molecules

Article Green Hydroselenation of Aryl Alkynes: Divinyl 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 species to aryl alkynes. The nucleophilic species was generates in situ, from the reaction of elemental 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 , 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; 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 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 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 as and standard using PEG-400starting materials as the solvent to perform (Table the 1). optimizationWe evaluated studies the influence under a of N 2temperatureatmosphere and and the using reaction PEG-400 time. as Firstly,the solvent a mixture (Table1 of). Weselenium evaluated 2a (0.5 the mmol) influence and of NaBH temperature4 (0.8 mmol) and the in reaction PEG-400 time. (3.0 Firstly,mL) was a mixture stirred atof room selenium temperature2a (0.5 mmol) to generate and NaBH in 4situ(0.8 the mmol) nucleophilic in PEG-400 selenium (3.0 mL) species. was stirred The atselenium room temperature reduction wasto generate accompanied in situ by the a nucleophilicchange in the selenium color of species.the reaction The mixture, selenium from reduction grey to was colorless accompanied (30 min byof stirring).a change After in the this color time, of the phenylacetylene reaction mixture, 1a (1.0 from mmol) grey towas colorless added (30in the min reaction of stirring). vessel After and thisthe desiredtime, phenylacetylene product 3a was1a obtained(1.0 mmol) in 12% was addedyield after in the 12 reaction h at room vessel temperature and the desired (Table product1, Entry3a 1).was By increasingobtained in the 12% temperature yield after 12to h40 at °C, room the temperaturereaction proceeds (Table smoothly1, Entry 1). and By the increasing desired the product temperature 3a was obtainedto 40 ◦C, thein 42% reaction yield proceeds in 12 h smoothly(Table 1, andEntry the 2). desired The temperature product 3a was had obtained a positive in 42%influence yield inin 12the h reaction(Table1, Entryof the 2).sodium The temperature selenide with had phen a positiveyl acetylene, influence and in a thesimilar reaction 40% ofyield the sodiumof 3a was selenide obtained with in 2phenyl h at 60 acetylene, °C (Table and 1, Entry a similar 3). Next, 40% yieldwe investigated of 3a was obtained the reaction in 2 htime at 60 and◦C (Tableobserved1, Entry that 3).5 h Next,gave thewe investigatedbest result, thewith reaction the desired time and divinyl observed selenide that 53a h gavebeing the isolated best result, as a withmixture the desiredof (Z,Z divinyl)- and (selenideZ,E)-isomers3a being (Z,Z isolated:Z,E ratio as aof mixture 80:20) in of 92% (Z,Z yield)- and (Table (Z,E)-isomers 1, Entries (Z ,4Z and:Z,E 5).ratio An of additional 80:20) in 92% testyield was performed,(Table1, Entries setting 4 and a time 5). An of additional5 h and increasing test was performed,the temperature setting to a 80 time °C; of however, 5 h and increasingthe yield was the lowertemperature than that to 80 under◦C; however, milder conditions the yield was (Table lower 1, Entry than that 6). Thus, under analyzing milder conditions the results (Table showed1, Entry in Table6). Thus, 1, we analyzing established the results the best showed reaction in Tableconditions1, we established as being the the previous best reaction reaction conditions of selenium as being 2a ◦ (0.5the previousmmol) and reaction NaBH of4 (0.8 selenium mmol)2a in(0.5 PEG-400 mmol) and(3.0 NaBHmL) at4 60(0.8 °C mmol) under in N PEG-4002 for 30 (3.0min. mL) Afterward, at 60 C phenylacetyleneunder N2 for 30 min.1a (1.0 Afterward, mmol) is phenylacetyleneadded dropwise 1aand(1.0 the mmol) resulting is added mixture dropwise is stirred and for the additional resulting 5mixture h at the is same stirred temperature. for additional 5 h at the same temperature.

Table 1. Optimization of the synthesissynthesis of divinyl selenide 3a aa..

