entry 4) or significantly diminished yields (diphenylsulfide 1e , Entry 5). Control experiments confirmed that none of the surveyed transition-metal-based photocatalysts outperform 4CzIPN (see Supplementary Information for Table S1 ). In accord with the superiority of reagent 1a , it exhibited the least negative half-wave potentials [ E p/2 = − 0.86 V versus SCE], implying facile electron transfer with 4CzIPN (Fig. 2 c). More strikingly, 1a features a LUMO with prominent antibonding character between the p(C1) and p(I) orbitals, rendering the C–I bond preferentially reactive over the C–S bond in the key bond-breaking event. Having established the efficient method to generate presumably reactive 1,3-dielectrophiles, we then explored their substitution chemistry (Fig. 2 d). Given the growing demands within biomedical research for azetidines 44 , the construction of this privileged scaffold would be an enticing possibility. Compared to their homologs—i.e. aziridines, pyrrolidines, and piperidines—azetidines exhibit conspicuous pharmacokinetic profile 45 , but their accessibility from diverse and readily available starting materials is far more limited. A notable exception is the recent work by Schindler on aza Paternò-Büchi reaction between photoexcited styrenes and imines 15 . Complementally, we found that the photocatalytic assembly of unactivated alkene 2 with 1.1 equivalent of 1a , followed by addition of a modest excess of p -methoxyaniline and sodium carbonate, led to the isolation of azetidine 4 in excellent yield (85%). The overall transformation could conveniently be performed in a one-pot manner on a preparative scale (4.0 mmol). The primary byproduct, thianthrene ( TT ), was recovered in 99% yield and could be recycled back to reagent 1a as needed. Reaction scope The generality of the homologative alkene difunctionalization was explored, and the results are summarized in Fig. 3 . A wide variety of unactivated alkenes were engaged in homologative coupling with p-methoxyaniline as a representative nitrogen source, providing structurally diverse azetidines in high yields ( 6 – 24 ). The p -methoxyphenyl group in the obtained product 4 could be readily deprotected to obtain NH -azeditine 5 in 89% yield. Ester ( 7 , 8 ), phthalimide ( 9 ), medicinally relevant piperidine ( 10 ), and sulfonamide ( 11 ) were accommodated by the transformation. Hydroxyl group ( 12 ) is well compatible without explicit protection. While steric perturbations in the substrate affected the reaction efficiency to some extent ( 13 ), the present method displays broad applicability across alkenes with electronically varied substituents. In addition to unactivated substrates, styrene derivatives underwent the desired azetidination smoothly ( 14 − 17 ). To our surprise, the present system is also amenable to functionalization of electron-deficient alkenes, affording α-ester azetidines ( 18 − 21 ). These observations run counter to the general paradigm dictated by radical polarity effects and underpins the unprecedented ambiphilic behavior of the presupposed α-thianthrenium methyl radical ( vide infra ). When alkenyl and alkynyl groups were present at the opposite terminal positions, alkyne-bearing azetidine 22 was formed with no detectable signs of the chemoisomeric product. Subjecting 1,4-pentadiene to the reaction resulted in monoazetidination as evidenced by the product 23 . The selectivity observed in this system may beckon as the retained C−C multiple bonds permits further derivatization. Relatedly, by adding doubled amount of the reaction components, 1,9-decadiene was converted into a doubly azetidinated product 24 in 47% yield. 25 o C. b Run with 1a (0.2 mmol). c Run with 1a (0.44 mmol) and amine (1.6 mmol). r.s. = regiospecificity. With respect to the amine-coupling partner, the electronic variations on the phenyl group had minimal impact on reaction efficiency ( 25 − 29 ). Arylamines bearing meta- and sterically congested ortho-substituent produced the corresponding azetidines ( 30 − 32 ). In the presence of reactive functional groups, such as boronic ester ( 29 ), pyridine ( 33 ), and phenol moieties ( 34 ), the desired azetidination took place without difficulty. Pleasingly, our protocol extended to both primary and secondary alkylamines under slightly modified conditions (2.0–4.0 equiv. of alkylamines and either Na 2 CO 3 or DIPEA base), yielding sp 3 -rich azetidine scaffolds ( 35 − 41 ). Heterocycles, including thiophene ( 37 ), NH-indole ( 38 ), and oxetane ( 41 ), could be incorporated. However, the use of tertiary alkylamines was unsuccessful (Fig. S4 ). The reaction is not limited to the construction of 4-membered rings; other nucleophiles could be incorporated to access a diverse array of linear 1,3-difunctionalized products (Fig. 5 b). For instance, the photocatalytic method, followed by the addition of sodium azide gave 1,3-diazide 42 , a key intermediate for useful 1,3-diamines, in excellent yield. The reaction conditions were tolerant of furan ( 43 ), piperidine ( 44 ), and benzyl ether ( 45 ). As with azetidination, styrene ( 46 ) and acrylate ( 47 ) proved suitable for the desired diazidation. The repertoire of this current tactic could be extended beyond nitrogen nucleophiles, beginning with 1,3-dihalide synthesis (Fig. 3 c). While classical synthetic procedures require multistep sequences (lengthy preparation of 1,3-diol precursor, mesylation, and halide displacement), homologative coupling between alkenes and inexpensive halide sources streamlines access to 1,3-dibromides ( 48 ), dichlorides ( 49 ), and diiodides ( 50 ). Given that the photocatalytically generated intermediate possesses two distinct electrophilic sites, regiospecific substitution could be envisioned. Indeed, the primary thianthrenium group could be selectively substituted with either bromide or chloride, while retaining the secondary iodide position, enabling the synthesis of unsymmetrical dihalides with perfect regiospecificity ( 51 and 52 ). To generalize the concept further, cesium acetate was employed as an oxygen donor, transforming alkene substrate into 1,3-dioxygenated product in one pot ( 53 , Fig. 3 d). Sulfur and seleniums were introduced at the 1,3-positions utilizing potassium thiocyanate, thioacetate, and diphenyl diselenide as external nucleophiles, respectively ( 54 − 56 ). Furthermore, sodium cyanide showed promise as a viable carbon source, delivering 57 in good yield. Synthetic applications The broad functional group tolerance and high reactivity prompted us to explore the applicability of the present methods in more complex settings (Fig. 4 a). Under the standard conditions, alkenes derived from medicines, such as Ezetimibe and Ibuprofen, were readily converted into the corresponding azetidines 58 and 59 , respectively. The azetidine moiety could be introduced into biorelevant scaffolds, including monosaccharide 60 and Probenecid ( 61 ) analogues. In parallel, other procedures also provide an efficient means of late-stage functionalization of bioactive substrates. As an illustrative example, the diazidation of Theobromine and Estrone derivatives afforded the desired 1,3-diazides 62 and 63 . Bicalutamide-containing 1,3-dihalides 64 were also prepared through homologative alkene dibromination. To further demonstrate the utility of this transformation in the context of pharmaceutical chemistry, we examined the capability of library diversification by the collective synthesis of structural derivatives of an azetidine pharmacophore (Fig. 4 b). A suite of N -substituted derivatives of tebanicline, a synthetic nicotinic analgesic, could be accessed in a divergent and modular fashion ( 66 – 68 ) when three primary amines were allowed to couple with alkene 65 , which can be readily prepared from 2-chloro-5-hydroxypyridine. Considering