Zinc triflate catalyzed solvent free synthesis of coumarins

Zinc triflate catalyzed solvent free synthesis of coumarins | 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 Zinc triflate catalyzed solvent free synthesis of coumarins Swapnilkumar S Kale, Nilkesh K Dhurve, Shaikh Tanveer, Mohammad Ali, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8490346/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract The Pechmann condensation remains one of the most direct routes to coumarin frameworks; however, its efficiency is often compromised by harsh Brønsted acids or solvent effects. An expeditious and efficient protocol for Pechmann condensation has been described. The synthesis of coumarin using phenols and β-ketoesters with catalytic amount of zinc triflate under solvent free conditions afforded good to excellent yields of the coumarins. The described protocol is operationally simple and ecofriendly. Coumarins Pechmann condensation Solvent free synthesis Zinc triflate Figures Figure 1 1. Introduction Coumarins are ubiquitous scaffolds within the realm of medicinal chemistry. Coumarins and its derivatives finds application in variety of fields including pharmaceuticals[ 1 ], treatment of cancer[ 2 ] and Alzheimer’s disease[ 3 ], therapeutic phytochemicals[ 4 ], fluorescence sensors[ 5 ], etc. They also serves as precursors of many important heterocycles[ 6 ] and industrially important chemical compounds. The wide and diverse applications in medical sciences, biomedical research and industry made them a candidate of interest for the synthetic chemists. Some coumarins of the biological importance are depicted in Fig. 1 . Coumarin and its derivatives can be obtained from a variety of natural resources[ 13 ]; however, this is a time-consuming process. Organic chemists have focused a significant attraction on the development of methods for its preparation. The various synthetic strategies leading to the synthesis of coumarin moiety includes Pechmann condensation, Perkin reaction, Knoevenagel condensation, Baylis–Hillman reaction and Michael addition and C-H activation pathway[ 14 – 16 ]. The Pechmann method is considered to be important as it utilizes readily available phenols and β-ketoesters in different conditions to give coumarins in good yields. Various homogeneous and heterogeneous Brӧnsted acid catalysis has been employed which includes the use concentrated H 2 SO 4 [ 17 ], trifluoroacetic acid[ 18 ], Nafion resin[ 19 ] and sulfated zirconia[ 20 ]. A few ionic liquid catalyzed pathways are also developed such as cholinium ionic liquid[ 21 ], 1,10-butylenebispyridinium hydrogen sulfate[ 22 ] and 1-Butyl-3-methylimidazolium chloroaluminate[ 23 ]. Lewis acid catalysts and nanocatalysts such as AlCl 3 [ 24 ], MnSb 2 O 6 -chitosan nanocomposite[ 25 ], Fe 3 O 4 @C@PrS-SO 3 H[ 26 ] and zirconia-based heterogeneous catalysts[ 27 ] have also been employed. Organic synthesis catalyzed by zinc have become a viable substitute for the usage of more costly or hazardous transition metal[ 28 , 29 ]. Zn(OTf) 2 has several catalytic uses because of its great thermal stability, low toxicity, accessibility and affordability. The catalytic potential of Zn(OTf) 2 has been greatly explored by us[ 30 , 31 ] and others[ 32 – 35 ] for organic transformations including multicomponent reactions. With an aim to synthesis coumarins by Pechmann condensation, we report and expeditious and efficient protocol for the synthesis of coumarins using inexpensive Zn(OTf) 2 under solvent-free conditions. In this work, we report a systematic investigation of zinc triflate catalyzed Pechmann condensation of activated phenols with β-ketoesters under neat conditions. The study highlights the pronounced solvent-dependent behavior of Zn(OTf)₂ and demonstrates an efficient route to structurally diverse coumarin derivatives, including benzoylacetate-derived systems of synthetic and functional relevance. 2. Results and Discussion The effects of different factors, such as solvent, temperature, reaction duration, and catalyst quantity, were first investigated in order to identify optimum reaction conditions. Table 1 displays the results. Based on the literature reports on the use of Bronsted acid catalysts[18, 36], we tried l-proline nitrate for the initial reaction of resorcinol (1a) with ethyl acetoacetate (2a), but to our dismay it does not result in the desired product. This outcome can be attributed to excessive protonation of the phenolic oxygen under acidic conditions, which diminishes its nucleophilicity and hampers electrophilic aromatic substitution. This result prompted a shift toward Lewis acid catalysis. Zinc-based catalysts were subsequently evaluated, beginning with ZnO nanoparticles under solvent-free conditions. Although trace formation of product was detected, the reaction proceeded sluggishly and afforded only a low yield after extended reaction time. Zinc triflate displayed markedly improved catalytic performance under identical conditions, highlighting the importance of Lewis acidity and carbonyl activation in promoting the Pechmann condensation. The effect of temperature was then examined using zinc triflate as the catalyst. Raising the reaction temperature from room temperature to 60 °C resulted in a significant increase in product yield, while further elevation to 80 °C led to near-quantitative conversion within a short reaction time. Although increasing the temperature to 100 °C accelerated the reaction further, a slight decrease in isolated yield was observed, possibly due to competing side reactions or thermal decomposition. Consequently, 80 °C was identified as the optimal temperature. Catalyst loading studies revealed that 10 mol % of zinc triflate was sufficient to achieve high yields, while further reduction in catalyst loading led to incomplete conversion. Increasing the catalyst amount beyond 20 mol % did not result in appreciable yield enhancement, indicating that the reaction is not limited by catalyst availability under optimized conditions. A noteworthy observation emerged from solvent screening experiments. The use of polar protic (ethanol) and polar aprotic (acetonitrile) solvents led to a dramatic suppression of reactivity, even under otherwise optimized conditions. These results strongly suggest that solvent coordination to the zinc center interferes with effective Lewis acid–substrate interactions. In contrast, solvent-free conditions maximize