Adaptive Alcohols-Alcohols Cross-Coupling via TFA Catalysis: Access of Unsymmetrical Ethers

Adaptive Alcohols-Alcohols Cross-Coupling via TFA Catalysis: Access of Unsymmetrical Ethers | 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 Research Article Adaptive Alcohols-Alcohols Cross-Coupling via TFA Catalysis: Access of Unsymmetrical Ethers Chengxiu Liu, Jiaxin Liang, Yuqiu Liang, Lu Ouyang, Youchun Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5218466/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Jan, 2025 Read the published version in BMC Chemistry → Version 1 posted 10 You are reading this latest preprint version Abstract Ethers are high value organic compounds widely applied in chemical industry, natural products, material, pharmaceuticals, argochemicals, as well as modern organic synthesis. Herein, we report an adaptive TFA-catalyzed cross-coupling of alcohols with various oxygen nucleophiles (nitro-, halogen-, sulfur-, nitrogen-, aryl-, and alkynyl-substituted aliphatic alcohols), delivering diverse unsymmetrical ethers under mild conditions and simple operation. This protocol features a broad range of substrate scope and high catalytic efficiency (52 examples, up to 99% yield). The decagram scale performance and one-step synthesis of drug molecules evidenced the potential industrial production and practicability of this protocol. Unsymmetrical etherification Alcohol-alcohol cross-coupling Catalytic nucleophilic substitution Introduction Ethers are high value organic compounds, which are widely used in chemical industry, natural products, material, pharmaceuticals, argochemicals, as well as modern organic synthesis (Scheme 1 ) [ 1 – 5 ]. In this content, the antihistamine compounds of ( S )-Neobenodine and Bepotastine are representatives of this class of molecules [ 6 ]. Traditional strategies for ether synthesis include Williamson etherification [ 7 , 8 ], Ullman reaction [ 9 , 10 ], as well as Buchwald-Harting C-O coupling [ 11 , 12 ]. However, the requirement of strong base, metal catalysts, undesired waste salts, and competing β -H elimination of halides hindered the practical applications of these methods. In addition, the preparation of toxic halide precursors from corresponding alcohols also reduced the step and atom efficiencies. Avoiding the traditional drawbacks of etherification, direct etherification is an alternative solution to address the aforementioned issues, the by-product of which just loses an equivalent of H 2 O. In this regard, the acid-mediated condensation of alcohols was recognized as the oldest method for the symmetrical ether synthesis. Nevertheless, the harsh conditions and the indispensable of strong acid also limited the application of this protocol. It is known that hydroxyl group (-OH), which is a useful synthetic handle for divers transformation, due to the high stability, low toxicity and wide availability of alcohols [ 13 , 14 ]. Recently, direct substitution of alcohols via OH-activation is not only identified as a critical issue by the ACS Green Chemistry Institute [ 15 ], but also emphasized as a key green chemistry research area by American Chemical Society Pharmaceutical Roundtable [ 16 ]. However, the poor leaving ability of -OH makes the direct substitution of -OH for final valuable products difficult, which needs pre-functionalization (Scheme 2 A) [ 17 ]. Therefore, direct substitution of alcohols with H 2 O as an only byproduct is consistent with the requirements of green chemistry [ 18 , 19 ]. Therefore, catalytic nucleophilic substitution of alcohols by transition metal catalysis via π-complexes [ 20 ] or hydrogen borrowing [ 21 – 25 ], and direct substitution using Lewis basic [ 21 – 28 ] or Lewis/Brønsted acidic catalysts [ 29 – 31 ] were developed for this purpose (Scheme 2 B). In recent decades, significant progress has been achieved in this field with active allylic alcohols, and propargylic alcohols as the electrophilicity parameters and different atom centers (C, N, O, S) as nucleophiles. For instance, the direct nucleophilic substitution of two different alcohols was realized by the catalytic system of organoboron B(C 6 H 5 ) 3 [ 32 ], F 5 C 6 B(OH) 2 ) [ 33 ], Fe (Fe(OTf) 2 [ 34 ], FeCl 2 ·4H 2 O) [ 35 ], ReBr(CO) 5 [ 36 ], NIS [ 37 ], Ph 2 CHBr [ 38 ], Zr(Cp) 2 (CF 3 SO 3 ) 2 [ 39 ], [(C 6 H 5 )(PCy 3 )(CO)RuH] + BF 4 − [ 40 ]. Despite great achievements have been made in direct nucleophilic substitution of allylic/propargyl alcohols, a general, mild, and green method for catalytic nucleophilic substitution of benzylic alcohols with protonic acid as catalyst is rare and in highly desirable. Very recently, we reported coupling reactions via benzylic carbocation process under acid conditions [ 41 – 43 ]. Based on the previous work, we envisioned the benzylic carbocation can be trapped not only by electron-rich nucleophiles, but also by alcohols containing lone-electron pairs. Herein, we presented an adaptive TFA-catalyzed cross-coupling of alcohols with various oxygen nucleophiles (nitro-, halogen-, sulfur-, nitrogen-, aryl-, and alkynyl-substituted aliphatic alcohols), delivering diverse unsymmetrical ethers under mild conditions and simple operation (Scheme 2 C). This protocol features a broad range of substrate scope and H 2 O as only byproduct. Results and Discussion The cross-coupling of diphenyl methanol ( 1a ) and nitro ethanol ( 2a ) was employed as model reaction to explore the optimal reaction conditions (Table 1 ). Firstly, the solvents were screened (Table 1 , entries 1–7) using trifluoroacetic acid (TFA) as catalyst, which found that dichloroethane (DCE) and p -xylene showed the optimal reaction medias, delivering the desired ether product of 3aa in full conversions (Table 1 , entries 5 and 6). Similar excellent yields of the corresponding 3aa were afforded even lowering the equivalent of nitro ethanol ( 2a ) (Table 1 , entries 8 and 9). In contrast, none of the target product 3aa was given without TFA (Table 1 , entry 10). The choice of acids was proven to be markedly affected the yield of this cross-coupling transformation (Table 1 , entries 11–14). The loading of TFA and reaction temperature also had influence on the yield of the reaction (Table 1 , entries 15–19), with 0.4 equivalent of TFA at 80 o C being the optimal conditions (Table 1 , entry 16). Table 1 Optimization of reaction conditions a Entry 2a (equiv.) Cat. (equiv.) Solvent Temp. (℃) Yield of 3aa (%) b 1 3 TFA (1.0) H 2 O 80 33 2 3 TFA (1.0) MeCN 80 68 3 3 TFA (1.0) THF 80 99 4 3 TFA (1.0) DMF 80 - 5 3 TFA (1.0) DCE 80 > 99 6 3 TFA (1.0) p -xylene 80 > 99 7 3 TFA (1.0) dioxane 80 20 8 1 TFA (1.0) DCE 80 93 9 2 TFA (1.0) DCE 80 97 10 3 - DCE 80 nr 11 3 TCA (1.0) DCE 80 92 12 3 PFPA (1.0) DCE 80 > 99 13 3 CAA (1.0) DCE 80 54 14 3 T f OH (1.0) DCE 80 31 15 3 TFA (0.2) DCE 80 96 16 3 TFA (0.4) DCE 80 > 99 (87) c 17 3 TFA (0.4) DCE 40 48 18 3 TFA (0.4) DCE 60 90 19 3 TFA (0.4) DCE 100 79 a Reaction conditions: 1a (0.5 mmol), with 2a reacted under air for 12 hours (TFA = CF 3 CO 2 H, TCA = CCl 3 CO 2 H, PFPA = CF 3 CF 2 CO 2 H, CAA = ClCH 2 CO 2 H). b The yield was