the extensive availability of primary amines from commercial vendors, we envision that the protocol could provide additional versatility for the drug modification through fragment coupling. In contemporary drug design, the modification of core structures in lead compounds while preserving peripheral substituents is a particularly sought-after strategy by medicinal chemists 46 . We applied our strategy to execute such isosteric replacements, surgically replacing the piperidine scaffold in established drugs with a smaller azetidine ring (Fig. 4 c). Flecainide is an approved antiarrhythmic agent marketed under the brand name Tambocor®. Using the homologative procedure, its azetidine analog 70 was successfully prepared from a commercial source in two steps. We next targeted perhexiline, a prophylactic antianginal agent in the scaffold-hopping effort. Starting from the dicarbohexyl-substiutted alkene 71 , azetidination led to the two-carbon-shorter homolog 72 in 48% yield. By virtue of the fact that both our homologative and previously reported vicinal alkene difunctionalization protocols utilize common starting materials (alkenes and nucleophiles), these substrates can be conveniently reused to prepare one-carbon homologs of vicinal products prepared by the existing methods (Fig. 4 d). For instance, the established photocatalytic protocol permits the vicinal diazidation ( 74 ) of ibuprofen-derived alkene 73 with sodium azide 47 . By contrast, our method enabled the formal elongation of the carbon chain spacer between azide functionalities ( 75 ). Similarly, naturally occurring alkaloid 78 from Petasites japonicus was previously synthesized based on the electrochemical coupling between alkenyl substrate 76 and cyclohexylamine 77 7 . Instead, by applying homologative alkene difunctionalization, the same ingredients underwent cyclization to afford the ring-extended product 79 in 48% yield. Mechanistic considerations A plausible mechanism, supported by experimental and computational clues, is outlined in Fig. 5 a (see Fig. S30 for detailed discussions). Upon blue LED irradiation, the photocatalyst ( PC ) is excited, and subsequently quenched by the reagent 1a via single electron transfer, with a quenching rate constant ( k q ) of 8.6 x 10 7 M − 1 s − 1 (Fig. S15). The reduced species [ 1a •− ] evolves by a unimolecular fragmentation to give α-thianthrenium methyl radical Int1 and iodide ion. The ensuing radical addition traverses TS1 with a low energy barrier of 9.2 kcal/mol. The radical adduct Int2 would abstract an iodine atom from an additional equivalent of 1a via transition state TS2 (ΔG ‡ =13.3 kcal/mol), furnishing 3-iodo-1-alkyl thianthrenium salt 3a . The coproduction of radical Int1 can gate another propagation cycle. Apart from the chain process, the radical cation [ PC •+ ] formed during initiation may convert back to its original state ( PC ) by oxidizing the initially generated iodide ions to I₂, as proposed by Giri and coworkers 48 . Thus, photocatalytic initiation could be sustained during the course of the reaction, as witnessed by the quantum yield measured to be less than 1 (Fig. S7). We sought to elucidate the fundamental aspects of the α-thianthrenium methyl radical that govern its unusual reactivity. As illustrated in Fig. 5 b, two conformers can exist, with the •CH₂ group favoring the axial position ( Int1 ) over the equatorial position ( Int1E ) by 3.6 kcal/mol. This conformational preference can be traced to key stereoelectronic interactions between the carbon radical and thianthrenium fragments. The axial orientation ( Int1 ) benefits from resonance donation of the sulfur (S1) lone pair to the radical center (C1), reminiscent of α-heteroatom effect. The spatial proximity between the secondary sulfur atom (S2) and the corresponding carbon center induces additional through-space radical delocalization in Int1 . Conversely, the equatorial conformation orients the H-C1-H plane perpendicular to the thianthrene moiety to mitigate allylic strain (A 1 , 3 ), precluding such stabilizing interactions. Taken together, the SOMO of Int1 is best described as the out-of-phase overlap between p x (C1) and p x (S1), with secondary mixing from the p z (S2) orbital. Evidently, the computed SOMO of Int1 lies at a higher energy level of −7.4 eV compared to that of Int1E (−8.2 eV), indicating greater stability at the expense of electrophilicity. For a deeper understanding of the effect of α-thianthrenium substitution, we interrogated quantitative metrics describing radical philicity and stability (Fig. 5 c). Inspired by a recent report by Nagib 49 , global electrophilicity index (GEI, ω) was selected as a measure of radical polarity. The radical stability score (RSS)—formulated based on two molecular descriptors: percent buried volume and maximum spin density—was chosen to encapsulate both kinetic and thermodynamic considerations for radical stability 50 . Through extensive benchmarking, the ω and RSSs for Int1 and Int1E , along with 354 carbon-centered radicals commonly encountered in chemical synthesis, could be evaluated and mapped onto a two-dimensional diagram in Fig. 5 c. Consistent with the FMO analysis, the extent of electronic delocalization varies with conformation: Int1 (ω = 2.31 eV, RSS = 58.9) is predicted to be more stable and less electrophilic than Int1E (ω = 2.67 eV, RSS = 54.2). The Mulliken spin density plot evidences this trend further. The spin density in Int1 is distributed over the carbon (C1: 0.88) and two sulfur atoms (S1: 0.22, S2: 0.05), whereas in Int1E , the spin is predominantly localized on the carbon (C1: 1.01). Furthermore, in head-to-head comparisons with other radicals, Int1 retains a superior electrophilic character, distinguishing it from typical nucleophilic α-heteroatom (nitrogen, oxygen, and halogens) radicals and closely resembling thedicarbonyl radical, which is known for its high reactivity in radical addition. These datasets substantiate that the intricate balance between electron withdrawal and spin delocalization conferred by the thianthrenium moiety endows Int1 with optimal stability and polarity, enabling our desired process to proceed with excellent efficiency and minimal electronic bias. Conclusion The results presented here constitute a general platform that reroutes conventional alkene difunctionalization, elaborating 1,3-difunctionalized products with high functional group compatibility. These findings exemplify an innovative advancement in reagent design that deploys a homologative synthetic logic at the forefront of chemical synthesis, diversifying the synthetic use of common substrates and unlocking previously inaccessible product spaces with vast potential applications in both academia and industry. Declarations Acknowledgments: We thank Prof. Sukbok Chang (KAIST), Prof. Chulbom Lee (SNU), and Prof. Sangwon Seo (DGIST) for helpful suggestions. We also acknowledge the groups of Chulbom Lee, Hong Geun Lee, and Eunsung Lee for sharing their chemical inventories. Additionally, we thank Mr. Seonghyun Min and Prof. Jaeyune Ryu (SNU) for their assistance with the electrochemical measurements. This work was supported by the Creative-Pioneering Researchers Program from Seoul National University, National Research Foundation (NRF) grant funded by the Korean government (MSIT) [no. RS-2023-00214144, no. RS-2024-00403103, and no. 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Catal. 3, 163–169 (2020). Chen, C., Wang, Z.-J., Lu, H., Zhao, Y. & Shi, Z. Generation of non-stabilized alkyl radicals from thianthrenium salts for C–B and C–C bond formation. Nat. Commun. 12, 4526 (2021). Zhang, L., Xie, Y., Bai, Z. & Ritter, T. Suzuki–Miyaura coupling of arylthianthrenium tetrafluoroborate salts under acidic conditions. Nat. Synth. 