Entry Temperature Time (h) Yield (%) b Entry Temperature Time (h) Yield (%) b 1 r.t. 12 12 1 r.t. 12 12 2 40 °C 12 42 2 40 ◦C 12 42 3 360 60 °C◦C 2 2 4040 4 460 60 °C◦C 3 3 7272 ◦ 5 560 60 °CC 5 5 9292 ◦ 6 680 80 °CC 5 5 3030 a Reactions performed in the presence of 1a (1.0 mmol), 2a (0.5 mmol), NaBH (0.8 mmol) and solvent (3.0 mL) a Reactions performed in the presence of 1a (1.0 mmol), 2a (0.5 mmol), NaBH4 4 (0.8 mmol) and solvent under N atmosphere. b Yields are given for isolated product 3a, which was obtained as a mixture of (Z,Z)- and 2 b (3.0(Z,E )-isomers.mL) under N2 atmosphere. Yields are given for isolated product 3a, which was obtained as a mixture of (Z,Z)- and (Z,E)-isomers. In order to demonstrate the efficiency of this protocol, we attempted to apply the designed method In order to demonstrate the efficiency of this protocol, we attempted to apply the designed to other aryl alkynes and the results are depicted in Table2. A closer inspection of Table2 reveals method to other aryl alkynes and the results are depicted in Table 2. A closer inspection of Table 2 that our protocol worked well for a range of substrates, delivering products 3a–f in good to excellent reveals that our protocol worked well for a range of substrates, delivering products 3a–f in good to yields and high selectivity to the (Z,Z)-isomer. The reactions are sensitive to the electronic effect of excellent yields and high selectivity to the (Z,Z)-isomer. The reactions are sensitive to the electronic the aromatic ring in the alkynes. The presence of strong electron-releasing group CH3O- in acetylenes effect of the aromatic ring in the alkynes. The presence of strong electron-releasing group CH3O- in 1c and 1f reduced the reactivity and a higher temperature (90 ◦C) was necessary to give good yields acetylenes 1c and 1f reduced the reactivity and a higher temperature (90 °C) was necessary to give of the respective divinyl selenides 3c,f (Table2, Entries 3 and 6). This deactivating effect was less good yields of the respective divinyl selenides 3c,f (Table 2, Entries 3 and 6). This deactivating effect pronounced in 4-tolyl acetylene 1b, which reacted under the standard conditions to afford the desired was less pronounced in 4-tolyl acetylene 1b, which reacted under the standard conditions to afford the divinyl selenide 3b after 5 h in 82% yield. In this example, a small amount of the (E,E)-isomer was desired divinyl selenide 3b after 5 h in 82% yield. In this example, a small amount of the (E,E)-isomer detected in addition to (Z,Z)- and (Z,E)-ones (Table2, Entry 2). The reaction is less affected by the was detected in addition to (Z,Z)- and (Z,E)-ones (Table 2, Entry 2). The reaction is less affected by the presence of electron-withdrawing groups. 3,4-Dichlorophenyl acetylene 1e afforded the respective presence of electron-withdrawing groups. 3,4-Dichlorophenyl acetylene 1e afforded the respective (Z,Z)-divinyl selenide 3e in 93% yield as the only isomer (Table2, Entry 5), while 4-ethynylbenzonitrile (Z,Z)-divinyl selenide 3e in 93% yield as the only isomer (Table 2, Entry 5), while 4-ethynylbenzonitrile 1d produced 3d in 74% yield as a mixture of (Z,Z)-, (Z,E)- and (E,E)-isomers in a 53:43:4 ratio (Table2, 1d produced 3d in 74% yield as a mixture of (Z,Z)-, (Z,E)- and (E,E)-isomers in a 53:43:4 ratio (Table 2, Entry 4). In additional studies, the performance of the reaction using 1,1-dimethylpropargyl alcohol 1g Entry 4). In additional studies, the performance of the reaction using 1,1-dimethylpropargyl alcohol

