Harnessing regioselective aryl migration of pyridone-based aryl-λ3‑iodonium salts to access iodine-substituted aryloxypyridines

Harnessing regioselective aryl migration of pyridone-based aryl-λ3‑iodonium salts to access iodine-substituted aryloxypyridines | 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 Harnessing regioselective aryl migration of pyridone-based aryl-λ 3 ‑iodonium salts to access iodine-substituted aryloxypyridines Shaoyu Mai, Linmei Zhao, Mengling He, Wankai Ma, Zequan Xiang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7844273/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract While 2- and 4-aryloxypyridines are ubiquitous in pharmaceutical molecules, efficient synthetic strategies—especially for synthesizing scaffolds with diverse multiple substituents on the pyridine core—remain limited. Here we report a hook-and-slide strategy for constructing these scaffolds, involving the in-situ generation of pyridonyl(aryl)iodonium salts from pyridones and Koser’s reagent (hook, C3 selectivity), followed by an iodine-to-oxygen aryl migration (slide, O selectivity). Such newly designed iodonium salts feature dual vicinal nucleophilic sites, and we demonstrate that using ionic liquids can exclusively transfer the aryl group to the strategic O site. This approach is transition-metal-free, scalable, and applicable to substrates with diverse electronic and steric properties or complex structures. Importantly, the resulting products retain − I and − NH 2 handles that are amenable to downstream derivatizations, enabling extensive exploration of previously inaccessible chemical space. The utility of this approach is further demonstrated through the concise synthesis of two pharmaceutical intermediates and a CRF 1 antagonist, CP-376395. Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Physical sciences/Chemistry/Green chemistry/Ionic liquids Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction The 2- and 4-aryloxypyridines are common structural motifs that can be found in a wide variety of bioactive molecules, drugs, and agrochemicals (Fig. 1 a) 1 – 12 . Indeed, over 70,000 compounds with promising biological activities (pX ≥ 4) are searchable in the Reaxys database, including nine approved drugs, six of which are tyrosine kinase inhibitors (TKIs) used for cancer therapy 10 . In particular, introducing multiple substituents on the pyridine core often plays a critical role in enhancing pharmaceutical properties (Fig. 1 b) 2 , 11 – 12 . As such, efficient synthesis of 2- and 4-aryloxypyridines with substituent and structural diversity is of great importance for drug discovery. Typically, these scaffolds are synthesized via S N Ar, although this approach often requires harsh reaction conditions and preferentially favors the coupling of electron-poor pyridines with electron-rich phenols 4 , 13 – 16 . On the other hand, transition-metal-catalyzed C − O couplings of pyridyl halides with phenols 17 – 20 as well as intramolecular decarboxylative C − O couplings 21 have been established as reliable methods. However, these methods are less general compared to well-developed C − C and C − N couplings due to the low nucleophilicity of phenols, often requiring the use of sophisticated catalysts/ligands or high-temperature conditions. The O-arylation of 2- and 4-pyridones represents an alternative method for the synthesis of electronically diverse pyridyl ethers (Fig. 1 c). However, such a disconnection is made challenging by the ambident nucleophilicity of pyridones, which predominantly affords corresponding N-arylated products. 22 – 26 To date, only two strategies have been developed to achieve satisfactory O-selectivity. The first strategy relies on the use of C6-substituted 2-pyridones, thereby facilitating arylation at the sterically less hindered O-terminus (Fig. 1 c, strategy A). 27–28 The second strategy perfectly addresses the issue of substrate dependence but requires the use of synthetically elaborate arylating reagents (Fig. 1 c, strategy B). 29–31 For example, in 2020, Kuriyama and Onomura reported a base-controlled O-selective arylation of 2- and 4-pyridones with symmetrical diaryliodonium salts (Ar 2 IX) in chlorobenzene under high-temperature conditions (130–140°C). 29 Of note, symmetrical Ar 2 IX are often more challenging to prepare than their counterparts with electronic or steric bias. 32 In 2022, the Ball group successfully achieved complete O-selectivity across a broader range of substrates using arylbismacycles as the arylating agents, which are prepared from arylboronic acids and a bismacycle tosylate that requires multistep synthesis. 31 Although extremely enabling, strategy B results in the generation of stoichiometric waste (e.g., ArI or bulky bismacycles) and presents challenges in synthesizing pyridyl ethers with multiple substituents on the pyridine ring. Inspired by the recently developed “hook-and-slide” strategy from the Dong group 33 , we envisioned a straightforward approach to achieve O-selective arylation of pyridones, while guaranteeing substituent diversity and facile derivatization (Fig. 1 d). The approach begins with an electrophilic substitution at the C3 position of pyridones, utilizing Koser’s reagent to in situ generate pyridone-based λ³-iodanes (hook) 34 . Next, such iodonium salts undergo aryl migration through an intramolecular S N Ar mechanism 35 – 37 , in which the aryl group migrates from iodine to the proximal oxygen site rather than the distal nitrogen site (slide). If feasible, our design will introduce a novel strategy to enable the O-selective arylation of 2- and 4-pyridones without relying on metal catalysts and generating stoichiometric amounts of iodoarene waste 38 . Importantly, the retention of iodine group allows a variety of downstream derivatizations, thereby significantly expanding the chemical space of medically important pyridyl ethers. However, attaching ArI + moieties to the C3 position often requires an electron-donating R group to confer adequate nucleophilicity, but this can create an additional proximal nucleophilic site, potentially leading to regioselectivity issues during aryl migration process. To the best of our knowledge, no examples have been reported in the literature on the regioselective control of aryl migration for Ar 2 IX species bearing dual vicinal nucleophilic sites 39 – 41 . Based on our ongoing interest in hypervalent iodine chemistry 42 – 45 , we herein describe our efforts in developing regioselective aryl migration of pyridonyl(aryl)iodonium salts, enabling highly efficient access to iodine-substituted aryloxypyridines that are otherwise difficult to prepare. Results Iodonium salt design and reaction optimization Given the significance of amino-substituted aryloxypyridines in drug discovery 4 and the synthetic versatility of the (free) NH 2 group 46 , we were motivated to use commercially available 4-aminopyridin-2(1 H )-one ( 1a ) as the model substrate (Fig. 2 a). To our delight, the reaction between 1a and hydroxy(tosyloxy)iodobenzene (HTIB, 2a ) smoothly proceeded on a 20 mmol scale, affording the pyridone-based aryl-λ 3 ‑iodonium salt ( 3 ) in 9.09 g with a 94% yield. X-ray crystal structure analysis of 3 indicated a classical T-shaped geometry at the iodine atom, with the pyridone moiety bound to the iodine through the C3 position. Indeed, subjecting 3 to t -BuOLi at 50 o C resulted in the formation of undesired N2-arylated pyridone 4 as the major product, while the O-arylated pyridone 5 , a synthetically more challenging product, was obtained in only 14% yield (Fig. 2 b). No formation of products 4 and 5 was observed when the reaction was conducted in EtOH using other common bases, such as t -BuOK, Na 2 CO 3 , Li 2 CO 3 , and Et 3 N. Notably, using K 2 CO 3 significantly inhibited the formation of 4 , while the desired product 5 was also detected in a low yield. Our optimization study then focused on the aryl migration reaction of in situ-generated iodonium salt 3 (Fig. 2 c). Using K 2 CO 3 as the base, the yield of 5 was further improved by increasing the reaction temperature from 50°C to 90°C (Fig. 2 c, entry 1). Substituting EtOH with other solvents, such as TFE, CH 3 CN, and 1,4-dioxane, did not lead to a significant improvement in either the selectivity or the yield of 5 (Fig. 2 c, entries 2–4). Ionic liquids are an attractive alternative to conventional organic solvents due to their high thermal stability, environmental friendliness, and reusability. 