3, 1490–1497 (2024). Ni, S. et al. Nickel Meets Aryl Thianthrenium Salts: Ni(I)-Catalyzed Halogenation of Arenes. J. Am. Chem. Soc. 145, 9988–9993 (2023). Chen, C., Wang, M., Lu, H., Zhao, B. & Shi, Z. Enabling the Use of Alkyl Thianthrenium Salts in Cross-Coupling Reactions by Copper Catalysis. Angew. Chem. Int. Ed. 60, 21756–21760 (2021). Timmann, S., Feng, Z. & Alcarazo, M. Recent Applications of Sulfonium Salts in Synthesis and Catalysis. Chem. Eur. J. 30, e202402768 (2024). Morosaki, T. et al. Synthesis, Electronic Structure, and Reactivities of Two-Sulfur-Stabilized Carbones Exhibiting Four-Electron Donor Ability. Chem. Eur. J. 23, 8694–8702 (2017). Parmar, D. R. et al. Azetidines of pharmacological interest. Arch. Pharm. 354, 2100062 (2021). Bauer, M. R. et al. Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 12, 448–471 (2021). Hu, Y., Stumpfe, D. & Bajorath, J. Recent Advances in Scaffold Hopping. J. Med. Chem. 60, 1238–1246 (2017). Bian, K.-J., Kao, S.-C., Nemoto, D., Chen, X.-W. & West, J. G. Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Nat. Commun. 13, 7881 (2022). Poudel, D. P., Pokhrel, A., Tak, R. K., Shankar, M. & Giri, R. Photosensitized O 2 enables intermolecular alkene cyclopropanation by active methylene compounds. Science 381, 545–553 (2023). Garwood, J. J. A., Chen, A. D. & Nagib, D. A. Radical Polarity. J. Am. Chem. Soc. 146, 28034–28059 (2024). Sowndarya S. V, S., St. John, P. C. & Paton, R. S. A quantitative metric for organic radical stability and persistence using thermodynamic and kinetic features. Chem. Sci. 12, 13158–13166 (2021). Additional Declarations There is NO Competing Interest. Supplementary Files SIGuide.docx SI guide 24.cif X-ray CIF file for compound 24 9.cif X-ray CIF file for compound 9 61.cif X-ray CIF file for compound 61 SIsubmitted.pdf Supplementary Information 1a.cif X-ray CIF file for compound 1a Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Nature Chemistry → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6070447","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":466630558,"identity":"c3399c6f-96c4-449e-948d-bb59991e305e","order_by":0,"name":"Seung Youn Hong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYFACHhBhA+MlEK0ljXQth0nQIj8j9+Djgl/n7c0lEhg//GBIyyeoxeBGXrLxzL7biTtnJDBL9jDkWDYQ1CKRYybN23M7weBGAoM0A0OFAREOA2s5Zw/UwvybKC0MN4BaeH4cYNxwI4ENaEsOYS0GZ94YG/M2JCduOPOwzbLHII0Ih7XnGD7m+WNnb3A8+fCNHxXJRDhMIIGBgbENxGJsAFpKWAMDA/8BIPGHGJWjYBSMglEwYgEAbF84kjl7gyoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-0113-5276","institution":"Seoul National University","correspondingAuthor":true,"prefix":"","firstName":"Seung","middleName":"Youn","lastName":"Hong","suffix":""},{"id":466630559,"identity":"f14d9d1c-60fc-4d91-a682-bf2128f883b8","order_by":1,"name":"Morgan Kim","email":"","orcid":"https://orcid.org/0009-0007-8676-1394","institution":"Seoul National University","correspondingAuthor":false,"prefix":"","firstName":"Morgan","middleName":"","lastName":"Kim","suffix":""},{"id":466630560,"identity":"c798b184-838f-4bab-b300-a0bf39a1407a","order_by":2,"name":"So Yeon Ahn","email":"","orcid":"https://orcid.org/0009-0007-0034-251X","institution":"Seoul National University","correspondingAuthor":false,"prefix":"","firstName":"So","middleName":"Yeon","lastName":"Ahn","suffix":""},{"id":466630561,"identity":"cc01cf53-1533-4b2c-bc7f-0de2bb8f49de","order_by":3,"name":"Seongmin Kim","email":"","orcid":"https://orcid.org/0009-0008-3822-7178","institution":"Seoul National University","correspondingAuthor":false,"prefix":"","firstName":"Seongmin","middleName":"","lastName":"Kim","suffix":""},{"id":466630562,"identity":"144a474c-8cb3-4002-ad81-1370f66107b1","order_by":4,"name":"Junhwan Won","email":"","orcid":"","institution":"Seoul National University","correspondingAuthor":false,"prefix":"","firstName":"Junhwan","middleName":"","lastName":"Won","suffix":""},{"id":466630563,"identity":"d25321ea-c88f-41b0-8d49-d3537ad9501c","order_by":5,"name":"Dongwook Kim","email":"","orcid":"https://orcid.org/0000-0003-4432-371X","institution":"Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science","correspondingAuthor":false,"prefix":"","firstName":"Dongwook","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2025-02-20 09:20:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6070447/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6070447/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41557-025-02037-x","type":"published","date":"2026-01-07T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84056853,"identity":"c438f77b-8898-4ca5-b891-a0b192343507","added_by":"auto","created_at":"2025-06-06 09:28:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77517,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBackground and Concept.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, Significance of homologs in medicinal chemistry. \u003cstrong\u003eb\u003c/strong\u003e, Schematic representation of homologative synthesis. \u003cstrong\u003ec\u003c/strong\u003e, This work: implementation of homologative synthesis in alkene difunctionalization for accessing 1,3-difunctionlized products.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/88b5d79b81ea000fcad94cdf.png"},{"id":84058195,"identity":"065eb8d8-992b-49f9-9cd4-f65422f05344","added_by":"auto","created_at":"2025-06-06 09:44:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":91088,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReaction Development\u003c/strong\u003e. \u003cstrong\u003ea\u003c/strong\u003e, Reagent design and mechanistic challenges. \u003cstrong\u003eb\u003c/strong\u003e, Optimization study. Reactions were performed in 0.025 mmol scale, using alkene \u003cstrong\u003e2 \u003c/strong\u003e(1.0 equiv.), \u003cstrong\u003e1\u003c/strong\u003e (1.1 equiv.), and photocatalysts (5 mol%) in MeCN-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e3\u003c/sub\u003e (0.2 mL) under blue LEDs (456 nm) at 5 \u003csup\u003eo\u003c/sup\u003eC for 3 hours; the product yields were measured with \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy. \u003cstrong\u003ec\u003c/strong\u003e, Structures and electrochemical properties of the optimal catalyst and reagent with LUMO of \u003cstrong\u003e1a\u003c/strong\u003e. \u003cem\u003eE\u003c/em\u003e\u003csub\u003ep/2\u003c/sub\u003e = half-peak potential. All potentials were referenced to a saturated calomel electrode (SCE). \u003cstrong\u003ed\u003c/strong\u003e, Direct alkene-to-azetidine conversion on a 4 mmol scale. Isolated yields. TT = thianthrene.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/7d1ae639f1fd35a66c12e997.png"},{"id":84057348,"identity":"b029b435-9d4e-4128-9ca7-21017e24312d","added_by":"auto","created_at":"2025-06-06 09:36:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":78846,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReaction Scope\u003c/strong\u003e. \u003cstrong\u003ea\u003c/strong\u003e, Azetidine synthesis. \u003cstrong\u003eb\u003c/strong\u003e,\u003cstrong\u003e \u003c/strong\u003e1,3-Diazide synthesis. \u003cstrong\u003ec\u003c/strong\u003e, 1,3-Dihalide synthesis. \u003cstrong\u003ed\u003c/strong\u003e, Incorporation of oxygen, sulfur, selenium, and carbon nucleophiles. Isolated yields. Reactions conditions: alkenes (0.2 mmol), \u003cstrong\u003e1a\u003c/strong\u003e (0.22 mmol), 4CzIPN (5 mol%) in MeCN solvent at 5 \u003csup\u003eo\u003c/sup\u003eC for 3-8 hours under irradiation, then amines (0.4-0.8 mmol), bases (Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e or DIPEA) or nucleophiles at 25-80 °C for 5-13 hours. See the Supplementary Information for full experimental details and conditions. \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003eIrradiation at\u003cbr\u003e\n25 \u003csup\u003eo\u003c/sup\u003eC. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003eRun with \u003cstrong\u003e1a \u003c/strong\u003e(0.2 mmol).