{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:46:52Z","timestamp":1753890412761,"version":"3.41.2"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/00313\/2020 UIDP\/00313\/2020 PTDC\/QUI-QOR\/0103\/2021"],"award-info":[{"award-number":["UIDB\/00313\/2020 UIDP\/00313\/2020 PTDC\/QUI-QOR\/0103\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-<jats:italic>c<\/jats:italic>]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-<jats:italic>c<\/jats:italic>]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMO<jats:sub>heterodiene<\/jats:sub>-HOMO<jats:sub>dienophile<\/jats:sub> controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-<jats:italic>c<\/jats:italic>]carbazole was explored and a new hexahydropyrido[4\u2032,3':4,5]pyrrolo[3,2-<jats:italic>c<\/jats:italic>]carbazole system was obtained in high yield via a one-pot, two-step procedure.<\/jats:p>","DOI":"10.3389\/fchem.2023.1229669","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:38:06Z","timestamp":1691498286000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Reactivity of ethyl nitrosoacrylate toward pyrrole, indole and pyrrolo[3,2-c]carbazole: an experimental and theoretical study"],"prefix":"10.3389","volume":"11","author":[{"given":"Alice","family":"Benzi","sequence":"first","affiliation":[]},{"given":"Susana M. M.","family":"Lopes","sequence":"additional","affiliation":[]},{"given":"Sandra C. C.","family":"Nunes","sequence":"additional","affiliation":[]},{"given":"Gianluca","family":"Giorgi","sequence":"additional","affiliation":[]},{"given":"Lara","family":"Bianchi","sequence":"additional","affiliation":[]},{"given":"Cinzia","family":"Tavani","sequence":"additional","affiliation":[]},{"given":"Alberto A. C. C.","family":"Pais","sequence":"additional","affiliation":[]},{"given":"Giovanni","family":"Petrillo","sequence":"additional","affiliation":[]},{"given":"Teresa M. V. D.","family":"Pinho e Melo","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6369","DOI":"10.1021\/jm901018f","article-title":"Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new pim kinase inhibitors","volume":"52","author":"Aku\u00e9-G\u00e9du","year":"2009","journal-title":"J. Med. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4011","DOI":"10.1002\/ejoc.201700453","article-title":"Hetero-diels\u2013alder and ring-opening reactions of furans applied to the synthesis of functionalized heterocycles","author":"Alves","year":"2017","journal-title":"Eur. J. Org. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1103\/PhysRevA.38.3098","article-title":"Density-functional exchange-energy approximation with correct asymptotic behavior","volume":"38","author":"Becke","year":"1988","journal-title":"Phys. Rev. A"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density\u2010functional thermochemistry. III. The role of exact exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3802","DOI":"10.3390\/molecules24203802","article-title":"Sequential annulations to interesting novel pyrrolo[3,2-c]carbazoles","volume":"24","author":"Benzi","year":"2019","journal-title":"Molecules"},{"key":"B6","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1007\/s11164-018-3661-0","article-title":"Synthesis, photophysical and antioxidant properties of pyrrolo[3,2-c]carbazole and dipyrrolo[3,2-c:2\u2032,3\u2032-g]Carbazole compounds","volume":"45","author":"Bingul","year":"2019","journal-title":"Res. Chem. Intermed."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2661","DOI":"10.1021\/acs.jchemed.1c00184","article-title":"One-pot synthetic approach to dipyrromethanes and bis(indolyl)methanes via nitrosoalkene chemistry","volume":"98","author":"Cardoso","year":"2021","journal-title":"J. Chem. Edu."},{"key":"B8","doi-asserted-by":"publisher","first-page":"6496","DOI":"10.1002\/chem.201600823","article-title":"From heteroaromatic acids and imines to azaspirocycles: Stereoselective synthesis and 3D shape analysis","volume":"22","author":"Chambers","year":"2016","journal-title":"Chem. Eur. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1021\/ja00839a011","article-title":"General definition of ring puckering coordinates","volume":"97","author":"Cremer","year":"1975","journal-title":"J. Am. Chem. Soc."},{"volume-title":"Gaussian 09, 2009","year":"2009","author":"Frisch","key":"B10"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1039\/P19930001391","article-title":"Reaction of pyrroles with ethyl 2-nitroso- and 2-Azo-propionates, and with ethyl cyanoformate N-oxide: A comparison of the reaction pathways","volume":"1","author":"Gilchrist","year":"1993","journal-title":"J. Chem. Soc. Perkin Trans."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1039\/P19830001283","article-title":"Addition and cycloaddition reactions of the electrophilic vinyl nitroso compounds 3-Nitrosobut-3-en-2-one, 2-nitrosopropenal, and ethyl 2-nitrosopropenoate","volume":"1","author":"Gilchrist","year":"1983","journal-title":"J. Chem. Soc. Perkin Trans."