47 – 48 Moreover, we speculated that the cation moiety of ionic liquids, which often act as a "soft acid", preferentially bound to the softer N-nucleophilic site rather than O-nucleophilic site, thereby facilitating O-selective aryl migration. Guided by this idea, we employed IL-1 as the solvent and observed the exclusive formation of 5 , albeit with a 30% yield (Fig. 2 c, entry 5). This result encouraged us to evaluate a series of commercially available ionic liquids (Fig. 2 c, entries 6–10), and we identified [Bmim][OTf] ( IL-5 ) as the optimal solvent. Moreover, desired product 5 was obtained in low yield when the reaction was conducted using IL-5 as the base and EtOH as the solvent (Fig. 2 c, entry 11). Substrate scope studies With the optimized conditions in hand, we initially examined the scope of Koser’s reagent for the synthesis of 2-aryloxypyridines using 1a as the coupling partner (Fig. 3 ). Arylating reagents bearing electron-neutral and electron-donating substituents, such as − Me ( 6 ), − t -Bu ( 7 ), and − OMe ( 8 ), were identified as suitable substrates to afford desired products smoothly. Moreover, the reaction was found to be compatible with 2- and 4-bromine-substituted substrates, giving the expected products 9 (54%) and 10 (71%), respectively. Of note, the reaction proceeded smoothly in the presence of electron-withdrawing groups, such as − CN, −Ac, −COOMe, −CF 3 , −OCF 3 , and − NO 2 , yielding the corresponding products 11 – 17 in 41 − 91% yields. These results further highlight the complementary nature of our approach in comparison to traditional S N Ar. Of particular note, the O-selective aryl migration strategy is highly effective for aryl partners bearing two ortho substituents ( 18 , 19 , 20) , including very bulky isopropyl group ( 20 ), thereby enabling convenient access to medically important aryloxypyridines with sterically demanding aryl moiety. On the other hand, 2-aminopyridin-4(1 H )-one ( 1b ) was also suitable for the iodine-to-O aryl migration process. It reacted with a diverse range of Koser’s reagents, which possess varying electronic and steric effects, to afford the desired 4-aryloxypyridines ( 21 – 28 ) in yields ranging from 37% to 67%. Among them, the structure of 21 was unambiguously confirmed by X-ray crystallographic analysis. Next, the generality of the substituted pyridones was investigated (Fig. 4 ). The introduction of a methyl or chloro group on the pyridine ring was feasible, giving the corresponding products 29 (87%) and 30 (57%), respectively. In contrast, the yield of the O-arylation reaction was observed to decrease when substrate containing a 6-fluoro substituent was employed ( 31 , 19%). For 4-aminoquinolin-2(1 H )-one, a substrate with an extended π system, the O-selective arylation reaction could still proceed efficiently, yielding the expected product 32 in 66% yield. Of note, satisfactory results were also achieved for 2-pyridones containing various substituted amino moieties, including PMB-protected ( 33 ), p -tolyl ethyl ( 34 ), and chiral alpha-branched ( 35 ) amino groups, all of which were well tolerated under the standard conditions. Replacing NH 2 moiety of 1a with benzyloxy group did not significantly affect the reaction process, affording the desired product 36 in 58% yield. It was found that two commercially available 4-pyridone derivatives, namely 2-methoxypyridin-4(1 H )-one and 2-aminoquinolin-4(1 H )-one, are also suitable substrates for this reaction, resulting in the formation of the corresponding 4-aryloxypyridines 37 (70%) and 38 (71%), respectively. To our delight, the developed methodology was successfully applied to various substituted pyrimidone substrates to afford medically relevant 4-aryloxypyrimidine derivatives 39 – 42 in 27–94% yield. Encouraged by these results, we then utilized this methodology to synthesize an iodine-substituted etravirine analogue 8 ( 43 , 64% yield) by selecting the appropriate Koser’s reagent and pyrimidone. Finally, the importance of our approach was further highlighted by the late-stage modification of complex structures. The oxetane ring, an important motif in drug discovery 49 , was well tolerated for this reaction, leading to the formation of 44 in 22% yield. Moreover, substrate bearing an adamantane moiety reacted smoothly to produce the desired product 45 in 31% yield, and our reaction successfully proceeded with a complex 2-pyridone containing a diterpene dehydroabietylamine moiety, affording 46 in 40% yield. Synthetic applications To further demonstrate the utility of this methodology, a gram-scale reaction using iodonium salt 3 was carried out (Fig. 5 a). Surprisingly, this transformation could be easily scaled up to 10.0 mmol, giving 5 in 2.22 g with 71% yield. The NH 2 group in the resulting product 5 may seem synthetically superfluous; however, it has proven to be useful in the synthesis of aryloxypyridines with various substituent patterns on the pyridine core—structures are valuable for drug discovery and otherwise difficult to synthesize. First, the treatment of 5 with NBS yielded brominated product 47 in 91% yield. Upon undergoing the Sandmeyer reaction with reagents such as CuCl, CuBr 2 , TMSN 3 , or SOCl 2 , 5 could be readily transformed into 48 (54%), 49 (72%), 50 (19%), and 51 (34%), respectively. Moreover, the iodine group of 5 could readily undergo Suzuki-Miyaura coupling with pyridin-3-ylboronic acid to give 52 in 67% yield. To our delight, 5 could be converted into novel heterocycle 53 through Pd-catalyzed isocyanide insertion-cyclization, and it could also undergo Pd-catalyzed tandem annulation with 1-phenylprop-2-yn-1-ol to afford novel 5-phenoxy-1,6-naphthyridine 54 . 50–51 4-Aryloxypyridine 55 , a key synthetic precursor for multiple selective Met kinase inhibitors 12 , was previously synthesized through iodination of 56 using n -BuLi and I 2 (5 equiv.), followed by deprotection and a high-temperature S N Ar reaction (Fig. 5 b). In contrast, our strategy enabled a one-pot, two-step synthesis of 55 by utilizing 1b and Koser's reagent 57 , thereby obviating the need for hazardous reagents and harsh reaction conditions. Furthermore, the synthesis of TWS 119—a glycogen synthase kinase-3β inhibitor—required the intermediacy of pyrrolo[2,3- d ]pyrimidine 58 (Fig. 5 c), which was previously prepared from 59 through a three-step procedure that required the use of a five-fold excess of alkyne 60 and a high-temperature S N Ar/cyclization cascade (180°C) 52 . By comparison, we developed a relatively mild route for 58 , which involved a one-pot iodination/O-arylation of the commercially available 61 with Koser's reagent 62 , followed by a Sonogashira coupling/cyclization cascade. The advantage of our approach was once again demonstrated in the synthesis of CP-376395 ( 63 ), an orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1 ) antagonist, which holds promise for treating depression, anxiety, and other stress-related neurological disorders 53 . As illustrated in Fig. 5 d, CP-376395 was previously synthesized in 7 steps with 32% overall yield, involving the S N Ar reaction between a pyridine N-oxide and phenol, as well as the reduction of an ester group to a methyl group. 