{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:39:28Z","timestamp":1760240368604,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T00:00:00Z","timestamp":1558396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["MFAG 18793"],"award-info":[{"award-number":["MFAG 18793"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universit\u00e0 del Piemonte Orientale","award":["Ricerca locale di Ateneo 2016"],"award-info":[{"award-number":["Ricerca locale di Ateneo 2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.<\/jats:p>","DOI":"10.3390\/molecules24101959","type":"journal-article","created":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T10:52:51Z","timestamp":1558435971000},"page":"1959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines"],"prefix":"10.3390","volume":"24","author":[{"given":"Ubaldina","family":"Galli","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 del Piemonte Orientale \u201cA. Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rejdia","family":"Hysenlika","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 del Piemonte Orientale \u201cA. Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6511-7360","authenticated-orcid":false,"given":"Fiorella","family":"Meneghetti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmaceutiche, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2398-5944","authenticated-orcid":false,"given":"Erika","family":"Del Grosso","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 del Piemonte Orientale \u201cA. Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sveva","family":"Pelliccia","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Universit\u00e0 degli Studi di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ettore","family":"Novellino","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Universit\u00e0 degli Studi di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6856-414X","authenticated-orcid":false,"given":"Mariateresa","family":"Giustiniano","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Universit\u00e0 degli Studi di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-400X","authenticated-orcid":false,"given":"Gian Cesare","family":"Tron","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco, Universit\u00e0 del Piemonte Orientale \u201cA. Avogadro\u201d, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1039\/C8NP00020D","article-title":"Total synthesis campaigns toward chlorophylls and related natural hydroporphyrins\u2014Diverse macrocycles, unrealized opportunities","volume":"35","author":"Liu","year":"2018","journal-title":"Nat. Prod. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Eckert, R. (2017). Synergy Effects in the Chemical Synthesis and Extensions of. Multicomponent Reactions (MCRs)\u2014The low energy way to ultra-short syntheses of tailor-made molecules. Molecules.","DOI":"10.20944\/preprints201701.0122.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1039\/a807961g","article-title":"Green chemistry: Challenges and opportunities","volume":"1","author":"Clark","year":"1999","journal-title":"Green Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/ijch.201700085","article-title":"Organic Synthesis: Wherefrom and whither? (Some very personal reflections)","volume":"58","author":"Denmark","year":"2018","journal-title":"Isr. J. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9094","DOI":"10.1002\/anie.201000723","article-title":"Isocyanides in the synthesis of nitrogen heterocycles","volume":"49","author":"Lygin","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8323","DOI":"10.1021\/cr400615v","article-title":"Small heterocycles in multicomponent reactions","volume":"114","author":"Rotstein","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1021\/cr100233r","article-title":"Chemistry and biology of multicomponent reactions","volume":"112","author":"Wang","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1055\/s-0032-1318222","article-title":"Efficiency, diversity, and complexity with multicomponent reactions","volume":"2013","author":"Ruijter","year":"2013","journal-title":"Synlett"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nenajdenko, V.G. (2012). Isocyanide Chemistry, Wiley-VCH.","DOI":"10.1002\/9783527652532"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Orru, R.V.A., and Ruijter, E. (2010). Synthesis of Heterocycles via Multicomponent Reactions I., Springer.","DOI":"10.1007\/978-3-642-15455-3"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Orru, R.V.A., and Ruijter, E. (2010). Synthesis of Heterocycles via Multicomponent Reactions II., Springer.","DOI":"10.1007\/978-3-642-15455-3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5235","DOI":"10.1021\/cr900411f","article-title":"Isocyanoacetate derivatives: Synthesis, reactivity, and application","volume":"110","author":"Gulevich","year":"2010","journal-title":"Chem. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3390\/80100053","article-title":"The Chemistry of isocyanides, their Multicomponent reactions and their libraries","volume":"8","author":"Ugi","year":"2003","journal-title":"Molecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2174\/0929867033368600","article-title":"\u201cMulti-component reactions: Emerging chemistry in drug discovery\u201d \u2018from xylocain to crixivan\u2019","volume":"10","author":"Hulme","year":"2003","journal-title":"Curr. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1055\/s-0035-1561672","article-title":"Nitrile N-oxides and nitrile imines as new fuels for the discovery of novel isocyanide-based multicomponent reactions","volume":"48","author":"Giustiniano","year":"2016","journal-title":"Synthesis"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wernerova, M., and Hudlicky, T. (2010). On the practical limits of determining isolated product yields and ratios of stereoisomers: Reflections, analysis, and redemption. Synlett, 2701\u20132707.","DOI":"10.1055\/s-0030-1259018"},{"key":"ref_17","first-page":"386","article-title":"Versuche mit Isonitrilen","volume":"71","author":"Ugi","year":"1959","journal-title":"Angew. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1002\/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U","article-title":"Multicomponent reactions with isocyanides","volume":"39","author":"Ugi","year":"2000","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nenajdenko, V.G. (2012). Isocyanide Chemistry: Applications in Synthesis and Material Science, Wiley-VCH.","DOI":"10.1002\/9783527652532"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.1055\/s-0037-1610193","article-title":"Interrupted Ugi and Passerini Reactions: An underexplored treasure Island","volume":"50","author":"Giustiniano","year":"2018","journal-title":"Synthesis"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"V\u00e1radi, A., Palmer, T.C., Dardashti, R.N., and Majumdar, S. (2016). Isocyanide-based multicomponent reactions for the rynthesis of heterocycles. Molecules.","DOI":"10.1002\/chin.201633234"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1016\/j.tet.2008.12.002","article-title":"Beyond the Ugi reaction: Less conventional interactions between isocyanides and iminium species","volume":"65","author":"Grimaud","year":"2009","journal-title":"Tetrahedron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1021\/acs.orglett.6b00580","article-title":"Transition-metal-free synthesis of 2-arylimidazolones via cascade reaction between arynes and \u03b1,\u03b1\u2032-disubstituted \u03b1-isocyanoacetamides","volume":"18","author":"Gesu","year":"2016","journal-title":"Org. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1055\/s-1998-1721","article-title":"Synthesis of imidazo[1,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation","volume":"1998","author":"Groebke","year":"1998","journal-title":"Synlett"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3635","DOI":"10.1016\/S0040-4039(98)00653-4","article-title":"Parallel Synthesis of 3-Aminoimidazo[1,2-a]pyridines and pyrazines by a new three-component condensation","volume":"39","author":"Blackburn","year":"1998","journal-title":"Tetrahedron Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1002\/(SICI)1521-3773(19980904)37:16<2234::AID-ANIE2234>3.0.CO;2-R","article-title":"New heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles","volume":"37","author":"Bouzid","year":"1998","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1021\/jo500723d","article-title":"Synthesis of diverse nitrogen-enriched heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions","volume":"79","author":"Ayaz","year":"2014","journal-title":"J. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1021\/ol050553k","article-title":"Revision of outcome and mechanism of a new multicomponent reaction","volume":"7","author":"Carballares","year":"2005","journal-title":"Org. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrd.2018.116","article-title":"Expanding the medicinal chemistry synthetic toolbox","volume":"17","author":"Brown","year":"2018","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1021\/acsmedchemlett.8b00459","article-title":"Exploiting chemical toolboxes for the expedited generation of tetracyclic quinolines as a novel class of PXR agonists","volume":"10","author":"Cerra","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6248","DOI":"10.1016\/j.bmc.2017.03.061","article-title":"An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors","volume":"25","author":"Paganoa","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1002\/anie.201307786","article-title":"Combining On-chip synthesis of a focused combinatorial library with computational target prediction reveals imidazopyridine GPCR ligands","volume":"53","author":"Reutlinger","year":"2014","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1107\/S0021889897003117","article-title":"ORTEP-3 for Windows\u2014A version of ORTEP-III with a Graphical User Interface (GUI)","volume":"30","author":"Farruja","year":"1997","journal-title":"J. Appl. Cryst."},{"key":"ref_34","doi-asserted-by":"crossref","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."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1002\/ejoc.201201660","article-title":"Off the Beaten Track: The Use of Secondary Amines in the Ugi Reaction","volume":"2013","author":"Tron","year":"2013","journal-title":"Eur. J. Org. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Baldwin, J.E. (1976). Rules for ring closure. J. Chem. Soc. Chem. Commun.","DOI":"10.1039\/c39760000734"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1021\/ar50156a003","article-title":"Stereospecific reactions of nitrilium ions and analogous 1,3-dipoles","volume":"13","author":"Hegarthy","year":"1980","journal-title":"Acc. Chem. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1039\/b202005j","article-title":"Rate-determining nitrogen inversion in the isomerisation of isoimides to imides and azides to tetrazoles: Direct observation of intermediates stabilized by trifluoroethyl groups","volume":"7","author":"Hegarty","year":"2002","journal-title":"J. Chem. Soc. Perkin Trans. 2"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/S0040-4020(01)82718-6","article-title":"Reactions of imines with t-butyl isocyanide","volume":"25","author":"Deyrup","year":"1969","journal-title":"Tetrahedron"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/10\/1959\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:54:03Z","timestamp":1760187243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/10\/1959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,21]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["molecules24101959"],"URL":"https:\/\/doi.org\/10.3390\/molecules24101959","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2019,5,21]]}}}