One Stone, Three Birds: Synthesis of Multifunctional Lactam-Substituted Alkyl Sulfones Using Rongalite as Electron Donor, Sulfone Source, and C1 Synthon

One Stone, Three Birds: Synthesis of Multifunctional Lactam-Substituted Alkyl Sulfones Using Rongalite as Electron Donor, Sulfone Source, and C1 Synthon | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 23 November 2025 V1 Latest version Share on One Stone, Three Birds: Synthesis of Multifunctional Lactam-Substituted Alkyl Sulfones Using Rongalite as Electron Donor, Sulfone Source, and C1 Synthon Authors : Hui-Ying Ren , Miao Wang 0009-0003-5143-7448 [email protected] , Shan Jiang , Zi-Xiang Bin , Xiao-Qing Li , and Bang Tun Zhao Authors Info & Affiliations https://doi.org/10.22541/au.176389933.35847480/v1 153 views 104 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Substantial progress has been made in the single and dual functionalization of the 3,3-difluoro- γ -lactam radical for the synthesis of related derivatives. However, achieving its triple functionalization presents a significant challenge, primarily due to difficulties in sequential control, site selectivity, and competing pathways. Herein, we report a novel rongalite-mediated triple functionalization of N -allyl bromodifluoroacetamides with electron-rich heteroarenes via a sulfonylation/methylation/heteroarylation sequence, enabling efficient access to multifunctional lactam-substituted alkyl sulfones. This protocol operates under metal-, oxidant-, and photocatalyst-free conditions, demonstrating high efficiency and broad substrate scope. Furthermore, the protocol facilitates late-stage modification of indole scaffolds derived from commercial pharmaceuticals, including ibuprofen, aspirin, and indomethacin. Mechanistic studies support a radical pathway, underscoring the triple role of rongalite as a super electron donor for reaction initiation, a “SO 2 ” source, and a “C1” precursor. Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.202500XXX One Stone, Three Birds: Synthesis of Multifunctional Lactam-Substituted Alkyl Sulfones Using Rongalite as Electron Donor, Sulfone Source, and C1 Synthon Hui-Ying Ren, a,b Miao Wang,* , a Shan Jiang, a Zi-Xiang Bin, a Xiao-Qing Li, a Bang-Tun Zhao* , a a College of Chemistry and Chemical Engineering, Key Laboratory of Fuction-Oriented Porous Materials of Henan Province, Luoyang Normal University, Luoyang, Henan 471934, P. R. China b College of Chemistry, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China Lactam-substituted alkyl Sulfones |Rongalite |Sulfone Source |C1 Synthon |3,3-Difluoro-γ-lactam radical |Triple functionalization |Radical cascade reaction| Cleavage reaction Comprehensive Summary Substantial progress has been made in the single and dual functionalization of the 3,3-difluoro- γ -lactam radical for the synthesis of related derivatives. However, achieving its triple functionalization presents a significant challenge, primarily due to difficulties in sequential control, site selectivity, and competing pathways. Herein, we report a novel rongalite-mediated triple functionalization of N -allyl bromodifluoroacetamides with electron-rich heteroarenes via a sulfonylation/methylation/heteroarylation sequence, enabling efficient access to multifunctional lactam-substituted alkyl sulfones. This protocol operates under metal-, oxidant-, and photocatalyst-free conditions, demonstrating high efficiency and broad substrate scope. Furthermore, the protocol facilitates late-stage modification of indole scaffolds derived from commercial pharmaceuticals, including ibuprofen, aspirin, and indomethacin. Mechanistic studies support a radical pathway, underscoring the triple role of rongalite as a super electron donor for reaction initiation, a “SO₂” source, and a “C1” precursor. Background and Originality Content Difluoromethylene (CF₂) group, a versatile fluorinated motif that acts as a bioisostere for hydroxyl, thiol, and carbonyl groups, [1] effectively modulates molecular properties such as lipophilicity, metabolic stability, and bioavailability. [2] A notable application is the incorporation CF 2 group into the small-molecule PD-1/PD-L1 inhibitor BMS-1002, which significantly enhanced its anticancer potency. [3] Meanwhile, the γ-lactam scaffold is widely