molecules Article Green Hydroselenation of Aryl Alkynes: Divinyl Selenides as a Precursor of Resveratrol Gelson Perin 1,*, Angelita M. Barcellos 1, Eduardo Q. Luz 1, Elton L. Borges 1, Raquel G. Jacob 1, Eder J. Lenardão 1, Luca Sancineto 2 and Claudio Santi 2,* 1 Laboratório de Síntese Orgânica Limpa-LASOL-CCQFA, Universidade Federal de Pelotas-UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil; [email protected] (A.M.B.); [email protected] (E.Q.L.); [email protected] (E.L.B.); [email protected] (R.G.J.); [email protected] (E.J.L.) 2 Department of Pharmaceutical Sciences, Group of Catalysis and Organic Green Chemistry, University of Perugia, Via del Liceo 1, 06100 Perugia, Italy; [email protected] * Correspondence: [email protected] (G.P.); [email protected] (C.S.); Tel./Fax: +55-53-3275-7533 (G.P.); Tel.: +39-07-5585-5102 (C.S.); Fax: +39-07-5585-5116 (C.S.) Academic Editor: Derek J. McPhee Received: 19 January 2017; Accepted: 16 February 2017; Published: 20 February 2017 Abstract: A simple and efficient protocol to prepare divinyl selenides has been developed by the regio- and stereoselective addition of sodium selenide species to aryl alkynes. The nucleophilic species was generates in situ, from the reaction of elemental selenium with NaBH4, utilizing PEG-400 as the solvent. Several divinyl selenides were obtained in moderate to excellent yields with selectivity for the (Z,Z)-isomer by a one-step procedure that was carried out at 60 ◦C in short reaction times. The methodology was extended to tellurium, giving the desired divinyl tellurides in good yields. Furthermore, the Fe-catalyzed cross-coupling reaction of bis(3,5-dimethoxystyryl) selenide 3f with (4-methoxyphenyl)magnesium bromide 5 afforded resveratrol trimethyl ether 6 in 57% yield. Keywords: selenium; PEG-400; tellurium; resveratrol; chalcogen alkenes 1. Introduction Chalcogen alkenes are attractive key intermediates in the synthesis of important compounds. They are useful synthons to access conjugated or isolated olefins with total control in the geometry of the double bond [1–5]. For instance, the iron- or nickel-catalyzed cross-coupling of divinyl chalcogenides with Grignard reagents [6], the direct coupling with terminal alkynes in the presence of a nickel/CuI catalyst [7], or similar transformations [8] are useful procedures to access functionalized alkenes. The synthesis of novel selenium heterocycles based on the reaction of selenium dichloride with divinyl sulfide [9–11] or divinyl selenide [12] was also reported. Divinyl selenides however, are less studied compared to synthetic intermediates, probably due to the limited number of general methods to prepare them in a selective way. They can be prepared by a stereoconservative three-step reaction of in situ generated vinyl selenide anions with (E)- or (Z)-bromo styrenes (Scheme1A) [ 13]. Divinyl selenides of (E,E)-configuration were predominantly formed by the Wittig–Horner reaction of chalcogen diphosphonate derivatives with aldehydes [14–16] (Scheme1B). Both approaches are very robust, despite the low atom efficiency and a high E factor [17]. A more atom-economic approach of preparing divinyl selenides and tellurides involves the electrophilic addition of chalcogen halides, such as selenium dichloride or dibromide and tellurium tetrachloride, to alkynes (Scheme1C). In these reactions, however, halo-substituted products are obtained and a reduction step is necessary to prepare the halogen-free divinyl chalcogenides [18–22]. Z,Z-bis(acylvinyl) selenides were exclusively obtained in moderate yields by the reaction of sodium selenide with ethynyl Molecules 2017, 22, 327; doi:10.3390/molecules22020327 www.mdpi.com/journal/molecules Molecules 2017, 22, 327 2 of 10 when bromoethynyl ketones were used, 1,3-diselenetanes were obtained instead of the respective divinyl selenides [23]. (Z,Z)-Divinyl tellurides were regio- and stereoselectively prepared by the hydrochalcogenation of alkynes via the anti-addition of Na2Te, generated in situ from Te0/NaBH4/EtOH in the presence of aqueous NaOH [24–26]. Alternatively, K2Te was used as nucleophile in the reaction with acetylene. The Molecules 2017, 22, 327 2 of 10 telluride anion was generated by heating a mixture of elemental tellurium and KOH in HMPA/H2O as the solvent at 110–120 °C under pressure [27]. These methods, however, are restricted to divinyl telluridesketones derived and require from heating aromatic for ketones. a long time Only in four the examplespresence of were a strong prepared base and(refluxing when for bromoethynyl up to 48 h), whichketones is werea problem used, 1,3-diselenetaneswith sensible substrates. were obtained instead of the respective divinyl selenides [23]. Scheme 1. PreviousPrevious general