On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents
Samo za registrovane korisnike
2023
Autori
Kop, TatjanaPavlović, Radoslav
Nešić, Marko
Stepanović, Olivera
Wang, Xiuze
Todorović, Nina
Rodić, Marko
Šmit, Biljana
Članak u časopisu (Objavljena verzija)
,
American chemical society
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Fluorinated piperidines find wide applications, most notably in the development of novel therapies and agrochemicals. Cyclization of alkenyl N-tosylamides promoted by BF3-activated aryliodine(III) carboxylates is an attractive strategy to construct 3-fluoropiperidines, but it suffers from selectivity issues arising from competitive oxoaminations and the inability to easily modulate the reactions diastereoselectivity. Herein, we report an itemized optimization of the reaction conditions carried out on both cyclic and acyclic substrates and outline the origins of substrate- and reagent-based stereo-, regio-, and chemoselectivity. Extensive mechanistic studies encompassing multinuclear NMR spectroscopy, deuterium labeling, rearrangements on stereodefined substrates, and careful structural analyses (NMR and X-ray) of the reaction products are performed. This revealed the processes and interactions crucial for achieving controlled preparation of 3-fluoropiperidines using I(III) chemistry an...d has provided an advanced understanding of the reaction mechanism. In brief, we propose that BF3-coordinated I(III) reagents attack C═C to produce the corresponding iodiranium(III) ion, which then undergoes diastereodetermining 5-exo-cyclization. Transiently formed pyrrolidines with an exocyclic σ-alkyl-I(III) moiety can further undergo aziridinium ion formation or reductive ligand coupling processes, which dictate not only the final product’s ring size but also the chemoselectivity. Importantly, the selectivity of the reaction depends on the nature of the ligand bound to I(III) and the presence of electrolytes such as TBABF4. Reported findings will facilitate the usage of ArI(III)-dicarboxylates in the reliable construction of fluorinated azaheterocycles.
Ključne reči:
Chemical reactions / Chemoselectivity / Cyclization / Ligands / ReagentsIzvor:
The Journal of Organic Chemistry, 2023, 88, 15, 10946-10959Izdavač:
- American Chemical Society (ACS)
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-MESTD-inst-2020-200026)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200168 (Univerzitet u Beogradu, Hemijski fakultet) (RS-MESTD-inst-2020-200168)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200125 (Univerzitet u Novom Sadu, Prirodno-matematički fakultet) (RS-MESTD-inst-2020-200125)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200378 (Institut za informacione tehnologije, Kragujevac) (RS-MESTD-inst-2020-200378)
DOI: 10.1021/acs.joc.3c00944
ISSN: 0022-3263
PubMed: 37449517
WoS: 001030461500001
Scopus: 2-s2.0-85166420930
Institucija/grupa
IHTMTY - JOUR AU - Kop, Tatjana AU - Pavlović, Radoslav AU - Nešić, Marko AU - Stepanović, Olivera AU - Wang, Xiuze AU - Todorović, Nina AU - Rodić, Marko AU - Šmit, Biljana PY - 2023 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/7113 AB - Fluorinated piperidines find wide applications, most notably in the development of novel therapies and agrochemicals. Cyclization of alkenyl N-tosylamides promoted by BF3-activated aryliodine(III) carboxylates is an attractive strategy to construct 3-fluoropiperidines, but it suffers from selectivity issues arising from competitive oxoaminations and the inability to easily modulate the reactions diastereoselectivity. Herein, we report an itemized optimization of the reaction conditions carried out on both cyclic and acyclic substrates and outline the origins of substrate- and reagent-based stereo-, regio-, and chemoselectivity. Extensive mechanistic studies encompassing multinuclear NMR spectroscopy, deuterium labeling, rearrangements on stereodefined substrates, and careful structural analyses (NMR and X-ray) of the reaction products are performed. This revealed the processes and interactions crucial for achieving