recognized as a privileged structure in pharmaceuticals and natural products, exhibits diverse bioactivities. [4] Introducing the CF₂ group into γ-lactam scaffold thus presents a promising strategy for expanding structural diversity and biological functionality. [5] This strategy is powerfully exemplified by the 3,3-difluoro-γ-lactam subunit, which demonstrates a broad spectrum of pharmacological activities, including agonism toward the androgen receptor (AR) and the EP4 receptor, as well as antagonism of the corticotropin-releasing factor (CRF) receptor (Scheme 1) . [6] Given their significant biological and pharmacological value, the synthesis of 3,3-difluoro-γ-lactams has long attracted considerable research interest. [7] Conventional approaches typically involve stepwise fluorination of γ-lactams using LDA/NFSI or nucleophilic difluorination of cyclic α-ketoamides. [8] However, these methods suffer from several limitations, such as multi-step operations, a narrow substrate scope, and harsh reaction conditions. Consequently, there is an urgent need to develop more efficient and generalizable synthetic strategies for accessing 3,3-difluoro-γ-lactam derivatives. Scheme 1 Selected drug active molecules containing 3,3-difluoro-γ-lactam scaffolds In recent years, substantial efforts have been devoted to the synthesis of 3,3-difluoro-γ-lactams via visible-light photoredox catalysis or transition metal-catalyzed carbon–halogen bond cleavage, followed by 5-exo-trig radical cyclization of N -allyl bromodifluoroacetamides. [9] Typically, these methods employ a two-component cyclization/tandem reaction system, incorporating transformations such as hydrogenation, [10a] boronation, [10b] halogenation, [10c] allylation, [10d] hydroxylation, [10e] sulfurization, [11a] selenization, [11b] phosphorothiolation, [11c] arylation, [11d] and heteroarylation [11e-g] to achieve functionalization of the 3,3-difluoro-γ-lactam radical, thereby enabling the synthesis of diverse products. Nevertheless, tandem double functionalization of the 3,3-difluoro-γ-lactam radical remains relatively unexplored, with only a few examples reported, such as carbo-thioesterification/amination, [12a] sulfonylation/heteroarylation, [12b] sulfonylation/alkylation, [12c-d] and sulfonylation/vinyl heteroarylation [12e] sequences (Scheme 2a) . However, the triple functionalization of this radical remains unexplored, which may be primarily due to three major challenges: 1) precise sequential control; 2) site selectivity control; 3) competing pathways of multi-component cascade reactions. Despite these obstacles, achieving triple functionalization of the 3,3-difluoro-γ-lactam radical to efficiently access structurally diverse and multifunctional derivatives remains a highly desirable goal. Building on our ongoing research into the applications of the bulk industrial reagent rongalite in organic synthesis, [13] we hypothesized that it could act as a multifunctional reagent capable of coupling with electron-rich aromatic heterocycles to achieve triple functionalization of the 3,3-difluoro-γ-lactam radical. Herein, we report the synthesis of multifunctional lactam-substituted alkyl sulfones using rongalite as a super electron donor, sulfone source and C1 synthon via sulfonylation / methylation / heteroarylation sequences (Scheme 2b) . To our knowledge, this work demonstrates the first triple functionalization of a 3,3-difluoro-γ-lactam radical, enabling a novel synthesis of multifunctional lactam-substituted alkyl sulfones under metal-, oxidant-, and photocatalyst-free conditions. Scheme 2 Recent advances in the functionalization of 3,3-difluoro-γ-lactam radicals and our strategy Results and Discussion In our preliminary investigations, we utilized N -allyl-2-bromo-2,2-difluoro- N -phenylacetamide ( 1a ), rongalite ( 2a ), and 2-phenylimidazo[1,2-a]pyridine ( 3a ) as model substrates to establish the optimal reaction parameters. Under the standard conditions, the triple functionalization reaction proceeded efficiently in DMSO at 100 °C for 2 hours, affording the target product 3,3-difluoro-1-phenyl-4-((((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)sulfonyl)methyl) pyrrolidin-2-one ( 4a ) in 82% yield (Table 1, entry 1). We then examined the influence of various bases, including