direct contact between the catalyst and the β-ketoester, thereby facilitating carbonyl activation and subsequent cyclization. This pronounced solvent dependence highlights a key mechanistic distinction between Lewis acid and Brønsted acid mediated Pechmann condensation. With this optimum condition in hand for coumarin synthesis, zinc triflate's catalytic potential was investigated by examining its activity in the reaction of several activated phenols with β-keto esters as shown in Table 2. Table 2 shows that a variety of activated phenols with β-keto esters produced corresponding coumarins in good to excellent yields. A comparison between methyl and ethyl acetoacetate revealed that ethyl esters consistently afforded higher yields across a range of substrates. This trend may be attributed to more favorable transesterification and cyclization kinetics associated with the ethyl ester under Lewis acidic conditions. Notably, the synthesis of 4-methylumbelliferyl acetate and related derivatives was accomplished efficiently using this protocol. These compounds are of particular interest due to their established applications as fluorescent probes for the detection of acetylcholinesterase inhibitors[37], underscoring the functional relevance of the present methodology beyond simple coumarin synthesis. To further evaluate the scope of the protocol, ethyl benzoylacetate was employed as a more sterically demanding β-ketoesters. In these cases, efficient coumarin formation was achieved at 120 °C using the same catalyst loading under solvent-free conditions. The successful incorporation of aryl-substituted β-ketoesters demonstrates the robustness of the zinc triflate catalytic system and its tolerance toward steric and electronic variation. The mechanism of Pechmann condensation is well documented it the literature[38, 39]. We believe that Zn(OTf) 2 acts as a Lewis acid by coordinating to the carbonyl oxygen of the β-ketoester, thereby enhancing its electrophilicity and facilitating transesterification. Subsequent enolization and intramolecular electrophilic aromatic substitution lead to C–C bond formation, followed by cyclization and dehydration to afford the coumarin framework (Scheme 1). 3. Methods 3.1 General All chemical reagents, purchased from CDH India were of high purity and suitable for organic synthesis. Thin-layer chromatography (TLC) was performed using Merck Kieselgel 60 F254 precoated plates. The Rf values of the compounds were determined using an ethyl acetate-hexane mixture (20% or 30% as appropriate). All melting points of the synthetic compounds were determined in open capillary using Thiele’s tube and are uncorrected. ¹ H NMR spectra were obtained at 400 MHz using an Avance AV500 Spectrometer (Bruker) with CDCl 3 orDSMO-d6 as the solvent. Mass spectra were recorded on MALDI-TOF mass spectrometer. 3.2 Preparation of the catalyst Zinc Triflate was prepared following the procedure reported in the literature[40]. Triflic acid (0.056mol) was added drop wise to a suspension of zinc carbonate (0.02 mol) in dry methanol (20 ml) at room temperature. During the addition, CO 2 was evolved. The reaction mixture was stirred at 25 ° C for 20 min. and then refluxed for 2 h. The clear solution was cooled to 25 ° C and concentrated under reduced pressure. The resulting white powder was dried at 125 ° C for 2 h to afford Zn(OTf) 2 . 3.3 General procedure for the synthesis of the compounds (3a-m) A screw capped borosilicate vial (10 mL) was charged with substituted phenol (1a-h) (1 mmol, 1 equiv.), β-keto-ester (2a-c ) (1 mmol, 1 equiv.), zinc triflate (10 mol%, 0.1 equiv.). The reaction mixture was stirred at a specified temperature for the time indicated in Table 1 and 2. The progress of the reaction was monitored using TLC. After completion of the reaction the reaction mixture was diluted with ethyl acetate (2x5 mL) and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2x10 mL). the combined organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified on column chromatography using silica gel (60-120) and EtOAc: hexane (10 % to 20 %) as an eluent to afford coumarins (3a-m) . 3.3.1 7-Hydroxy-4-methyl coumarin (3a): Pale Yellow solid; yield 162 mg, 92 %; m. p. 231-232 °C (lit. 230-232 °C); Rf 0.515 (40% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 6.34 (s, 1H), 6.15 (d, J = 1.2 Hz, 1H), 2.41 (s, 3H). 3.3.2 7,8-Diydroxy-4-methyl coumarin (3b): Pale Yellow solid; yield 174 mg, 91 %; m. p. 242-243 °C (lit. 243-245 °C)[41]; Rf 0.35 (40% EtOAc:Hexane); 1 H NMR (400MHz, DMSO-d 6 ) δ 9.28 (br. s., 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.19 - 5.99 (m, 1H), 2.38 - 2.29 (m, 3H). 3.3.3 8-Hydroxy-4-methyl coumarin (3c): Pale Yellow solid; yield 132 mg, 75 %; m. p. 137-138 °C (lit. 137-139 °C)[42]; Rf 0.42(40% EtOAc:Hexane); 1 H NMR (400 MHz, ,DMSO-d 6 ) δ 7.54 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 2.2, 8.7 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 6.08 (s, 1H), 2.33 (s, 3H). 3.3.4 6-Nitro-4-methyl coumarin (3d): Yellow solid; yield 222 mg, 93 %; m. p. 151-152 °C (lit. 152-153 °C)[22]; Rf 0.36 (20% EtOAc:Hexane). 3.3.5 4-Methyl-2H-benzo[h]chromen-2-one (3e) Light brown solid; yield 160 mg, 76 %; m. p. 155-157 °C (lit. 155-156 °C)[42]; Rf 0.35 (20% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 – 8.51 (m, 1H), 7.94 – 7.83 (m, 1H), 7.70 (dd, J = 8.8, 3.4 Hz, 1H), 7.66 – 7.56 (m, 3H), 6.38 (s, ,1H), 2.53 (s, 3H). 3.3.6 4-Methyl coumarin (3f) Pale yellow solid; yield 120 mg, 75 %; m. p. 84-85 °C (lit. 83 °C)[43]; Rf 0.42 (20% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ): δ 7.64 (d, J = 8.4 Hz, 2H), 6.43 – 6.36 (m, 2H), 6.40 – 6.35 (m, 1H), 2.56 (s, 3H). 3.3.7 6-Hydroxy-4-methyl coumarin (3g): Pale yellow solid; yield 144 mg, 82 %; m. p. 242-244 °C (lit. 242-244 °C)[44]; Rf 0.19 (20% EtOAc:Hexane; HRMS (ESI): m/z [M+H] + calc. for C 10 H 9 O 3 177.0552, found 177.0258. 3.3.8 7-Hydroxy-4-phenyl coumarin (3h): Light brown solid; yield 200 mg, 84 %; m. p. 253-255 °C (lit. 254 °C)[45]; Rf 0.23(20% EtOAc:Hexane. 3.3.9 7,8-Diydroxy-4-phenyl coumarin (3i): Light brown solid; yield 173 mg, 68 %; m. p. 194-196 °C (lit. 196-198 °C)[46]; Rf 0.21 (20% EtOAc:Hexane); 1 H NMR (400MHz ,DMSO-d 6 ) δ 7.57 - 7.52 (m, 3H), 7.52 - 7.46 (m, 2H), 6.82 - 6.71 (m, 2H), 6.13 (s, 1H). 3.3.10 8-Hydroxy-4-phenyl coumarin (3j): Light brown solid; yield 195 mg, 82 %; m. p. 231-232 °C Rf 0.25(20% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 – 7.92 (m, 2H), 7.84 (d, J = 3.0 Hz, 1H), 7.58 – 7.48 (m, 5H), 7.31 (dd, J = 9.0, 3.0 Hz, 1H), 6.84 (s, 1H). 