Molecules 2017, 22, 327 4 of 10 Molecules 2017, 22, 327 4 of 10 MoleculesMolecules 2017, 22 2017, 327, 22 , 327 4 of 10 4 of 10 MoleculesMolecules 2017, 22 2017, 327, 22 , 327 4 of 10 4 of 10 MoleculesMolecules 2017, 201722, 327, 22 , 327 4 of 104 of 10 1gandMolecules and hept-1-yneMolecules hept-1-yne 2017, 22 2017, 1h327, 22 1hwas, 327 was studied; studied; however, however, there there was was no formationno formation of theof the expected expected products products and 4and theof 10 4 of 10 MoleculesMolecules 2017 2017, 22, ,327 22, 327 4 of 410 of 10 thestarting1g startingMoleculesandMolecules1g materialshept-1-yne and 2017materials hept-1-yne2017, 22,, were 22327 1h, 327were recoveredwas 1h recovered studied;was studied; (Table however, (Table2, Entrieshowever, 2, Entriesthere 7 and therewas 7 8).and nowas 8).fo rmationno formation of the of expected the expected products products and4 of 4 10ofand 10 Molecules1g1g and and1gMolecules hept-1-yne2017 andhept-1-yne, 22 hept-1-yne2017, 327, 22 1h , 1h327 was was 1h studied; wasstudied; studied; however, however, however, there there therewas was no wasno fo fo rmationnormation formation of of the the of expected expectedthe expected products products products4 ofand and 10 4 ofand 10 1gthe and starting1gthe hept-1-yne and starting materials hept-1-yne materials 1h werewas 1h studied;wererecoveredwas studied;recovered however, (Table however, (Table 2, there Entries 2, therewas Entries 7 and nowas fo7 8). andrmationno fo 8).rmation of the of expected the expected products products and and thethe1g starting startingandthe1g and startinghept-1-yne materials materialshept-1-yne materials 1h were were was1h wererecovered wasrecovered studied; studied;recovered (Tablehowever, (Table however, (Table 2, 2, Entries Entriesthere 2, there Entries was 7 7 and wasand no 7 8). 8).andfono rmation fo 8).rmation of theof theexpected expected products products and and the1g starting the1gand andstarting hept-1-yne TableTablematerials hept-1-yne materials 2. Synthesis were1h 1hwas wererecoveredwas of studied; divinyl studied;recovered (Tableselenides however, however, (Table 2, 3Entries bythere 2, thethere Entries hydroselenation7was and was no7 8). andno fo rmationfo 8).rmation of aryl of alkynesofthe the expected expected 1 aa.. products products and and 1gthe and the1gstarting hept-1-yne and starting hept-1-yne materials materials 1h was were1h studied; werewas recovered studied;recovered however, (Table however, (Table there 2, Entries 2, therewas Entries no 7was and fo7 andrmationno 8). fo 8).rmation of the of expected the expected products products and and thethe starting startingTable materials materials Table2. Synthesis 2.were Synthesis were ofrecovered divinylrecovered of divinyl selenides (Table (Table selenides 2, 3 byEntries2, Entriesthe 3 by hydroselenation 7the and 7 hydroselenationand 8). 8). of aryl of alkynes aryl alkynes 1 a. 1 a. Table 2. Synthesis of divinyl selenides 3 by the hydroselenation of aryl alkynes 1 a. a the startingthe starting materialsTable materialsTable 2. wereSynthesis 2. Synthesis wererecovered of recovereddivinyl of divinyl(Table selenides (Table selenides2, Entries 3 2,by Entries the3 7by andhydroselenation the 7 8).hydroselenation and 8). of aryl of alkynesaryl alkynes 1 a. 1 a. TableTable 2. Synthesis 2. Synthesis of divinyl of divinyl selenides selenides 3 by the 3 by hydroselenation the hydroselenation of aryl of alkynes aryl alkynes 1 a. 1 a. TableTable 2. Synthesis 2. Synthesis of divinyl of divinyl selenides selenides 3 by 3 the by thehydroselenation hydroselenation of aryl of aryl alkynes alkynes 1 a. 1 a. TableTable 2. Synthesis2. Synthesis of divinylof divinyl selenides selenides 3 by 3 bythe the hydroselenation hydroselenation of arylof aryl alkynes alkynes 1 a .1 a. Table Table2. Synthesis 2. Synthesis of divinyl of divinyl selenides selenides 3 by the 3 by hydroselenation the hydroselenation of aryl of alkynes aryl alkynes 1 a. 1 a.