\u003cstrong\u003e \u003c/strong\u003e\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003eRun with \u003cstrong\u003e1a\u003c/strong\u003e (0.44 mmol) and amine (1.6 mmol). r.s. = regiospecificity.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/6bdf5631d27f1a6d506cc990.png"},{"id":84056855,"identity":"6bab08bc-dc00-450d-88a6-872a6fbbc404","added_by":"auto","created_at":"2025-06-06 09:28:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":100340,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthetic Applications\u003c/strong\u003e. \u003cstrong\u003ea\u003c/strong\u003e, Late-stage applications. \u003cstrong\u003eb\u003c/strong\u003e, Divergent Synthesis of Tebanicline derivatives. \u003cstrong\u003ec\u003c/strong\u003e, Scaffold hopping of piperidine-containing drugs. \u003cstrong\u003ed\u003c/strong\u003e, Access to one-carbon higher homologs of compounds previously obtained through alkene difunctionalization methods. Diazidation retrieved from Ref 47. Aziridination retrieved from Ref 7.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/8364e5dde4dd28dd97cbf43c.png"},{"id":84056870,"identity":"df5f17fd-0495-407b-9c2e-75ff7958b5a9","added_by":"auto","created_at":"2025-06-06 09:28:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":164131,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanistic Considerations.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, Proposed pathway. \u003cstrong\u003eb\u003c/strong\u003e, Computed structure of α-thianthrenium methyl radical\u003cstrong\u003e Int1\u003c/strong\u003e and \u003cstrong\u003eInt1E \u003c/strong\u003eand\u003cstrong\u003e \u003c/strong\u003econceptual molecular orbital diagram. \u003cstrong\u003ec\u003c/strong\u003e, Radical polarity and stability. Radical polarity retrieved from Ref 49. Radical stability score (RSS) calculated according to Ref 50; %\u003cem\u003eV\u003c/em\u003e\u003csub\u003ebur\u003c/sub\u003e + 50 × (1 − max. spin). \u003cem\u003eω\u003c/em\u003e = global electrophilicity index. %\u003cem\u003eV\u003c/em\u003e\u003csub\u003ebur\u003c/sub\u003e = percent buried volume. max. spin = maximum spin density. ∆G in kcal mol\u003csup\u003e–1\u003c/sup\u003e.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/3b4f6f374e1e78c807acfe4e.png"},{"id":99766615,"identity":"a15544f5-c440-4dbc-adb5-556a61701c0e","added_by":"auto","created_at":"2026-01-08 08:13:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1099303,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/bd8d2636-3f16-4d46-86e2-322f0f7d0ad4.pdf"},{"id":84057346,"identity":"461e8af3-57dc-4859-b2ae-d20c46f56f6c","added_by":"auto","created_at":"2025-06-06 09:36:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14847,"visible":true,"origin":"","legend":"SI guide","description":"","filename":"SIGuide.docx","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/bbeea7269f5a2266ad7878dc.docx"},{"id":84057349,"identity":"1a874dfb-ffab-40ec-b9e7-acfa16230650","added_by":"auto","created_at":"2025-06-06 09:36:52","extension":"cif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":318589,"visible":true,"origin":"","legend":"X-ray CIF file for compound 24","description":"","filename":"24.cif","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/1f319d09c89083b263e9fa2e.cif"},{"id":84058196,"identity":"02bf1793-aac7-4a26-b945-295b673fad65","added_by":"auto","created_at":"2025-06-06 09:44:52","extension":"cif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":435328,"visible":true,"origin":"","legend":"X-ray CIF file for compound 9","description":"","filename":"9.cif","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/61c8d21ae10b4e9e2af44d52.cif"},{"id":84057352,"identity":"253be250-0f2d-4c7c-8a63-b6536e29441b","added_by":"auto","created_at":"2025-06-06 09:36:52","extension":"cif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1020344,"visible":true,"origin":"","legend":"X-ray CIF file for compound 61","description":"","filename":"61.cif","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/7899c5aabc720748e98f3b10.cif"},{"id":84056877,"identity":"80def9e7-5526-4871-bb68-bef6ba36bac0","added_by":"auto","created_at":"2025-06-06 09:28:52","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":18776443,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SIsubmitted.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/e16f141a788539097feb2208.pdf"},{"id":84056868,"identity":"8e894723-9438-474a-8111-ce6d22e64687","added_by":"auto","created_at":"2025-06-06 09:28:52","extension":"cif","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":1126761,"visible":true,"origin":"","legend":"X-ray CIF file for compound 1a","description":"","filename":"1a.cif","url":"https://assets-eu.researchsquare.com/files/rs-6070447/v1/65a1cda7c8fa0f65d39522ee.cif"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Homologative Alkene Difunctionalization","fulltext":[{"header":"Main","content":"\u003cp\u003eHomologous series\u0026mdash;compounds sharing identical functionality but differing in the number of repeating methylene (\u0026minus;\u0026thinsp;CH₂\u0026minus;) units\u0026mdash;have long been mainstay targets in drug design and discovery\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Subtle variations in carbon chain lengths or ring sizes can profoundly alter molecular dynamics and physicochemical behaviors, imparting distinct pharmacological attributes to each member of these chemical families\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In particular, one-carbon elongation of lead compounds has been widely recognized for its beneficial impacts on desired activity such as binding affinity and potency and, as a corollary, has become a routine practice in drug discovery campaigns (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea)\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Practically, however, preparing homologs is often non-trivial, as the structural similarity does not necessarily translate into the comparable synthetic accessibility. For instance, aziridines and azetidines are both privileged \u003cem\u003eN\u003c/em\u003e-heterocycles that differ only in ring size, while they are synthesized through entirely different synthetic schemes; alkene aziridination\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e or nucleophilic ring-closure\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e for aziridines versus lactam reduction\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, strain-release transformations\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, or [2\u0026thinsp;+\u0026thinsp;2] cycloaddition\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e for azetidines. Such disparity necessitates orthogonal sets of starting materials and reaction plans, imposing a substantial synthetic burden.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOne prominent strategy to this challenge is homologation, a process that inserts a methylene component into a preformed bond to generate the next homolog in the series\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. To implement the carbon elongation sequence, existing methods primarily rely on specific functional handles on substrates, often in conjugation with high-energy C1-delivering reagents\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The prevailing exemplars in this regard are the carbon-extension functionalization of carbonyl compounds\u003csup\u003e\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and boron-mediated homologation\u003csup\u003e\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. On the contrary, further generalization to other compound classes has lagged behind. This substrate specificity of current homologation techniques underscores the clear need for an alternative solution. A conceptually distinct approach to accessing homologs would be incorporating a single-carbon unit during the assembly of building blocks, rather than post-modifying established molecular frameworks. This \u0026ldquo;homologative synthesis\u0026rdquo; allows substrates originally primed for parent compound synthesis (easy) to be harnessed for the preparation of one-carbon-extended analogs (difficult), which require lengthy processes or were previously inaccessible (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Thus, establishing this shortcut from common starting points effectively bridges the synthetic gap between homologs and augments the technical capacity to explore structure-activity relationships. Despite its readily conceivable potential, such transformations that ideally leverage abundant substructures remain largely untapped.