methods to prepare divinyl selenides and the present work. In(Z ,Zrecent)-Divinyl years, tellurides new synthetic were regio- methodologies and stereoselectively have been prepared developed by the aiming hydrochalcogenation to increase the of 0 efficiencyalkynes via and the yieldsanti-addition under mild of Na reaction2Te, generated conditions in situ [28,29]. from In Te this/NaBH regard,4/EtOH polyethylene in the presence glycol (PEG)of aqueous has been NaOH extensively [24–26]. used Alternatively, as a thermally K2 Testab wasle, nontoxic, used as cheap, nucleophile and non-volatile in the reaction solvent with in theacetylene. synthesis The of telluride organochalcogen anion was generatedcompounds by [30]. heating Some a mixture of us have of elemental recently telluriumdescribed and the KOH in situ in ◦ generationHMPA/H2 Oof aschalcogenolate the solvent at anions 110–120 usingC under the system pressure RYYR/NaBH [27]. These4/PEG-400 methods, (Y however, = S, Se, Te) are restrictedand their useto divinyl in selective tellurides Michael and additions, require heating the hydrochalcog for a long timeenation in the of presence alkynes [31–33 of a strong], and base the ring-opening (refluxing for ofup non-activated to 48 h), which aziridines is a problem [34]. with sensible substrates. OnIn recentthe other years, hand, new resveratrol synthetic (3,4 methodologies′,5-trihydroxystilbene) have been is a developedstilbene-type aiming polyphenolic to increase product the thatefficiency is present and yieldsin grapes, under peanuts, mild reaction mulberries, conditions and particularly [28,29]. In in this red regard, wine [35]. polyethylene Resveratrol glycol and (PEG)methoxylated has been analogues extensively are well used known as a thermally due to their stable, multiple nontoxic, biological cheap, activities, and non-volatile including solvent powerful in antioxidantthe synthesis properties, of organochalcogen which are associated compounds with [30 an].ti-inflammatory Some of us have [36], recently anticancer described [37], antibacterial the in situ [38]generation and neuroprotective of chalcogenolate effects anions [39]. using However, the system these compounds RYYR/NaBH are4/PEG-400 obtained (Yonly = S, in Se, small Te) andamounts their byuse the in selectiveextraction Michael of plants; additions, therefore, the the hydrochalcogenation development of general of alkynes and simple [31–33 ],synthetic and the ring-openingstrategies for theof non-activated preparation of aziridines stilbenoids [34 has]. become an important task [40–43]. AsOn mentioned the other hand, above, resveratrol despite the (3,4 0high,5-trihydroxystilbene) versatility of divinyl is a stilbene-typeselenides in organic polyphenolic synthesis, product the methodsthat is present of preparing in grapes, them peanuts,in a selective mulberries, way are and limited particularly and atom-intensive. in red wine Thus, [35]. the Resveratrol need for efficientand methoxylated and selective analogues methods areto access well knownthis class due of compounds to their multiple is imperative. biological Aiming activities, to contribute including to powerfulfill this gap, antioxidant we present properties, here our full which results are on associated the hydroselenation with anti-inflammatory of aryl alkynes [36 ],using anticancer the system [37], Seantibacterial0/NaBH4/PEG-400 [38] and to neuroprotective prepare (Z,Z)-divinyl effects selenides [39]. However, (Scheme these 1D). compounds The possibility are obtainedof exploring only the in usesmall of amountsdivinyl selenide by the extraction in the synthesis of plants; of re therefore,sveratrol the trimethyl development ether was of general also investigated. and simple synthetic strategies for the preparation of stilbenoids has become an important task [40–43]. As mentioned above, despite the high versatility of divinyl selenides in organic synthesis, the methods of preparing them in a selective way are limited and atom-intensive. Thus, the need for efficient and selective methods to access this class of compounds is imperative. Aiming to contribute to fill this gap, we present here our full results on the hydroselenation of aryl alkynes using the system 0 Se /NaBH4/PEG-400 to prepare (Z,Z)-divinyl selenides (Scheme1D). The possibility of exploring the use of divinyl selenide in the synthesis of resveratrol trimethyl ether was also investigated. Molecules 2017,, 22,, 327 327 3 of 10 2. Results and Discussion 2. Results and Discussion In our preliminary experiments, we chose phenylacetylene 1a and selenium powder 2a as standardIn our starting preliminary materials experiments, to perform we chosethe optimization phenylacetylene studies1a andunder selenium a N2 atmosphere powder 2a