Entry Alkynes 1 Product 3 Yield (%) b Ratio ( Z,Z/Z,E/E,E ) Entry Alkynes 1 Product 3 b Ratio (Z ,Z/Z,E/E,E) Yield (%) b b Entry Entry Alkynes Alkynes 1 1 Product Product 3 3 Yield Yield(%) b (%)Ratiob Ratio(Z,Z/Z,E/E,E (Z,Z/Z,E/E,E) ) Entry Entry Alkynes Alkynes 1 1 Product Product 3 3 Yield Yield(%) b (%)Ratiob Ratio(Z,Z/Z,E/E,E (Z,Z/Z,E/E,E) ) EntryEntry Alkynes Alkynes 1 1 Product Product 3 3 Yield Yield (%)b (%)RatioRatio ( Z,Z/Z,E/E,E (Z,Z/Z,E/E,E) ) Entry Entry Alkynes Alkynes 1 1 Product Product 3 3 Yield Yield(%) (%)Ratiob Ratio(Z, Z/Z,E/E,E (cZ,Z/Z,E/E,E) ) 1 EntryEntry Alkynes Alkynes 1 1 Product Product 3 3 Yield92 Yield (%) (%)b bRatio80/20/00 Ratio (Z,Z/Z,E/E,E (Z ,Z/Z,E/E,E) ) Entry Alkynes 1 Product 3 Yield (%)b b Ratio c(Z,Z/Z,E/E,E) 1Entry 1 1 Alkynes 1 Product 392 Yield92 (%)b92 80/20/00b Ratio80/20/00 (Z80/20/00,Z/Z,E/E,E c c ) Entry1 Entry Alkynes Alkynes 1 1 Product Product 3 3 Yield92 Yield(%) (%)Ratio80/20/00 Ratio(Z,Z/Z,E/E,E (Z c, Z/Z,E/E,E) c ) 1 1 92 92 80/20/0080/20/00 c c 1 1 92 92 80/20/0080/20/00 c c 1 1 92 92 80/20/0080/20/00 c c 1 92 80/20/00c c 1 92 80/20/00c c 1 1 92 92 80/20/0080/20/00 d 2 82 71/15/14 2 2 82 82 71/15/1471/15/14 d d 2 2 82 82 71/15/1471/15/14d d d 2 2 82 82 71/15/1471/15/14 d d 2 2 82 82 71/15/1471/15/14 d d 2 2 82 82 71/15/1471/15/14 d d 2 2 82 82 71/15/1471/15/14 d d 2 2 82 82 71/15/1471/15/14 d d

3 77 77/23/00 d,e 3 3 77 77 77/23/0077/23/00 d,e d,e 3 77 77/23/00 d,e d,e 33 3 77 77 77 77/23/0077/23/0077/23/00d,e d,e d,e 3 3 77 77 77/23/0077/23/00 d,e d,e 3 3 77 77 77/23/0077/23/00 d,e d,e 3 3 77 77 77/23/0077/23/00 d,e d,e 3 77 77/23/00 d,e d,e 3 77 77/23/00

4 74 53/43/04 c 4 4 74 74 53/43/0453/43/04 c c 4 74 53/43/04 c c 4 4 74 74 53/43/0453/43/04 c c 4 4 4 7474 74 53/43/0453/43/0453/43/04c c c 4 4 74 74 53/43/0453/43/04 c c 4 4 74 74 53/43/0453/43/04 c c 4 74 53/43/04 c c 4 74 53/43/04

5 93 100/00/00 c 5 5 93 93 100/00/00100/00/00 c c 5 93 100/00/00 c c 5 5 93 93 100/00/00100/00/00 c c 5 5 93 93 100/00/00100/00/00 c c 55 5 9393 93 100/00/00100/00/00100/00/00c c c 5 93 100/00/00c c 5 93 100/00/00c c 5 5 93 93 100/00/00100/00/00

6 78 80/20/00 c,e c,e c,e 6 6 78 78 80/20/0080/20/00 c,e c,e 6 6 78 78 80/20/0080/20/00 c,e c,e 6 6 78 78 80/20/0080/20/00c,e c,e 6 6 78 78 80/20/0080/20/00 c,e c,e 6 6 78 78 80/20/0080/20/00 c,e 6 6 6 7878 78 80/20/0080/20/0080/20/00c,e c,e 6 6 78 78 80/20/0080/20/00 c,e c,e

7 nr - 7 7 nr nr - - 7 nr - 7 7 nr nr - - 7 7 nr nr - - 7 7 nr nr - - 7 7 nr nr - - 8 7 7 nrnr nr - - - 7 nr - 8 8 nr nr - - 8 nr - 8 8 nr nr - - a8 8 nr nr - - Reactions8 8 performed in the presence of aryl alkynes 1 (1.0 mmol), seleniumnr 2a nr(0.5 mmol), NaBH- 4 - 8 8 nr nr - - a a b 4 4 (0.88 a8 Reactions mmol),8 a Reactions and performed PEG-400 performed in (3.0 the mL) inpresence the under presence ofN 2aryl atmosphere. of alkynes aryl alkynes 1 (1.0Yields 1mmol), (1.0 are mmol),givennr selenium fornr selenium isolated 2anr (0.5 2aproducts mmol), (0.5 - mmol), -NaBH 3a–f. -NaBH Reactionsa a Reactions performed performed in the inpresence the presence of aryl of alkynes aryl alkynes 1 (1.0 1mmol), (1.0 mmol), selenium selenium 2a (0.5 2a mmol), (0.5 mmol), NaBH NaBH4 4 c ReactionsReactions performed1 performed in the in presence the presence of aryl of alkynesaryld alkynes 1 b(1.0 1 mmol),(1.0b mmol), selenium selenium 2a (0.5 2a mmol),(0.5 mmol), NaBH NaBH4 4 a(0.8 mmol),a(0.8 mmol), and PEG-400 and PEG-400 (3.0 mL) (3.0 under mL) under N2 atmosphere. N2 atmosphere. Yields Yields are given are givenfor isolated for isolated products products 3a–f4. 