determined by NMR method using 1,3,5-trimethoxybenzene as the internal standard. c Isolated yield of 3aa . With the optimized conditions in hand, the scope of this alcohol-alcohol cross- coupling was investigated. As shown in Scheme 3 , using nitro ethanol ( 2a ) as nucleophile, various diphenyl alcohols could be cross-coupled to unsymmetric aryl ethers, affording the corresponding products 3ba - 3ja in good to excellent yields. Diphenyl alcohols with electron-donating groups, such as methyl ( 1b , 1c and 1h ) and methoxy ( 1f and 1g ), and electron-withdrawing groups, including fluorine ( 1i ), bromine ( 1e ), and chlorine ( 1d and 1j ), were component cross-coupling partners. Notably, similar excellent yield of the product ( 3ka ) was observed when the more sterically hindered alcohol of 9-phenyl-9 H -fluoren-9-ol ( 1k ) was loaded as substrate. Moreover, introducing the aryl allyl alcohol in this system gave the corresponding cross coupling product ( 3la ) in 93% yield. Mono-aryl alcohols were also tolerated as well under these standard conditions, delivering the coupling products ( 3ma-3xa ) in good to excellent yields. For instance, the 2-naphthalene ethanol ( 1m ) and phenyl ethanols ( 1n-1q ) gave the desired products ( 3ma , 3na-3qa ) in good to excellent yields just extending the reaction time. However, only moderate yields of the ether products ( 3ra-3wa ) were produced using longer chain of phenyl alkyl alcohols ( 1r-1w ) as substrates even under conditions of prolonged reaction time. Similar results were showcased when aryl cyclic and aliphatic alcohols ( 1x and 1y ) were utilized as substrates. Noteworthily, triphenyl methanol could be coupled efficiently to afford the corresponding the cross-coupling ether product ( 3za ) in 80% yield. Next, the scope of the nucleophiles of aliphatic alcohols in this TFA-catalyzed cross-coupling using diphenyl methanol ( 1a ) as substrate was also investigated (Scheme 4 ). As showcased in Scheme 4 , various substituted halogenated ethanols ( 2b - 2e , 2l ) reacted smoothly with diphenyl methanol ( 1a ), offering the desired ether products ( 3ab - 3ae , 3al ) in high yields. Notably, the substituted straight-chain halogenated propanols could produce the coupling products with similar high yields, while the branch-chain gave the desired product ( 3ai ) in only moderate yield, comparable yield of product ( 3aj ) was afforded by using trifluoromethyl substituted propanol ( 1j ) as nucleophile. Notably, the cross-coupling of sulfur- and nitrogen-substituted aliphatic alcohols with diphenyl methanol ( 1a ) was explored, but almost both reactions offered the corresponding products ( 3ak and 3am ) in low yields. It should also be noted that alcohols bearing the aryl group were suitable nucleophiles in this cross-coupling system, delivering the products ( 3an - 3ay ) in differential yields. Moreover, alkynyl alcohols underwent this cross-coupling smoothly, providing the target products ( 3az , 3cc - 3cd ) in moderate to excellent yields. Isoxazolines are valuable molecules widely applied in the chemical and life science industries [ 44 ]. Firstly, a large scale at 50.0 mmol experiment of model reaction was performed under standard conditions, affording the 12.4 g cross-coupling product 3aa in 96% yield (Scheme 5a ). With the 3aa in hand, isoxazolines of 5aa - 5ac were synthesized under differential conditions (see the Supporting Information, Section D). The above results indicated that this cross-coupling showcased potential industrial production and these compounds can be used as important precursors of bioactive molecules. To investigate the applicability of this cross-coupling reaction in drug synthesis, the construction of Orphenadrine and Neobenodine was conducted (Scheme 6 ). As anticipated, the Orphenadrine and Neobenodine were obtained in 41% and 46% yield respectively via the cross-coupling of diphenyl methanols ( 1b and 1c ) with amino alcohol ( 4d ) under this standard conditions. Conclusion In summary, we had established adaptive TFA-catalyzed cross-coupling between various aryl alcohols-alcohols. This protocol produced diverse unsymmetrical aryl ethers in generally high yields with good functional group tolerance (56 examples, up to 99% yield). More importantly, the robustness of this TFA-catalyzed cross-coupling transformation was documented by decagram scale and one-step synthesis drug molecules. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding This work was funded by the Fundamental Research Funds for Gannan Medical University (QD202019, QD202106, TD202310), the Ganzhou Bureau of Science and Technology (2022-YB1402). Author Contribution Liu CX and Liang JX: conceptualization, methodology, data curation and original draft; Liang YQ: formal analysis; Ouyang L and Liu YC: project administration, funding acquisition, resources, supervision, review & editing. All authors read and approved the final manuscript. Acknowledgement Not applicable. Availability of data and materials The data underlying this study are available in the published article and its online supplementary material. References Mandal S, Mandal S, Ghosh SK, Sar P, Ghosh A, Saha R, Saha B. A review on the advancement of ether synthesis from organic solvent to water. RSC Adv. 2016;6:69605–14. Cook A, Newman SG. Alcohols as Substrates in Transition-Metal-Catalyzed Arylation, Alkylation, and Related Reactions. Chem Rev. 2024;124:6078–144. Pitsinos EN, Vidali VP, Couladouros EA. Diaryl Ether Formation in the Synthesis of Natural Products. Eur J Org Chem. 2011; 2011:1207-22. Liu B, Shi BF. Transition-metal-catalyzed etherification of unactivated C-H bonds. Tetrahedron Lett. 2015;56:15–22. Keerthi KK, Ujwaldev SM, Sindhu Kallikkakam S, Anilkumar G. Recent advances in the transition metal catalyzed etherification reactions. Tetrahedron. 2016;72:7393–407. Li K, Hu N, Luo R, Yuan W, Tang W. A Chiral Ruthenium-Monophosphine Catalyst for Asymmetric Addition of Arylboronic Acids to Aryl Aldehydes. J Org Chem. 2013;78:6350–55. Williamson AW. Theory of an Etherification. J Chem Soc 1852; 4:229–39. Larock RC. Comprehensive Organic Transformations. 2nd ed. New York: Wiley-VCH Verlag GmbH; 1996. Monnier F, Taillefer M, Catalytic C-C. Ullmann-Type Coupling Reactions. Angew Chem Int Ed. 2009;48:6954–71. Ley SV, Thomas AW. Modern Synthetic Methods for Copper-Mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S Bond Formation. Angew Chem Int Ed. 2003;42:5400–49. Hartwig JF. Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism. Angew Chem Int Ed. 1998;37:2046–67. Schlummer B, Scholz U, Palladium-Catalyzed C-N, Coupling C-O. -A Practical Guide from an Industrial Vantage Point. Adv Synth Catal. 2004: 3461599–626. Dryzhakov M, Richmond E, Moran J. Recent Advances in Direct Catalytic Dehydrative Substitution of Alcohols. Synthesis. 