\u003c/p\u003e \u003cp\u003eAlkenes are among the most widely used building blocks in synthesis\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, readily undergoing 1,2-difunctionalization via classical dihalogenations as well as transition-metal-catalysed\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, photochemical\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, and electrochemical addition reactions\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, left). Consequently, vicinal motifs frequently appear in a myriad of important organic commodities. By contrast, their homologs with 1,3-disubstitution patterns are significantly underrepresented due to the lack of reliable methods for introducing two functional groups at distal positions. While a handful of 1,3-difunctionalizations have been disclosed based on chain-walking process, they invariably require specialized alkenes to achieve regioselectivity\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Very recently, Maulide and coworkers further advanced this nascent field by utilizing charge relocation in a Friedel\u0026ndash;Crafts-type reaction of unactivated alkenes\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, this methodology is inherently limited to acylation.\u003c/p\u003e \u003cp\u003eHerein, we present a distinct strategy of homologative synthesis, in which the synthetic scheme of alkene difunctionalization is redirected towards 1,3-difunctionalization with a one-carbon elongation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, right). We have identified a new class of a methylene dication (CH₂\u0026sup2;⁺) reagent capable of transforming alkenes into a 1,3-dication synthon, which serve as points for nucleophilic entrapment with complete regiochemical fidelity under operationally simple, one-pot conditions. While the majority of the reported methods for alkene difunctionalization furnish vicinal compounds, our approach enables the formal insertion of a single carbon unit between two reactive sites on alkenes, granting unified access to their underexplored homologs such as azetidines, 1,3-diazides, and 1,3-dihalides from various alkene/nucleophile substrate pairs.\u003c/p\u003e\n\u003ch3\u003eReaction development\u003c/h3\u003e\n\u003cp\u003eIn pursuing the proposed homologative alkene difunctionalization, two key components must be addressed: (i) the identification of an appropriate CH₂\u0026sup2;⁺ equivalent and (ii) the development of an efficient transfer method. We hypothesized that halomethylsulfonium salts (\u003cb\u003e1\u003c/b\u003e) could be ideally suited for grafting functional handles (halogen and sulfonium motifs) at 1,3-positions via photocatalytic atom transfer radical addition\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea right, the designed process is believed to proceed through α-sulfonium methyl radicals. Compared to the extensive body of electrophilic C-centered radicals bearing multiple electron-withdrawing groups, the sulfonium substituent alone may impart the requisite polarity. Despite their virtually unknown synthetic use, these putative species could, in principle, be generated from halomethylsulfonium salts (1) through mesolytic cleavage of C\u0026ndash;X bonds (X\u0026thinsp;=\u0026thinsp;halogens). However, a fundamental challenge in this seemingly simple approach lies in the propensity of C\u0026ndash;S bonds for facile fragmentation, which has been noted under nucleophilic\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, photolytic\u003csup\u003e\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, and transition-metal catalytic conditions\u003csup\u003e\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, left). As a result, the general consensus is that C\u0026ndash;S bond in sulfonium salts is a notional strategic site for retrosynthetic disconnection\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Moreover, as the targeting incipient product itself contains a fragile C\u0026ndash;S linkage, product degradation through conventional pathways poses an additional challenge in reaction design.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWith these considerations in mind, we commenced our investigation by evaluating a series of halomethylsulfonium salts \u003cb\u003e1\u003c/b\u003e in the model reaction with 4-phenyl-1-butene \u003cb\u003e2\u003c/b\u003e under photocatalytic conditions (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). This class of compounds can be readily prepared in a single step and isolated as bench-stable solids\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e (Fig. \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). After thorough optimization, iodomethylthianthrenium salt (\u003cb\u003e1a\u003c/b\u003e) was identified to be most promising, affording the desired 1,3-dielectrophile \u003cb\u003e3a\u003c/b\u003e in nearly quantitative yield (95%, Entry 1). The catalytic system comprised of 5 mol% of carbazole-based photocatalyst (4CzIPN) in acetonitrile solvent at 5\u0026deg;C was optimal and operated efficiently without the need for external additive, highlighting the mild and redox-neutral nature of the process. The identity of the CH₂\u0026sup2;⁺ donors was found to be crucial for the success of the reaction; brominated (\u003cb\u003e1b\u003c/b\u003e, Entry 2) and chlorinated analogs (\u003cb\u003e1c\u003c/b\u003e, Entry 3) were unproductive. Replacing thianthrene with other sulfide moieties resulted in either no reaction (dibenzothiophene \u003cb\u003e1d\u003c/b\u003e, Entry 4) or significantly diminished yields (diphenylsulfide \u003cb\u003e1e\u003c/b\u003e, Entry 5). Control experiments confirmed that none of the surveyed transition-metal-based photocatalysts outperform 4CzIPN (see Supplementary Information for Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). In accord with the superiority of reagent \u003cb\u003e1a\u003c/b\u003e, it exhibited the least negative half-wave potentials [\u003cem\u003eE\u003c/em\u003e\u003csub\u003ep/2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.86 V versus SCE], implying facile electron transfer with 4CzIPN (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). More strikingly, \u003cb\u003e1a\u003c/b\u003e features a LUMO with prominent antibonding character between the p(C1) and p(I) orbitals, rendering the C\u0026ndash;I bond preferentially reactive over the C\u0026ndash;S bond in the key bond-breaking event.