both inorganic bases (Na₂CO₃, Cs₂CO₃) and organic bases (DBU, Et₃N); however, all proved detrimental, leading to notable decline in the yield of 4a . Moreover, the introduction of metal catalysts, including FeCl₃, Fe(OTf)₃, and Cu(OTf)₂, had little impact on the reaction efficiency. (Table 1, entry 3). Furthermore, a solvent screening study covering DMF, 1,4-dioxane, PhMe, and DCE further confirmed DMSO as the most suitable medium (Table 1, entries 1 and 4–7). Deviations from the optimized temperature, either higher or lower, were also found to adversely affect the yield (Table 1, entry 8). Finally, varying the loading of rongalite confirmed that deviations from the optimal dose resulted in no yield improvement (Table 1, entry 9). With the optimized conditions established, we proceeded to evaluate the substrate scope of this triple functionalization reaction (Scheme 3). To our delight, this transformation demonstrated broad functional group tolerance and compatibility with a wide range of substituted N -allylbromoacetamides and imidazo[1,2-a]pyridines. Initially, we examined aryl-substituted N -allylbromoacetamides. The reaction proceeded smoothly to afford the desired lactam-substituted alkyl sulfones ( 4a – 4n ) in moderate to good yields (50–82%), regardless of whether the aromatic ring bore electron-neutral (4-H), electron-donating (3-Me, 4-Me, 3,5-Me 2 , 4-Et, 4- n Bu, 4- t Bu, 4-OMe, 3,4-OMe 2 , 4-OEt, 3-OBn, 4-OBn, 3,4-OCH 2 O), or electron-withdrawing (3-CN) substituents. Furthermore, halogenated substrates (4-F, 4-Cl, 4-I) were also compatible, yielding the corresponding products ( 4o – 4q ) in 62–80% yield; these halogen handles offer potential for further derivatization. The reaction also accommodated various N -alkyl substituents, including n -octyl, benzyl, and 2-thienylmethyl groups, furnishing products 4r – 4t in 65–78% yield. Notably, substituents at the 1- or 2-position of the double bond were well tolerated, providing products 4u and 4v in 59% and 61% yields, respectively. The protocol was also successful when fluorine was replaced by a methyl group, affording product 4w in 70% yield. Subsequently, we explored the scope with respect to imidazo[1,2-a]pyridines. Remarkably, the reaction tolerated a wide range of substituents, including electron-neutral (H), electron-donating (Me, OMe), and electron-withdrawing groups (CO 2 Me, F, Cl, Ph, CN, 1-Np), delivering the hybrid products ( 4a , 4x – 4af ) in 58–82% yields. Finally, replacing the allyl group with a propargyl group also proceeded smoothly, yielding the corresponding vinyl sulfone product 4ag in 39% yield. Table 1 Optimization of the reaction conditions a 1 None 82 2 With Na 2 CO 3 / Cs 2 CO 3 / DBU / Et 3 N 0 / 0 / trace/ 0 3 With 0.5 equiv FeCl 3 / Fe(OTf) 3 / Cu(OTf) 2 78 / 75 / 80 4 DMF instead of DMSO 67 5 1,4-dioxane instead of DMSO 0 6 PhMe instead of DMSO 0 7 DCE instead of DMSO 0 8 At 90 o C / 110 o C 75 / 69 9 Rongalite loading: 1.0 / 1.5 /2.5 equiv. 68 / 74 / 78 a Reactions conditions: 1a (0.22 mmol), 2 (0.40 mmol), and 3a (0.20 mmol) were heated in 2.0 mL DMSO in a sealed vessel at 100 °C in an oil bath for 2 h. b Isolated yield based on 3a . Building on these promising results, we expanded our investigation to a broader range of electron-rich aromatic heterocycles (Scheme 4). The reaction exhibited excellent functional group tolerance, converting 2-arylindoles bearing electron-donating (2-Me), electron-neutral (4-H), or electron-withdrawing (4-CO₂Me) groups on the benzene ring into the corresponding lactam-substituted alkyl sulfones in moderate to good yields ( 4ah – 4aj , 49–60%). Notably, N -methyl indole afforded the desired product 4ak in 55% yield. In addition, chlorinated N -allylbromoacetamide reacted with 2-phenylindole to provide the corresponding product 4al in 57% yield. Interestingly, electron-rich aniline was also compatible with this reaction, delivering the desired lactam-substituted alkyl sulfone 4am in a high yield of 73%. With the substrate scope determined, we proceeded to investigate the reaction mechanism. First, the reaction was significantly suppressed when N -allyl-2-bromo-2,2-difluoro- N -phenylacetamide ( 1a ), rongalite ( 2a ), and 2-phenylimidazo[1,2-a]pyridine ( 3a ) were treated with radical scavengers (TEMPO