2016;48:935–59. Estopiná-Durán S, Taylor JE. Brønsted Acid-Catalysed Dehydrative Substitution Reactions of Alcohols. Chem Eur J. 2021;27:106–20. Constable DJC, Dunn PJ, Hayler JD, Humphrey GR, Leazer JJL, Linderman RJ, Lorenz K, Manley J, Pearlman BA, Wells A, Zaks A, Zhang TY. Key green chemistry research areas-a perspective from pharmaceutical manufacturers. Green Chem. 2007;9:411–20. Bryan MC, Dunn PJ, Entwistle D, Gallou F, Koenig SG, Hayler JD, Hickey MR, Hughes S, Kopach ME, Moine G, Richardson P, Roschangar F, Steven A, Weiberth FJ. Key Green Chemistry research areas from a pharmaceutical manufacturers’ perspective revisited. Green Chem. 2018;20:5082–103. Larock RC. Comprehensive organic transformations. Weinheim: Wiley-VCH; 2010. Newhouse T, Baran PS, Hoffmann RW. The economies of synthesis. Chem Soc Rev. 2009;38:3010–21. Wender PA, Verma VA, Paxton TJ, Pillow TH. Function-Oriented Synthesis, Step Economy, and Drug Design. Acc Chem Res. 2008;41:40–9. Sundararaju B, Achard M, Bruneau C. Transition metal catalyzed nucleophilic allylic substitution: activation of allylic alcohols via π-allylic species. Chem Soc Rev. 2012;41:4467–83. Hamid MHSA, Slatford PA, Williams JMJ. Borrowing Hydrogen in the Activation of Alcohols. Adv Synth Catal. 2007;349:1555–75. Dobereiner GE, Crabtree RH. Dehydrogenation as a Substrate-Activating Strategy in Homogeneous Transition-Metal Catalysis. Chem Rev. 2010;110:681–703. Huang F, Liu Z, Yu Z. C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation. Angew Chem Int Ed. 2016;55:862–75. Chelucci G. Ruthenium and Osmium Complexes in C-C Bond-Forming Reactions by Borrowing Hydrogen Catalysis. Coord Chem Rev. 2017;331:1–36. Corma A, Navas J, Sabater MJ. Advances in One-Pot Synthesis through Borrowing Hydrogen Catalysis. Chem Rev. 2018;118:1410–59. Huy PH. Lewis Base Catalysis Promoted Nucleophilic Substitutions-Recent Advances and Future Directions. Eur J Org Chem. 2020; 2020:10–27. Huy PL, Hauch T, Filbrich I. Lewis Base Catalyzed Nucleophilic Substitutions of Alcohols. Synlett. 2016;27:2631–6. Emer E, Sinisi R, Capdevila MG, Petruzziello D, De Vincentiis F, Cozzi PG. Direct Nucleophilic SN1-Type Reactions of Alcohols. Eur J Org Chem. 2011;2011:647–66. Ortiz R, Heerrera RP. Direct Substitution of Alcohols in Pure Water by Brønsted Acid Catalysis. Molecules. 2017;22:574. Sanz R, Martínez A, Miguel D, Álvarez-Gutiérrez JM, Rodríguez F. Brønsted Acid-Catalyzed Nucleophilic Substitution of Alcohols. Adv Synth Catal. 2006;348:1841–5. Baeza A, Nájera C. Recent Advances in the Direct Nucleophilic Substitution of Allylic Alcohols through SN1-Type Reactions. Synthesis. 2014;46:25–34. Meng SS, Wang Q, Huang GB, Lin LR, Zhao JL, Chan ASC. B(C 6 F 5 ) 3 catalyzed direct nucleophilic substitution of benzylic alcohols: an effective method of constructing C-O, C-S and C-C bonds from benzylic alcohols. RSC Adv. 2018;8:30946–9. Barreiro E, Sanz-Vidal A, Tan E, Lau SH, Sheppard TD, Díez-González S. HBF 4 -Catalysed Nucleophilic Substitutions of Propargylic Alcohols. Eur J Org Chem. 2015; 2015:7544-9. Zhang L, Gonzalez-de-Castro A, Chena C, Li F, Xi S, Xua L, Xiao J. Iron-catalyzed cross etherification of alcohols to form unsymmetrical benzyl ethers. Mol Catal. 2017;433:62–7. Slimi H, Litim Z, Ollevier T, Kraïem J. Eco-Friendly Homo- and Cross-Etherification of Benzyl Alcohols Catalyzed by Iron(II/III) Chloride in Propylene Carbonate as a Green and Recyclable Solvent. ACS Omega. 2023;8:44558–70. Biswas S, Samec JSM. The Efficiency of the Metal Catalysts in the Nucleophilic Substitution of Alcohols is Dependent on the Nucleophile and Not on the Electrophile. Chem Asian J. 2013;8:974–81. Ajvazi N, Stavber S. Direct Cross-Coupling of Alcohols with O-Nucleophiles Mediated by N-Iodosuccinimide as a Precatalyst under Mild Reaction Conditions. Catalysts. 2021; 11:858. Xu Q, Xie H, Chen P, Yu L, Chen J, Hu X. Organohalide-catalyzed dehydrative O-alkylation between alcohols: a facile etherification method for aliphatic ether synthesis. Green Chem. 2015;17:2774–9. Margarita C, Villo P, Tuñon H, Dalla-Santa O, Camaj D, Carlsson R, Lill M, Ramström A, Lundberg H. Zirconium-catalysed direct substitution of alcohols: enhancing the selectivity by kinetic analysis. Catal Sci Technol. 2021;11:7420–30. Kim J, Lee DH, Kalutharage N, Yi CS. Selective Catalytic Synthesis of Unsymmetrical Ethers from the Dehydrative Etherification of Two Different Alcohols. ACS Catal. 2014;4:3881–5. Luo R, Liang Y, Wang S, Liao J, Ouyang L. Iridium-catalyzed selective para-C-alkylation of anilines/phenols with aryl alkynes. J Catal. 2023;428:115184. Ouyang L, Liang Y, Wang S, Liao J, Luo R. Access of arylmethanes via iridium-catalyzed deoxygenative cross-coupling of aryl ketones with anilines/phenols. J Catal. 2024;433:115492. Liang Y, Liu C, Li Y, Ouyang L. TsOH-catalyzed dehydroxylative cross-coupling of alcohols with phenols: rapid access to propofol derivatives. RSC Adv. 2024;14:26857–62. Liao J, Ouyang L, Jin Q, Zhang J, Luo R. Recent advances in the oxime-participating synthesis of isoxazolines. Org Biomol Chem. 2020;18:4709–16. Schemes Schemes 1 to 6 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files GA.png Scheme1.png Scheme 1Represented bioactiveether molecules. Scheme2.png Scheme 2 Strategies for activation of alcohols for the synthesis of ether. Scheme3.png Scheme 3 Electrophilic substrate scope of aryl alcohols in TFA-catalyzed cross-coupling a a Reaction conditions: 1 (0.5 mmol) and 2a (3.0 equiv.) reacted in DCE (1.0 mL) at 80 o C under air. The yield was isolated yield. b TFA (1.0 equiv.), 100 ℃. Scheme4.png Scheme 4 Nucleophilic substrate scope of aliphatic alcohols in TFA-catalyzed cross-coupling a a Reaction conditions: 1a (0.5 mmol) and 2 (3.0 equiv.) reacted in DCE (1.0 mL) under air. The yield was isolated yield. b TFA (1.0 equiv.), 100 ℃. Scheme5.png Scheme 5 Gram-scale performance and product derivatization. Scheme6.png Scheme 6 One-step synthesis of Orphenadrine and Neobenodine. SI20241007.doc Cite Share Download PDF Status: Published Journal Publication published 12 Jan, 2025 Read the published version in BMC Chemistry → Version 1 posted Editorial decision: Revision requested 05 Dec, 2024 Reviews received at journal 02 Dec, 2024 Reviewers agreed at journal 22 Nov, 2024 Reviews received at journal 26 Oct, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers invited by journal 15 Oct, 2024 Editor invited by journal 14 Oct, 2024 Editor assigned by journal 07 Oct, 2024 Submission checks completed at journal 07 Oct, 2024 First submitted to journal 07 Oct, 2024 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5218466","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":389962454,"identity":"c91161ee-1c52-4382-a1cb-a037023cb61d","order_by":0,"name":"Chengxiu Liu","email":"","orcid":"","institution":"Gannan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chengxiu","middleName":"","lastName":"Liu","suffix":""},{"id":389962455,"identity":"8325fc10-0d7b-49da-b626-875e4c8e2ddc","order_by":1,"name":"Jiaxin Liang","email":"","orcid":"","institution":"Gannan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiaxin","middleName":"","lastName":"Liang","suffix":""},{"id":389962456,"identity":"726e2034-3fca-44fe-83fb-2ba17d34eaf3","order_by":2,"name":"Yuqiu Liang","email":"","orcid":"","institution":"Gannan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuqiu","middleName":"","lastName":"Liang","suffix":""},{"id":389962457,"identity":"28c1e981-89c5-496e-8f8b-6a61fb477ba6","order_by":3,"name":"Lu