3a–f. DeterminedReactionsa Reactions performed by H-NMR performed in ofthe the inpresence thepurified presence of product. aryl of alkynes aryl Determined alkynes 1 (1.0b 1mmol), (1.0b by mmol),GC/MS selenium selenium of the2a (0.5purified 2a mmol), (0.5 product. mmol), NaBH NaBH 4 (0.8Reactions mmol),(0.8a Reactions mmol), and performed PEG-400 performedand PEG-400 in(3.0 the in mL) (3.0thepresence under presencemL) under Nof2 atmosphere.aryl of N aryl alkynes2 atmosphere. alkynes 1 bYields (1.0 1 (1.0bmmol), Yields are mmol), given areselenium givenforselenium isolated for2a (0.5 isolated2a products (0.5mmol), mmol), products 3aNaBH– fNaBH. 3a4 –f4. e c (0.8a mmol),a(0.8c mmol), and 1PEG-400 and PEG-4001 (3.0 mL) (3.0 undermL) under N2 atmosphere. N2 atmosphere.d d Yields Yields are given are given for isolated for isolated products products 3a–f. 3a–f. a DeterminedReactionsReactionsDetermined by performed performedH-NMR by H-NMR inof the inthe the presence ofpurified presencethe purified ofproduct.2 arylof arylproduct. alkynes alkynesDetermined b 1Determined (1.0 1 (1.0b mmol), by mmol), GC/MS byselenium seleniumGC/MS of the 2a ofpurified 2a(0.5 the (0.5 mmol),purified mmol),product. NaBH product. NaBH 4 4 Reactiona(0.8cReactions mmol),(0.8ca performed performedmmol), and PEG-4001 and inat thePEG-400901 (3.0 presence°C; nrmL) (3.0 = no ofunder mL) arylreaction. under alkynesN atmosphere. N12 (1.0atmosphere.d mmol), d Yields b selenium Yields are given2a are(0.5 givenfor mmol), isolated for NaBH isolated products4 (0.8 products mmol), 3a–f4. 3a–f.4 ReactionsDeterminedc c DeterminedReactions performed by performedH-NMR1 by in1H-NMR the of inpresencethe the ofpurified thepresence ofpurified arylproduct. of2 alkynes arylproduct.2 alkynesdDetermined 1 (1.0 d Determined 1mmol), (1.0b by mmol), seleniumGC/MS by GC/MSselenium of 2a the (0.5 ofpurified 2a themmol), (0.5 purified mmol),product. NaBH product. NaBH e Determined(0.8 (0.8emmol), Determined mmol), andby and PEG-400H-NMR by PEG-400H-NMR of(3.0 the (3.0mL) of purified themL) under purified under Nproduct. atmosphere. N product. atmosphere. Determined Determined bYields b Yields by are GC/MS givenareby givenGC/MS for of isolatedforthe of isolatedpurified the productspurified products product. 3aproduct.– f 3a. –f. andc Reaction PEG-400(0.8c(0.8 Reactionmmol), mmol),performed (3.0 and mL) performed1 and PEG-400 under atPEG-4001 90 N °C; at (3.0atmosphere. 90nr (3.0 mL) °C;= nomL) nr under reaction. = under nob YieldsNreaction.2 N atmosphere.2 areatmosphere.d givend for Yields isolated Yields are productsare given given for3a for –isolatedf. isolatedc Determined products products by 3a– 3af. –f. e Determinede Determined by H-NMR by H-NMR of2 the ofpurified the purified product.2 product.2 Determined b Determinedb by GC/MS by GC/MS of the of purified the purified product. product. (0.8Reactione c Determined mmol),ec(0.8 Reaction mmol),performed and byPEG-400performed and 1H-NMR at PEG-4001 90 (3.0 °C; at of mL) 90nr (3.0the °C;= under nopurifiedmL) nr reaction. = underNno atmosphere.reaction.product. N atmosphere. d Determined d Yields Yields are by given areGC/MS givenfor isolated of for the isolated purified products products product. 