\u003c/p\u003e \u003cp\u003eHaving established the efficient method to generate presumably reactive 1,3-dielectrophiles, we then explored their substitution chemistry (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). Given the growing demands within biomedical research for azetidines\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e, the construction of this privileged scaffold would be an enticing possibility. Compared to their homologs\u0026mdash;i.e. aziridines, pyrrolidines, and piperidines\u0026mdash;azetidines exhibit conspicuous pharmacokinetic profile\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, but their accessibility from diverse and readily available starting materials is far more limited. A notable exception is the recent work by Schindler on aza Patern\u0026ograve;-B\u0026uuml;chi reaction between photoexcited styrenes and imines\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Complementally, we found that the photocatalytic assembly of unactivated alkene \u003cb\u003e2\u003c/b\u003e with 1.1 equivalent of \u003cb\u003e1a\u003c/b\u003e, followed by addition of a modest excess of \u003cem\u003ep\u003c/em\u003e-methoxyaniline and sodium carbonate, led to the isolation of azetidine \u003cb\u003e4\u003c/b\u003e in excellent yield (85%). The overall transformation could conveniently be performed in a one-pot manner on a preparative scale (4.0 mmol). The primary byproduct, thianthrene (\u003cb\u003eTT\u003c/b\u003e), was recovered in 99% yield and could be recycled back to reagent \u003cb\u003e1a\u003c/b\u003e as needed.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eReaction scope\u003c/h2\u003e \u003cp\u003eThe generality of the homologative alkene difunctionalization was explored, and the results are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. A wide variety of unactivated alkenes were engaged in homologative coupling with p-methoxyaniline as a representative nitrogen source, providing structurally diverse azetidines in high yields (\u003cb\u003e6\u003c/b\u003e\u0026ndash;\u003cb\u003e24\u003c/b\u003e). The \u003cem\u003ep\u003c/em\u003e-methoxyphenyl group in the obtained product 4 could be readily deprotected to obtain \u003cem\u003eNH\u003c/em\u003e-azeditine \u003cb\u003e5\u003c/b\u003e in 89% yield. Ester (\u003cb\u003e7\u003c/b\u003e, \u003cb\u003e8\u003c/b\u003e), phthalimide (\u003cb\u003e9\u003c/b\u003e), medicinally relevant piperidine (\u003cb\u003e10\u003c/b\u003e), and sulfonamide (\u003cb\u003e11\u003c/b\u003e) were accommodated by the transformation. Hydroxyl group (\u003cb\u003e12\u003c/b\u003e) is well compatible without explicit protection. While steric perturbations in the substrate affected the reaction efficiency to some extent (\u003cb\u003e13\u003c/b\u003e), the present method displays broad applicability across alkenes with electronically varied substituents. In addition to unactivated substrates, styrene derivatives underwent the desired azetidination smoothly (\u003cb\u003e14\u003c/b\u003e\u0026minus;\u003cb\u003e17\u003c/b\u003e). To our surprise, the present system is also amenable to functionalization of electron-deficient alkenes, affording α-ester azetidines (\u003cb\u003e18\u003c/b\u003e\u0026minus;\u003cb\u003e21\u003c/b\u003e). These observations run counter to the general paradigm dictated by radical polarity effects and underpins the unprecedented ambiphilic behavior of the presupposed α-thianthrenium methyl radical (\u003cem\u003evide infra\u003c/em\u003e). When alkenyl and alkynyl groups were present at the opposite terminal positions, alkyne-bearing azetidine \u003cb\u003e22\u003c/b\u003e was formed with no detectable signs of the chemoisomeric product. Subjecting 1,4-pentadiene to the reaction resulted in monoazetidination as evidenced by the product \u003cb\u003e23\u003c/b\u003e. The selectivity observed in this system may beckon as the retained C\u0026minus;C multiple bonds permits further derivatization. Relatedly, by adding doubled amount of the reaction components, 1,9-decadiene was converted into a doubly azetidinated product \u003cb\u003e24\u003c/b\u003e in 47% yield.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e25 \u003csup\u003eo\u003c/sup\u003eC. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003eRun with \u003cb\u003e1a\u003c/b\u003e (0.2 mmol). \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003eRun with \u003cb\u003e1a\u003c/b\u003e (0.44 mmol) and amine (1.6 mmol). r.s. = regiospecificity.\u003c/p\u003e \u003cp\u003eWith respect to the amine-coupling partner, the electronic variations on the phenyl group had minimal impact on reaction efficiency (\u003cb\u003e25\u003c/b\u003e\u0026minus;\u003cb\u003e29\u003c/b\u003e). Arylamines bearing meta- and sterically congested ortho-substituent produced the corresponding azetidines (\u003cb\u003e30\u003c/b\u003e\u0026minus;\u003cb\u003e32\u003c/b\u003e). In the presence of reactive functional groups, such as boronic ester (\u003cb\u003e29\u003c/b\u003e), pyridine (\u003cb\u003e33\u003c/b\u003e), and phenol moieties (\u003cb\u003e34\u003c/b\u003e), the desired azetidination took place without difficulty. Pleasingly, our protocol extended to both primary and secondary alkylamines under slightly modified conditions (2.0\u0026ndash;4.0 equiv. of alkylamines and either Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e or DIPEA base), yielding sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e-rich azetidine scaffolds (\u003cb\u003e35\u003c/b\u003e\u0026minus;\u003cb\u003e41\u003c/b\u003e). Heterocycles, including thiophene (\u003cb\u003e37\u003c/b\u003e), NH-indole (\u003cb\u003e38\u003c/b\u003e), and oxetane (\u003cb\u003e41\u003c/b\u003e), could be incorporated. However, the use of tertiary alkylamines was unsuccessful (Fig. \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe reaction is not limited to the construction of 4-membered rings; other nucleophiles could be incorporated to access a diverse array of linear 1,3-difunctionalized products (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb). For instance, the photocatalytic method, followed by the addition of sodium azide gave 1,3-diazide \u003cb\u003e42\u003c/b\u003e, a key intermediate for useful 1,3-diamines, in excellent yield. The reaction conditions were tolerant of furan (\u003cb\u003e43\u003c/b\u003e), piperidine (\u003cb\u003e44\u003c/b\u003e), and benzyl ether (\u003cb\u003e45\u003c/b\u003e). As with azetidination, styrene (\u003cb\u003e46\u003c/b\u003e) and acrylate (\u003cb\u003e47\u003c/b\u003e) proved suitable for the desired diazidation.\u003c/p\u003e \u003cp\u003eThe repertoire of this current tactic could be extended beyond nitrogen nucleophiles, beginning with 1,3-dihalide synthesis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). While classical synthetic procedures require multistep sequences (lengthy preparation of 1,3-diol precursor, mesylation, and halide displacement), homologative coupling between alkenes and inexpensive halide sources streamlines access to 1,3-dibromides (\u003cb\u003e48\u003c/b\u003e), dichlorides (\u003cb\u003e49\u003c/b\u003e), and diiodides (\u003cb\u003e50\u003c/b\u003e). Given that the photocatalytically generated intermediate possesses two distinct electrophilic sites, regiospecific substitution could be envisioned. Indeed, the primary thianthrenium group could be selectively substituted with either bromide or chloride, while retaining the secondary iodide position, enabling the synthesis of unsymmetrical dihalides with perfect regiospecificity (\u003cb\u003e51\u003c/b\u003e and \u003cb\u003e52\u003c/b\u003e). To generalize the concept further, cesium acetate was employed as an oxygen donor, transforming alkene substrate into 1,3-dioxygenated product in one pot (\u003cb\u003e53\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). Sulfur and seleniums were introduced at the 1,3-positions utilizing potassium thiocyanate, thioacetate, and diphenyl diselenide as external nucleophiles, respectively (\u003cb\u003e54\u003c/b\u003e\u0026minus;\u003cb\u003e56\u003c/b\u003e). Furthermore, sodium cyanide showed promise as a viable carbon source, delivering \u003cb\u003e57\u003c/b\u003e in good yield.