Ouyang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYFAC5uYHif/Y5NjY2w8Qq4WxzeADG58xH8+ZBKK1NEjOYJNLnCfhYECcBn6JxAZjHh6z9DYJhgSGHxXbCGuRnJHY8JhHIi23TbrxAGPPmduEtRjcANlicCy3TeZAAjNjG5FapHkS/qezSSQYEK9FcsYBtgTitUj2PGwz+NjAZtgGDOSDRPmFnz358IPEBjZ5+fb2gw9+VBChhUEgAcE+QIR6kDVEqhsFo2AUjIIRDAC2OzwjT/E96AAAAABJRU5ErkJggg==","orcid":"","institution":"Gannan Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lu","middleName":"","lastName":"Ouyang","suffix":""},{"id":389962458,"identity":"68b4bc8a-f9a4-4f7e-8645-4ef8689e151b","order_by":4,"name":"Youchun Li","email":"","orcid":"","institution":"Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Youchun","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-10-07 13:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5218466/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5218466/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13065-025-01379-4","type":"published","date":"2025-01-12T15:57:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73694155,"identity":"5c316eb8-6d32-4e80-a10c-269285944184","added_by":"auto","created_at":"2025-01-13 16:11:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":637264,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/a20ebe66-0aee-443c-ad07-d499934d3cf7.pdf"},{"id":72158580,"identity":"db6a9b61-eacf-4aa7-8795-d78b05544858","added_by":"auto","created_at":"2024-12-23 09:14:52","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":48722,"visible":true,"origin":"","legend":"","description":"","filename":"GA.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/09b7b02a90c9080e467d4f92.png"},{"id":72158581,"identity":"e623e3e9-efba-4e3d-b877-ce607b43fef9","added_by":"auto","created_at":"2024-12-23 09:14:52","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":54620,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1\u003c/strong\u003eRepresented bioactiveether molecules.\u003c/p\u003e","description":"","filename":"Scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/1c0159584c6fd0e28161c535.png"},{"id":72158579,"identity":"408d665a-117b-4190-ac86-852ddd0f6be7","added_by":"auto","created_at":"2024-12-23 09:14:52","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":112388,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2 \u003c/strong\u003eStrategies for activation of alcohols for the synthesis of ether.\u003c/p\u003e","description":"","filename":"Scheme2.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/604b508bc69916d00108737f.png"},{"id":72158582,"identity":"62b530d4-1eaf-492a-89fb-64b898b4aa72","added_by":"auto","created_at":"2024-12-23 09:14:53","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":47492,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3\u003c/strong\u003e Electrophilic substrate scope of aryl alcohols in TFA-catalyzed cross-coupling \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003csup\u003e \u003c/sup\u003eReaction conditions: \u003cstrong\u003e1\u003c/strong\u003e (0.5 mmol) and \u003cstrong\u003e2a \u003c/strong\u003e(3.0 equiv.) reacted in DCE (1.0 mL) at 80\u003csup\u003eo\u003c/sup\u003eC under air. The yield was isolated yield. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003csup\u003e \u003c/sup\u003eTFA (1.0 equiv.), 100 ℃.\u003c/p\u003e","description":"","filename":"Scheme3.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/c57e580cee657587539320d2.png"},{"id":72159040,"identity":"452fde9a-54f1-4eb0-a908-011a07ee6a40","added_by":"auto","created_at":"2024-12-23 09:22:59","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":58361,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 4\u003c/strong\u003e Nucleophilic substrate scope of aliphatic alcohols in TFA-catalyzed cross-coupling \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cem\u003ea \u003c/em\u003e\u003c/sup\u003eReaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e (0.5 mmol) and \u003cstrong\u003e2 \u003c/strong\u003e(3.0 equiv.) reacted in DCE (1.0 mL) under air. The yield was isolated yield. \u003csup\u003e\u003cem\u003eb \u003c/em\u003e\u003c/sup\u003eTFA (1.0 equiv.), 100 ℃.\u003c/p\u003e","description":"","filename":"Scheme4.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/394b52313dc84d3b4cf35c99.png"},{"id":72158586,"identity":"15d95420-0474-4563-b16a-5c9d88806197","added_by":"auto","created_at":"2024-12-23 09:14:59","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":55460,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 5 \u003c/strong\u003eGram-scale performance and product derivatization.\u003c/p\u003e","description":"","filename":"Scheme5.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/1d2c7bd35ae92642b1a50f5e.png"},{"id":72158578,"identity":"bc60f668-0d07-4c16-a396-5c319ecd8083","added_by":"auto","created_at":"2024-12-23 09:14:52","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":26781,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 6 \u003c/strong\u003eOne-step synthesis of Orphenadrine and Neobenodine.\u003c/p\u003e","description":"","filename":"Scheme6.png","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/afaad8e63f4566b6ab5a107f.png"},{"id":72158583,"identity":"4e1293ae-289f-4f38-bb65-d1cee669b33f","added_by":"auto","created_at":"2024-12-23 09:14:53","extension":"doc","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":60449758,"visible":true,"origin":"","legend":"","description":"","filename":"SI20241007.doc","url":"https://assets-eu.researchsquare.com/files/rs-5218466/v1/161621d5bf51262ca7b77eda.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adaptive Alcohols-Alcohols Cross-Coupling via TFA Catalysis: Access of Unsymmetrical Ethers","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEthers are high value organic compounds, which are widely used in chemical industry, natural products, material, pharmaceuticals, argochemicals, as well as modern organic synthesis (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In this content, the antihistamine compounds of (\u003cem\u003eS\u003c/em\u003e)-Neobenodine and Bepotastine are representatives of this class of molecules [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Traditional strategies for ether synthesis include Williamson etherification [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], Ullman reaction [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], as well as Buchwald-Harting C-O coupling [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the requirement of strong base, metal catalysts, undesired waste salts, and competing \u003cem\u003eβ\u003c/em\u003e-H elimination of halides hindered the practical applications of these methods. In addition, the preparation of toxic halide precursors from corresponding alcohols also reduced the step and atom efficiencies.\u003c/p\u003e \u003cp\u003eAvoiding the traditional drawbacks of etherification, direct etherification is an alternative solution to address the aforementioned issues, the by-product of which just loses an equivalent of H\u003csub\u003e2\u003c/sub\u003eO. In this regard, the acid-mediated condensation of alcohols was recognized as the oldest method for the symmetrical ether synthesis. Nevertheless, the harsh conditions and the indispensable of strong acid also limited the application of this protocol.