3a◦ –f. 3a –f. 1H-NMRReactionc c DeterminedReaction of the performed purified performed by1 product. at1H-NMR 90 at°C;d 90Determined nr of°C; = the nonr purifiedreaction.= no by GC/MSreaction. product. of thed purifiedd Determined product. bye ReactionGC/MS performedof the purified at 90 C;product. Afterward,ce Determinedec Determined we examined by1 byH-NMR 1H-NMR the of possibilitytheof the purified purified of product. using product.d ourDetermined d Determinedprotocol byto byprepareGC/MS GC/MS of the theof divinylthe purified purified tellurides product. product. DeterminedReactione e ReactionDetermined performed by performedH-NMR by at H-NMR90 of°C; at the 90 nr of °C;purified= nothe nr reaction. =purified no product. reaction. product. Determined Determined by GC/MS by GC/MS of the ofpurified the purified product. product. nr = noeReaction reaction.e Reaction performed performed at 90 at °C; 90 nr°C; = nr no = reaction. no reaction. analogueseAfterward, Reaction 4eAfterward,. Reaction Firstly, weperformed weperformed examined we performed examined at 90at the 90°C; the°C; possibilitynr the reaction=nr no possibility= noreaction. reaction. oftellurium using of using our powder protocol our protocol(0.5 to mmol) prepare to withprepare the NaBH divinyl the4 (0.8divinyl tellurides mmol) tellurides Afterward,ReactionAfterward,Afterward,Reaction performed we we performed examined examined we at examined 90 °C; at the the90nr °C;possibility= possibility theno nr reaction. possibility= no reaction. of of using using of using our our protocol protocolour protocol to to prepare prepare to prepare the the divinyl divinylthe divinyl tellurides tellurides tellurides inanalogues PEG-400Afterward,analoguesAfterward, 4(3.0. Firstly, mL) 4we. Firstly, examinedweat we 60performed examined we°C performedunder the possibility the the N reaction2 possibility atmospherethe reaction of tellurium using of untiltellurium using our powder consumptionprotocol our powder protocol (0.5 to mmol) prepare (0.5 ofto mmol)theprepare with thetellurium NaBH withdivinyl the NaBH divinyl4 (0.8(30 tellurides mmol)min).4 (0.8 tellurides mmol) analoguesanaloguesAfterward, 4. Firstly, 4. Firstly,we we examined performed we performed the the possibility reaction the reaction telluriumof using tellurium our powder protocol powder (0.5 mmol)to (0.5 prepare mmol) with the NaBHwith divinyl NaBH4 (0.8 tellurides mmol)4 (0.8 mmol) analoguesAfterward,analoguesAfterward, 4. Firstly, we4. Firstly, examined wewe performed examinedwe performed the possibility the reactionpossibility the reaction of using tellurium of tellurium ourusing protocolpowder our powder protocol (0.5 to prepare mmol)(0.5 to mmol) prepare thewithdivinyl with NaBH the NaBH divinyl4 tellurides (0.84 mmol)(0.8 tellurides mmol) Then,analoguesin PEG-400 phenylacetyleneanaloguesin Afterward,PEG-400 4 . (3.0Firstly, 4 mL) . (3.0Firstly, we we at1amL) examined performed 60(1.0 we at°C performed mmol)60 under °Cthe the under waspossibility Nreaction 2the atmosphereadded Nreaction2 atmosphere tellurium andof using telluriumth untile mixturepowderour untilconsumption protocol powder consumption was(0.5 mmol) stirred to(0.5 prepareof mmol) the withunder of tellurium theNaBHthewith N divinyl2tellurium NaBHat4 (0.8the (30 telluridesmmol)4same (0.8min). (30 mmol) min). in PEG-400Afterward,in PEG-400Afterward, (3.0 wemL) (3.0 examined atwemL) 