{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:26Z","timestamp":1787029106932,"version":"build-2736575974"},"reference-count":67,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["18-13-00136"],"award-info":[{"award-number":["18-13-00136"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Halogenation of 2-trifluoromethylindole afforded 3-chloro-, 3-bromo- and 3-iodo derivatives in up to 98% yield. Methyl-, benzyl- and tosyl-groups can be installed at the nitrogen atom of prepared indoles in high yields by base catalyzed reaction with the corresponding alkylating (sulfonylating) reagents. A high synthetic utility of the prepared haloindoles in the reaction with various nucleophilies was shown. The reaction with 4-methylthiophenol and copper cyanide afforded the corresponding sulfides and nitriles in high yield. Palladium catalyzed cross-coupling with phenyl boronic acid and phenylacetylene gave the corresponding 3-phenyl-2-CF3-indoles and acetylenic derivatives in 72\u201398% yield.<\/jats:p>","DOI":"10.3390\/molecules27248822","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T03:32:32Z","timestamp":1670902352000},"page":"8822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Synthesis and Reactions of 3-Halogenated 2-CF3-Indoles"],"prefix":"10.3390","volume":"27","author":[{"given":"Vasiliy M.","family":"Muzalevskiy","sequence":"first","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoia A.","family":"Sizova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9162-5169","authenticated-orcid":false,"given":"Valentine G.","family":"Nenajdenko","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/jlac.18661400306","article-title":"On the reduction of aromatic compounds by means of zinc dust","volume":"140","author":"Baeyer","year":"1866","journal-title":"Ann. Chem. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1002\/ange.201511149","article-title":"Metal-free synthesis of fluorinated indoles enabled by oxidative dearomatization","volume":"128","author":"Vitaku","year":"2016","journal-title":"Angew. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jhet.5570250101","article-title":"Synthetically attractive indolization processes and newer methods for the preparation of selectively substituted indole","volume":"25","author":"Pindur","year":"1988","journal-title":"J. Heterocycl. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1021\/cr040639b","article-title":"Synthesis and functionalization of indoles through palladium-catalyzed reactions","volume":"105","author":"Cacchi","year":"2005","journal-title":"Chem. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1021\/cr0505270","article-title":"Practical methodologies for the synthesis of indoles","volume":"106","author":"Humphrey","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7195","DOI":"10.1016\/j.tet.2011.06.040","article-title":"Indole synthesis: A review and proposed classification","volume":"67","author":"Taber","year":"2011","journal-title":"Tetrahedron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3929","DOI":"10.1039\/c2cs15350e","article-title":"Progress in palladium-based catalytic systems for the sustainable synthesis of annulated heterocycles: A focus on indole backbones","volume":"41","author":"Platon","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_8","unstructured":"Sundberg, R. (1996). Indoles, Academic Press."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gribble, G.W. (2016). Indole Ring Synthesis, John Wiley & Sons.","DOI":"10.1002\/9781118695692"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"782","DOI":"10.2174\/138955709788452649","article-title":"From nature to drug discovery: The indole scaffold as a \u201cprivileged structure\u201d","volume":"9","author":"Barreiro","year":"2009","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10257","DOI":"10.1021\/jm501100b","article-title":"Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals","volume":"57","author":"Vitaku","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.ejmech.2019.07.019","article-title":"An insight into the medicinal perspective of synthetic analogs of indole: A review","volume":"180","author":"Thanikachalam","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1021\/ed1003806","article-title":"A graphical journey of innovative organic architectures that have improved our lives","volume":"87","author":"McGrath","year":"2010","journal-title":"J. Chem. Educ."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8214","DOI":"10.1002\/anie.201206566","article-title":"Introduction of fluorine and fluorine-containing functional groups","volume":"52","author":"Liang","year":"2013","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1021\/cr500277b","article-title":"Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions","volume":"115","author":"Yang","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1021\/cr500257c","article-title":"Functionalization of fluorinated molecules by transition metal mediated C\u2212F bond activation to access fluorinated building blocks","volume":"115","author":"Ahrens","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1021\/cr500465n","article-title":"Polyfluorinated ethanes as versatile fluorinated C2-building blocks for organic synthesis","volume":"115","author":"Nenajdenko","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14676","DOI":"10.1002\/chem.201702311","article-title":"Difluoromethylation reactions of organic compounds","volume":"23","author":"Yerien","year":"2017","journal-title":"Chem. Eur. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1002\/cbic.200300833","article-title":"The unique role of fluorine in the design of active ingredients for modern crop protection","volume":"5","author":"Jeschke","year":"2004","journal-title":"ChemBioChem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/ps.1829","article-title":"The unique role of halogen substituents in the design of modern agrochemicals","volume":"66","author":"Jeschke","year":"2010","journal-title":"Pest Manag. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jfluchem.2014.06.014","article-title":"Successful fluorine-containing herbicide agrochemicals","volume":"167","author":"Fujiwara","year":"2014","journal-title":"J. Fluor. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/ps.4540","article-title":"Latest generation of halogen-containing pesticides","volume":"73","author":"Jeschke","year":"2017","journal-title":"Pest Manag. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"B\u00e9gu\u00e9, J.P., and Bonnet-Delpon, D. (2008). Bioorganic and Medicinal Chemistry of Fluorine, John Wiley & Sons.","DOI":"10.1002\/9780470281895"},{"key":"ref_24","unstructured":"Tressaud, A., and Haufe, G. (2008). Fluorine and Health. Molecular Imaging, Biomedical Materials and Pharmaceuticals, Elsevier."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kirsch, P. (2013). Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH.","DOI":"10.1002\/9783527651351"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1039\/B610213C","article-title":"Fluorine in medicinal chemistry","volume":"37","author":"Purser","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1021\/jm800219f","article-title":"The many roles for fluorine in medicinal chemistry","volume":"51","author":"Hagmann","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1021\/cr4002879","article-title":"Fluorine in pharmaceutical industry: Fluorine-containing drugs introduced to the market in the last decade (2001\u20132011)","volume":"114","author":"Wang","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.1021\/jm401375q","article-title":"Data-mining for sulfur and fluorine: An evaluation of pharmaceuticals to reveal opportunities for drug design and discovery","volume":"57","author":"Ilardi","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jfluchem.2014.06.026","article-title":"Recent advances in the trifluoromethylation methodology and new CF3-containing drugs","volume":"167","author":"Zhu","year":"2014","journal-title":"J. Fluor. Chem."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1021\/acs.chemrev.5b00392","article-title":"Next generation of fluorine containing pharmaceuticals, compounds currently in phase II\u2212III clinical trials of major pharmaceutical companies: New structural trends and therapeutic areas","volume":"116","author":"Zhou","year":"2016","journal-title":"Chem. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5822","DOI":"10.1021\/acs.jmedchem.7b01788","article-title":"Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design","volume":"61","author":"Meanwell","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10633","DOI":"10.1021\/acsomega.0c00830","article-title":"Contribution of organofluorine compounds to pharmaceuticals","volume":"5","author":"Inoue","year":"2020","journal-title":"ACS Omega"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"De la Torre, B.G., and Albericio, F. (2022). The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules, 27.","DOI":"10.3390\/molecules27031075"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Nenajdenko, V.G. (2014). Fluorine in Heterocyclic Chemistry, Springer.","DOI":"10.1007\/978-3-319-04435-4"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Nenajdenko, V.G. (2014). Fluorine in Heterocyclic Chemistry, Springer.","DOI":"10.1007\/978-3-319-04435-4"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Petrov, V.A. (2009). Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications, Wiley.","DOI":"10.1002\/9780470528952"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gakh, A., and Kirk, K.L. (2008). Fluorinated Heterocycles, Oxford University Press.","DOI":"10.1021\/bk-2009-1003"},{"key":"ref_40","first-page":"3905","article-title":"Synthesis of trifluoromethyl pyrroles and their benzo analogues","volume":"20","author":"Muzalevskiy","year":"2009","journal-title":"Synthesis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1055\/s-0030-1260088","article-title":"Synthesis of fluorinated thiophenes and their analogues","volume":"2011","author":"Serdyuk","year":"2011","journal-title":"Synthesis"},{"key":"ref_42","first-page":"2115","article-title":"Synthesis and properties of fluoropyrroles and their analogues","volume":"2012","author":"Serdyuk","year":"2012","journal-title":"Synthesis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1070\/RCR4871","article-title":"Organofluorine chemistry: Promising growth areas and challenges","volume":"88","author":"Politanskaya","year":"2019","journal-title":"Russ. Chem. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6991","DOI":"10.1016\/j.tet.2009.06.048","article-title":"Selective synthesis of \u03b1-trifluoromethyl-\u03b2-arylenamines or vinylogous guanidinium salts by treatment of \u03b2-halo-\u03b2-trifluoromethylstyrenes with secondary amines under different conditions","volume":"65","author":"Muzalevskiy","year":"2009","journal-title":"Tetrahedron"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5679","DOI":"10.1021\/jo101107t","article-title":"Fragmentation of Trifluoromethylated Alkenes and Acetylenes by N,N-Binucleophiles. Synthesis of Imidazolines or Imidazolidines (Oxazolidines) Controlled by Substituent","volume":"75","author":"Nenajdenko","year":"2010","journal-title":"J. Org. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1002\/ejoc.200900926","article-title":"A cascade approach to captodative trifluoromethylated enamines or vinylogous guanidinium salts: Aromatic substituents as switches of reaction direction","volume":"2010","author":"Rulev","year":"2010","journal-title":"Eur. J. Org. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.jfluchem.2011.06.030","article-title":"Synthesis of alpha-trifluoromethyl-phenethylamines from alpha-trifluoromethyl beta-aryl enamines and beta-chloro-beta-(trifluoromethyl)styrenes","volume":"132","author":"Muzalevskiy","year":"2011","journal-title":"J. Fluor. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1021\/acs.joc.0c02516","article-title":"\u03b1,\u03b2-Disubstituted CF3-enones as a trifluoromethyl building block: Regioselective preparation of totally substituted 3-CF3-pyrazoles","volume":"86","author":"Muzalevskiy","year":"2021","journal-title":"J. Org. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1039\/D1OB00098E","article-title":"Synthesis of 2-trifluoromethylated quinolines from CF3-alkenes","volume":"19","author":"Muzalevskiy","year":"2021","journal-title":"Org. Biomol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5973","DOI":"10.1021\/acs.orglett.1c02061","article-title":"Modular construction of functionalized 2-CF3-indoles","volume":"23","author":"Muzalevskiy","year":"2021","journal-title":"Org. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7553","DOI":"10.1016\/j.tet.2009.06.120","article-title":"\u03b1-Trifluoromethyl-\u03b2-aryl enamines in the synthesis of trifluoromethylated heterocycles by the Fischer and the Pictet\u2013Spengler reactions","volume":"65","author":"Muzalevskiy","year":"2009","journal-title":"Tetrahedron"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Muzalevskiy, V.M., Sizova, Z.A., and Nenajdenko, V.G. (2021). An Efficient Synthesis of 2-CF3-3-Benzylindoles. Molecules, 26.","DOI":"10.3390\/molecules26165084"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1007\/s11172-008-0306-2","article-title":"New approaches to the synthesis of 2-(trifluoromethyl)indole and 2-amino-3-(trifluoromethyl)quinoline","volume":"57","author":"Muzalevskiy","year":"2008","journal-title":"Russ. Chem. Bull."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Muzalevskiy, V.M., Sizova, Z.A., Abaev, V.T., and Nenajdenko, V.G. (2021). An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes. Molecules, 26.","DOI":"10.3390\/molecules26237365"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1021\/ml400066a","article-title":"The 2\u2032-trifluoromethyl analogue of indomethacin is a potent and selective COX-2 inhibitor","volume":"4","author":"Blobaum","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.1021\/jm5000672","article-title":"Optimization studies of cinnamic amide EP2 antagonists","volume":"57","author":"Ganesh","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1021\/jm501997q","article-title":"Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity","volume":"5","author":"Trabbic","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ejmech.2016.06.016","article-title":"Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity","volume":"122","author":"Trabbic","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_59","unstructured":"Rheinheimer, J., Rath, R., Kulkarni, S., Rosenbaum, C., Wiebe, C., Brahm, L., Siepe, I., Haden, E., Roehl, F., and Khanna, S. (2019). Indole and Azaindole Compounds with Substitued 6-Membered Aryl and Heteroaryl Rings as Agrochemical Fungicides. (WO201957660), Patent."},{"key":"ref_60","unstructured":"Wang, S., Ran, X., Zhao, Y., Yang, C.-Y., Liu, L., Bai, L., McEachern, D., Stuckey, J., Meagher, J.L., and Sun, D. (2014). Preparation of pyridoindole, pyridazinoindole and pyrimidinoindole compounds as BET bromodomain inhibitors. (20140256706 A1), U.S. Patent."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/chem.201405505","article-title":"Graphitic Carbon Nitride Polymer as a Recyclable Photoredox Catalyst for Fluoroalkylation of Arenes","volume":"21","author":"Baar","year":"2015","journal-title":"Chem. Eur. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s00706-022-02930-y","article-title":"Facile metal-free visible-light-mediated chlorotrifluoromethylation of terminal alkenes","volume":"153","author":"Rao","year":"2022","journal-title":"Monatsh. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1021\/cr00080a006","article-title":"Cyanation of aromatic halides","volume":"87","author":"Ellis","year":"1987","journal-title":"Chem. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1139\/v85-019","article-title":"Mechanisms and models for homogeneous copper mediated ligand exchange reactions of the type: CuNu + ArX \u2192 ArNu + CuX","volume":"63","author":"Couture","year":"1985","journal-title":"Can. J. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Connor, J.A., Leeming, S.W., and Price, R.J. (1990). Influence of substrate structure on copper(I)-assisted cyanide substitution in aryl halides. Chem. Soc. Perkin Trans. 1, 1127\u20131132.","DOI":"10.1039\/p19900001127"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5947","DOI":"10.1016\/j.tetlet.2010.09.027","article-title":"Direct C2-trifluoromethylation of indole derivatives catalyzed by copper acetate","volume":"51","author":"Shimizu","year":"2010","journal-title":"Tetrahedron Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3906","DOI":"10.1021\/acscatal.9b00470","article-title":"Copper-Catalyzed Tandem O-Vinylation of Arylhydroxylamines\/[3,3]-Rearrangement\/Cyclization: Synthesis of Highly Substituted Indoles and Benzoindoles","volume":"9","author":"Yuan","year":"2019","journal-title":"ACS Catal."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/24\/8822\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:40:00Z","timestamp":1760146800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/24\/8822"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,12]]},"references-count":67,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["molecules27248822"],"URL":"https:\/\/doi.org\/10.3390\/molecules27248822","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,12]]}}}