4 Even though useful, the previous route required the use of harsh or dangerous reagents, such as POCl 3 , PCl 3 , AlCl 3 , LiAlH 4 , and urea-HOOH. In contrast, our synthetic route (5 steps, 38% total yield) considerably addressed these issues, commencing with a mild S N Ar between 64 and 65 , decarboxylation, one-pot iodination/O-arylation (51% yield), and a Suzuki–Miyaura cross-coupling with easily available MeB(OH) 2 . Mechanistic considerations To elucidate the reaction mechanism, a crossover experiment employing two structurally similar substrates ( 3 and 66 ) was performed (Fig. 6 ). A mixture of two conserved products ( 5 and 67 ) was detected, with no crossover products observed. This result provides evidence for the involvement of an intramolecular aryl migration pathway. This study also systematically investigates the divergent aryl migration selectivity of diaryliodonium salts bearing dual nucleophilic sites under distinct reaction conditions through density functional theory (DFT) calculations. All geometry optimizations were performed at the B3LYP-GD3(BJ) /def2-SVP level using Gaussian 16 A03, with subsequent single-point energy calculations conducted via the M06-2X/def2-TZVP method (see Supplementary information for full details). The potential energy surfaces presented in Fig. 7 were generated under implicit solvent model (SMD, solvent = ethanol) and an explicit-implicit hybrid solvent model for ionic liquid systems, respectively, to account for the interaction of ionic liquid. 54 In the t -BuOLi-mediated system, mechanistic analysis reveals a kinetically controlled N-arylation pathway (Fig. 7 a). The reaction initiates through deprotonation of the acidic hydroxyl group by t -BuOLi. Due to the significantly higher acidity of the hydroxyl proton compared to the amine proton, the bulky strong base t -BuOLi preferentially and irreversibly deprotonates the hydroxyl group. This reaction leads to the formation of the intermediate Li-IM1 , in which Li + ion is coordinated by two oxygen atoms from the p -toluenesulfonyl group. This coordination stabilizes the eight-membered ring intermediate ( Li-IM1 ) with a substantial 61.4 kcal/mol energy. Subsequent nucleophilic attack on the iodonium-bound phenyl group by the amine proceeds via transition state Li-TS with an activation barrier of 31.4 kcal/mol. This is identified as the rate-determining step. The resulting intermediate Li-IM2 undergoes an intramolecular proton transfer, followed by the elimination of LiOTs, ultimately yielding the N-arylated product. Conversely, the ionic liquid ( IL-5 )/K₂CO₃ system exhibits O-arylation selectivity (Fig. 7 b). The reaction commences with nucleophilic displacement of the OTs group by a carbonate ion on the cationic intermediate ( ON-IM1 ), thereby generating NO-IM2 . Two distinct proton transfer pathways then occur from NH 2 and OH of NO-IM2 , producing the intermediates O-IM3 and N-IM3 , respectively. Computational analysis reveals that O-IM3 is thermodynamically more stable than N-IM3 by 3.9 kcal/mol. This stability difference primarily stems from the stronger acidity of pyridinone group compared to the amine, as well as more significant hydrogen-bonding interactions within the dialkylimidazolium cation. Whereas, due to the rapid nature of proton transfer, the interconversion between these intermediates remains reversible. Subsequently, aryl migration transition to oxygen is favored over nitrogen, with an energy barrier of 24.6 kcal/mol. The energy difference of 3.0 kcal/mol between the two pathways aligns with the experimental observations, in which only the O-arylation product is detected. Following aryl migration, elimination of the imidazolium bicarbonate moiety to form the final product releases an energy of 13.5 kcal/mol ( O-IM4 ) and 5.2 kcal/mol ( N-IM4 ), respectively. These computational findings indicate that the observed O-selectivity in ionic liquids arises primarily from thermodynamic stabilization of oxygen-centered intermediates. The mechanistic analysis between the two systems—kinetic control via lithium coordination in protic media versus thermodynamic control through hydrogen-bonding interactions in ionic liquids—provide critical insights for designing regioselective arylation strategies. Discussion We have developed a novel approach utilizing pyridones and Koser’s reagent for the synthesis of 2- and 4-aryloxypyridines featuring an iodine handle—a class of platform molecules that, despite their synthetic versatility, have been underexplored and remain challenging to access. The success of this transformation hinges critically on the regioselective aryl migration of in situ-generated pyridone-based aryliodonium salts. This novel class of heterocyclic aryliodonium salts contains dual vicinal nucleophilic N and O sites, and we have demonstrated for the first time that using ionic liquid as solvent can exclusively transfer the aryl group from iodine to the strategic O site. The present reaction can be performed on a gram scale with good yield and is applicable to substrates exhibiting diverse electronic and steric properties, as well as complex molecular architectures. Moreover, it is also effective with pyrimidones, yielding iodine-substituted etravirine analogs. Importantly, we have also demonstrated that the resulting products, which retain both iodine and amino functional handles, are suitable for downstream derivatizations, enabling extensive exploration of the untapped chemical space of medically important pyridyl ethers. The effectiveness of this approach is further illustrated through the concise synthesis of two pharmaceutical intermediates and the CRF 1 antagonist CP-376395, avoiding the need for high-temperature S N Ar. DFT calculations are performed to elucidate the aryl migration regioselectivity, offering critical insights into the design of regioselective arylation strategies. This facile transformation tolerates air and moisture and does not require the use of any sophisticated catalysts/ligands, which might find wide synthetic applications in both pharmaceutical industry and academic research. Methods General procedure for the synthesis of aryloxypyridines/pyrimidines Pyridones/pyrimidines (0.2 mmol, 1.0 equiv.), Koser’s reagent (0.22 mmol, 1.1 equiv.) were added into a Schlenk tube in EtOH (1 mL), and the reaction mixture was stirred at 0 o C for 1 h. After the reaction completed, the solvent was removed under vacuum condition. Subsequently, K 2 CO 3 (0.2 mmol, 28 mg, 1.0 equiv.) and IL-5 ([Bmim][OTf], 1 mL) were added to above reaction mixture. The resulting reaction mixture was stirred at 90 o C for 5.5 h. After the reaction completed, the resulting solvent was diluted with H 2 O and extracted with EA (3 times). Finally, the combined organic phase was evaporated and dried, and then purified by column chromatography on silica gel (PE/DCM/EA: 4/1/1, v/v/v) to give the desired product. Declarations Competing interests The authors declare no competing financial interests. Additional information Supplementary information The online version contains Supplementary material available at http://doi.org/xxxxxxxxx Author contributions S.M. designed the project. H.T. and S.M. directed the project. L.Z. and M.H. performed the experiments. Z.X. helped collecting experimental data. S.M. and L.S. wrote the manuscript. L.Z. and S.M. prepared the Supplementary Information. L.Z. and M.H. contributed equally to this work. L.S. supervised the DFT study. W.M. performed the calculations. All authors discussed the results and commented on the manuscript. Acknowledgements We gratefully acknowledge the National Natural Science Foundation of China (22203023), the Key-Area Research and Development Program of Guangdong Province (2023B1111050008), and the Natural Science Foundation of Guangdong Province (2024A1515011051). This work was also supported by the Shenzhen Bay Laboratory Supercomputing Center. Data availability Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre under the deposition numbers CCDC 2450244 ( 3 ), 2450246 ( 4 ), 2450245 ( 5 ) and 2450247 ( 21 ). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/ . The experimental procedures, characterization of new compounds, and all other data supporting the findings are available in the Supplementary Information. Data supporting the findings of this manuscript are also available from the corresponding author upon request. 