TY - JOUR

T1 - Azide-based in situ preparation of fused heterocyclic imines and their multicomponent reactions

AU - Paramonova, P.

AU - Lebedev, R.

AU - Sokolov, A.

AU - Dar'in, D.

AU - Kanov, E.

AU - Murtazina, R.

AU - Gainetdinov, R.

AU - Kalinin, S.

AU - Bakulina, O.

N1 - Export Date: 21 October 2024 CODEN: OBCRA Адрес для корреспонденции: Bakulina, O.; Institute of Chemistry, Russian Federation; эл. почта: o.bakulina@spbu.ru Сведения о финансировании: Russian Science Foundation, RSF, 19-75-30008-P Текст о финансировании 1: This research was funded by the Russian Science Foundation Project Grant No. 19-75-30008-P. We thank LLC Accellenna, Russia, for continuous support. We are grateful to the Research Centre for Magnetic Resonance, the Centre for Chemical Analysis and Materials Research, the Research Centre for X-ray Diffraction Studies, the Research Centre for Molecular and Cell Technologies, and the Cryogenic Department of Saint Petersburg State University Research Park for the analytical data.

PY - 2024/9/19

Y1 - 2024/9/19

N2 - 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. © 2024 The Royal Society of Chemistry.

AB - 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. © 2024 The Royal Society of Chemistry.

KW - Amines

KW - Ketones

KW - Synthesis (chemical)

KW - % reductions

KW - Diazepines

KW - Heterocycles

KW - Imidazol

KW - In-situ preparations

KW - Multicomponents

KW - One pot

KW - Pyrazines

KW - Synthesised

KW - Tandem reaction

KW - Addition reactions

UR - https://www.mendeley.com/catalogue/a45ec4f9-22cd-3ede-8ead-a6f7afc919b5/

U2 - 10.1039/d4ob01321b

DO - 10.1039/d4ob01321b

M3 - статья

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

ER -