60 examined at°C 60 theunder °C possibility theunder N possibility2 atmosphere N 2of atmosphere using of using untilour protocol untilconsumptionour protocolconsumption to prepare toof preparethe theof tellurium the divinyl the tellurium divinyl 4tellurides(30 min). tellurides(30 min). inanalogues PEG-400inanalogues PEG-400 4(3.0. Firstly, 4 . (3.0mL)Firstly, mL)weat 60weperformed at °C performed60 under °C underthe N thereaction2 atmosphere Nreaction2 atmosphere tellurium tellurium until powderuntil consumption powder consumption (0.5 (0.5 mmol) ofmmol) the withof tellurium thewith NaBH tellurium NaBH (0.8(304 (0.8 mmol)min).(30 mmol) min). analoguesThen,analoguesanaloguesThen, phenylacetylene4. phenylacetylene Firstly, 4. Firstly,4. Firstly, we performedwe1a we (1.0performed 1aperformed mmol) (1.0 the mmol) reactionthewas the reaction added was reaction tellurium added andtellurium tellurium th and powdere mixture thpowdere powder mixture (0.5 was (0.5 mmol) (0.5stirred wasmmol) mmol) with stirred under with NaBH with under NaBHN 4NaBH2 (0.8at N4the (0.82 mmol) 4at (0.8same mmol)the mmol) same temperatureanaloguesin PEG-400inanalogues PEG-400 4 for. (3.0Firstly, an 4 mL). (3.0 additionalFirstly, we atmL) performed60 we at°C 5 performed 60 h,under affording°C the under Nreaction 2the atmosphere theN reaction2 desiredatmosphere tellurium tellurium untildivinyl powder untilconsumption telluride powder consumption (0.5 mmol) (0.54a ofin mmol) 40%thewith of tellurium yield theNaBHwith tellurium ( NaBHZ4 ,(0.8Z -isomer,(30 mmol)4 (0.8min). (30 mmol) min). Then,in PEG-400Then,in phenylacetylene PEG-400 phenylacetylene (3.0 (3.0 mL) mL) 1aat (1.0 ◦60at 1a °C 60mmol) (1.0 °Cunder mmol)under was N 2added atmospherewasN2 atmosphere added and th and untile mixture untilth econsumption mixture consumption was stirred was of stirred undertheof thetellurium under Ntellurium2 at Nthe 2(30 at same (30themin). min).same intemperatureThen, PEG-400in inThen,temperaturePEG-400 phenylacetylenePEG-400 (3.0phenylacetylene for (3.0 mL)an (3.0for additionalmL) at anmL) 60 1aadditionalat at(1.060C 1a under560°C mmol)(1.0h, °C underaffording 5 mmol) under Nh, 2 wasaffording atmosphereN 2 was N addedtheatmosphere2 atmosphere desiredadded the and desired until andthdivinyl untile consumptionmixtureuntilth divinyl econsumption telluridemixture consumption was telluride wasstirred4a of in theofstirred 4a40% oftheunder telluriumin theyield 40% telluriumunder telluriumN yield(2Z at , (30NZ the-isomer,2 ((30atZ min). , sameZ(30the -isomer,min). min). same only).inThen, PEG-400 InterestedThen,in phenylacetylene PEG-400 phenylacetylene(3.0 in mL) the(3.0 excellent atmL) 1a 60 (1.0 at°C 1a 60 selectivitymmol) under(1.0 °C mmol)under wasN2 andatmosphere added wasN aimi2 atmosphere added ngand to untilth andimprovee mixture untilthconsumptione mixture the consumption was yield, stirredwas theof thestirred reaction underof tellurium the under Nwastellurium2 at repeated N(30the2 at min).same (30the samemin). temperaturetemperatureThen,temperatureThen, phenylacetylene phenylacetylene for for an an for additional additional an additional 1a (1.01a 5 5 h,(1.0 h,mmol) affording affording5 mmol) h, affordingwas wasthe addedthe desired addeddesired the and desired anddivinyl thdivinyle thmixture divinyle telluridemixture telluride telluridewas was4a 4astirred in instirred 4a40% 40% inunder