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Supplementary Files SINatCommunOarylation20251012.docx Supplementary Information Cite Share Download PDF Status: Under Review 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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08:12:09","extension":"xml","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":112437,"visible":true,"origin":"","legend":"","description":"","filename":"NCOMMS25817910structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/9e9e0aa2236a7832aa9d5f28.xml"},{"id":94000008,"identity":"036f008b-85cc-441e-8e77-8014d1912e06","added_by":"auto","created_at":"2025-10-21 08:04:09","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123824,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/6cca10bd996ec9cd9d41f817.html"},{"id":93999827,"identity":"3ba33edb-2672-45a0-9708-88ac8a7aca35","added_by":"auto","created_at":"2025-10-21 07:56:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90156,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBackground. a \u003c/strong\u003eThe importance of 2- and 4-aryloxypyridines in pharmaceuticals and bioactive molecules.\u003cstrong\u003e b \u003c/strong\u003eThe critical role of substituent patterns on the pyridine core in enhancing pharmaceutical properties, such as selectivity and binding affinity. \u003cstrong\u003ec \u003c/strong\u003eSynthetic strategies based on O-selective arylation of pyridone. \u003cstrong\u003ed \u003c/strong\u003eOur reaction design.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/2eca0c220fbfb9f027468593.png"},{"id":93999829,"identity":"905d654f-27a8-4055-979d-a1a1b7a50378","added_by":"auto","created_at":"2025-10-21 07:56:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66632,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIodonium salt design and reaction development. a\u003c/strong\u003e Lage-scale preparation of pyridonyl(aryl)iodonium salt \u003cstrong\u003e3\u003c/strong\u003e.\u003cstrong\u003e b \u003c/strong\u003ePreliminary reaction results. \u003cstrong\u003ec \u003c/strong\u003eReaction optimization. \u003csup\u003ea\u003c/sup\u003eReaction conditions: \u003cstrong\u003e1a \u003c/strong\u003e(0.2 mmol) and \u003cstrong\u003e2a \u003c/strong\u003e(0.22 mmol) in EtOH (1 mL) at 0 \u003csup\u003eo\u003c/sup\u003eC for 1 h under air; after evaporating the EtOH, solvent (1 mL) and base (1 equiv.) were added in sequence and then stirred at 90 \u003csup\u003eo\u003c/sup\u003eC for 5.5 h; isolated yield. N.D. = not detected.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/58f9edab45bbbb4b9c9250cb.png"},{"id":93999831,"identity":"3aaf5c16-61ad-4870-9069-93b7a9a7e4e2","added_by":"auto","created_at":"2025-10-21 07:56:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":58459,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScope of Koser’s reagent.\u003c/strong\u003e Reaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e or \u003cstrong\u003e1b\u003c/strong\u003e (0.2 mmol), \u003cstrong\u003e2\u003c/strong\u003e (0.22 mmol) in EtOH (1 mL) at 0 \u003csup\u003eo\u003c/sup\u003eC for 1 h under air; after evaporating the EtOH, \u003cstrong\u003eIL-5\u003c/strong\u003e (1 mL) and K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (0.2 mmol) were added and then stirred at 90 \u003csup\u003eo\u003c/sup\u003eC for 5.5 h; isolated yield.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/ed56420ed0b79328c304ef12.png"},{"id":94000003,"identity":"eb9e19ee-f32d-4ce3-8b1c-eb4fb2dd03b7","added_by":"auto","created_at":"2025-10-21 08:04:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":54221,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScope of substituted pyridones/pyrimidines.\u003c/strong\u003e Reaction conditions: pyridones or pyrimidines (0.2 mmol), Koser’s reagent (0.22 mmol) in EtOH (1 mL) at 0 \u003csup\u003eo\u003c/sup\u003eC for 1 h under air; after evaporating the EtOH, \u003cstrong\u003eIL-5\u003c/strong\u003e (1 mL) and K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (0.2 mmol) were added in sequence and then stirred at 90 \u003csup\u003eo\u003c/sup\u003eC for 5.5 h; isolated yield. \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003eCorresponding Koser’s reagent (0.22 mmol) was used.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/1cc4622a897fee2094f90928.png"},{"id":93999833,"identity":"c6be9532-8615-4337-affd-d0a1e3588b06","added_by":"auto","created_at":"2025-10-21 07:56:09","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":87460,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthetic applications.\u003c/strong\u003e \u003cstrong\u003ea \u003c/strong\u003eGram-scale synthesis and downstream derivatizations. \u003cstrong\u003eb \u003c/strong\u003eSynthesis of pharmaceutical intermediate \u003cstrong\u003e55\u003c/strong\u003e. \u003cstrong\u003eb \u003c/strong\u003eSynthesis of pharmaceutical intermediate \u003cstrong\u003e58\u003c/strong\u003e. \u003cstrong\u003ed \u003c/strong\u003eSynthesis of CP-376395.\u003c/p\u003e","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/9a2c72a1ea241ae442f23540.png"},{"id":94000968,"identity":"55a1b327-5d88-4e68-a066-1b5bcb24c42c","added_by":"auto","created_at":"2025-10-21 08:12:09","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":20552,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCrossover experiment.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/ae1488869a2dc1abd6bc60c4.png"},{"id":93999835,"identity":"01da2fdb-e640-48a1-addd-0a0120209338","added_by":"auto","created_at":"2025-10-21 07:56:09","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":134366,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComputed energy profile of the regioselective aryl migration reaction of aryl-λ³-iodonium salts.\u003c/strong\u003e \u003cstrong\u003ea \u003c/strong\u003eAryl migration\u003cem\u003e \u003c/em\u003eunder \u003cem\u003et\u003c/em\u003e-BuOLi-mediated system. \u003cstrong\u003eb \u003c/strong\u003eAryl migration\u003cem\u003e \u003c/em\u003eunder ionic liquid/K₂CO₃ system. Relative free energies are in kcal/mol. The geometry of some key intermediates is listed at the bottom (distances are in Å).\u003c/p\u003e","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/94ed4dc2ed4fa365b3d3a5d3.png"},{"id":94001046,"identity":"5cd2f4ca-e9b4-45cf-b1b9-0717972c64ff","added_by":"auto","created_at":"2025-10-21 08:20:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1576419,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/978f89ee-eed4-4b84-8f6d-b158f483b626.pdf"},{"id":93999836,"identity":"4a80522e-48ff-4548-a30c-12f428c9a7d9","added_by":"auto","created_at":"2025-10-21 07:56:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10415789,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SINatCommunOarylation20251012.docx","url":"https://assets-eu.researchsquare.com/files/rs-7844273/v1/dc51f6a6b0e8e1d0819c179c.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Harnessing regioselective aryl migration of pyridone-based aryl-λ\u003csup\u003e3\u003c/sup\u003e‑iodonium salts to access iodine-substituted aryloxypyridines","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe 2- and 4-aryloxypyridines are common structural motifs that can be found in a wide variety of bioactive molecules, drugs, and agrochemicals (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea) \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Indeed, over 70,000 compounds with promising biological activities (pX\u0026thinsp;\u0026ge;\u0026thinsp;4) are searchable in the Reaxys database, including nine approved drugs, six of which are tyrosine kinase inhibitors (TKIs) used for cancer therapy\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In particular, introducing multiple substituents on the pyridine core often plays a critical role in enhancing pharmaceutical properties (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. As such, efficient synthesis of 2- and 4-aryloxypyridines with substituent and structural diversity is of great importance for drug discovery. Typically, these scaffolds are synthesized via S\u003csub\u003eN\u003c/sub\u003eAr, although this approach often requires harsh reaction conditions and preferentially favors the coupling of electron-poor pyridines with electron-rich phenols\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. On the other hand, transition-metal-catalyzed C\u0026thinsp;\u0026minus;\u0026thinsp;O couplings of pyridyl halides with phenols\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e as well as intramolecular decarboxylative C\u0026thinsp;\u0026minus;\u0026thinsp;O couplings\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e have been established as reliable methods. However, these methods are less general compared to well-developed C\u0026thinsp;\u0026minus;\u0026thinsp;C and C\u0026thinsp;\u0026minus;\u0026thinsp;N couplings due to the low nucleophilicity of phenols, often requiring the use of sophisticated catalysts/ligands or high-temperature conditions.