{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:17:48Z","timestamp":1790083068177,"version":"4.0.1"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["463498885"],"award-info":[{"award-number":["463498885"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>The use of organo-catalysis in continuous-flow reactor systems is gaining attention in medicinal chemistry due to its cost-effectiveness and reduced chemical waste. In this study, bioactive curcumin (CUM) derivatives were synthesized in a continuously operated microfluidic reactor (MFR), using piperidine-based polymeric networks as catalysts. Piperidine methacrylate and piperidine acrylate were synthesized and subsequently copolymerized with complementary monomers (MMA or DMAA) and crosslinkers (EGDMA or MBAM) via photopolymerization, yielding different polymeric networks. Initially, batch reactions were optimized for the organo-catalytic Knoevenagel condensation between CUM and 4-nitrobenzaldehyde, under various conditions, in the presence of polymer networks. Conversion was assessed using offline 1H NMR spectroscopy, revealing an increase in conversion with enhanced swelling properties of the polymer networks, which facilitated greater accessibility of catalytic sites. In continuous-flow MFR experiments, optimized polymer gel dots exhibited superior catalytic performance, achieving a conversion of up to 72%, compared to other compositions. This improvement was attributed to the enhanced swelling in the reaction mixture (DMSO\/methanol, 7:3 v\/v) at 40 \u00b0C over 72 h. Furthermore, the MFR system enabled the efficient synthesis of a series of CUM derivatives, demonstrating significantly higher conversion rates than traditional batch reactions. Notably, while batch reactions required 90% catalyst loading in the gel, the MFR system achieved a comparable or superior performance with only 50% catalyst, resulting in a higher turnover number. These findings underscore the advantages of continuous-flow organo-catalysis in enhancing catalytic efficiency and sustainability in organic synthesis.<\/jats:p>","DOI":"10.3390\/gels11040278","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T11:05:02Z","timestamp":1744110302000},"page":"278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis of Curcumin Derivatives via Knoevenagel Reaction Within a Continuously Driven Microfluidic Reactor Using Polymeric Networks Containing Piperidine as a Catalyst"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8772-6848","authenticated-orcid":false,"given":"Naresh","family":"Killi","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Rumpke","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6003-151X","authenticated-orcid":false,"given":"Dirk","family":"Kuckling","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20723","DOI":"10.1021\/acs.jmedchem.4c02736","article-title":"Natural Products Driven Medicinal Chemistry","volume":"67","author":"Bharate","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20091","DOI":"10.3390\/molecules191220091","article-title":"The chemistry of curcumin: From extraction to therapeutic agent","volume":"19","author":"Priyadarsini","year":"2014","journal-title":"Molecules"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4464","DOI":"10.1039\/C4NJ01936A","article-title":"Antibacterial non-woven nanofibers of curcumin acrylate oligomers","volume":"39","author":"Killi","year":"2015","journal-title":"New J. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fuloria, S., Mehta, J., Chandel, A., Sekar, M., Rani, N.N.I.M., Begum, M.Y., Subramaniyan, V., Chidambaram, K., Thangavelu, L., and Nordin, R. (2022). A Comprehensive Review on the Therapeutic Potential of Curcuma longa Linn. in Relation to its Major Active Constituent Curcumin. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.820806"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Giordano, A., and Tommonaro, G. (2019). Curcumin and Cancer. Nutrients, 11.","DOI":"10.3390\/nu11102376"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Arifian, H., Maharani, R., Megantara, S., Gazzali, A.M., and Muchtaridi, M. (2022). Amino-Acid-Conjugated Natural Compounds: Aims, Designs and Results. Molecules, 27.","DOI":"10.3390\/molecules27217631"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.foodchem.2009.10.047","article-title":"Curcumin\u2013amino acid conjugates: Synthesis, antioxidant and antimutagenic attributes","volume":"120","author":"Parvathy","year":"2010","journal-title":"Food Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ejmech.2012.05.020","article-title":"Synthesis and evaluation of antimicrobial activity of 4H-pyrimido2,1-bbenzothiazole, pyrazole and benzylidene derivatives of curcumin","volume":"54","author":"Sahu","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8260","DOI":"10.1021\/jm1004545","article-title":"Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-\u03baB signaling pathway","volume":"53","author":"Qiu","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1590\/s2175-97902017000400084","article-title":"Molecular docking, synthesis and in vitro antimalarial evaluation of certain novel curcumin analogues","volume":"53","author":"Dohutia","year":"2018","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.1021\/acs.jpcb.7b03191","article-title":"Mechanism of the Piperidine-Catalyzed Knoevenagel Condensation Reaction in Methanol: The Role of Iminium and Enolate Ions","volume":"121","author":"Dalessandro","year":"2017","journal-title":"J. Phys. Chem. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e202300053","DOI":"10.1002\/ejoc.202300053","article-title":"Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives","volume":"26","author":"Peterse","year":"2023","journal-title":"Eur. J. Org. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5623","DOI":"10.1007\/s11164-018-3444-7","article-title":"Four-component stereoselective synthesis of tetracyano-substituted piperidines","volume":"44","author":"Vereshchagin","year":"2018","journal-title":"Res. Chem. Intermed."