3.3.11 4,6,7-trimethyl coumarin (3k): Off white solid; yield 128 mg, 68 %; m. p. 171-173 °C (lit. 171-173 °C)[47]; Rf 0.4 (20% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (s, 1H), 7.12 (s, 1H), 6.22 (s, 1H), 2.41 (s, Hz, 3H), 2.35 (s, 3 H), 2.33 (s, 3H). 3.3.12 4-methylumbelliferyl acetate (3l): White solid; yield 152 mg, 71 %; m. p. 151-152 °C (lit. 152-153 °C)[48]; Rf 0.28 (20% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 8.6 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.26 (d, J = 1.1 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3 H). 3.3.13 4-methylumbelliferyl benzoate (3m): White solid; yield 188 mg, 67 %; m. p. 161-163 °C (lit. 161-163 °C)[48]; Rf 0.36 (20% EtOAc:Hexane); 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 - 8.18 (m, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.59 - 7.50 (m, 2H), 7.26 (d, J = 2.1 Hz, 1H), 7.22 (dd, J = 2.3, 8.6 Hz, 1H), 6.30 (d, J = 1.1 Hz, 1H), 2.47 (d, J = 1.1 Hz, 3H). 4. Conclusion In summary, a zinc triflate mediated Pechmann condensation has been developed for the efficient synthesis of coumarin derivatives under solvent-free conditions. The protocol enables the direct condensation of activated phenols with β-ketoesters using low catalyst loading and moderate reaction temperatures. Systematic evaluation of reaction parameters revealed a pronounced dependence of catalytic efficiency on the reaction environment, with coordinating solvents significantly suppressing reactivity. Zinc triflate promotes the transformation through effective carbonyl activation and facilitates transesterification and cyclization steps under neat conditions. The method exhibits broad substrate scope, including tolerance toward sterically demanding and aryl-substituted β-ketoesters, and enables access to functionally relevant coumarin derivatives such as umbelliferone-based fluorophores. This developed process has several of positive aspects, including high reaction speeds, great yields, avoidance of standard solvents, and green attributes due to the use of nontoxic catalysts. The catalyst's simplicity of handling and preparation, lower loading, and a straightforward experimental process are its noteworthy characteristics. The benefits of the current method include the catalyst's exceptional efficiency in sustainable and eco-friendly coumarin synthesis and its straightforward design. Declarations Supplementary information. Copies of 1 H NMR and mass spectra of the selected compounds are provided in the supporting information file. Acknowledgements. Tanveer shaikh is thankful to the University Grants Commission (UGC) for the award of the Junior Research Fellowship (JRF) (Award Letter No.211610055118 dated 19/04/2022) for the financial support during this research work. Ethical approval No human participants, animal trials, or protected/endangered plant species were involved in this study.. Consent to participate Not applicable Consent to Publish All authors approve publication of this manuscript. Data Availability All data generated or analyzed during this study are included in this published article Competing Interest The authors declare no competing interest. Funding No external funding was received. Author contribution SSK and NKD prepared original manuscript draft along with collection of sample and analysis. TS, MA, ABI, NSS and RRD contributed in preparation of catalyst, reaction optimization, library preparation, data curation and manuscript review, and editing. HSC was responsible for supervision, concept formulation, manuscript review and editing. All authors examined and consented to the final manuscript. All authors have read and agreed to the published version of the manuscripts. 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ARKIVOC 2007:18–23. https://doi.org/10.3998/ark.5550190.0008.f03 Shirini F, Yahyazadeh A, Mohammadi K (2015) A solvent-free synthesis of coumarins using 1,3-disulfonic acid imidazolium hydrogen sulfate as a reusable and effective ionic liquid catalyst. Res Chem Intermed 41:6207–6218. https://doi.org/10.1007/s11164-014-1733-3 Sánchez-Recillas A, Navarrete-Vázquez G, Hidalgo-Figueroa S, Rios MY, Ibarra-Barajas M, Estrada-Soto S (2014) Semisynthesis, ex vivo evaluation, and SAR studies of coumarin derivatives as potential antiasthmatic drugs. Eur J Med Chem 77:400–408. https://doi.org/https://doi.org/10.1016/j.ejmech.2014.03.029 Tables Tables 1 and 2 are available in the supplementary files section Scheme Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files CoumarinarticleSI.docx Scheme1.docx Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 16 Apr, 2026 Reviews received at journal 10 Apr, 2026 Reviewers agreed at journal 06 Apr, 2026 Reviewers agreed at journal 01 Apr, 2026 Reviews received at journal 23 Mar, 2026 Reviews received at journal 17 Mar, 2026 Reviewers agreed at journal 13 Mar, 2026 Reviewers agreed at journal 12 Mar, 2026 Reviews received at journal 20 Feb, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviewers invited by journal 03 Feb, 2026 Editor invited by journal 29 Jan, 2026 Editor assigned by journal 06 Jan, 2026 Submission checks completed at journal 06 Jan, 2026 First submitted to journal 31 Dec, 2025 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. 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Commerce College, Khamgaon","correspondingAuthor":false,"prefix":"","firstName":"Nilkesh","middleName":"K","lastName":"Dhurve","suffix":""},{"id":584987936,"identity":"e00168e2-09e3-4e50-b11b-58c35adeef70","order_by":2,"name":"Shaikh Tanveer","email":"","orcid":"","institution":"G S Science, Arts and Commerce College, Khamgaon","correspondingAuthor":false,"prefix":"","firstName":"Shaikh","middleName":"","lastName":"Tanveer","suffix":""},{"id":584987939,"identity":"10d446ee-b638-4ab6-b1c8-2dab012ed1c1","order_by":3,"name":"Mohammad Ali","email":"","orcid":"","institution":"G S Science, Arts and Commerce College, Khamgaon","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Ali","suffix":""},{"id":584987941,"identity":"58f49ce5-9736-4938-9814-b6819a023560","order_by":4,"name":"Abhijit B Ingle","email":"","orcid":"","institution":"G S Science, Arts and Commerce College, Khamgaon","correspondingAuthor":false,"prefix":"","firstName":"Abhijit","middleName":"B","lastName":"Ingle","suffix":""},{"id":584987944,"identity":"9a7ca395-1954-4cb6-bd38-bbfe8cac1916","order_by":5,"name":"Nilesh