molecules Article Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Secondary Amines: A Combined Experimental and Theoretical Investigation Giovanni Ribaudo 1 , Marco Bortoli 2,3 , Erika Oselladore 1, Alberto Ongaro 1 , Alessandra Gianoncelli 1 , Giuseppe Zagotto 4 and Laura Orian 2,* 1 Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123 Brescia, Italy; [email protected] (G.R.); [email protected] (E.O.); [email protected] (A.O.); [email protected] (A.G.) 2 Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1, 35131 Padova, Italy; [email protected] 3 Departament de Química, Institut de Química Computacional i Catàlisi, Universitat de Girona, C/M.A. Capmany 69, 17003 Girona, Spain 4 Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via Marzolo 5, 35131 Padova, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-049-8275140 Abstract: We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination- triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under oxidative conditions, we observed and characterized the formation of primary and secondary amines Citation: Ribaudo, G.; Bortoli, M.; as elimination products of such compounds, paving the way for a novel strategy to selectively release Oselladore, E.; Ongaro, A.; bioactive molecules. The underlying mechanism was investigated using NMR, mass spectrometry Gianoncelli, A.; Zagotto, G.; Orian, L. and density functional theory (DFT). Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Keywords: selenoxide elimination; one-pot; imine-enamine; reaction mechanism; DFT calcula- Secondary Amines: A Combined Experimental and Theoretical tions; selenium Investigation. Molecules 2021, 26, 2770. https://doi.org/10.3390/molecules 26092770 1. Introduction Academic Editor: Israel Fernández In the past few decades, the selenoxide elimination reaction has been used to obtain alkenes and has been largely applied in the synthesis of small molecules such as natural Received: 15 April 2021 products and bioactive compounds [1–4]. Generally, the organoselenides required for such Accepted: 5 May 2021 a reaction can be straightforwardly synthesized from electrophilic phenylselenyl chloride Published: 8 May 2021 or using diphenyl diselenides as precursors for the nucleophilic selenate. In the presence of oxidants, such as peroxides or other reactive oxygen species (ROS), organoselenium Publisher’s Note: MDPI stays neutral compounds are readily oxidized to selenoxides [5–7]. Then, an intramolecular syn elim- with regard to jurisdictional claims in ination occurs in opportune substrates, involving the hydrogen atom in vicinal position published maps and institutional affil- with respect to the selenium nucleus. This leads to the formation of the corresponding iations. trans-olefine [8–10]. In the context of our studies on selenium-based derivatives of compounds of phar- maceutical interest, we observed a peculiar behavior of amino organoselenides [10]. In particular, under oxidative conditions, we previously detected the formation of primary Copyright: © 2021 by the authors. and secondary amines from mono- or disubstituted 2-phenyl-2-(phenylselanyl)ethan-1- Licensee MDPI, Basel, Switzerland. amines (Scheme1). This article is an open access article Among the functional groups of biological relevance, the amino moiety is one of the distributed under the terms and most frequently occurring. Nevertheless, drugs containing primary or secondary amines, conditions of the Creative Commons despite being very common, are endowed with some pharmacokinetic limitations such as Attribution (CC BY) license (https:// poor diffusion through membranes or blood–brain barrier under particular physiologic con- creativecommons.org/licenses/by/ ditions. Moreover, instability affects such compounds, as amines physiologically undergo 4.0/). Molecules 2021, 26, 2770. https://doi.org/10.3390/molecules26092770 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 13 conditions. Moreover, instability affects such compounds, as amines physiologically undergo metabolic phase 1 transformations such as oxidations or dealkylations or Molecules 2021, 26, 2770 conjugations in phase 2. These limitations can be partially overcome by derivatization2 of 13to generate prodrugs that can be “unmasked” under certain conditions that can be pH-, redox- or enzyme-dependent [11]. Recent reports showed that selenoxide elimination can metabolicbe employed phase by 1 drug transformations-like derivatives such asresponsive oxidations toor reactive dealkylations oxygen or species conjugations (ROS) inin phaseinnovative 2. These targeted limitations therapeutic can be partially strategies overcome [12]. Moreover, by derivatization we previously to generate showed prodrugs that thatcompounds can be “unmasked”endowed with under bioactivity certain can conditions be generated that after can release be pH-, from redox- such or substrates. enzyme- dependentMolecules [selectively11]. Recent providing reports showed elimination that selenoxide products eliminationin response can to beoxidative employed stress by drug-likerepresent derivativesattractive tools, responsive in particular to reactive in the oxygen context species of central (ROS) nervous in innovative system targeted (CNS) therapeuticdrugs [10]. strategies [12]. Moreover, we previously showed that compounds endowed with bioactivityTaking the canstep be from generated these considerations, after release from we suchinvestigated substrates. and Molecules characterized selectively a one- providingpot model elimination reaction consisting products in in a response selenoxide to oxidative elimination stress-triggered represent enamine attractive hydrolysis tools, in particularthat allows in the the formation context of of central primary nervous and secondary system (CNS) amines drugs under [10 ].oxidative conditions. SchemeScheme 1.1. Proposed mechanismmechanism forfor selenoxideselenoxide elimination-triggeredelimination-triggered enamineenamine hydrolysis.hydrolysis. TakingAdditionally, the step this from combined these considerations, process is endowed we investigated with synthetic and characterized value, as it represents a one-pot modelan innovative reaction approach consisting for in aobtaining selenoxide primary elimination-triggered and secondary enamine amines hydrolysisas elimination that allowsproducts the under formation these ofspecific primary conditions. and secondary Although amines selenium under-catalyzed oxidative organic conditions. reactions, and Additionally,particularly thisselenoxide combined elimination process is, endowedhave been with extensively synthetic value,studied as it[13 represents–15], no anexamples innovative of selenium approach-based for obtaining mechanisms primary for and obtaining secondary such amines amines as eliminationwere previously prod- uctsreported under in these the literature. specific conditions. Although selenium-catalyzed organic reactions, and particularly selenoxide elimination, have been extensively studied [13–15], no examples of selenium-based2. Results and Discussi mechanismson for obtaining such amines were previously reported in the literature. From the point of view of the molecular mechanism, the considered oxidation- 2.triggered Results elimination and Discussion is distinctive of organoselenium compounds having protons in the β-position with respect to the chalcogen atom. This process occurs through a syn From the point of view of the molecular mechanism, the considered oxidation- mechanism and promotes the formation of olefins with high trans selectivity [8]. The triggered elimination is distinctive of organoselenium compounds having protons in the β- reaction is initiated by the oxidation of the selenium atom to the corresponding position with respect to the chalcogen atom. This process occurs through a syn mechanism selenoxide, a step which can be induced by different agents such as hydrogen peroxide, and promotes the formation of olefins with high trans selectivity [8]. The reaction is initi- meta-chloroperoxybenzoic acid (mCPBA) and ozone [7,16,17]. Then, an intramolecular ated by the oxidation of the selenium atom to the corresponding selenoxide, a step which syn elimination takes place: the Se-C bond breaks producing the trans-olefin and selenenic can be induced by different agents such as hydrogen peroxide, meta-chloroperoxybenzoic acid, that is readily oxidized to seleninic acid [10]. Interestingly, in the case of the studied acid (mCPBA) and ozone [7,16,17]. Then, an intramolecular syn elimination takes place: compounds (Scheme 2), an enamine is produced after the oxidation–elimination step. This the Se-C bond breaks producing the trans-olefin and selenenic acid, that is readily oxidized can be protonated on both the nitrogen atom and the β-carbon atom in acidic conditions. to seleninic acid [10]. Interestingly, in the case of the studied compounds (Scheme2), an enamineThe latter is producedevent is afterfavored the oxidation–eliminationand the molecule, rearranging step. This canto bean protonatediminium ion on bothand theundergoing nitrogen atomhydrolysis, and the subsequentlyβ-carbon atom pr inoduces acidic the conditions. corresponding The latter amine event (Scheme is favored 1) and[18,19] the. molecule, rearranging to an iminium