\u003c/p\u003e\u003cp\u003eThe O-arylation of 2- and 4-pyridones represents an alternative method for the synthesis of electronically diverse pyridyl ethers (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). However, such a disconnection is made challenging by the ambident nucleophilicity of pyridones, which predominantly affords corresponding N-arylated products.\u003csup\u003e\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e To date, only two strategies have been developed to achieve satisfactory O-selectivity.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe first strategy relies on the use of C6-substituted 2-pyridones, thereby facilitating arylation at the sterically less hindered O-terminus (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, strategy A).\u003csup\u003e27\u0026ndash;28\u003c/sup\u003e The second strategy perfectly addresses the issue of substrate dependence but requires the use of synthetically elaborate arylating reagents (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, strategy B).\u003csup\u003e29\u0026ndash;31\u003c/sup\u003e For example, in 2020, Kuriyama and Onomura reported a base-controlled O-selective arylation of 2- and 4-pyridones with symmetrical diaryliodonium salts (Ar\u003csub\u003e2\u003c/sub\u003eIX) in chlorobenzene under high-temperature conditions (130\u0026ndash;140\u0026deg;C).\u003csup\u003e29\u003c/sup\u003e Of note, symmetrical Ar\u003csub\u003e2\u003c/sub\u003eIX are often more challenging to prepare than their counterparts with electronic or steric bias.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e In 2022, the Ball group successfully achieved complete O-selectivity across a broader range of substrates using arylbismacycles as the arylating agents, which are prepared from arylboronic acids and a bismacycle tosylate that requires multistep synthesis.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Although extremely enabling, strategy B results in the generation of stoichiometric waste (e.g., ArI or bulky bismacycles) and presents challenges in synthesizing pyridyl ethers with multiple substituents on the pyridine ring.\u003c/p\u003e\u003cp\u003eInspired by the recently developed \u0026ldquo;hook-and-slide\u0026rdquo; strategy from the Dong group\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, we envisioned a straightforward approach to achieve O-selective arylation of pyridones, while guaranteeing substituent diversity and facile derivatization (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). The approach begins with an electrophilic substitution at the C3 position of pyridones, utilizing Koser\u0026rsquo;s reagent to in situ generate pyridone-based λ\u0026sup3;-iodanes (hook)\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Next, such iodonium salts undergo aryl migration through an intramolecular S\u003csub\u003eN\u003c/sub\u003eAr mechanism\u003csup\u003e\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, in which the aryl group migrates from iodine to the proximal oxygen site rather than the distal nitrogen site (slide). If feasible, our design will introduce a novel strategy to enable the O-selective arylation of 2- and 4-pyridones without relying on metal catalysts and generating stoichiometric amounts of iodoarene waste\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Importantly, the retention of iodine group allows a variety of downstream derivatizations, thereby significantly expanding the chemical space of medically important pyridyl ethers. However, attaching ArI\u003csup\u003e+\u003c/sup\u003e moieties to the C3 position often requires an electron-donating R group to confer adequate nucleophilicity, but this can create an additional proximal nucleophilic site, potentially leading to regioselectivity issues during aryl migration process. To the best of our knowledge, no examples have been reported in the literature on the regioselective control of aryl migration for Ar\u003csub\u003e2\u003c/sub\u003eIX species bearing dual vicinal nucleophilic sites\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. Based on our ongoing interest in hypervalent iodine chemistry\u003csup\u003e\u003cspan additionalcitationids=\"CR43 CR44\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, we herein describe our efforts in developing regioselective aryl migration of pyridonyl(aryl)iodonium salts, enabling highly efficient access to iodine-substituted aryloxypyridines that are otherwise difficult to prepare.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eIodonium salt design and reaction optimization\u003c/h2\u003e\u003cp\u003eGiven the significance of amino-substituted aryloxypyridines in drug discovery\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and the synthetic versatility of the (free) NH\u003csub\u003e2\u003c/sub\u003e group\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, we were motivated to use commercially available 4-aminopyridin-2(1\u003cem\u003eH\u003c/em\u003e)-one (\u003cb\u003e1a\u003c/b\u003e) as the model substrate (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). To our delight, the reaction between \u003cb\u003e1a\u003c/b\u003e and hydroxy(tosyloxy)iodobenzene (HTIB, \u003cb\u003e2a\u003c/b\u003e) smoothly proceeded on a 20 mmol scale, affording the pyridone-based aryl-λ\u003csup\u003e3\u003c/sup\u003e‑iodonium salt (\u003cb\u003e3\u003c/b\u003e) in 9.09 g with a 94% yield. X-ray crystal structure analysis of \u003cb\u003e3\u003c/b\u003e indicated a classical T-shaped geometry at the iodine atom, with the pyridone moiety bound to the iodine through the C3 position. Indeed, subjecting \u003cb\u003e3\u003c/b\u003e to \u003cem\u003et\u003c/em\u003e-BuOLi at 50 \u003csup\u003eo\u003c/sup\u003eC resulted in the formation of undesired N2-arylated pyridone \u003cb\u003e4\u003c/b\u003e as the major product, while the O-arylated pyridone \u003cb\u003e5\u003c/b\u003e, a synthetically more challenging product, was obtained in only 14% yield (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). No formation of products \u003cb\u003e4\u003c/b\u003e and \u003cb\u003e5\u003c/b\u003e was observed when the reaction was conducted in EtOH using other common bases, such as \u003cem\u003et\u003c/em\u003e-BuOK, Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, Li\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, and Et\u003csub\u003e3\u003c/sub\u003eN. Notably, using K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e significantly inhibited the formation of \u003cb\u003e4\u003c/b\u003e, while the desired product \u003cb\u003e5\u003c/b\u003e was also detected in a low yield.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOur optimization study then focused on the aryl migration reaction of in situ-generated iodonium salt \u003cb\u003e3\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Using K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e as the base, the yield of \u003cb\u003e5\u003c/b\u003e was further improved by increasing the reaction temperature from 50\u0026deg;C to 90\u0026deg;C (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, entry 1). Substituting EtOH with other solvents, such as TFE, CH\u003csub\u003e3\u003c/sub\u003eCN, and 1,4-dioxane, did not lead to a significant improvement in either the selectivity or the yield of \u003cb\u003e5\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, entries 2\u0026ndash;4). Ionic liquids are an attractive alternative to conventional organic solvents due to their high thermal stability, environmental friendliness, and reusability.