S Shelke","email":"","orcid":"","institution":"G S Science, Arts and Commerce College, Khamgaon","correspondingAuthor":false,"prefix":"","firstName":"Nilesh","middleName":"S","lastName":"Shelke","suffix":""},{"id":584987945,"identity":"b27ab585-04e3-43ff-9e42-7897b27cba35","order_by":6,"name":"Rohinee R Dharamkar","email":"","orcid":"","institution":"G S Science, Arts and Commerce College, Khamgaon","correspondingAuthor":false,"prefix":"","firstName":"Rohinee","middleName":"R","lastName":"Dharamkar","suffix":""},{"id":584987948,"identity":"b8314d7f-9ce7-491e-9dbd-c3ca39584b0a","order_by":7,"name":"Hemant S Chandak","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYDACCSjNDyISCojXYsAg2QDSYkCKFoMDEJow4J/dfHTDzx1/7I3Pr0788MCAQZ5f7AABS+4cS7vZe8YgcduNt5slgA4znDk7Ab8WA4kcsxu8bQYJZjfObgBpSTC4TVBL/rebf9sM7I1nnN38g0gtOWy3gbYwbuDv3UacLRI30sxuy7YZJ864wbvNIsFAgrBf+GckP7v5tk3Onr//7OabPyps5PmlCWhBsg+sUoKAKlT7DpCiehSMglEwCkYSAACzsUVwKQrHKQAAAABJRU5ErkJggg==","orcid":"","institution":"G S Science, Arts and Commerce College, Khamgaon","correspondingAuthor":true,"prefix":"","firstName":"Hemant","middleName":"S","lastName":"Chandak","suffix":""}],"badges":[],"createdAt":"2025-12-31 14:08:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8490346/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8490346/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101959816,"identity":"1e017968-b588-431e-8806-32b4573f4d5f","added_by":"auto","created_at":"2026-02-05 12:27:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43680,"visible":true,"origin":"","legend":"\u003cp\u003eSome coumarins of the biological importance\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8490346/v1/b207a3fd1cae7d7438e54034.png"},{"id":101959825,"identity":"a2ab9adc-6281-482b-8ec5-a9602eab22ea","added_by":"auto","created_at":"2026-02-05 12:27:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":743986,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8490346/v1/bb4ced91-3932-4dec-b125-12704a8cd435.pdf"},{"id":101959779,"identity":"7130a94d-f475-4968-b275-c91b6762d130","added_by":"auto","created_at":"2026-02-05 12:27:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":980352,"visible":true,"origin":"","legend":"","description":"","filename":"CoumarinarticleSI.docx","url":"https://assets-eu.researchsquare.com/files/rs-8490346/v1/d14d883ed03131c8a72c69be.docx"},{"id":101959815,"identity":"c2fefe4d-ff74-4c77-86de-4a552688df1d","added_by":"auto","created_at":"2026-02-05 12:27:16","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":108628,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8490346/v1/73abf1c0617f27b7af8687be.docx"},{"id":101959789,"identity":"d33d4823-b1d1-4867-932b-a8c6e95022b8","added_by":"auto","created_at":"2026-02-05 12:27:08","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":156381,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8490346/v1/b19feba9426770057cc96f5b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Zinc triflate catalyzed solvent free synthesis of coumarins","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCoumarins are ubiquitous scaffolds within the realm of medicinal chemistry. Coumarins and its derivatives finds application in variety of fields including pharmaceuticals[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], treatment of cancer[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and Alzheimer\u0026rsquo;s disease[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], therapeutic phytochemicals[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], fluorescence sensors[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], etc. They also serves as precursors of many important heterocycles[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and industrially important chemical compounds. The wide and diverse applications in medical sciences, biomedical research and industry made them a candidate of interest for the synthetic chemists.\u003c/p\u003e \u003cp\u003eSome coumarins of the biological importance are depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCoumarin and its derivatives can be obtained from a variety of natural resources[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]; however, this is a time-consuming process. Organic chemists have focused a significant attraction on the development of methods for its preparation. The various synthetic strategies leading to the synthesis of coumarin moiety includes Pechmann condensation, Perkin reaction, Knoevenagel condensation, Baylis\u0026ndash;Hillman reaction and Michael addition and C-H activation pathway[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The Pechmann method is considered to be important as it utilizes readily available phenols and β-ketoesters in different conditions to give coumarins in good yields. Various homogeneous and heterogeneous Brӧnsted acid catalysis has been employed which includes the use concentrated H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], trifluoroacetic acid[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], Nafion resin[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and sulfated zirconia[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A few ionic liquid catalyzed pathways are also developed such as cholinium ionic liquid[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], 1,10-butylenebispyridinium hydrogen sulfate[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and 1-Butyl-3-methylimidazolium chloroaluminate[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Lewis acid catalysts and nanocatalysts such as AlCl\u003csub\u003e3\u003c/sub\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], MnSb\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e6\u003c/sub\u003e-chitosan nanocomposite[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@C@PrS-SO\u003csub\u003e3\u003c/sub\u003eH[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and zirconia-based heterogeneous catalysts[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] have also been employed.