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIt is known that hydroxyl group (-OH), which is a useful synthetic handle for divers transformation, due to the high stability, low toxicity and wide availability of alcohols [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Recently, direct substitution of alcohols via OH-activation is not only identified as a critical issue by the ACS Green Chemistry Institute [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], but also emphasized as a key green chemistry research area by American Chemical Society Pharmaceutical Roundtable [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, the poor leaving ability of -OH makes the direct substitution of -OH for final valuable products difficult, which needs pre-functionalization (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, direct substitution of alcohols with H\u003csub\u003e2\u003c/sub\u003eO as an only byproduct is consistent with the requirements of green chemistry [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, catalytic nucleophilic substitution of alcohols by transition metal catalysis via π-complexes [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] or hydrogen borrowing [\u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and direct substitution using Lewis basic [\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25 CR26 CR27\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] or Lewis/Br\u0026oslash;nsted acidic catalysts [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] were developed for this purpose (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). In recent decades, significant progress has been achieved in this field with active allylic alcohols, and propargylic alcohols as the electrophilicity parameters and different atom centers (C, N, O, S) as nucleophiles. For instance, the direct nucleophilic substitution of two different alcohols was realized by the catalytic system of organoboron B(C\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e5\u003c/sub\u003e)\u003csub\u003e3\u003c/sub\u003e [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], F\u003csub\u003e5\u003c/sub\u003eC\u003csub\u003e6\u003c/sub\u003eB(OH)\u003csub\u003e2\u003c/sub\u003e) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], Fe (Fe(OTf)\u003csub\u003e2\u003c/sub\u003e [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], FeCl\u003csub\u003e2\u003c/sub\u003e\u0026middot;4H\u003csub\u003e2\u003c/sub\u003eO) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], ReBr(CO)\u003csub\u003e5\u003c/sub\u003e [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], NIS [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], Ph\u003csub\u003e2\u003c/sub\u003eCHBr [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], Zr(Cp)\u003csub\u003e2\u003c/sub\u003e(CF\u003csub\u003e3\u003c/sub\u003eSO\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], [(C\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e5\u003c/sub\u003e)(PCy\u003csub\u003e3\u003c/sub\u003e)(CO)RuH]\u003csup\u003e+\u003c/sup\u003e BF\u003csub\u003e4\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Despite great achievements have been made in direct nucleophilic substitution of allylic/propargyl alcohols, a general, mild, and green method for catalytic nucleophilic substitution of benzylic alcohols with protonic acid as catalyst is rare and in highly desirable.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eVery recently, we reported coupling reactions via benzylic carbocation process under acid conditions [\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Based on the previous work, we envisioned the benzylic carbocation can be trapped not only by electron-rich nucleophiles, but also by alcohols containing lone-electron pairs. Herein, we presented an adaptive TFA-catalyzed cross-coupling of alcohols with various oxygen nucleophiles (nitro-, halogen-, sulfur-, nitrogen-, aryl-, and alkynyl-substituted aliphatic alcohols), delivering diverse unsymmetrical ethers under mild conditions and simple operation (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). This protocol features a broad range of substrate scope and H\u003csub\u003e2\u003c/sub\u003eO as only byproduct.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eThe cross-coupling of diphenyl methanol (\u003cstrong\u003e1a\u003c/strong\u003e) and nitro ethanol (\u003cstrong\u003e2a\u003c/strong\u003e) was employed as model reaction to explore the optimal reaction conditions (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Firstly, the solvents were screened (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 1\u0026ndash;7) using trifluoroacetic acid (TFA) as catalyst, which found that dichloroethane (DCE) and \u003cem\u003ep\u003c/em\u003e-xylene showed the optimal reaction medias, delivering the desired ether product of \u003cstrong\u003e3aa\u003c/strong\u003e in full conversions (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 5 and 6). Similar excellent yields of the corresponding \u003cstrong\u003e3aa\u003c/strong\u003e were afforded even lowering the equivalent of nitro ethanol (\u003cstrong\u003e2a\u003c/strong\u003e) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 8 and 9). In contrast, none of the target product \u003cstrong\u003e3aa\u003c/strong\u003e was given without TFA (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 10). The choice of acids was proven to be markedly affected the yield of this cross-coupling transformation (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 11\u0026ndash;14). The loading of TFA and reaction temperature also had influence on the yield of the reaction (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 15\u0026ndash;19), with 0.4 equivalent of TFA at 80 \u003csup\u003eo\u003c/sup\u003eC being the optimal conditions (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 16).\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Optimization of reaction conditions \u003cem\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e\u003cimg src=\"data:image/png;base64,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\" style=\"width: 486px;\"\u003e\u003c/sup\u003e\u003c/em\u003e\u003cbr\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEntry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e2a (equiv.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCat. (equiv.