\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e Moreover, we speculated that the cation moiety of ionic liquids, which often act as a \"soft acid\", preferentially bound to the softer N-nucleophilic site rather than O-nucleophilic site, thereby facilitating O-selective aryl migration. Guided by this idea, we employed \u003cb\u003eIL-1\u003c/b\u003e as the solvent and observed the exclusive formation of \u003cb\u003e5\u003c/b\u003e, albeit with a 30% yield (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, entry 5). This result encouraged us to evaluate a series of commercially available ionic liquids (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, entries 6\u0026ndash;10), and we identified [Bmim][OTf] (\u003cb\u003eIL-5\u003c/b\u003e) as the optimal solvent. Moreover, desired product \u003cb\u003e5\u003c/b\u003e was obtained in low yield when the reaction was conducted using \u003cb\u003eIL-5\u003c/b\u003e as the base and EtOH as the solvent (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, entry 11).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSubstrate scope studies\u003c/h3\u003e\n\u003cp\u003eWith the optimized conditions in hand, we initially examined the scope of Koser\u0026rsquo;s reagent for the synthesis of 2-aryloxypyridines using \u003cb\u003e1a\u003c/b\u003e as the coupling partner (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Arylating reagents bearing electron-neutral and electron-donating substituents, such as \u0026minus;\u0026thinsp;Me (\u003cb\u003e6\u003c/b\u003e), \u0026minus;\u003cem\u003et\u003c/em\u003e-Bu (\u003cb\u003e7\u003c/b\u003e), and \u0026minus;\u0026thinsp;OMe (\u003cb\u003e8\u003c/b\u003e), were identified as suitable substrates to afford desired products smoothly. Moreover, the reaction was found to be compatible with 2- and 4-bromine-substituted substrates, giving the expected products \u003cb\u003e9\u003c/b\u003e (54%) and \u003cb\u003e10\u003c/b\u003e (71%), respectively. Of note, the reaction proceeded smoothly in the presence of electron-withdrawing groups, such as \u0026minus;\u0026thinsp;CN, \u0026minus;Ac, \u0026minus;COOMe, \u0026minus;CF\u003csub\u003e3\u003c/sub\u003e, \u0026minus;OCF\u003csub\u003e3\u003c/sub\u003e, and \u0026minus;\u0026thinsp;NO\u003csub\u003e2\u003c/sub\u003e, yielding the corresponding products \u003cb\u003e11\u003c/b\u003e\u0026ndash;\u003cb\u003e17\u003c/b\u003e in 41\u0026thinsp;\u0026minus;\u0026thinsp;91% yields. These results further highlight the complementary nature of our approach in comparison to traditional S\u003csub\u003eN\u003c/sub\u003eAr. Of particular note, the O-selective aryl migration strategy is highly effective for aryl partners bearing two \u003cem\u003eortho\u003c/em\u003e substituents (\u003cb\u003e18\u003c/b\u003e, \u003cb\u003e19\u003c/b\u003e, \u003cb\u003e20)\u003c/b\u003e, including very bulky isopropyl group (\u003cb\u003e20\u003c/b\u003e), thereby enabling convenient access to medically important aryloxypyridines with sterically demanding aryl moiety. On the other hand, 2-aminopyridin-4(1\u003cem\u003eH\u003c/em\u003e)-one (\u003cb\u003e1b\u003c/b\u003e) was also suitable for the iodine-to-O aryl migration process. It reacted with a diverse range of Koser\u0026rsquo;s reagents, which possess varying electronic and steric effects, to afford the desired 4-aryloxypyridines (\u003cb\u003e21\u003c/b\u003e\u0026ndash;\u003cb\u003e28\u003c/b\u003e) in yields ranging from 37% to 67%. Among them, the structure of \u003cb\u003e21\u003c/b\u003e was unambiguously confirmed by X-ray crystallographic analysis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, the generality of the substituted pyridones was investigated (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The introduction of a methyl or chloro group on the pyridine ring was feasible, giving the corresponding products \u003cb\u003e29\u003c/b\u003e (87%) and \u003cb\u003e30\u003c/b\u003e (57%), respectively. In contrast, the yield of the O-arylation reaction was observed to decrease when substrate containing a 6-fluoro substituent was employed (\u003cb\u003e31\u003c/b\u003e, 19%). For 4-aminoquinolin-2(1\u003cem\u003eH\u003c/em\u003e)-one, a substrate with an extended π system, the O-selective arylation reaction could still proceed efficiently, yielding the expected product \u003cb\u003e32\u003c/b\u003e in 66% yield. Of note,\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003esatisfactory results were also achieved for 2-pyridones containing various substituted amino moieties, including PMB-protected (\u003cb\u003e33\u003c/b\u003e), \u003cem\u003ep\u003c/em\u003e-tolyl ethyl (\u003cb\u003e34\u003c/b\u003e), and chiral alpha-branched (\u003cb\u003e35\u003c/b\u003e) amino groups, all of which were well tolerated under the standard conditions. Replacing NH\u003csub\u003e2\u003c/sub\u003e moiety of \u003cb\u003e1a\u003c/b\u003e with benzyloxy group did not significantly affect the reaction process, affording the desired product \u003cb\u003e36\u003c/b\u003e in 58% yield. It was found that two commercially available 4-pyridone derivatives, namely 2-methoxypyridin-4(1\u003cem\u003eH\u003c/em\u003e)-one and 2-aminoquinolin-4(1\u003cem\u003eH\u003c/em\u003e)-one, are also suitable substrates for this reaction, resulting in the formation of the corresponding 4-aryloxypyridines \u003cb\u003e37\u003c/b\u003e (70%) and \u003cb\u003e38\u003c/b\u003e (71%), respectively. To our delight, the developed methodology was successfully applied to various substituted pyrimidone substrates to afford medically relevant 4-aryloxypyrimidine derivatives \u003cb\u003e39\u003c/b\u003e\u0026ndash;\u003cb\u003e42\u003c/b\u003e in 27\u0026ndash;94% yield. Encouraged by these results, we then utilized this methodology to synthesize an iodine-substituted etravirine analogue\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e (\u003cb\u003e43\u003c/b\u003e, 64% yield) by selecting the appropriate Koser\u0026rsquo;s reagent and pyrimidone. Finally, the importance of our approach was further highlighted by the late-stage modification of complex structures. The oxetane ring, an important motif in drug discovery\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, was well tolerated for this reaction, leading to the formation of \u003cb\u003e44\u003c/b\u003e in 22% yield. Moreover, substrate bearing an adamantane moiety reacted smoothly to produce the desired product \u003cb\u003e45\u003c/b\u003e in 31% yield, and our reaction successfully proceeded with a complex 2-pyridone containing a diterpene dehydroabietylamine moiety, affording \u003cb\u003e46\u003c/b\u003e in 40% yield.\u003c/p\u003e\n\u003ch3\u003eSynthetic applications\u003c/h3\u003e\n\u003cp\u003eTo further demonstrate the utility of this methodology, a gram-scale reaction using iodonium salt \u003cb\u003e3\u003c/b\u003e was carried out (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). Surprisingly, this transformation could be easily scaled up to 10.0 mmol, giving \u003cb\u003e5\u003c/b\u003e in 2.22 g with 71% yield. The NH\u003csub\u003e2\u003c/sub\u003e group in the resulting product \u003cb\u003e5\u003c/b\u003e may seem synthetically superfluous; however, it has proven to be useful in the synthesis of aryloxypyridines with various substituent patterns on the pyridine core\u0026mdash;structures are valuable for drug discovery and otherwise difficult to synthesize. First, the treatment of \u003cb\u003e5\u003c/b\u003e with NBS yielded brominated product \u003cb\u003e47\u003c/b\u003e in 91% yield. Upon undergoing the Sandmeyer reaction with reagents such as CuCl, CuBr\u003csub\u003e2\u003c/sub\u003e, TMSN\u003csub\u003e3\u003c/sub\u003e, or SOCl\u003csub\u003e2\u003c/sub\u003e, \u003cb\u003e5\u003c/b\u003e could be readily transformed into \u003cb\u003e48\u003c/b\u003e (54%), \u003cb\u003e49\u003c/b\u003e (72%), \u003cb\u003e50\u003c/b\u003e (19%), and \u003cb\u003e51\u003c/b\u003e (34%), respectively. Moreover, the iodine group of \u003cb\u003e5\u003c/b\u003e could readily undergo Suzuki-Miyaura coupling with pyridin-3-ylboronic acid to give \u003cb\u003e52\u003c/b\u003e in 67% yield. To our delight, \u003cb\u003e5\u003c/b\u003e could be converted into novel heterocycle \u003cb\u003e53\u003c/b\u003e through Pd-catalyzed isocyanide insertion-cyclization, and it could also undergo Pd-catalyzed tandem annulation with 1-phenylprop-2-yn-1-ol to afford novel 5-phenoxy-1,6-naphthyridine \u003cb\u003e54\u003c/b\u003e.