\u003c/p\u003e \u003cp\u003eOrganic synthesis catalyzed by zinc have become a viable substitute for the usage of more costly or hazardous transition metal[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Zn(OTf)\u003csub\u003e2\u003c/sub\u003e has several catalytic uses because of its great thermal stability, low toxicity, accessibility and affordability. The catalytic potential of Zn(OTf)\u003csub\u003e2\u003c/sub\u003e has been greatly explored by us[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and others[\u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] for organic transformations including multicomponent reactions.\u003c/p\u003e \u003cp\u003eWith an aim to synthesis coumarins by Pechmann condensation, we report and expeditious and efficient protocol for the synthesis of coumarins using inexpensive Zn(OTf)\u003csub\u003e2\u003c/sub\u003e under solvent-free conditions. In this work, we report a systematic investigation of zinc triflate catalyzed Pechmann condensation of activated phenols with β-ketoesters under neat conditions. The study highlights the pronounced solvent-dependent behavior of Zn(OTf)₂ and demonstrates an efficient route to structurally diverse coumarin derivatives, including benzoylacetate-derived systems of synthetic and functional relevance.\u003c/p\u003e"},{"header":"2. Results and Discussion","content":"\u003cp\u003eThe effects of different factors, such as solvent, temperature, reaction duration, and catalyst quantity, were first investigated in order to identify optimum reaction conditions. Table 1 displays the results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on the literature reports on the use of Bronsted acid catalysts[18, 36], we tried l-proline nitrate for the initial reaction of resorcinol (1a) with ethyl acetoacetate (2a), but to our dismay it does not result in the desired product. This outcome can be attributed to excessive protonation of the phenolic oxygen under acidic conditions, which diminishes its nucleophilicity and hampers electrophilic aromatic substitution. This result prompted a shift toward Lewis acid catalysis. Zinc-based catalysts were subsequently evaluated, beginning with ZnO nanoparticles under solvent-free conditions. Although trace formation of product was detected, the reaction proceeded sluggishly and afforded only a low yield after extended reaction time. \u0026nbsp;Zinc triflate displayed markedly improved catalytic performance under identical conditions, highlighting the importance of Lewis acidity and carbonyl activation in promoting the Pechmann condensation. The effect of temperature was then examined using zinc triflate as the catalyst. Raising the reaction temperature from room temperature to 60 \u0026deg;C resulted in a significant increase in product yield, while further elevation to 80 \u0026deg;C led to near-quantitative conversion within a short reaction time. Although increasing the temperature to 100 \u0026deg;C accelerated the reaction further, a slight decrease in isolated yield was observed, possibly due to competing side reactions or thermal decomposition. Consequently, 80 \u0026deg;C was identified as the optimal temperature. Catalyst loading studies revealed that 10 mol % of zinc triflate was sufficient to achieve high yields, while further reduction in catalyst loading led to incomplete conversion. Increasing the catalyst amount beyond 20 mol % did not result in appreciable yield enhancement, indicating that the reaction is not limited by catalyst availability under optimized conditions.\u003c/p\u003e\n\u003cp\u003eA noteworthy observation emerged from solvent screening experiments. The use of polar protic (ethanol) and polar aprotic (acetonitrile) solvents led to a dramatic suppression of reactivity, even under otherwise optimized conditions. These results strongly suggest that solvent coordination to the zinc center interferes with effective Lewis acid\u0026ndash;substrate interactions. In contrast, solvent-free conditions maximize direct contact between the catalyst and the \u0026beta;-ketoester, thereby facilitating carbonyl activation and subsequent cyclization. This pronounced solvent dependence highlights a key mechanistic distinction between Lewis acid and Br\u0026oslash;nsted acid mediated Pechmann condensation.\u003c/p\u003e\n\u003cp\u003eWith this optimum condition in hand for coumarin synthesis, zinc triflate\u0026apos;s catalytic potential was investigated by examining its activity in the reaction of several activated phenols with \u0026beta;-keto esters as shown in\u0026nbsp;Table 2.\u0026nbsp;Table 2\u0026nbsp;shows that a variety of activated phenols with \u0026beta;-keto esters produced corresponding coumarins in good to excellent yields. A comparison between methyl and ethyl acetoacetate revealed that ethyl esters consistently afforded higher yields across a range of substrates. This trend may be attributed to more favorable transesterification and cyclization kinetics associated with the ethyl ester under Lewis acidic conditions.\u003c/p\u003e\n\u003cp\u003eNotably, the synthesis of 4-methylumbelliferyl acetate and related derivatives was accomplished efficiently using this protocol. These compounds are of particular interest due to their established applications as fluorescent probes for the detection of acetylcholinesterase inhibitors[37], underscoring the functional relevance of the present methodology beyond simple coumarin synthesis.\u003c/p\u003e\n\u003cp\u003eTo further evaluate the scope of the protocol, ethyl benzoylacetate was employed as a more sterically demanding \u0026beta;-ketoesters. In these cases, efficient coumarin formation was achieved at 120 \u0026deg;C using the same catalyst loading under solvent-free conditions. The successful incorporation of aryl-substituted \u0026beta;-ketoesters demonstrates the robustness of the zinc triflate catalytic system and its tolerance toward steric and electronic variation.\u003c/p\u003e\n\u003cp\u003eThe mechanism of Pechmann condensation is well documented it the literature[38, 39]. \u0026nbsp; We believe that Zn(OTf)\u003csub\u003e2\u0026nbsp;\u003c/sub\u003eacts as a Lewis acid by coordinating to the carbonyl oxygen of the \u0026beta;-ketoester, thereby enhancing its electrophilicity and facilitating transesterification. Subsequent enolization and intramolecular electrophilic aromatic substitution lead to C\u0026ndash;C bond formation, followed by cyclization and dehydration to afford the coumarin framework (Scheme 1).