},{"key":"B13","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.ejmech.2012.08.029","article-title":"Synthesis and biological activities of 4-substituted pyrrolo[2,3-a]carbazole pim kinase inhibitors","volume":"56","author":"Giraud","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5025","DOI":"10.1002\/ejoc.201900269","article-title":"Synthesis and applications of dihydropyrrolocarbazoles","volume":"2019","author":"Giraud","year":"2019","journal-title":"Eur. J. Org. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1007\/s00706-019-02421-7","article-title":"Natural deep eutectic solvents in the hetero-diels-alder approach to bis(indolyl)methanes","volume":"150","author":"Grosso","year":"2019","journal-title":"Monatsh. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ejmech.2015.01.050","article-title":"Novel approach to bis(indolyl)methanes: De novo synthesis of 1-hydroxyiminomethyl derivatives with anti-cancer properties","volume":"93","author":"Grosso","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1016\/j.bmc.2016.12.028","article-title":"Hetero-diels-alder approach to bis(indolyl)methanes","volume":"25","author":"Grosso","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2868","DOI":"10.1055\/s-0034-1379306","article-title":"Conjugate addition of pyrazoles to halogenated nitroso- and azoalkenes: A new entry to novel bis(pyrazol-1-yl)methanes","volume":"25","author":"Grosso","year":"2014","journal-title":"Synlett"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2856","DOI":"10.1002\/chem.201503835","article-title":"Synthesis of spirocyclic indolenine","volume":"22","author":"James","year":"2016","journal-title":"Chem. Eur. J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1002\/cmdc.201700152","article-title":"Biological evaluation of dipyrromethanes in cancer cell lines: Antiproliferative and pro-apoptotic properties","volume":"12","author":"Jorda","year":"2017","journal-title":"ChemMedChem"},{"key":"B21","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the colle-salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"B22","doi-asserted-by":"publisher","first-page":"11324","DOI":"10.1021\/acs.chemrev.8b00375","article-title":"Recent advances in the chemistry of conjugated nitrosoalkenes and azoalkenes","volume":"118","author":"Lopes","year":"","journal-title":"Chem. Rev."},{"key":"B23","doi-asserted-by":"publisher","first-page":"6146","DOI":"10.1002\/ejoc.201500878","article-title":"Exploring the chemistry of furans: Synthesis of functionalized bis(furan-2-yl)-methanes and 1,6-dihydropyridazines","volume":"2015","author":"Lopes","year":"2015","journal-title":"Eur. J. Org. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"6756","DOI":"10.1016\/j.tetlet.2010.10.095","article-title":"A hetero-diels-alder approach to functionalized 1H-tetrazoles: Synthesis of tetrazolyl-1,2-oxazine, -oximes and 5-(1-aminoalkyl)-1H-tetrazoles","volume":"51","author":"Lopes","year":"2010","journal-title":"Tetrahedron Lett."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1016\/j.ejmech.2017.11.052","article-title":"Hetero-diels-alder reactions of novel 3-Triazolyl-nitrosoalkenes as an approach to functionalized 1,2,3-triazoles with antibacterial profile","volume":"143","author":"Lopes","year":"","journal-title":"Eur. J. Med. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1007\/s00706-016-1763-1","article-title":"Reactivity of 1-arylnitrosoethylenes towards indole derivatives","volume":"147","author":"Lopes","year":"2016","journal-title":"Monatsh. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"8902","DOI":"10.1016\/j.tet.2011.09.051","article-title":"Diels-alder reactions of 3-(1H-Tetrazol-5-yl)-nitrosoalkenes: Synthesis of functionalized 5-(substituted)-1H-tetrazoles","volume":"67","author":"Lopes","year":"2011","journal-title":"Tetrahedron"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3328","DOI":"10.1021\/acs.joc.9b03151","article-title":"Meso-Substituted corrodes from nitrosoalkenes and dipyrromethanes","volume":"85","author":"Lopes","year":"2020","journal-title":"J. Org. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1016\/j.tet.2019.01.004","article-title":"An overview on synthetic entries to tetrahydro-\u03b2-carbolines","volume":"75","author":"Maity","year":"2019","journal-title":"Tetrahedron"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3564","DOI":"10.1021\/jo01286a061","article-title":"Reaction of.alpha.-halo oximes with triphenylphosphine. Formation of imidoyl bromide of oximinophophonium salts by a novel catalytic effect of bases","volume":"32","author":"Masaki","year":"1967","journal-title":"J. Org. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"7244","DOI":"10.1021\/acs.joc.9b00924","article-title":"Michael addition of P-nucleophiles to conjugated nitrosoalkenes","volume":"84","author":"Naumovich","year":"2019","journal-title":"J. Org. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"10456","DOI":"10.1021\/jo502095k","article-title":"Reactions of nitrosoalkenes with dipyrromethanes and pyrroles: Insight into the mechanistic pathway","volume":"79","author":"Nunes","year":"2014","journal-title":"J. Org. Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.ejmech.2019.05.085","article-title":"New 3-Tetrazolyl-\u03b2-carbolines and \u03b2-Carboline-3-carboxylates with anti-cancer activity","volume":"179","author":"Panice","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1055\/s-0033-1340300","article-title":"On-water synthesis of dipyrromethanes via bis-hetero-diels-alder reaction of azo- and nitrosoalkenes with pyrrole","volume":"25","author":"Pereira","year":"2014","journal-title":"Synlett"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.3390\/ph15121510","article-title":"3-(1,2,3-Triazol-4-yl)-\u03b2-Carbolines and 3-(1H-Tetrazol-5-yl)-\u03b2-Carbolines: Synthesis and evaluation as anticancer agents","volume":"15","author":"Ribeiro","year":"2022","journal-title":"Pharmaceuticals"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.2174\/1385272825666210706151631","article-title":"Reduction of oximes and hydrazones: Asymmetric and diastereoselective approaches","volume":"25","author":"Ribeiro","year":"2021","journal-title":"Curr. Org. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3164","DOI":"10.1080\/00397911.2021.1966040","article-title":"Synthesis of pyrrolo[3,2-c]carbazole-2-carbohydrazides and pyrrolo[3,2-c]carbazol-2-yl-1,3,4-oxadiazoles and their in vitro antibacterial evaluation","volume":"51","author":"Saglam","year":"2021","journal-title":"Synth. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1002\/jcc.540141112","article-title":"General atomic and molecular electronic structure system","volume":"14","author":"Schmidt","year":"1993","journal-title":"J. Comput. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1055\/s-0035-1560601","article-title":"Synthesis of novel pyrrolo[3,2-c]carbazole and dipyrrolo[3,2-c:2\u2032,3\u2032-g]carbazole derivatives","volume":"27","author":"Sengul","year":"2016","journal-title":"Synlett"},{"key":"B40","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Cryst. A"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal structure refinement with SHELXL","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Cryst. C"},{"key":"B42","doi-asserted-by":"publisher","first-page":"9139","DOI":"10.3390\/app11199139","article-title":"A nitrocarbazole as a new microtubule-targeting agent in breast cancer treatment","volume":"11","author":"Sinicropi","year":"2021","journal-title":"Appl. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.3390\/molecules27041304","article-title":"Diels-alder cycloaddition reactions in sustainable media","volume":"27","author":"Soares","year":"2022","journal-title":"Molecules"},{"key":"B44","doi-asserted-by":"publisher","first-page":"8538","DOI":"10.1002\/anie.201008071","article-title":"The Pictet\u2013spengler reaction in nature and in organic chemistry","volume":"50","author":"St\u00f6ckigt","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"B45","doi-asserted-by":"publisher","first-page":"575","DOI":"10.3390\/sym12040575","article-title":"Unsubstituted oximes as potential therapeutic agents","volume":"12","author":"Surowiak","year":"2020","journal-title":"Symmetry"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1855","DOI":"10.1055\/s-0037-1611899","article-title":"Nitrosoalkenes: Underappreciated reactive intermediates for formation of carbon\u2013carbon bonds","volume":"30","author":"Weinreb","year":"2019","journal-title":"Synlett"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1039\/C29700001605","article-title":"Biogenetically patterned synthesis of the spiro[indoline-3,4\u2032-proline] system","author":"Williams","year":"1970","journal-title":"J. Chem. Soc. Chem. Commun."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1039\/C7NP00018A","article-title":"Total synthesis of the dictyodendrins as an arena to highlight emerging synthetic technologies","volume":"34","author":"Zhang","year":"2017","journal-title":"Nat. Prod. Rep."},{"key":"B49","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1021\/acs.accounts.0c00074","article-title":"Exploring the chemistry of spiroindolenines by mechanistically-driven reaction development: Asymmetric Pictet\u2013spengler-type reactions and beyond","volume":"53","author":"Zheng","year":"2020","journal-title":"Acc. Chem. Res."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2023.1229669\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:38:14Z","timestamp":1691498294000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2023.1229669\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,8]]},"references-count":49,"alternative-id":["10.3389\/fchem.2023.1229669"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2023.1229669","relation":{},"ISSN":["2296-2646"],"issn-type":[{"type":"electronic","value":"2296-2646"}],"subject":[],"published":{"date-parts":[[2023,8,8]]},"article-number":"1229669"}}