\u003csup\u003e50\u0026ndash;51\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e4-Aryloxypyridine \u003cb\u003e55\u003c/b\u003e, a key synthetic precursor for multiple selective Met kinase inhibitors\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, was previously synthesized through iodination of \u003cb\u003e56\u003c/b\u003e using \u003cem\u003en\u003c/em\u003e-BuLi and I\u003csub\u003e2\u003c/sub\u003e (5 equiv.), followed by deprotection and a high-temperature S\u003csub\u003eN\u003c/sub\u003eAr reaction (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb). In contrast, our strategy enabled a one-pot, two-step synthesis of \u003cb\u003e55\u003c/b\u003e by utilizing \u003cb\u003e1b\u003c/b\u003e and Koser's reagent \u003cb\u003e57\u003c/b\u003e, thereby obviating the need for hazardous reagents and harsh reaction conditions. Furthermore, the synthesis of TWS 119\u0026mdash;a glycogen synthase kinase-3β inhibitor\u0026mdash;required the intermediacy of pyrrolo[2,3-\u003cem\u003ed\u003c/em\u003e]pyrimidine \u003cb\u003e58\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec), which was previously prepared from \u003cb\u003e59\u003c/b\u003e through a three-step procedure that required the use of a five-fold excess of alkyne \u003cb\u003e60\u003c/b\u003e and a high-temperature S\u003csub\u003eN\u003c/sub\u003eAr/cyclization cascade (180\u0026deg;C)\u003csup\u003e52\u003c/sup\u003e. By comparison, we developed a relatively mild route for \u003cb\u003e58\u003c/b\u003e, which involved a one-pot iodination/O-arylation of the commercially available \u003cb\u003e61\u003c/b\u003e with Koser's reagent \u003cb\u003e62\u003c/b\u003e, followed by a Sonogashira coupling/cyclization cascade.\u003c/p\u003e\u003cp\u003eThe advantage of our approach was once again demonstrated in the synthesis of CP-376395 (\u003cb\u003e63\u003c/b\u003e), an orally active clinical candidate of corticotropin-releasing factor 1 (CRF\u003csub\u003e1\u003c/sub\u003e) antagonist, which holds promise for treating depression, anxiety, and other stress-related neurological disorders\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ed, CP-376395 was previously synthesized in 7 steps with 32% overall yield, involving the S\u003csub\u003eN\u003c/sub\u003eAr reaction between a pyridine N-oxide and phenol, as well as the reduction of an ester group to a methyl group.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Even though useful, the previous route required the use of harsh or dangerous reagents, such as POCl\u003csub\u003e3\u003c/sub\u003e, PCl\u003csub\u003e3\u003c/sub\u003e, AlCl\u003csub\u003e3\u003c/sub\u003e, LiAlH\u003csub\u003e4\u003c/sub\u003e, and urea-HOOH. In contrast, our synthetic route (5 steps, 38% total yield) considerably addressed these issues, commencing with a mild S\u003csub\u003eN\u003c/sub\u003eAr between \u003cb\u003e64\u003c/b\u003e and \u003cb\u003e65\u003c/b\u003e, decarboxylation, one-pot iodination/O-arylation (51% yield), and a Suzuki\u0026ndash;Miyaura cross-coupling with easily available MeB(OH)\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e\n\u003ch3\u003eMechanistic considerations\u003c/h3\u003e\n\u003cp\u003eTo elucidate the reaction mechanism, a crossover experiment employing two structurally similar substrates (\u003cb\u003e3\u003c/b\u003e and \u003cb\u003e66\u003c/b\u003e) was performed (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). A mixture of two conserved products (\u003cb\u003e5\u003c/b\u003e and \u003cb\u003e67\u003c/b\u003e) was detected, with no crossover products observed. This result provides evidence for the involvement of an intramolecular aryl migration pathway.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThis study also systematically investigates the divergent aryl migration selectivity of diaryliodonium salts bearing dual nucleophilic sites under distinct reaction conditions through density functional theory (DFT) calculations. All geometry optimizations were performed at the B3LYP-GD3(BJ) /def2-SVP level using Gaussian 16 A03, with subsequent single-point energy calculations conducted via the M06-2X/def2-TZVP method (see Supplementary information for full details). The potential energy surfaces presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e were generated under implicit solvent model (SMD, solvent\u0026thinsp;=\u0026thinsp;ethanol) and an explicit-implicit hybrid solvent model for ionic liquid systems, respectively, to account for the interaction of ionic liquid.\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn the \u003cem\u003et\u003c/em\u003e-BuOLi-mediated system, mechanistic analysis reveals a kinetically controlled N-arylation pathway (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea). The reaction initiates through deprotonation of the acidic hydroxyl group by \u003cem\u003et\u003c/em\u003e-BuOLi. Due to the significantly higher acidity of the hydroxyl proton compared to the amine proton, the bulky strong base \u003cem\u003et\u003c/em\u003e-BuOLi preferentially and irreversibly deprotonates the hydroxyl group. This reaction leads to the formation of the intermediate \u003cb\u003eLi-IM1\u003c/b\u003e, in which Li\u003csup\u003e+\u003c/sup\u003e ion is coordinated by two oxygen atoms from the \u003cem\u003ep\u003c/em\u003e-toluenesulfonyl group. This coordination stabilizes the eight-membered ring intermediate (\u003cb\u003eLi-IM1\u003c/b\u003e) with a substantial 61.4 kcal/mol energy. Subsequent nucleophilic attack on the iodonium-bound phenyl group by the amine proceeds via transition state \u003cb\u003eLi-TS\u003c/b\u003e with an activation barrier of 31.4 kcal/mol. This is identified as the rate-determining step. The resulting intermediate \u003cb\u003eLi-IM2\u003c/b\u003e undergoes an intramolecular proton transfer, followed by the elimination of LiOTs, ultimately yielding the N-arylated product.\u003c/p\u003e\u003cp\u003eConversely, the ionic liquid (\u003cb\u003eIL-5\u003c/b\u003e)/K₂CO₃ system exhibits O-arylation selectivity (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eb). The reaction commences with nucleophilic displacement of the OTs group by a carbonate ion on the cationic intermediate (\u003cb\u003eON-IM1\u003c/b\u003e), thereby generating \u003cb\u003eNO-IM2\u003c/b\u003e. Two distinct proton transfer pathways then occur from NH\u003csub\u003e2\u003c/sub\u003e and OH of \u003cb\u003eNO-IM2\u003c/b\u003e, producing the intermediates \u003cb\u003eO-IM3\u003c/b\u003e and \u003cb\u003eN-IM3\u003c/b\u003e, respectively. Computational analysis reveals that \u003cb\u003eO-IM3\u003c/b\u003e is thermodynamically more stable than \u003cb\u003eN-IM3\u003c/b\u003e by 3.9 kcal/mol. This stability difference primarily stems from the stronger acidity of pyridinone group compared to the amine, as well as more significant hydrogen-bonding interactions within the dialkylimidazolium cation. Whereas, due to the rapid nature of proton transfer, the interconversion between these intermediates remains reversible. Subsequently, aryl migration transition to oxygen is favored over nitrogen, with an energy barrier of 24.6 kcal/mol. The energy difference of 3.0 kcal/mol between the two pathways aligns with the experimental observations, in which only the O-arylation product is detected. Following aryl migration, elimination of the imidazolium bicarbonate moiety to form the final product releases an energy of 13.5 kcal/mol (\u003cb\u003eO-IM4\u003c/b\u003e) and 5.2 kcal/mol (\u003cb\u003eN-IM4\u003c/b\u003e), respectively.