\u003c/p\u003e"},{"header":"3. Methods","content":"\u003ch2\u003e3.1\u0026nbsp;General\u003c/h2\u003e\n\u003cp\u003eAll chemical reagents, purchased from CDH India were of high purity and suitable for organic synthesis. Thin-layer chromatography (TLC) was performed using Merck Kieselgel 60 F254 precoated plates. The Rf values of the compounds were determined using an ethyl acetate-hexane mixture (20% or 30% as appropriate). \u0026nbsp;All melting points of the synthetic compounds were determined in open capillary using Thiele’s tube and are uncorrected. ¹\u003cem\u003eH\u003c/em\u003e NMR spectra were obtained at 400 MHz using an Avance AV500 Spectrometer (Bruker) with CDCl\u003csub\u003e3\u0026nbsp;\u003c/sub\u003eorDSMO-d6 as the solvent. Mass spectra were recorded on MALDI-TOF mass spectrometer.\u003c/p\u003e\n\u003ch2\u003e3.2\u0026nbsp;Preparation of the catalyst\u003c/h2\u003e\n\u003cp\u003eZinc Triflate was prepared following the procedure reported in the literature[40]. Triflic acid (0.056mol) was added drop wise to a suspension of zinc carbonate (0.02 mol) in dry methanol (20 ml) at room temperature. During the addition, CO\u003csub\u003e2\u003c/sub\u003e was evolved. The reaction mixture was stirred at 25\u003csup\u003e°\u003c/sup\u003eC for 20 min. and then refluxed for 2 h. The clear solution was cooled to 25\u003csup\u003e°\u003c/sup\u003eC and concentrated under reduced pressure. The resulting white powder was dried at 125\u003csup\u003e°\u003c/sup\u003eC for 2 h to afford Zn(OTf)\u003csub\u003e2\u003c/sub\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003ch2\u003e3.3\u0026nbsp;General procedure for the synthesis of the compounds (3a-m)\u003c/h2\u003e\n\u003cp\u003e\u0026nbsp;A screw capped borosilicate vial (10 mL) was charged with substituted phenol \u003cstrong\u003e(1a-h)\u003c/strong\u003e (1 mmol, 1 equiv.), β-keto-ester \u003cstrong\u003e(2a-c\u003c/strong\u003e) (1 mmol, 1 equiv.), zinc triflate (10 mol%, 0.1 equiv.). The reaction mixture was stirred at a specified temperature for the time indicated in Table 1 and 2. The progress of the reaction was monitored using TLC. After completion of the reaction the reaction mixture was diluted with ethyl acetate (2x5 mL) and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2x10 mL). the combined organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified on column chromatography using silica gel (60-120) and EtOAc: hexane (10 % to 20 %) as an eluent to afford coumarins \u003cstrong\u003e(3a-m)\u003c/strong\u003e. \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e3.3.1\u0026nbsp; \u0026nbsp;7-Hydroxy-4-methyl coumarin (3a):\u003c/h3\u003e\n\u003cp\u003ePale Yellow solid; yield 162 mg, 92 %; m. p. 231-232\u0026nbsp;°C (lit. 230-232\u0026nbsp;°C); Rf 0.515 (40% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.49 (d, \u003cem\u003eJ\u003c/em\u003e = 8.7 Hz, 1H), 6.92 (d, \u003cem\u003eJ\u003c/em\u003e = 2.5 Hz, 1H), 6.83 (dd, \u003cem\u003eJ\u003c/em\u003e = 8.7, 2.5 Hz, 1H), 6.34 (s, 1H), 6.15 (d, \u003cem\u003eJ\u003c/em\u003e = 1.2 Hz, 1H), 2.41 (s, 3H).\u003c/p\u003e\n\u003ch3\u003e3.3.2\u0026nbsp; \u0026nbsp;7,8-Diydroxy-4-methyl coumarin (3b):\u003c/h3\u003e\n\u003cp\u003ePale Yellow solid; yield 174 mg, 91 %; m. p. 242-243\u0026nbsp;°C (lit. 243-245\u0026nbsp;°C)[41]; Rf 0.35 (40% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.28 (br. s., 1H), 7.08 (d, \u003cem\u003eJ\u003c/em\u003e = 8.8 Hz, 1H), 6.81 (d, \u003cem\u003eJ\u003c/em\u003e = 8.8 Hz, 1H), 6.19 - 5.99 (m, 1H), 2.38 - 2.29 (m, 3H).\u003c/p\u003e\n\u003ch3\u003e3.3.3\u0026nbsp; \u0026nbsp;8-Hydroxy-4-methyl coumarin (3c):\u003c/h3\u003e\n\u003cp\u003ePale Yellow solid; yield 132 mg, 75 %; m. p. 137-138\u0026nbsp;°C (lit. 137-139 \u0026nbsp;°C)[42]; Rf 0.42(40% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, ,DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 7.54 (d, \u003cem\u003eJ\u003c/em\u003e = 8.6 Hz, 1H), 6.78 (dd, \u003cem\u003eJ\u003c/em\u003e = 2.2, 8.7 Hz, 1H), 6.68 (d, \u003cem\u003eJ\u003c/em\u003e = 2.1 Hz, 1H), 6.08 (s, 1H), 2.33 (s, 3H).\u003c/p\u003e\n\u003ch3\u003e3.3.4\u0026nbsp; \u0026nbsp;6-Nitro-4-methyl coumarin (3d):\u003c/h3\u003e\n\u003cp\u003eYellow solid; yield 222 mg, 93 %; m. p. 151-152\u0026nbsp;°C (lit. 152-153\u0026nbsp;°C)[22]; Rf 0.36 (20% EtOAc:Hexane).\u003c/p\u003e\n\u003ch3\u003e3.3.5\u0026nbsp; \u0026nbsp;4-Methyl-2H-benzo[h]chromen-2-one (3e)\u003c/h3\u003e\n\u003cp\u003eLight brown solid; yield 160 mg, 76 %; m. p. 155-157\u0026nbsp;°C (lit. 155-156\u0026nbsp;°C)[42]; Rf 0.35 (20% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.62 – 8.51 (m, 1H), 7.94 – 7.83 (m, 1H), 7.70 (dd, \u003cem\u003eJ\u003c/em\u003e = 8.8, 3.4 Hz, 1H), 7.66 – 7.56 (m, 3H), 6.38 (s, ,1H), 2.53 (s, 3H).\u003c/p\u003e\n\u003ch3\u003e3.3.6\u0026nbsp; \u0026nbsp;4-Methyl coumarin (3f)\u003c/h3\u003e\n\u003cp\u003ePale yellow solid; yield 120 mg, 75 %; m. p. 84-85\u0026nbsp;°C (lit. 83\u0026nbsp;°C)[43]; Rf 0.42 (20% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e): δ 7.64 (d, \u003cem\u003eJ\u003c/em\u003e = 8.4 Hz, 2H), 6.43 – 6.36 (m, 2H), 6.40 – 6.35 (m, 1H), 2.56 (s, 3H).\u003c/p\u003e\n\u003ch3\u003e3.3.7\u0026nbsp; \u0026nbsp;6-Hydroxy-4-methyl coumarin (3g):\u003c/h3\u003e\n\u003cp\u003ePale yellow solid; yield 144 mg, 82 %; m. p. 242-244\u0026nbsp;°C (lit. 242-244\u0026nbsp;°C)[44]; Rf 0.19 (20% EtOAc:Hexane; HRMS (ESI): m/z [M+H]\u003csup\u003e+\u003c/sup\u003e calc. for C\u003csub\u003e10\u003c/sub\u003eH\u003csub\u003e9\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e 177.0552, found 177.0258.\u003c/p\u003e\n\u003ch3\u003e3.3.8\u0026nbsp; \u0026nbsp; 7-Hydroxy-4-phenyl coumarin (3h):\u003c/h3\u003e\n\u003cp\u003eLight brown solid; yield 200 mg, 84 %; m. p. 253-255\u0026nbsp;°C (lit. 254\u0026nbsp;°C)[45]; Rf 0.23(20% EtOAc:Hexane.\u003c/p\u003e\n\u003ch3\u003e3.3.9\u0026nbsp; \u0026nbsp; 7,8-Diydroxy-4-phenyl coumarin (3i):\u003c/h3\u003e\n\u003cp\u003eLight brown solid; yield 173 mg, 68 %; m. p. 194-196\u0026nbsp;°C (lit. 196-198\u0026nbsp;°C)[46]; Rf 0.21 (20% EtOAc:Hexane); \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eH\u003c/em\u003e NMR (400MHz ,DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 7.57 - 7.52 (m, 3H), 7.52 - 7.46 (m, 2H), 6.82 - 6.71 (m, 2H), 6.13 (s, 1H).\u003c/p\u003e\n\u003ch3\u003e3.3.10\u0026nbsp; \u0026nbsp; \u0026nbsp;8-Hydroxy-4-phenyl coumarin (3j):\u003c/h3\u003e\n\u003cp\u003eLight brown solid; yield 195 mg, 82 %; m. p. 231-232\u0026nbsp;°C Rf 0.25(20% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.97 – 7.92 (m, 2H), 7.84 (d, \u003cem\u003eJ\u003c/em\u003e = 3.0 Hz, 1H), 7.58 – 7.48 (m, 5H), 7.31 (dd, \u003cem\u003eJ\u003c/em\u003e = 9.0, 3.0 Hz, 1H), 6.84 (s, 1H).