or 1,1-diphenylethylene). Consequently, the formation of the target compound 4a was inhibited (Scheme 5a−b), with HRMS analyses identifying the radical trapping products 5a – 5c (see Figures S1−S3 in the Supporting Information). These results indicate that the reaction proceeds via a radical pathway involving the formation of a 5-exo-trig cyclization radical intermediate. We then employed HRMS to monitor potential intermediates under the standard reaction conditions using substrates 1a , 2 , and 3a (Scheme 5c). Delightfully, the sulfinate anion intermediate 5d was successfully detected (see Figures S4 in the Supporting Information). Further evaluation of various sulfur dioxide reagents, including Na₂S₂O₄, Na₂S₂O₅, and DABSO, revealed that the target product 4a was obtained only in the case of Na₂S₂O₄ combined with formaldehyde instead of rongalite, albeit in a low yield of 19% (Scheme 5d). These findings suggest that the sulfur dioxide insertion in this reaction likely proceeds via the SO₂ •− radical and that rongalite exhibits superior reactivity as a C1 source compared to formaldehyde. Finally, when p -toluenesulfinate ( 8 ), rongalite ( 2 ), and compound 3a were reacted, the corresponding sulfone 9 was successfully detected by HRMS (Scheme 5e). This result further suggests that the reaction pathway likely proceeds via a sulfinate anion intermediate. Scheme 3 Scope of substrates. a a Reactions conditions: 1 (0.22 mmol), 2 (0.40 mmol), and 3 (0.20 mmol) in DMSO (2.0 mL) was stirred at 100 o C in an oil bath for 2.0 h in a pressure vessel. Isolated yield based on 3 . Scheme 4 Scope of electron-rich aromatic heterocycles. a a Reactions conditions: 1 (0.22 mmol), 2 (0.40 mmol), and 3 (0.20 mmol) in DMSO (2.0 mL) was stirred at 100 o C in an oil bath for 2.0 h in a pressure vessel. Isolated yield based on 3 . Scheme 5 Control experiments Based on the above experimental results and previous reports, [14] we propose a plausible mechanism for this triple functionalization reaction in Scheme 6, using N -allyl-2-bromo-2,2-difluoro- N -phenylacetamide ( 1a ), rongalite ( 2 ), and 2-phenylimidazo[1,2-a]pyridine ( 3a ) as a representative case. The mechanism commences when rongalite decomposes upon heating, releasing an electron, formaldehyde, SO₂ •− , and a proton (H⁺). [15] The liberated electron reduces N -allyl-2-bromo-2,2-difluoro- N -phenylacetamide ( 1a ), forming radical anion intermediate I . This intermediate then eliminates a bromide ion to produce difluoroalkyl radical II , which in turn undergoes a 5-exo-trig cyclization, affording carbon radical III . The carbon radical III then reacts with SO₂ •− , generating the sulfinate anion IV and sulfonyl anion V in equilibrium. Simultaneously, nucleophilic attack of 2-phenylimidazo[1,2-a]pyridine ( 3a ) on rongalite’s carbon center affords hydroxymethyl intermediate VI , liberating SO₂²⁻ and a proton. Subsequent protonation of VI gives VII , triggering dehydration to form the iminium ion VIII . Furthermore, a final Michael addition between sulfonyl anion V and iminium ion VIII affords the target multifunctional lactam-substituted alkyl sulfone 4a . Schem e 6 Proposed mechanism The applicability of the triple functionalization reaction in organic synthesis was further investigated, as illustrated in Scheme 7. A gram-scale reaction of N -allyl-2-bromo-2,2-difluoro- N -phenylacetamide ( 1a ), rongalite ( 2 ), and 2-phenylimidazo[1,2-a]pyridine ( 3a ) successfully afforded the target compound 4a in 73% yield (Scheme 7a). Subsequently, the reaction was applied to the late-stage modification of indole analogues derived from commercial drugs. Notably, substrates bearing ibuprofen, aspirin, or indomethacin all participated efficiently, achieving the corresponding lactam-substituted alkyl sulfones 4an – 4ap in moderate yields (43–54%) (Scheme 7b). Scheme 7 Synthetic applicability Conclusions In summary, we have established an efficient rongalite-mediated triple functionalization of N -allyl bromodifluoroacetamides with electron-rich heteroarenes via a sulfonylation/methylation/heteroarylation sequence, enabling efficient access to multifunctional lactam-substituted alkyl sulfones. This protocol operates under metal-, oxidant-, and photocatalyst-free conditions, demonstrating high efficiency