\u003c/p\u003e\u003cp\u003eThese computational findings indicate that the observed O-selectivity in ionic liquids arises primarily from thermodynamic stabilization of oxygen-centered intermediates. The mechanistic analysis between the two systems\u0026mdash;kinetic control via lithium coordination in protic media versus thermodynamic control through hydrogen-bonding interactions in ionic liquids\u0026mdash;provide critical insights for designing regioselective arylation strategies.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe have developed a novel approach utilizing pyridones and Koser’s reagent for the synthesis of 2- and 4-aryloxypyridines featuring an iodine handle—a class of platform molecules that, despite their synthetic versatility, have been underexplored and remain challenging to access. The success of this transformation hinges critically on the regioselective aryl migration of in situ-generated pyridone-based aryliodonium salts. This novel class of heterocyclic aryliodonium salts contains dual vicinal nucleophilic N and O sites, and we have demonstrated for the first time that using ionic liquid as solvent can exclusively transfer the aryl group from iodine to the strategic O site. The present reaction can be performed on a gram scale with good yield and is applicable to substrates exhibiting diverse electronic and steric properties, as well as complex molecular architectures. Moreover, it is also effective with pyrimidones, yielding iodine-substituted etravirine analogs. Importantly, we have also demonstrated that the resulting products, which retain both iodine and amino functional handles, are suitable for downstream derivatizations, enabling extensive exploration of the untapped chemical space of medically important pyridyl ethers. The effectiveness of this approach is further illustrated through the concise synthesis of two pharmaceutical intermediates and the CRF\u003csub\u003e1\u003c/sub\u003e antagonist CP-376395, avoiding the need for high-temperature S\u003csub\u003eN\u003c/sub\u003eAr. DFT calculations are performed to elucidate the aryl migration regioselectivity, offering critical insights into the design of regioselective arylation strategies. This facile transformation tolerates air and moisture and does not require the use of any sophisticated catalysts/ligands, which might find wide synthetic applications in both pharmaceutical industry and academic research.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Methods","content":"\u003ch2\u003eGeneral procedure for the synthesis of aryloxypyridines/pyrimidines\u003c/h2\u003e\u003cp\u003ePyridones/pyrimidines (0.2 mmol, 1.0 equiv.), Koser’s reagent (0.22 mmol, 1.1 equiv.) were added into a Schlenk tube in EtOH (1 mL), and the reaction mixture was stirred at 0 \u003csup\u003eo\u003c/sup\u003eC for 1 h. After the reaction completed, the solvent was removed under vacuum condition. Subsequently, K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (0.2 mmol, 28 mg, 1.0 equiv.) and \u003cb\u003eIL-5\u003c/b\u003e ([Bmim][OTf], 1 mL) were added to above reaction mixture. The resulting reaction mixture was stirred at 90 \u003csup\u003eo\u003c/sup\u003eC for 5.5 h. After the reaction completed, the resulting solvent was diluted with H\u003csub\u003e2\u003c/sub\u003eO and extracted with EA (3 times). Finally, the combined organic phase was evaporated and dried, and then purified by column chromatography on silica gel (PE/DCM/EA: 4/1/1, v/v/v) to give the desired product.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe online version contains Supplementary material available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.org/xxxxxxxxx\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ch2\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003eS.M. designed the project. H.T. and S.M. directed the project. L.Z. and M.H. performed the experiments. Z.X. helped collecting experimental data. S.M. and L.S. wrote the manuscript. L.Z. and S.M. prepared the Supplementary Information. L.Z. and M.H. contributed equally to this work. L.S. supervised the DFT study. W.M. performed the calculations. All authors discussed the results and commented on the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe gratefully acknowledge the National Natural Science Foundation of China (22203023), the Key-Area Research and Development Program of Guangdong Province (2023B1111050008), and the Natural Science Foundation of Guangdong Province (2024A1515011051). This work was also supported by the Shenzhen Bay Laboratory Supercomputing Center.\u003c/p\u003e\n\u003ch3\u003eData availability\u003c/h3\u003e\n\u003cp\u003eCrystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre under the deposition numbers CCDC 2450244 (\u003cstrong\u003e3\u003c/strong\u003e), 2450246 (\u003cstrong\u003e4\u003c/strong\u003e), 2450245 (\u003cstrong\u003e5\u003c/strong\u003e) and 2450247 (\u003cstrong\u003e21\u003c/strong\u003e). Copies of the data can be obtained free of charge via \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ccdc.cam.ac.uk/structures/\u003c/span\u003e\u003c/span\u003e. The experimental procedures, characterization of new compounds, and all other data supporting the findings are available in the Supplementary Information. Data supporting the findings of this manuscript are also available from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBraun M-G et al (2024) Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model. J Med Chem 67:8708\u0026ndash;8729\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartini ML et al (2019) Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci 10:4160\u0026ndash;4182\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLetavic MA et al (2010) Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development. 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J Phys Chem B 116:9122\u0026ndash;9129\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":false,"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-7844273/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7844273/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile 2- and 4-aryloxypyridines are ubiquitous in pharmaceutical molecules, efficient synthetic strategies\u0026mdash;especially for synthesizing scaffolds with diverse multiple substituents on the pyridine core\u0026mdash;remain limited. Here we report a hook-and-slide strategy for constructing these scaffolds, involving the in-situ generation of pyridonyl(aryl)iodonium salts from pyridones and Koser\u0026rsquo;s reagent (hook, C3 selectivity), followed by an iodine-to-oxygen aryl migration (slide, O selectivity). Such newly designed iodonium salts feature dual vicinal nucleophilic sites, and we demonstrate that using ionic liquids can exclusively transfer the aryl group to the strategic O site. This approach is transition-metal-free, scalable, and applicable to substrates with diverse electronic and steric properties or complex structures. Importantly, the resulting products retain\u0026thinsp;\u0026minus;\u0026thinsp;I and \u0026minus;\u0026thinsp;NH\u003csub\u003e2\u003c/sub\u003e handles that are amenable to downstream derivatizations, enabling extensive exploration of previously inaccessible chemical space. The utility of this approach is further demonstrated through the concise synthesis of two pharmaceutical intermediates and a CRF\u003csub\u003e1\u003c/sub\u003e antagonist, CP-376395.\u003c/p\u003e","manuscriptTitle":"Harnessing regioselective aryl migration of pyridone-based aryl-λ3‑iodonium salts to access iodine-substituted aryloxypyridines","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 07:56:04","doi":"10.21203/rs.3.rs-7844273/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1fd85231-aef0-4759-9234-8a8bb6db8d06","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56583621,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"},{"id":56583622,"name":"Physical sciences/Chemistry/Green chemistry/Ionic liquids"}],"tags":[],"updatedAt":"2025-11-20T10:24:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 07:56:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7844273","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7844273","identity":"rs-7844273","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}