Polina Paramonova, Rodion Lebedev, Alexander Sokolov, Dmitry Dar'in, Evgeny Kanov, Ramilya Murtazina, Raul Gainetdinov, Stanislav Kalinin, Olga Bakulina
{"title":"Azide-based <i>in situ</i> preparation of fused heterocyclic imines and their multicomponent reactions.","authors":"Polina Paramonova, Rodion Lebedev, Alexander Sokolov, Dmitry Dar'in, Evgeny Kanov, Ramilya Murtazina, Raul Gainetdinov, Stanislav Kalinin, Olga Bakulina","doi":"10.1039/d4ob01321b","DOIUrl":null,"url":null,"abstract":"<p><p>Structurally diverse pyrroles, indoles and imidazoles bearing an <i>N</i>-ω-azidoalkyl moiety and an aldehyde or ketone function were prepared and successfully introduced into <i>in situ</i> imine generation <i>via</i> the intramolecular Staudinger/aza-Wittig tandem reaction. Reduction of the generated imines led to medicinally relevant nitrogen-containing fused heterocycles such as tetrahydropyrrolo[1,2-<i>a</i>]pyrazines and diazepines. Rare 8-membered hexahydropyrrolo[1,2-<i>a</i>][1,4]diazocine and 9-membered dihydro-4,8-(metheno)pyrrolo[1,2-<i>a</i>][1,4]diazacycloundecine were also synthesized. In addition, several one-pot transformations involving cyclic anhydrides or isocyanides (Castagnoli-Cushman, Ugi and azido-Ugi reactions) were added to the Staudinger/aza-Wittig sequence to afford novel fused polyheterocyclic delta-lactams, cyclic bisamides and tetrazoles in a multicomponent fashion. The synthesized compounds were profiled against human Trace Amine-Associated Receptor 1 (hTAAR1), and the best performing compound showed low nanomolar agonistic activity with an EC<sub>50</sub> of 0.025 μM.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic & Biomolecular Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4ob01321b","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
引用次数: 0
Abstract
Structurally diverse pyrroles, indoles and imidazoles bearing an N-ω-azidoalkyl moiety and an aldehyde or ketone function were prepared and successfully introduced into in situ imine generation via the intramolecular Staudinger/aza-Wittig tandem reaction. Reduction of the generated imines led to medicinally relevant nitrogen-containing fused heterocycles such as tetrahydropyrrolo[1,2-a]pyrazines and diazepines. Rare 8-membered hexahydropyrrolo[1,2-a][1,4]diazocine and 9-membered dihydro-4,8-(metheno)pyrrolo[1,2-a][1,4]diazacycloundecine were also synthesized. In addition, several one-pot transformations involving cyclic anhydrides or isocyanides (Castagnoli-Cushman, Ugi and azido-Ugi reactions) were added to the Staudinger/aza-Wittig sequence to afford novel fused polyheterocyclic delta-lactams, cyclic bisamides and tetrazoles in a multicomponent fashion. The synthesized compounds were profiled against human Trace Amine-Associated Receptor 1 (hTAAR1), and the best performing compound showed low nanomolar agonistic activity with an EC50 of 0.025 μM.