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSolvent\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTemp. (℃)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYield of 3aa\u003c/p\u003e\n \u003cp\u003e(%)\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMeCN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTHF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDMF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-xylene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edioxane\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enr\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTCA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePFPA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCAA (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003ef\u003c/sub\u003eOH (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;99 (87)\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFA (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u0026nbsp;\u003cem\u003ea\u003c/em\u003e\u0026nbsp;\u003c/sup\u003e Reaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e (0.5 mmol), with \u003cstrong\u003e2a\u003c/strong\u003e reacted under air for 12 hours (TFA\u0026thinsp;=\u0026thinsp;CF\u003csub\u003e3\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003eH, TCA\u0026thinsp;=\u0026thinsp;CCl\u003csub\u003e3\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003eH, PFPA\u0026thinsp;=\u0026thinsp;CF\u003csub\u003e3\u003c/sub\u003eCF\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003eH, CAA\u0026thinsp;=\u0026thinsp;ClCH\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003eH). \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e The yield was determined by NMR method using 1,3,5-trimethoxybenzene as the internal standard. \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e Isolated yield of \u003cstrong\u003e3aa\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eWith the optimized conditions in hand, the scope of this alcohol-alcohol cross- coupling was investigated. As shown in Scheme \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, using nitro ethanol (\u003cstrong\u003e2a\u003c/strong\u003e) as nucleophile, various diphenyl alcohols could be cross-coupled to unsymmetric aryl ethers, affording the corresponding products \u003cstrong\u003e3ba\u003c/strong\u003e-\u003cstrong\u003e3ja\u003c/strong\u003e in good to excellent yields. Diphenyl alcohols with electron-donating groups, such as methyl (\u003cstrong\u003e1b\u003c/strong\u003e, \u003cstrong\u003e1c\u003c/strong\u003e and \u003cstrong\u003e1h\u003c/strong\u003e) and methoxy (\u003cstrong\u003e1f\u003c/strong\u003e and \u003cstrong\u003e1g\u003c/strong\u003e), and electron-withdrawing groups, including fluorine (\u003cstrong\u003e1i\u003c/strong\u003e), bromine (\u003cstrong\u003e1e\u003c/strong\u003e), and chlorine (\u003cstrong\u003e1d\u003c/strong\u003e and \u003cstrong\u003e1j\u003c/strong\u003e), were component cross-coupling partners. Notably, similar excellent yield of the product (\u003cstrong\u003e3ka\u003c/strong\u003e) was observed when the more sterically hindered alcohol of 9-phenyl-9\u003cem\u003eH\u003c/em\u003e-fluoren-9-ol (\u003cstrong\u003e1k\u003c/strong\u003e) was loaded as substrate. Moreover, introducing the aryl allyl alcohol in this system gave the corresponding cross coupling product (\u003cstrong\u003e3la\u003c/strong\u003e) in 93% yield. Mono-aryl alcohols were also tolerated as well under these standard conditions, delivering the coupling products (\u003cstrong\u003e3ma-3xa\u003c/strong\u003e) in good to excellent yields. For instance, the 2-naphthalene ethanol (\u003cstrong\u003e1m\u003c/strong\u003e) and phenyl ethanols (\u003cstrong\u003e1n-1q\u003c/strong\u003e) gave the desired products (\u003cstrong\u003e3ma\u003c/strong\u003e, \u003cstrong\u003e3na-3qa\u003c/strong\u003e) in good to excellent yields just extending the reaction time. However, only moderate yields of the ether products (\u003cstrong\u003e3ra-3wa\u003c/strong\u003e) were produced using longer chain of phenyl alkyl alcohols (\u003cstrong\u003e1r-1w\u003c/strong\u003e) as substrates even under conditions of prolonged reaction time. Similar results were showcased when aryl cyclic and aliphatic alcohols (\u003cstrong\u003e1x\u003c/strong\u003e and \u003cstrong\u003e1y\u003c/strong\u003e) were utilized as substrates. Noteworthily, triphenyl methanol could be coupled efficiently to afford the corresponding the cross-coupling ether product (\u003cstrong\u003e3za\u003c/strong\u003e) in 80% yield.\u003c/p\u003e\n\u003cp\u003eNext, the scope of the nucleophiles of aliphatic alcohols in this TFA-catalyzed cross-coupling using diphenyl methanol (\u003cstrong\u003e1a\u003c/strong\u003e) as substrate was also investigated (Scheme \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAs showcased in Scheme \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, various substituted halogenated ethanols (\u003cstrong\u003e2b\u003c/strong\u003e-\u003cstrong\u003e2e\u003c/strong\u003e, \u003cstrong\u003e2l\u003c/strong\u003e) reacted smoothly with diphenyl methanol (\u003cstrong\u003e1a\u003c/strong\u003e), offering the desired ether products (\u003cstrong\u003e3ab\u003c/strong\u003e-\u003cstrong\u003e3ae\u003c/strong\u003e, \u003cstrong\u003e3al\u003c/strong\u003e) in high yields. Notably, the substituted straight-chain halogenated propanols could produce the coupling products with similar high yields, while the branch-chain gave the desired product (\u003cstrong\u003e3ai\u003c/strong\u003e) in only moderate yield, comparable yield of product (\u003cstrong\u003e3aj\u003c/strong\u003e) was afforded by using trifluoromethyl substituted propanol (\u003cstrong\u003e1j\u003c/strong\u003e) as nucleophile. Notably, the cross-coupling of sulfur- and nitrogen-substituted aliphatic alcohols with diphenyl methanol (\u003cstrong\u003e1a\u003c/strong\u003e) was explored, but almost both reactions offered the corresponding products (\u003cstrong\u003e3ak\u003c/strong\u003e and \u003cstrong\u003e3am\u003c/strong\u003e) in low yields. It should also be noted that alcohols bearing the aryl group were suitable nucleophiles in this cross-coupling system, delivering the products (\u003cstrong\u003e3an\u003c/strong\u003e-\u003cstrong\u003e3ay\u003c/strong\u003e) in differential yields. Moreover, alkynyl alcohols underwent this cross-coupling smoothly, providing the target products (\u003cstrong\u003e3az\u003c/strong\u003e, \u003cstrong\u003e3cc\u003c/strong\u003e-\u003cstrong\u003e3cd\u003c/strong\u003e) in moderate to excellent yields.\u003c/p\u003e\n\u003cp\u003eIsoxazolines are valuable molecules widely applied in the chemical and life science industries [\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e]. Firstly, a large scale at 50.0 mmol experiment of model reaction was performed under standard conditions, affording the 12.4 g cross-coupling product \u003cstrong\u003e3aa\u003c/strong\u003e in 96% yield (Scheme \u003cspan class=\"InternalRef\"\u003e5a\u003c/span\u003e). With the \u003cstrong\u003e3aa\u003c/strong\u003e in hand, isoxazolines of \u003cstrong\u003e5aa\u003c/strong\u003e-\u003cstrong\u003e5ac\u003c/strong\u003e were synthesized under differential conditions (see the Supporting Information, Section D). The above results indicated that this cross-coupling showcased potential industrial production and these compounds can be used as important precursors of bioactive molecules.