\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e3.3.11\u0026nbsp; \u0026nbsp; \u0026nbsp; 4,6,7-trimethyl coumarin (3k):\u003c/h3\u003e\n\u003cp\u003eOff white solid; yield 128 mg, 68 %; m. p. 171-173\u0026nbsp;°C (lit. 171-173\u0026nbsp;°C)[47]; Rf 0.4 (20% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.33 (s, 1H), 7.12 (s, 1H), 6.22 (s, 1H), 2.41 (s, Hz, 3H), 2.35 (s, 3 H), 2.33 (s, 3H).\u003c/p\u003e\n\u003ch3\u003e3.3.12\u0026nbsp; \u0026nbsp; 4-methylumbelliferyl acetate (3l):\u003c/h3\u003e\n\u003cp\u003eWhite solid; yield 152 mg, 71 %; m. p. 151-152\u0026nbsp;°C (lit. 152-153\u0026nbsp;°C)[48]; Rf 0.28 (20% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.61 (d, \u003cem\u003eJ\u003c/em\u003e = 8.6 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.26 (d, \u003cem\u003eJ\u003c/em\u003e = 1.1 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3 H).\u003c/p\u003e\n\u003ch3\u003e3.3.13\u0026nbsp; \u0026nbsp; \u0026nbsp; 4-methylumbelliferyl benzoate (3m):\u003c/h3\u003e\n\u003cp\u003eWhite solid; yield 188 mg, 67 %; m. p. 161-163\u0026nbsp;°C (lit. 161-163\u0026nbsp;°C)[48]; Rf 0.36 (20% EtOAc:Hexane); \u003cem\u003e\u003csup\u003e1\u003c/sup\u003eH\u0026nbsp;\u003c/em\u003eNMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.26 - 8.18 (m, 2H), 7.67 (d, \u003cem\u003eJ\u003c/em\u003e = 8.6 Hz, 2H), 7.59 - 7.50 (m, 2H), 7.26 (d, \u003cem\u003eJ\u003c/em\u003e = 2.1 Hz, 1H), 7.22 (dd, \u003cem\u003eJ\u003c/em\u003e = 2.3, 8.6 Hz, 1H), 6.30 (d, \u003cem\u003eJ\u003c/em\u003e = 1.1 Hz, 1H), 2.47 (d, \u003cem\u003eJ\u003c/em\u003e = 1.1 Hz, 3H).\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eIn summary, a zinc triflate mediated Pechmann condensation has been developed for the efficient synthesis of coumarin derivatives under solvent-free conditions. The protocol enables the direct condensation of activated phenols with β-ketoesters using low catalyst loading and moderate reaction temperatures. Systematic evaluation of reaction parameters revealed a pronounced dependence of catalytic efficiency on the reaction environment, with coordinating solvents significantly suppressing reactivity.\u003c/p\u003e \u003cp\u003eZinc triflate promotes the transformation through effective carbonyl activation and facilitates transesterification and cyclization steps under neat conditions. The method exhibits broad substrate scope, including tolerance toward sterically demanding and aryl-substituted β-ketoesters, and enables access to functionally relevant coumarin derivatives such as umbelliferone-based fluorophores.\u003c/p\u003e \u003cp\u003eThis developed process has several of positive aspects, including high reaction speeds, great yields, avoidance of standard solvents, and green attributes due to the use of nontoxic catalysts. The catalyst's simplicity of handling and preparation, lower loading, and a straightforward experimental process are its noteworthy characteristics. The benefits of the current method include the catalyst's exceptional efficiency in sustainable and eco-friendly coumarin synthesis and its straightforward design.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupplementary information.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCopies of \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eH\u0026nbsp;\u003c/em\u003eNMR and mass spectra of the selected compounds are provided in the supporting information file.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTanveer shaikh is thankful to the University Grants Commission (UGC) for the award of the Junior Research Fellowship (JRF) (Award Letter No.211610055118 dated 19/04/2022) for the financial support during this research work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo human participants, animal trials, or protected/endangered plant species were involved in this study..\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors approve publication of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSSK and NKD prepared original manuscript draft along with collection of sample and analysis. TS, MA, ABI, NSS and RRD contributed in preparation of catalyst, reaction optimization, library preparation, data curation and manuscript review, and editing. \u0026nbsp;HSC was responsible for supervision, concept formulation, manuscript review and editing. All authors examined and consented to the final manuscript. All authors have read and agreed to the published version of the manuscripts.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNasr T, Bondock S, Youns M (2014) Anticancer activity of new coumarin substituted hydrazide\u0026ndash;hydrazone derivatives. Eur J Med Chem 76:539\u0026ndash;548. https://doi.org/https://doi.org/10.1016/j.ejmech.2014.02.026\u003c/li\u003e\n \u003cli\u003eAkkol EK, Gen\u0026ccedil; Y, Karpuz B, Sobarzo-S\u0026aacute;nchez E, Capasso R (2020) Coumarins and coumarin-related Compounds in Pharmacotherapy of Cancer. 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Nanoscale Res Lett 11:345. https://doi.org/10.1186/s11671-016-1525-3\u003c/li\u003e\n \u003cli\u003eKeerthi Krishnan K, Ujwaldev SM, Saranya S, Anilkumar G, Beller M (2019) Recent advances and perspectives in the synthesis of heterocycles via zinc catalysis. Adv Synth Catal 361:382\u0026ndash;404\u003c/li\u003e\n \u003cli\u003eEnthaler S, Wu X-F (2015) Zinc catalysis: applications in organic synthesis. John Wiley \u0026amp; Sons\u003c/li\u003e\n \u003cli\u003eSarode PB, Bahekar SP, Chandak HS (2016) Zn(OTf)\u0026lt;inf\u0026gt;2\u0026lt;/inf\u0026gt;-Mediated Expeditious and Solvent-Free Synthesis of Propargylamines via C-H Activation of Phenylacetylene. Synlett 27:. https://doi.org/10.1055/s-0035-1562114\u003c/li\u003e\n \u003cli\u003eSarode PB, Bahekar SP, Chandak HS (2016) Zn(OTf)\u0026lt;inf\u0026gt;2\u0026lt;/inf\u0026gt;-mediated C[sbnd]H activation: An expeditious and solvent-free synthesis of aryl/alkyl substituted quinolines. 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Curr Org Synth 14:272\u0026ndash;278\u003c/li\u003e\n \u003cli\u003eKhaligh NG (2012) Synthesis of coumarins via Pechmann reaction catalyzed by 3-methyl-1-sulfonic acid imidazolium hydrogen sulfate as an efficient, halogen-free and reusable acidic ionic liquid. Catal Sci Technol 2:1633\u0026ndash;1636. https://doi.org/10.1039/C2CY20196H\u003c/li\u003e\n \u003cli\u003eGainche M, Delporte N, Michelin C, Jagu E (2023) Fluorescent probe for the detection of acetylcholinesterase inhibitors using high performance thin layer chromatography effect-directed assay in complex matrices. J Chromatogr A 1708:464330. https://doi.org/https://doi.org/10.1016/j.chroma.2023.464330\u003c/li\u003e\n \u003cli\u003eDyrager C (2012) Design and Synthesis of Chalcone and Chromone Derivatives as Novel Anticancer Agents. Tesis doctoral.