{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T22:29:19Z","timestamp":1783117759630,"version":"3.54.6"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T00:00:00Z","timestamp":1699574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81960883"],"award-info":[{"award-number":["81960883"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["20224BAB203010"],"award-info":[{"award-number":["20224BAB203010"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["GJJ201504"],"award-info":[{"award-number":["GJJ201504"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["YB201903"],"award-info":[{"award-number":["YB201903"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["81960883"],"award-info":[{"award-number":["81960883"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20224BAB203010"],"award-info":[{"award-number":["20224BAB203010"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["GJJ201504"],"award-info":[{"award-number":["GJJ201504"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["YB201903"],"award-info":[{"award-number":["YB201903"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific Research Fund of Jiangxi Provincial Education Department","award":["81960883"],"award-info":[{"award-number":["81960883"]}]},{"name":"Scientific Research Fund of Jiangxi Provincial Education Department","award":["20224BAB203010"],"award-info":[{"award-number":["20224BAB203010"]}]},{"name":"Scientific Research Fund of Jiangxi Provincial Education Department","award":["GJJ201504"],"award-info":[{"award-number":["GJJ201504"]}]},{"name":"Scientific Research Fund of Jiangxi Provincial Education Department","award":["YB201903"],"award-info":[{"award-number":["YB201903"]}]},{"name":"Scientific Research Project of Gannan Medical University","award":["81960883"],"award-info":[{"award-number":["81960883"]}]},{"name":"Scientific Research Project of Gannan Medical University","award":["20224BAB203010"],"award-info":[{"award-number":["20224BAB203010"]}]},{"name":"Scientific Research Project of Gannan Medical University","award":["GJJ201504"],"award-info":[{"award-number":["GJJ201504"]}]},{"name":"Scientific Research Project of Gannan Medical University","award":["YB201903"],"award-info":[{"award-number":["YB201903"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel\u2013Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp2)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope.<\/jats:p>","DOI":"10.3390\/molecules28227522","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:46:47Z","timestamp":1699843607000},"page":"7522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel\u2013Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature"],"prefix":"10.3390","volume":"28","author":[{"given":"Juanjuan","family":"Gao","sequence":"first","affiliation":[{"name":"College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowen","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhui","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2487-707X","authenticated-orcid":false,"given":"Zhixi","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-8974","authenticated-orcid":false,"given":"Kai","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gannan Medical University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5628","DOI":"10.1021\/acs.jmedchem.9b00604","article-title":"CF2H, a functional group-dependent hydrogen-bond donor: Is it a more or less lipophilic bioisostere of OH, SH and CH3?","volume":"62","author":"Zafrani","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1021\/acs.jmedchem.5b00258","article-title":"Applications of Fluorine in Medicinal Chemistry","volume":"58","author":"Gillis","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4844","DOI":"10.1021\/acs.orglett.0c01671","article-title":"Free-radical-promoted Dehydrogenative coupling of polyfluorinated alcohol with quinone, chromone, and coumarin","volume":"22","author":"Liu","year":"2020","journal-title":"Org. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1021\/acs.jmedchem.6b01691","article-title":"Difluoromethyl bioisostere: Examining the \u201clipophilic hydrogen bond donor\u201d concept","volume":"60","author":"Zafrani","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1021\/acs.orglett.1c01177","article-title":"Synthesis of \u03b1-difluoromethyl aryl ketones through a photoredox difluoromethylation of enol silanes","volume":"23","author":"Zhang","year":"2021","journal-title":"Org. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7787","DOI":"10.1021\/acs.orglett.1c02819","article-title":"Visible-light-induced radical difluoromethylation\/cyclization of unactivated alkenes: Access to CF2H-substituted quinazolinones","volume":"23","author":"Chen","year":"2021","journal-title":"Org. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/s41467-020-14494-8","article-title":"Direct C-H difluoromethylation of heterocycles via organic photoredox catalysis","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_8","first-page":"4417","article-title":"Evaluation of the antitumor activity of gemcitabine (2\u2032,2\u2032-Difluoro-2\u2032-deox-ycytidine)","volume":"50","author":"Hertel","year":"1990","journal-title":"Cancer Res."},{"key":"ref_9","unstructured":"Rudd, M.T., Bennett, D.J., Wai, J., and Meng, Z. (2017). Homobispiperidinyl Derivatives as Liver X Receptor Beta Agonists, Compositions, and Their Use. (WO2017095758A1), Patent."},{"key":"ref_10","unstructured":"Tanaka, Y., Kikuchi, F., Yamamoto, T., Nakamura, M., Takami, K., Murakami, M., Daini, M., Wada, Y., Kakegawa, K., and Kasahara, T. (2021). Heterocyclic Compound for Gaucher Disease. (WO2021020363), Patent."},{"key":"ref_11","unstructured":"Wacker, D.A., Nara, S.J., Cheruku, S., Sarkunam, K., Jaipuri, F.A., Thangavel, S., Narayan, R., Bandreddy, S.R., Jogi, S., and Kathi, P.K. (2020). Substituted Bicyclic Compounds as Farnesoid X Receptor Modulators and Their Preparation. (WO2020168143), Patent."},{"key":"ref_12","unstructured":"Boisnard, S., El-Ahmad, Y., Fett, E., Halley, F., Nicolai, E., Tabart, M., Terrier, C., and Vivet, B. (2021). Preparation of Novel Substituted 6,7-Dihydro-5H-benzo[7]annulene Compounds as Inhibitors and Degraders of Estrogen Receptors. (WO2021063967), Patent."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5478","DOI":"10.1021\/acs.orglett.7b02828","article-title":"Copper-catalyzed synthesis of indol-3-yl \u03b1-(difluoromethyl)-\u03b1-(trifluoromethyl)carbinols: Construction of difluoromethylated sp3 carbon centers","volume":"19","author":"Zhang","year":"2017","journal-title":"Org. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14364","DOI":"10.1021\/acs.joc.2c01797","article-title":"Ruthenium-catalyzed ortho-C\u2013H hydroxyfluoroalkylation of arenes with fluorinated alcohols","volume":"87","author":"Liu","year":"2022","journal-title":"J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.2174\/1568026616666160506145539","article-title":"Medicinal attributes of imidazo[1,2-a]pyridine derivatives: An update","volume":"16","author":"Devi","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1021\/jm980330i","article-title":"A Novel Class of Orally Active Non-Peptide Bradykinin B2 Receptor Antagonists. 4. Discovery of Novel Frameworks Mimicking the Active Conformation","volume":"41","author":"Abe","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.bmc.2003.10.050","article-title":"Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands","volume":"12","author":"Okubo","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5850","DOI":"10.1016\/j.bmc.2012.07.052","article-title":"Antibacterial activities of Groebke\u2013Blackburn\u2013Bienaym\u00e9-derived imidazo[1,2-a]pyridin-3-amines","volume":"20","author":"Shukla","year":"2012","journal-title":"Biorg. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1021\/acsmedchemlett.5b00008","article-title":"Discovery of Imidazopyridine Derivatives as Highly Potent Respiratory Syncytial Virus Fusion Inhibitors","volume":"6","author":"Feng","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.bmc.2007.10.042","article-title":"Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines","volume":"16","author":"Ismail","year":"2008","journal-title":"Biorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1021\/jm101582z","article-title":"Design and synthesis of imidazopyridine analogues as inhibitors of phosphoinositide 3-kinase signaling and angiogenesis","volume":"54","author":"Kim","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9302","DOI":"10.1039\/D1NJ00704A","article-title":"Functionalization of imidazo[1,2-a]pyridines via radical reactions","volume":"45","author":"Ma","year":"2021","journal-title":"New J. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29766","DOI":"10.1039\/C5RA02888D","article-title":"Direct trifluoromethylation of imidazoheterocycles in a recyclable medium at room temperature","volume":"38","author":"Ji","year":"2015","journal-title":"RSC Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1021\/acs.orglett.1c00031","article-title":"TEMPO-mediated cross-dehydrogenative coupling of indoles and imidazo[1,2-a]pyridines with fluorinated alcohols","volume":"23","author":"Nipate","year":"2021","journal-title":"Org. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1039\/C5CC09881E","article-title":"Photoorganocatalysed and visible light photoredox catalysed trifluoromethylation of olefins and (hetero)aromatics in batch and continuous flow","volume":"52","author":"Lefebvre","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7344","DOI":"10.1021\/jo301049w","article-title":"Fluorinated Alcohols As Promoters for the Metal-Free Direct Substitution Reaction of Allylic Alcohols with Nitrogenated, Silylated, and Carbon Nucleophiles","volume":"77","author":"Tfilla","year":"2012","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1002\/ajoc.201700320","article-title":"Hexafluoroisopropanol-Promoted Metal-Free Allylation of Silyl Enol Ethers with Allylic Alcohols","volume":"6","author":"Baeza","year":"2017","journal-title":"Asian J. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1021\/acs.joc.2c02812","article-title":"Synthesis of difluoromethylated carbinols via a HFIP-promoted hydroxy-difluoromethylation of aniline, indole, and pyrrole derivatives with difluoroacetaldehyde ethyl hemiacetal","volume":"88","author":"Yang","year":"2023","journal-title":"J. Org. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12544","DOI":"10.1021\/acs.chemrev.1c00749","article-title":"HFIP in organic synthesis","volume":"122","author":"Motiwala","year":"2022","journal-title":"Chem. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1021\/acs.joc.0c01207","article-title":"HFIP promoted C3 alkylation of lawsone and 4-hydroxycoumarin with alcohols by dehydrative cross-coupling","volume":"85","author":"Chen","year":"2020","journal-title":"J. Org. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1021\/acs.joc.1c02504","article-title":"Synthesis of 2,2-Difluoro-3-hydroxy-1,4-diketones via an HFIP-Catalyzed Mukaiyama Aldol Reaction of Glyoxal Monohydrates with Difluoroenoxysilanes","volume":"87","author":"Yang","year":"2022","journal-title":"J. Org. Chem."},{"key":"ref_32","unstructured":"(2023, October 11). CCDC: 2295549 (for 3b) Contain the Supplementary Crystallographic Data for This Paper. These Data Are Provided Free of Charge from the Cambridge Crystallographic Data Centre. Available online: www.ccdc.cam.ac.uk\/data_request\/cif."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7264","DOI":"10.1021\/acs.orglett.1c02659","article-title":"HFIP-catalyzed diflfluoroalkylation of propargylic alcohols to access tetrasubstituted diflfluoroalkyl allenes","volume":"23","author":"Li","year":"2021","journal-title":"Org. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1039\/b926684d","article-title":"Friedel-Crafts alkylation of arenes with epoxides promoted by fluorinated alcohols or water","volume":"46","author":"Li","year":"2010","journal-title":"Chem. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6352","DOI":"10.1021\/acs.joc.1c03155","article-title":"HFIP-Promoted selective hydroxyalkylation of aniline derivatives with arylglyoxal hydrates","volume":"87","author":"Yang","year":"2022","journal-title":"J. Org. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11788","DOI":"10.1021\/acs.joc.6b02242","article-title":"Design and performance validation of a conductively heated sealed-vessel reactor for organic Synthesis","volume":"81","author":"Obermayer","year":"2016","journal-title":"J. Org. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1080\/00397911.2018.1434893","article-title":"Green procedure for highly efficient, rapid synthesis of imidazo[1,2-a]pyridine and its late stage functionalization","volume":"48","author":"Ghosh","year":"2018","journal-title":"Synth. Commun."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/22\/7522\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:21:06Z","timestamp":1760131266000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/22\/7522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,10]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["molecules28227522"],"URL":"https:\/\/doi.org\/10.3390\/molecules28227522","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,10]]}}}