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSynthetic applications\u003c/h3\u003e\n\u003cp\u003eThe broad functional group tolerance and high reactivity prompted us to explore the applicability of the present methods in more complex settings (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). Under the standard conditions, alkenes derived from medicines, such as Ezetimibe and Ibuprofen, were readily converted into the corresponding azetidines \u003cb\u003e58\u003c/b\u003e and \u003cb\u003e59\u003c/b\u003e, respectively. The azetidine moiety could be introduced into biorelevant scaffolds, including monosaccharide \u003cb\u003e60\u003c/b\u003e and Probenecid (\u003cb\u003e61\u003c/b\u003e) analogues. In parallel, other procedures also provide an efficient means of late-stage functionalization of bioactive substrates. As an illustrative example, the diazidation of Theobromine and Estrone derivatives afforded the desired 1,3-diazides \u003cb\u003e62\u003c/b\u003e and \u003cb\u003e63\u003c/b\u003e. Bicalutamide-containing 1,3-dihalides \u003cb\u003e64\u003c/b\u003e were also prepared through homologative alkene dibromination.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo further demonstrate the utility of this transformation in the context of pharmaceutical chemistry, we examined the capability of library diversification by the collective synthesis of structural derivatives of an azetidine pharmacophore (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). A suite of \u003cem\u003eN\u003c/em\u003e-substituted derivatives of tebanicline, a synthetic nicotinic analgesic, could be accessed in a divergent and modular fashion (\u003cb\u003e66\u003c/b\u003e\u0026ndash;\u003cb\u003e68\u003c/b\u003e) when three primary amines were allowed to couple with alkene \u003cb\u003e65\u003c/b\u003e, which can be readily prepared from 2-chloro-5-hydroxypyridine. Considering the extensive availability of primary amines from commercial vendors, we envision that the protocol could provide additional versatility for the drug modification through fragment coupling.\u003c/p\u003e \u003cp\u003eIn contemporary drug design, the modification of core structures in lead compounds while preserving peripheral substituents is a particularly sought-after strategy by medicinal chemists\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. We applied our strategy to execute such isosteric replacements, surgically replacing the piperidine scaffold in established drugs with a smaller azetidine ring (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec). Flecainide is an approved antiarrhythmic agent marketed under the brand name Tambocor\u0026reg;. Using the homologative procedure, its azetidine analog \u003cb\u003e70\u003c/b\u003e was successfully prepared from a commercial source in two steps. We next targeted perhexiline, a prophylactic antianginal agent in the scaffold-hopping effort. Starting from the dicarbohexyl-substiutted alkene \u003cb\u003e71\u003c/b\u003e, azetidination led to the two-carbon-shorter homolog \u003cb\u003e72\u003c/b\u003e in 48% yield.\u003c/p\u003e \u003cp\u003eBy virtue of the fact that both our homologative and previously reported vicinal alkene difunctionalization protocols utilize common starting materials (alkenes and nucleophiles), these substrates can be conveniently reused to prepare one-carbon homologs of vicinal products prepared by the existing methods (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed). For instance, the established photocatalytic protocol permits the vicinal diazidation (\u003cb\u003e74\u003c/b\u003e) of ibuprofen-derived alkene \u003cb\u003e73\u003c/b\u003e with sodium azide\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. By contrast, our method enabled the formal elongation of the carbon chain spacer between azide functionalities (\u003cb\u003e75\u003c/b\u003e). Similarly, naturally occurring alkaloid \u003cb\u003e78\u003c/b\u003e from Petasites japonicus was previously synthesized based on the electrochemical coupling between alkenyl substrate \u003cb\u003e76\u003c/b\u003e and cyclohexylamine \u003cb\u003e77\u003c/b\u003e\u003csup\u003e7\u003c/sup\u003e. Instead, by applying homologative alkene difunctionalization, the same ingredients underwent cyclization to afford the ring-extended product \u003cb\u003e79\u003c/b\u003e in 48% yield.\u003c/p\u003e\n\u003ch3\u003eMechanistic considerations\u003c/h3\u003e\n\u003cp\u003eA plausible mechanism, supported by experimental and computational clues, is outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea (see Fig. S30 for detailed discussions). Upon blue LED irradiation, the photocatalyst (\u003cb\u003ePC\u003c/b\u003e) is excited, and subsequently quenched by the reagent 1a via single electron transfer, with a quenching rate constant (\u003cem\u003ek\u003c/em\u003e\u003csub\u003eq\u003c/sub\u003e) of 8.6 x 10\u003csup\u003e7\u003c/sup\u003e M\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003es\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (Fig. S15). The reduced species [\u003cb\u003e1a\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026bull;\u0026minus;\u003c/b\u003e\u003c/sup\u003e] evolves by a unimolecular fragmentation to give α-thianthrenium methyl radical \u003cb\u003eInt1\u003c/b\u003e and iodide ion. The ensuing radical addition traverses \u003cb\u003eTS1\u003c/b\u003e with a low energy barrier of 9.2 kcal/mol. The radical adduct \u003cb\u003eInt2\u003c/b\u003e would abstract an iodine atom from an additional equivalent of 1a via transition state \u003cb\u003eTS2\u003c/b\u003e (ΔG\u003csup\u003e\u0026Dagger;\u003c/sup\u003e =13.3 kcal/mol), furnishing 3-iodo-1-alkyl thianthrenium salt \u003cb\u003e3a\u003c/b\u003e. The coproduction of radical Int1 can gate another propagation cycle. Apart from the chain process, the radical cation [\u003cb\u003ePC\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026bull;+\u003c/b\u003e\u003c/sup\u003e] formed during initiation may convert back to its original state (\u003cb\u003ePC\u003c/b\u003e) by oxidizing the initially generated iodide ions to I₂, as proposed by Giri and coworkers\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. Thus, photocatalytic initiation could be sustained during the course of the reaction, as witnessed by the quantum yield measured to be less than 1 (Fig. S7).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe sought to elucidate the fundamental aspects of the α-thianthrenium methyl radical that govern its unusual reactivity. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb, two conformers can exist, with the \u0026bull;CH₂ group favoring the axial position (\u003cb\u003eInt1\u003c/b\u003e) over the equatorial position (\u003cb\u003eInt1E\u003c/b\u003e) by 3.6 kcal/mol. This conformational preference can be traced to key stereoelectronic interactions between the carbon radical and thianthrenium fragments. The axial orientation (\u003cb\u003eInt1\u003c/b\u003e) benefits from resonance donation of the sulfur (S1) lone pair to the radical center (C1), reminiscent of α-heteroatom effect. The spatial proximity between the secondary sulfur atom (S2) and the corresponding carbon center induces additional through-space radical delocalization in \u003cb\u003eInt1\u003c/b\u003e. Conversely, the equatorial conformation orients the H-C1-H plane perpendicular to the thianthrene moiety to mitigate allylic strain (A\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e), precluding such stabilizing interactions. Taken together, the SOMO of \u003cb\u003eInt1\u003c/b\u003e is best described as the out-of-phase overlap between p\u003csub\u003ex\u003c/sub\u003e(C1) and p\u003csub\u003ex\u003c/sub\u003e(S1), with secondary mixing from the p\u003csub\u003ez\u003c/sub\u003e(S2) orbital. Evidently, the computed SOMO of \u003cb\u003eInt1\u003c/b\u003e lies at a higher energy level of \u0026minus;7.4 eV compared to that of \u003cb\u003eInt1E\u003c/b\u003e (\u0026minus;8.2 eV), indicating greater stability at the expense of electrophilicity.