\u003c/li\u003e\n \u003cli\u003eKhan Y, Sadia H, Ali Shah SZ, Khan MN, Shah AA, Ullah N, Ullah MF, Bibi H, Bafakeeh OT, Khedher N Ben (2022) Classification, synthetic, and characterization approaches to nanoparticles, and their applications in various fields of nanotechnology: A review. Catalysts 12:1386\u003c/li\u003e\n \u003cli\u003eCorey EJ, Shimoji K (1983) Magnesium and zinc-catalyzed thioketalization. Tetrahedron Lett 24:169\u0026ndash;172\u003c/li\u003e\n \u003cli\u003eGhodke S, Chudasama U (2013) Solvent free synthesis of coumarins using environment friendly solid acid catalysts. Appl Catal A Gen 453:219\u0026ndash;226\u003c/li\u003e\n \u003cli\u003eKour M, Paul S (2017) A green and convenient approach for the one-pot solvent-free synthesis of coumarins and \u0026beta;-amino carbonyl compounds using Lewis acid grafted sulfonated carbon@ titania composite. Monatshefte f\u0026uuml;r Chemie-Chemical Mon 148:327\u0026ndash;337\u003c/li\u003e\n \u003cli\u003eGadakh SK, Dey S, Sudalai A (2015) Rh-catalyzed synthesis of coumarin derivatives from phenolic acetates and acrylates via C\u0026ndash;H bond activation. J Org Chem 80:11544\u0026ndash;11550\u003c/li\u003e\n \u003cli\u003eKour M, Paul S (2017) A green and convenient approach for the one-pot solvent-free synthesis of coumarins and b -amino carbonyl compounds using Lewis acid grafted sulfonated carbon @ titania composite. Monatshefte f\u0026uuml;r Chemie - Chem Mon 148:327\u0026ndash;337. https://doi.org/10.1007/s00706-016-1752-4\u003c/li\u003e\n \u003cli\u003eRosa IA, de Almeida L, Alves KF, Marques MJ, Fregnan AM, Silva CA, Giacoppo JOS, Ramalho TC, Carvalho DT, dos Santos MH (2017) Synthesis and in vitro evaluation of leishmanicidal activity of 7-hydroxy-4-phenylcoumarin derivatives. Med Chem Res 26:131\u0026ndash;139\u003c/li\u003e\n \u003cli\u003eKumar S, Saini A, Sandhu JS (2007) LiBr-mediated, solvent free von Pechmann reaction: facile and efficient method for the synthesis of 2\u003cem\u003eH\u003c/em\u003e-chromen-2-ones. ARKIVOC 2007:18\u0026ndash;23. https://doi.org/10.3998/ark.5550190.0008.f03\u003c/li\u003e\n \u003cli\u003eShirini F, Yahyazadeh A, Mohammadi K (2015) A solvent-free synthesis of coumarins using 1,3-disulfonic acid imidazolium hydrogen sulfate as a reusable and effective ionic liquid catalyst. Res Chem Intermed 41:6207\u0026ndash;6218. https://doi.org/10.1007/s11164-014-1733-3\u003c/li\u003e\n \u003cli\u003eS\u0026aacute;nchez-Recillas A, Navarrete-V\u0026aacute;zquez G, Hidalgo-Figueroa S, Rios MY, Ibarra-Barajas M, Estrada-Soto S (2014) Semisynthesis, ex vivo evaluation, and SAR studies of coumarin derivatives as potential antiasthmatic drugs. Eur J Med Chem 77:400\u0026ndash;408. https://doi.org/https://doi.org/10.1016/j.ejmech.2014.03.029\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the supplementary files section\u003c/p\u003e"},{"header":"Scheme","content":"\u003cp\u003eScheme 1 is 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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Chemistry](https://link.springer.com/journal/44371)","snPcode":"44371","submissionUrl":"https://submission.nature.com/new-submission/44371/3","title":"Discover Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Coumarins, Pechmann condensation, Solvent free synthesis, Zinc triflate","lastPublishedDoi":"10.21203/rs.3.rs-8490346/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8490346/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe Pechmann condensation remains one of the most direct routes to coumarin frameworks; however, its efficiency is often compromised by harsh Br\u0026oslash;nsted acids or solvent effects. An expeditious and efficient protocol for Pechmann condensation has been described. The synthesis of coumarin using phenols and β-ketoesters with catalytic amount of zinc triflate under solvent free conditions afforded good to excellent yields of the coumarins. The described protocol is operationally simple and ecofriendly.\u003c/p\u003e","manuscriptTitle":"Zinc triflate catalyzed solvent free synthesis of coumarins","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-05 12:26:49","doi":"10.21203/rs.3.rs-8490346/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-16T13:05:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-10T17:30:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"24554665751444139415856644292998067961","date":"2026-04-07T03:45:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56740885398162827213408174804189825197","date":"2026-04-01T08:34:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T04:02:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-17T06:53:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148670574489223727394392105114484173760","date":"2026-03-13T09:31:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"205002396670632676819093303312572999415","date":"2026-03-12T06:15:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-20T12:37:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"168571962195939100974551578230778585384","date":"2026-02-09T19:46:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-03T11:02:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-29T10:18:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-06T07:11:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-06T07:05:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Chemistry","date":"2025-12-31T14:03:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Chemistry](https://link.springer.com/journal/44371)","snPcode":"44371","submissionUrl":"https://submission.nature.com/new-submission/44371/3","title":"Discover Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"88d735f3-d3f3-42fe-b42c-913b328ef27b","owner":[],"postedDate":"February 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-05T12:26:51+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-05 12:26:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8490346","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8490346","identity":"rs-8490346","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}