controlled preparation of 3-fluoropiperidines using I(III) chemistry and has provided an advanced understanding of the reaction mechanism. In brief, we propose that BF3-coordinated I(III) reagents attack C═C to produce the corresponding iodiranium(III) ion, which then undergoes diastereodetermining 5-exo-cyclization. Transiently formed pyrrolidines with an exocyclic σ-alkyl-I(III) moiety can further undergo aziridinium ion formation or reductive ligand coupling processes, which dictate not only the final product’s ring size but also the chemoselectivity. Importantly, the selectivity of the reaction depends on the nature of the ligand bound to I(III) and the presence of electrolytes such as TBABF4. Reported findings will facilitate the usage of ArI(III)-dicarboxylates in the reliable construction of fluorinated azaheterocycles. PB - American Chemical Society (ACS) T2 - The Journal of Organic Chemistry T1 - On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents VL - 88 IS - 15 SP - 10946 EP - 10959 DO - 10.1021/acs.joc.3c00944 ER -
@article{ author = "Kop, Tatjana and Pavlović, Radoslav and Nešić, Marko and Stepanović, Olivera and Wang, Xiuze and Todorović, Nina and Rodić, Marko and Šmit, Biljana", year = "2023", abstract = "Fluorinated piperidines find wide applications, most notably in the development of novel therapies and agrochemicals. Cyclization of alkenyl N-tosylamides promoted by BF3-activated aryliodine(III) carboxylates is an attractive strategy to construct 3-fluoropiperidines, but it suffers from selectivity issues arising from competitive oxoaminations and the inability to easily modulate the reactions diastereoselectivity. Herein, we report an itemized optimization of the reaction conditions carried out on both cyclic and acyclic substrates and outline the origins of substrate- and reagent-based stereo-, regio-, and chemoselectivity. Extensive mechanistic studies encompassing multinuclear NMR spectroscopy, deuterium labeling, rearrangements on stereodefined substrates, and careful structural analyses (NMR and X-ray) of the reaction products are performed. This revealed the processes and interactions crucial for achieving controlled preparation of 3-fluoropiperidines using I(III) chemistry and has provided an advanced understanding of the reaction mechanism. In brief, we propose that BF3-coordinated I(III) reagents attack C═C to produce the corresponding iodiranium(III) ion, which then undergoes diastereodetermining 5-exo-cyclization. Transiently formed pyrrolidines with an exocyclic σ-alkyl-I(III) moiety can further undergo aziridinium ion formation or reductive ligand coupling processes, which dictate not only the final product’s ring size but also the chemoselectivity. Importantly, the selectivity of the reaction depends on the nature of the ligand bound to I(III) and the presence of electrolytes such as TBABF4. Reported findings will facilitate the usage of ArI(III)-dicarboxylates in the reliable construction of fluorinated azaheterocycles.", publisher = "American Chemical Society (ACS)", journal = "The Journal of Organic Chemistry", title = "On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents", volume = "88", number = "15", pages = "10946-10959", doi = "10.1021/acs.joc.3c00944" }
Kop, T., Pavlović, R., Nešić, M., Stepanović, O., Wang, X., Todorović, N., Rodić, M.,& Šmit, B.. (2023). On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents. in The Journal of Organic Chemistry American Chemical Society (ACS)., 88(15), 10946-10959. https://doi.org/10.1021/acs.joc.3c00944
Kop T, Pavlović R, Nešić M, Stepanović O, Wang X, Todorović N, Rodić M, Šmit B. On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents. in The Journal of Organic Chemistry. 2023;88(15):10946-10959. doi:10.1021/acs.joc.3c00944 .
Kop, Tatjana, Pavlović, Radoslav, Nešić, Marko, Stepanović, Olivera, Wang, Xiuze, Todorović, Nina, Rodić, Marko, Šmit, Biljana, "On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents" in The Journal of Organic Chemistry, 88, no. 15 (2023):10946-10959, https://doi.org/10.1021/acs.joc.3c00944 . .