\u003c/p\u003e \u003cp\u003eFor a deeper understanding of the effect of α-thianthrenium substitution, we interrogated quantitative metrics describing radical philicity and stability (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec). Inspired by a recent report by Nagib\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, global electrophilicity index (GEI, ω) was selected as a measure of radical polarity. The radical stability score (RSS)\u0026mdash;formulated based on two molecular descriptors: percent buried volume and maximum spin density\u0026mdash;was chosen to encapsulate both kinetic and thermodynamic considerations for radical stability\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Through extensive benchmarking, the ω and RSSs for \u003cb\u003eInt1\u003c/b\u003e and \u003cb\u003eInt1E\u003c/b\u003e, along with 354 carbon-centered radicals commonly encountered in chemical synthesis, could be evaluated and mapped onto a two-dimensional diagram in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec. Consistent with the FMO analysis, the extent of electronic delocalization varies with conformation: \u003cb\u003eInt1\u003c/b\u003e (ω\u0026thinsp;=\u0026thinsp;2.31 eV, RSS\u0026thinsp;=\u0026thinsp;58.9) is predicted to be more stable and less electrophilic than \u003cb\u003eInt1E\u003c/b\u003e (ω\u0026thinsp;=\u0026thinsp;2.67 eV, RSS\u0026thinsp;=\u0026thinsp;54.2). The Mulliken spin density plot evidences this trend further. The spin density in \u003cb\u003eInt1\u003c/b\u003e is distributed over the carbon (C1: 0.88) and two sulfur atoms (S1: 0.22, S2: 0.05), whereas in \u003cb\u003eInt1E\u003c/b\u003e, the spin is predominantly localized on the carbon (C1: 1.01). Furthermore, in head-to-head comparisons with other radicals, \u003cb\u003eInt1\u003c/b\u003e retains a superior electrophilic character, distinguishing it from typical nucleophilic α-heteroatom (nitrogen, oxygen, and halogens) radicals and closely resembling thedicarbonyl radical, which is known for its high reactivity in radical addition. These datasets substantiate that the intricate balance between electron withdrawal and spin delocalization conferred by the thianthrenium moiety endows \u003cb\u003eInt1\u003c/b\u003e with optimal stability and polarity, enabling our desired process to proceed with excellent efficiency and minimal electronic bias.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results presented here constitute a general platform that reroutes conventional alkene difunctionalization, elaborating 1,3-difunctionalized products with high functional group compatibility. These findings exemplify an innovative advancement in reagent design that deploys a homologative synthetic logic at the forefront of chemical synthesis, diversifying the synthetic use of common substrates and unlocking previously inaccessible product spaces with vast potential applications in both academia and industry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We thank Prof. Sukbok Chang (KAIST), Prof. Chulbom Lee (SNU), and Prof. Sangwon Seo (DGIST) for helpful suggestions. We also acknowledge the groups of Chulbom Lee, Hong Geun Lee, and Eunsung Lee for sharing their chemical inventories. Additionally, we thank Mr. Seonghyun Min and Prof. Jaeyune Ryu (SNU) for their assistance with the electrochemical measurements. This work was supported by the Creative-Pioneering Researchers Program from Seoul National University, National Research Foundation (NRF) grant funded by the Korean government (MSIT) [no. RS-2023-00214144, no. RS-2024-00403103, and no. RS-2024-00409659], the Global-LAMP Program of NRF grant funded by the Ministry of Education (no. RS-2023-00301976) and POSCO Science Fellowship of POSCO TJ Park Foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e S.Y.H., M.K., S.Y.A., and S.K. designed the project and wrote the manuscript. M.K., S.Y.A., S.K., and J.W. carried out the experiments. S.Y.H. conducted the DFT calculations. D.K. performed the X-ray diffraction analysis. M.K., S.Y.A. and S.K. contributed equally.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e X-ray data for compounds \u003cstrong\u003e1a\u003c/strong\u003e, \u003cstrong\u003e9\u003c/strong\u003e, \u003cstrong\u003e24\u003c/strong\u003e, and \u003cstrong\u003e61\u0026nbsp;\u003c/strong\u003eare freely available at the Cambridge Crystallographic Data Centre under deposition numbers 2416215-2416218. All other data are available in the main text or the Supplementary Information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWermuth, C. 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A quantitative metric for organic radical stability and persistence using thermodynamic and kinetic features. Chem. Sci. 12, 13158\u0026ndash;13166 (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6070447/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6070447/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSystematic evaluation of homologous series plays a pivotal role in synthetic and medicinal chemistry\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Despite their structural resemblance, the preparation of homologs often requires individual synthetic planning tailored to distinct precursors and reactions. Here, we introduce a conceptually new strategy that integrates single-carbon insertion into established methods, specifically redirecting alkene vicinal difunctionalization towards direct routes for 1,3-difunctionalized products. This transformation is enabled by a designer methylene dication reagent, iodomethylthianthrenium salt, which facilitates the photocatalytic conversion of alkenes into linchpin 1,3-dielectrophilic intermediates, allowing seamless incorporation of nucleophiles at distal positions. Mechanistic studies suggest that the reaction proceeds via an α-thianthrenium methyl radical with unusual ambiphilic reactivity governed by multiple stereoelectronic effects. This approach shows high compatibility in pharmaceutical and late-stage settings, providing broad access to diverse 1,3-difunctionalized products, including azetidines, 1,3-diazides, and 1,3-dihalides. This work establishes \u0026ldquo;homologative alkene difunctionalization\u0026rdquo; as a powerful platform for repurposing ubiquitous alkenes as meritorious synthetic intermediates to unveil heretofore unknown 1,3-substitution patterns.\u003c/p\u003e","manuscriptTitle":"Homologative Alkene Difunctionalization","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-06 09:28:47","doi":"10.21203/rs.3.rs-6070447/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-chemistry","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nchem","sideBox":"Learn more about [Nature Chemistry](http://www.nature.com/nchem/)","snPcode":"","submissionUrl":"","title":"Nature Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"713df5cd-895d-49af-ac2b-c55aa53f0730","owner":[],"postedDate":"June 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":49545289,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":49545290,"name":"Physical sciences/Chemistry/Catalysis/Photocatalysis"}],"tags":[],"updatedAt":"2026-01-08T08:13:21+00:00","versionOfRecord":{"articleIdentity":"rs-6070447","link":"https://doi.org/10.1038/s41557-025-02037-x","journal":{"identity":"nature-chemistry","isVorOnly":false,"title":"Nature Chemistry"},"publishedOn":"2026-01-07 05:00:00","publishedOnDateReadable":"January 7th, 2026"},"versionCreatedAt":"2025-06-06 09:28:47","video":"","vorDoi":"10.1038/s41557-025-02037-x","vorDoiUrl":"https://doi.org/10.1038/s41557-025-02037-x","workflowStages":[]},"version":"v1","identity":"rs-6070447","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6070447","identity":"rs-6070447","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}