\u003c/p\u003e\n\u003cp\u003eTo investigate the applicability of this cross-coupling reaction in drug synthesis, the construction of Orphenadrine and Neobenodine was conducted (Scheme \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). As anticipated, the Orphenadrine and Neobenodine were obtained in 41% and 46% yield respectively via the cross-coupling of diphenyl methanols (\u003cstrong\u003e1b\u003c/strong\u003e and \u003cstrong\u003e1c\u003c/strong\u003e) with amino alcohol (\u003cstrong\u003e4d\u003c/strong\u003e) under this standard conditions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we had established adaptive TFA-catalyzed cross-coupling between various aryl alcohols-alcohols. This protocol produced diverse unsymmetrical aryl ethers in generally high yields with good functional group tolerance (56 examples, up to 99% yield). More importantly, the robustness of this TFA-catalyzed cross-coupling transformation was documented by decagram scale and one-step synthesis drug molecules.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was funded by the Fundamental Research Funds for Gannan Medical University (QD202019, QD202106, TD202310), the Ganzhou Bureau of Science and Technology (2022-YB1402).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLiu CX and Liang JX: conceptualization, methodology, data curation and original draft; Liang YQ: formal analysis; Ouyang L and Liu YC: project administration, funding acquisition, resources, supervision, review \u0026amp; editing. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eThe data underlying this study are available in the published article and its online supplementary material.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMandal S, Mandal S, Ghosh SK, Sar P, Ghosh A, Saha R, Saha B. A review on the advancement of ether synthesis from organic solvent to water. RSC Adv. 2016;6:69605\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCook A, Newman SG. Alcohols as Substrates in Transition-Metal-Catalyzed Arylation, Alkylation, and Related Reactions. Chem Rev. 2024;124:6078\u0026ndash;144.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePitsinos EN, Vidali VP, Couladouros EA. Diaryl Ether Formation in the Synthesis of Natural Products. Eur J Org Chem. 2011; 2011:1207-22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu B, Shi BF. Transition-metal-catalyzed etherification of unactivated C-H bonds. Tetrahedron Lett. 2015;56:15\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeerthi KK, Ujwaldev SM, Sindhu Kallikkakam S, Anilkumar G. Recent advances in the transition metal catalyzed etherification reactions. Tetrahedron. 2016;72:7393\u0026ndash;407.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi K, Hu N, Luo R, Yuan W, Tang W. A Chiral Ruthenium-Monophosphine Catalyst for Asymmetric Addition of Arylboronic Acids to Aryl Aldehydes. J Org Chem. 2013;78:6350\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliamson AW. Theory of an Etherification. J Chem Soc 1852; 4:229\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLarock RC. Comprehensive Organic Transformations. 2nd ed. New York: Wiley-VCH Verlag GmbH; 1996.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonnier F, Taillefer M, Catalytic C-C. Ullmann-Type Coupling Reactions. Angew Chem Int Ed. 2009;48:6954\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLey SV, Thomas AW. Modern Synthetic Methods for Copper-Mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S Bond Formation. Angew Chem Int Ed. 2003;42:5400\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHartwig JF. Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism. Angew Chem Int Ed. 1998;37:2046\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchlummer B, Scholz U, Palladium-Catalyzed C-N, Coupling C-O. -A Practical Guide from an Industrial Vantage Point. Adv Synth Catal. 2004: 3461599\u0026ndash;626.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDryzhakov M, Richmond E, Moran J. Recent Advances in Direct Catalytic Dehydrative Substitution of Alcohols. Synthesis. 2016;48:935\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEstopin\u0026aacute;-Dur\u0026aacute;n S, Taylor JE. Br\u0026oslash;nsted Acid-Catalysed Dehydrative Substitution Reactions of Alcohols. Chem Eur J. 2021;27:106\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConstable DJC, Dunn PJ, Hayler JD, Humphrey GR, Leazer JJL, Linderman RJ, Lorenz K, Manley J, Pearlman BA, Wells A, Zaks A, Zhang TY. Key green chemistry research areas-a perspective from pharmaceutical manufacturers. Green Chem. 2007;9:411\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBryan MC, Dunn PJ, Entwistle D, Gallou F, Koenig SG, Hayler JD, Hickey MR, Hughes S, Kopach ME, Moine G, Richardson P, Roschangar F, Steven A, Weiberth FJ. Key Green Chemistry research areas from a pharmaceutical manufacturers\u0026rsquo; perspective revisited. Green Chem. 2018;20:5082\u0026ndash;103.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLarock RC. Comprehensive organic transformations. Weinheim: Wiley-VCH; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNewhouse T, Baran PS, Hoffmann RW. The economies of synthesis. Chem Soc Rev. 2009;38:3010\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWender PA, Verma VA, Paxton TJ, Pillow TH. Function-Oriented Synthesis, Step Economy, and Drug Design. Acc Chem Res. 2008;41:40\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSundararaju B, Achard M, Bruneau C. Transition metal catalyzed nucleophilic allylic substitution: activation of allylic alcohols via π-allylic species. Chem Soc Rev. 2012;41:4467\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamid MHSA, Slatford PA, Williams JMJ. Borrowing Hydrogen in the Activation of Alcohols. Adv Synth Catal. 2007;349:1555\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDobereiner GE, Crabtree RH. Dehydrogenation as a Substrate-Activating Strategy in Homogeneous Transition-Metal Catalysis. Chem Rev. 2010;110:681\u0026ndash;703.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang F, Liu Z, Yu Z. C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation. Angew Chem Int Ed. 2016;55:862\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChelucci G. Ruthenium and Osmium Complexes in C-C Bond-Forming Reactions by Borrowing Hydrogen Catalysis. Coord Chem Rev. 2017;331:1\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorma A, Navas J, Sabater MJ. Advances in One-Pot Synthesis through Borrowing Hydrogen Catalysis. Chem Rev. 2018;118:1410\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuy PH. Lewis Base Catalysis Promoted Nucleophilic Substitutions-Recent Advances and Future Directions. Eur J Org Chem. 2020; 2020:10\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuy PL, Hauch T, Filbrich I. Lewis Base Catalyzed Nucleophilic Substitutions of Alcohols. Synlett. 2016;27:2631\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEmer E, Sinisi R, Capdevila MG, Petruzziello D, De Vincentiis F, Cozzi PG. Direct Nucleophilic SN1-Type Reactions of Alcohols. Eur J Org Chem. 2011;2011:647\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrtiz R, Heerrera RP. Direct Substitution of Alcohols in Pure Water by Br\u0026oslash;nsted Acid Catalysis. Molecules. 