TY  - 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 . .