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101212","DOI":"10.1016\/j.rechem.2023.101212","article-title":"Alternatives to piperidine in Knoevenagel condensation of 2-cyanoacetamide with benzaldehydes","volume":"6","author":"Stec","year":"2023","journal-title":"Results Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1039\/D2OB00135G","article-title":"An overview of metal-free sustainable nitrogen-based catalytic knoevenagel condensation reaction","volume":"20","author":"Johari","year":"2022","journal-title":"Org. Biomol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1007\/s10562-014-1297-2","article-title":"Piperidine and Piperazine Immobilized on Iron Oxide Nanoparticles as Magnetically Recyclable Heterogeneous Catalysts for One-Pot Synthesis of \u03b2-Phosphonomalonates","volume":"144","author":"Sobhani","year":"2014","journal-title":"Catal. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Miceli, M., Frontera, P., Macario, A., and Malara, A. (2021). Recovery\/Reuse of Heterogeneous Supported Spent Catalysts. Catalysts, 11.","DOI":"10.3390\/catal11050591"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1016\/j.materresbull.2012.05.015","article-title":"Synthesis and characterization of Piperidine-4-carboxylic acid functionalized Fe3O4 nanoparticles as a magnetic catalyst for Knoevenagel reaction","volume":"47","author":"Baykal","year":"2012","journal-title":"Mater. Res. Bull."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106689","DOI":"10.1016\/j.sab.2023.106689","article-title":"Analytical approach of elemental impurities in pharmaceutical products: A worldwide review","volume":"205","author":"Aleluia","year":"2023","journal-title":"Spectrochim. Acta Part B At. Spectrosc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"960","DOI":"10.2174\/1573412916999200711151147","article-title":"Metallic Impurities in Pharmaceuticals: An Overview","volume":"17","author":"Kushwaha","year":"2021","journal-title":"CPA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8996","DOI":"10.1021\/acsapm.2c01330","article-title":"Quinuclidine-Immobilized Porous Polymeric Microparticles as a Compelling Catalyst for the Baylis\u2013Hillman Reaction","volume":"4","author":"Kumar","year":"2022","journal-title":"ACS Appl. Polym. Mater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1002\/adsc.200606096","article-title":"Immobilization of Organic Catalysts: When, Why, and How","volume":"348","author":"Cozzi","year":"2006","journal-title":"Adv. Synth Catal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.molcata.2010.11.039","article-title":"Highly efficient mesoporous base catalyzed Knoevenagel condensation of different aromatic aldehydes with malononitrile and subsequent noncatalytic Diels\u2013Alder reactions","volume":"335","author":"Mondal","year":"2011","journal-title":"J. Mol. Catal. A Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6465","DOI":"10.1021\/acs.joc.9b00450","article-title":"Synthesis of Acrylamides via the Doebner-Knoevenagel Condensation","volume":"84","author":"Zacuto","year":"2019","journal-title":"J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5750","DOI":"10.1002\/anie.201400988","article-title":"Accessing new chemical entities through microfluidic systems","volume":"53","author":"Rodrigues","year":"2014","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5708","DOI":"10.1002\/chem.200305212","article-title":"Continuous flow techniques in organic synthesis","volume":"9","author":"Jas","year":"2003","journal-title":"Chemistry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1039\/C9BM00238C","article-title":"Microfluidics for silica biomaterials synthesis: Opportunities and challenges","volume":"7","author":"Hao","year":"2019","journal-title":"Biomater. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alias, A.B., Mishra, S., Pendharkar, G., Chen, C.-S., Liu, C.-H., Liu, Y.-J., and Yao, D.-J. (2022). Microfluidic Microalgae System: A Review. Molecules, 27.","DOI":"10.3390\/molecules27061910"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1002\/ejoc.202100268","article-title":"Direct Asymmetric Aldol Reaction in Continuous Flow Using Gel-Bound Organocatalysts","volume":"2021","author":"Schmiegel","year":"2021","journal-title":"Eur. J. Org. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1002\/ejoc.202100006","article-title":"Continuous Flow Synthesis of Azoxybenzenes by Reductive Dimerization of Nitrosobenzenes with Gel-Bound Catalysts","volume":"2021","author":"Schmiegel","year":"2021","journal-title":"Eur. J. Org. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Killi, N., Bartenbach, J., and Kuckling, D. (2023). Polymeric Networks Containing Amine Derivatives as Organocatalysts for Knoevenagel Reaction within Continuously Driven Microfluidic Reactors. Gels, 9.","DOI":"10.3390\/gels9030171"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1002\/ejoc.202000978","article-title":"Novel Application of Polymer Networks Carrying Tertiary Amines as a Catalyst Inside Microflow Reactors Used for Knoevenagel Reactions","volume":"2020","author":"Berg","year":"2020","journal-title":"Eur. J. Org. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rozhkova, Y.A., Burin, D.A., Galkin, S.V., and Yang, H. (2022). Review of Microgels for Enhanced Oil Recovery: Properties and Cases of Application. Gels, 8.","DOI":"10.3390\/gels8020112"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S1381-1169(01)00305-3","article-title":"Catalysis and polymer networks\u2014The role of morphology and molecular accessibility","volume":"177","author":"Simon","year":"2001","journal-title":"J. Mol. Catal. A Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1002\/macp.1991.021921010","article-title":"Phenyl-2,4,6-trimethylbenzoylphosphinates as water-soluble photoinitiators. Generation and reactivity of O\u1e56(C6H5)(O\u2212) radical anions","volume":"192","author":"Majima","year":"1991","journal-title":"Makromol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1039\/C8RE00180D","article-title":"Hydrogel\/enzyme dots as adaptable tool for non-compartmentalized multi-enzymatic reactions in microfluidic devices","volume":"4","author":"Simon","year":"2019","journal-title":"React. Chem. Eng."}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/11\/4\/278\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:12:10Z","timestamp":1760029930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/11\/4\/278"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,8]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["gels11040278"],"URL":"https:\/\/doi.org\/10.3390\/gels11040278","relation":{},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,8]]}}}