and broad substrate scope. Furthermore, the protocol facilitates late-stage modification of indole scaffolds derived from commercial pharmaceuticals, including ibuprofen, aspirin, and indomethacin. Mechanistic studies have supported a radical pathway, underscoring the triple role of rongalite as a super electron donor for reaction initiation, a ”SO₂” source, and a ”C1” precursor. Further studies on the in-depth mechanistic details of this reaction and the synthetic applications of rongalite are currently underway in our laboratory. Experimental Gene ral procedure for the synthesis of products 4 A mixture of N -allyl-2-bromo-2,2-difluoro- N -phenylacetamide (1a) (0.22 mmol, 63.9 mg), rongalite ( 2a ) (0.4 mmol, 61.6 mg), and 2-phenylimidazo[1,2-a]pyridine ( 3a , 38.8 mg) in DMSO (2.0 mL) was stirred at 100 o C in an oil bath for 2.0 h in a pressure vessel. The resulting mixture was dropped into 50 mL H 2 O and extracted with EtOAc 3 times (3 × 50 mL). The organic extract was dried with anhydrous Na 2 SO 4 , filtered and concentrated. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc = 1/1) to afford the product 3,3-difluoro-1-phenyl-4-((((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)sulfonyl)met-hyl) pyrr-olidin-2-one (4a) as white solid (79.0 mg, 82%) . Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.202500xxx. Acknowledgement We are grateful to the Natural Science Foundation of Henan Province (232300420390) for financial support. References 1. (a) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept. J. Med. Chem. 2017 , 60 , 797–804. (b) Meanwell, N. A. 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Rongalite as C1 Synthon and Sulfone Source: A Practical Sulfonylmethylation Based on the Separate-Embedding Strategy. Org. Lett. 2021 , 24 , 223 – 227. (c) Laha, J. K.; Gupta, P. Sulfoxylate Anion Radical-Induced Aryl Radical Generation and Intramolecular Arylation for the Synthesis of Biarylsultams. J. Org. Chem. 2022 , 87 , 4204 – 4214. Manuscript received: XXXX, 2025 Manuscript revised: XXXX, 2025 Manuscript accepted: XXXX, 2025 Version of record online: XXXX, 2025 Left to Right: Hui-Ying Ren, Miao Wang, Shan Jiang, Zi-Xiang Bin, Xiao-Qing Li, Bang-Tun Zhao Entry for the Table of Contents Herein, we report a novel rongalite-mediated triple functionalization of N -allyl bromodifluoroacetamides with electron-rich heteroarenes via a sulfonylation / methylation / heteroarylation sequence, enabling efficient access to multifunctional lactam-substituted alkyl sulfones. The scalability of this method and the accessibility of its products to late-stage modification significantly broaden its application potential. Information & Authors Information Version history V1 Version 1 23 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords 3 3-difluoro-γ-lactam radical c1 synthon lactam-substituted alkyl sulfones rongalite sulfone source triple functionalization Authors Affiliations Hui-Ying Ren Luoyang Normal University View all articles by this author Miao Wang 0009-0003-5143-7448 [email protected] Luoyang Normal University View all articles by this author Shan Jiang Luoyang Normal University View all articles by this author Zi-Xiang Bin Luoyang Normal University View all articles by this author Xiao-Qing Li Luoyang Normal University View all articles by this author Bang Tun Zhao Luoyang Normal University View all articles by this author Metrics & Citations Metrics Article Usage 153 views 104 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Hui-Ying Ren, Miao Wang, Shan Jiang, et al. One Stone, Three Birds: Synthesis of Multifunctional Lactam-Substituted Alkyl Sulfones Using Rongalite as Electron Donor, Sulfone Source, and C1 Synthon. Authorea . 23 November 2025. DOI: https://doi.org/10.22541/au.176389933.35847480/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); Cited by Hui-Ying Ren, Miao Wang, Shan Jiang, Zi-Xiang Bin, Xiao-Qing Li, Bang-Tun Zhao, Synthesis of multifunctional lactam-substituted alkyl sulfones using rongalite as an electron donor, sulfone source, and C1 synthon, Chemical Communications, 62 , 11, (3606-3610), (2026). https://doi.org/10.1039/D5CC06679D Crossref Loading... View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. 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