2017;22:574.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanz R, Mart\u0026iacute;nez A, Miguel D, \u0026Aacute;lvarez-Guti\u0026eacute;rrez JM, Rodr\u0026iacute;guez F. Br\u0026oslash;nsted Acid-Catalyzed Nucleophilic Substitution of Alcohols. Adv Synth Catal. 2006;348:1841\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaeza A, N\u0026aacute;jera C. Recent Advances in the Direct Nucleophilic Substitution of Allylic Alcohols through SN1-Type Reactions. Synthesis. 2014;46:25\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeng SS, Wang Q, Huang GB, Lin LR, Zhao JL, Chan ASC. B(C\u003csub\u003e6\u003c/sub\u003eF\u003csub\u003e5\u003c/sub\u003e)\u003csub\u003e3\u003c/sub\u003e catalyzed direct nucleophilic substitution of benzylic alcohols: an effective method of constructing C-O, C-S and C-C bonds from benzylic alcohols. RSC Adv. 2018;8:30946\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarreiro E, Sanz-Vidal A, Tan E, Lau SH, Sheppard TD, D\u0026iacute;ez-Gonz\u0026aacute;lez S. HBF\u003csub\u003e4\u003c/sub\u003e-Catalysed Nucleophilic Substitutions of Propargylic Alcohols. Eur J Org Chem. 2015; 2015:7544-9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Gonzalez-de-Castro A, Chena C, Li F, Xi S, Xua L, Xiao J. Iron-catalyzed cross etherification of alcohols to form unsymmetrical benzyl ethers. Mol Catal. 2017;433:62\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlimi H, Litim Z, Ollevier T, Kra\u0026iuml;em J. Eco-Friendly Homo- and Cross-Etherification of Benzyl Alcohols Catalyzed by Iron(II/III) Chloride in Propylene Carbonate as a Green and Recyclable Solvent. ACS Omega. 2023;8:44558\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiswas S, Samec JSM. The Efficiency of the Metal Catalysts in the Nucleophilic Substitution of Alcohols is Dependent on the Nucleophile and Not on the Electrophile. Chem Asian J. 2013;8:974\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAjvazi N, Stavber S. Direct Cross-Coupling of Alcohols with O-Nucleophiles Mediated by N-Iodosuccinimide as a Precatalyst under Mild Reaction Conditions. Catalysts. 2021; 11:858.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu Q, Xie H, Chen P, Yu L, Chen J, Hu X. Organohalide-catalyzed dehydrative O-alkylation between alcohols: a facile etherification method for aliphatic ether synthesis. Green Chem. 2015;17:2774\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMargarita C, Villo P, Tu\u0026ntilde;on H, Dalla-Santa O, Camaj D, Carlsson R, Lill M, Ramstr\u0026ouml;m A, Lundberg H. Zirconium-catalysed direct substitution of alcohols: enhancing the selectivity by kinetic analysis. Catal Sci Technol. 2021;11:7420\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim J, Lee DH, Kalutharage N, Yi CS. Selective Catalytic Synthesis of Unsymmetrical Ethers from the Dehydrative Etherification of Two Different Alcohols. ACS Catal. 2014;4:3881\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo R, Liang Y, Wang S, Liao J, Ouyang L. Iridium-catalyzed selective para-C-alkylation of anilines/phenols with aryl alkynes. J Catal. 2023;428:115184.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOuyang L, Liang Y, Wang S, Liao J, Luo R. Access of arylmethanes via iridium-catalyzed deoxygenative cross-coupling of aryl ketones with anilines/phenols. J Catal. 2024;433:115492.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang Y, Liu C, Li Y, Ouyang L. TsOH-catalyzed dehydroxylative cross-coupling of alcohols with phenols: rapid access to propofol derivatives. RSC Adv. 2024;14:26857\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiao J, Ouyang L, Jin Q, Zhang J, Luo R. Recent advances in the oxime-participating synthesis of isoxazolines. Org Biomol Chem. 2020;18:4709\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 6 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccjo","sideBox":"Learn more about [BMC Chemistry](https://bmcchem.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ccjo/default.aspx","title":"BMC Chemistry","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Unsymmetrical etherification, Alcohol-alcohol cross-coupling, Catalytic nucleophilic substitution","lastPublishedDoi":"10.21203/rs.3.rs-5218466/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5218466/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEthers are high value organic compounds widely applied in chemical industry, natural products, material, pharmaceuticals, argochemicals, as well as modern organic synthesis. Herein, we report an adaptive TFA-catalyzed cross-coupling of alcohols with various oxygen nucleophiles (nitro-, halogen-, sulfur-, nitrogen-, aryl-, and alkynyl-substituted aliphatic alcohols), delivering diverse unsymmetrical ethers\u003cstrong\u003e \u003c/strong\u003eunder mild conditions and simple operation. This protocol features a broad range of substrate scope and high catalytic efficiency (52 examples, up to 99% yield). The decagram scale performance and one-step synthesis of drug molecules evidenced the potential industrial production and practicability of this protocol.\u003c/p\u003e","manuscriptTitle":"Adaptive Alcohols-Alcohols Cross-Coupling via TFA Catalysis: Access of Unsymmetrical Ethers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-23 09:14:46","doi":"10.21203/rs.3.rs-5218466/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-05T15:25:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-02T11:15:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"305165314994973051833164334091512310061","date":"2024-11-23T02:44:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-26T14:46:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30562315468587259475879278202332893019","date":"2024-10-21T12:17:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-15T11:21:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-14T10:49:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-08T03:21:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-08T03:18:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Chemistry","date":"2024-10-07T13:13:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccjo","sideBox":"Learn more about [BMC Chemistry](https://bmcchem.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ccjo/default.aspx","title":"BMC Chemistry","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6cea49cd-3b02-4533-8a78-1ef7943b53b7","owner":[],"postedDate":"December 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-13T16:05:52+00:00","versionOfRecord":{"articleIdentity":"rs-5218466","link":"https://doi.org/10.1186/s13065-025-01379-4","journal":{"identity":"bmc-chemistry","isVorOnly":false,"title":"BMC Chemistry"},"publishedOn":"2025-01-12 15:57:17","publishedOnDateReadable":"January 12th, 2025"},"versionCreatedAt":"2024-12-23 09:14:46","video":"","vorDoi":"10.1186/s13065-025-01379-4","vorDoiUrl":"https://doi.org/10.1186/s13065-025-01379-4","workflowStages":[]},"version":"v1","identity":"rs-5218466","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5218466","identity":"rs-5218466","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}