yield 40% yieldunder Nyield( Z(2Z ,atZN,Z-isomer, 2 -isomer,the (atZ, Z thesame-isomer, same intemperatureonly). theThen, presencetemperatureThen,only). Interested phenylacetylene Interestedphenylacetylene for of an inNaOH for theadditional anin excellent (1.1theadditional 1a excellent equiv), 1a(1.0 5 h,(1.0selectivity mmol) affording 5 similarlymmol) h,selectivity affording was and wasthe describedadded aimi anddesiredadded theng aimi anddesired to andbydivinyl ng improveth Tucci etoth mixturedivinyl eimprove telluridemixture and the tellurideco-workers yield,was the was4a stirredyield, thein stirred 4a40% reaction thein under yielda40% reactionunder closely was yield(NZ 2,NZ at repeated related-isomer,was2 ( atZthe, Z therepeated -isomer,same same Then,only).temperatureonly).temperatureThen, Interestedphenylacetylene Interestedphenylacetylene for in foran the additional anin excellent 1a theadditional (1.0 excellent 1a mmol) selectivity(1.05 h, 5 mmol)affording h,selectivity was affording andadded was theaimi andadded theanddesiredng aimi desired toth and ngeimprove divinylmixture toth divinyl eimprove mixture thetelluride was tellurideyield, thestirred was yield,4a the stirred in4a reactionunder 40% thein 40% reactionunderyield N was 2yield at ( NZ therepeated ,was2 Z (atZ -isomer,same, Z therepeated-isomer, same inonly). thetemperaturetemperatureonly).in presence Interested the Interestedpresence forof inforNaOH an the of aninadditional NaOHexcellent theadditional (1.1 excellent equiv), (1.1 selectivity5 h, equiv),5 similarlyaffordingh,selectivity affording similarly and describedthe aimiand the desired describedngaimi desired to ngby improve divinyl toTucci divinyl improveby Tucci and telluridethe telluride yield,co-workers theand yield, 4a co-workersthe 4ain reaction thein40% in 40% reactiona yield closely in yieldwas a (closelyZ wasrepeated ,(relatedZZ-isomer,,Z repeated-isomer, related temperatureonly).in theonly).intemperature Interestedpresence the Interestedpresence for of anin NaOHfor theadditional of anin excellent NaOH theadditional (1.1 excellent equiv),5 (1.1 h,selectivity affording equiv),5 similarlyselectivityh, affording andsimilarly the describedaimi anddesired theng describedaimi desired to divinyl ngimproveby toTucci divinyl improveby telluride Tucci theand tellurideyield, co-workers theand 4a yield, theinco-workers 40%4a reaction thein in yield 40% reactiona closely wasin yield(Z a,Z closelyrepeated was-isomer, related(Z,Z repeated-isomer, related inonly). theonly).in presence theInterested Interestedpresence of inNaOH ofthe in NaOH theexcellent (1.1 excellent equiv),(1.1 selectivity equiv), selectivity similarly similarly and describedand aimi describedaiming tong by improve to Tucci improveby Tucci and the theco-workersyield,and yield, co-workers the thereaction in reaction a closelyin was a closely was repeated related repeated related only).in theonly).in Interestedpresence the Interested presence of in NaOH thein of the excellent NaOH (1.1excellent equiv), (1.1 selectivity selectivityequiv), similarly andsimilarly and describedaimi aiming described ngto improvebyto improveTucci by Tucci theand the yield, co-workers and yield, theco-workers the reaction reactionin a closely wasin awas closelyrepeated related repeated related in theinonly). thepresence presenceInterested of NaOH of in NaOH the (1.1 excellent (1.1 equiv), equiv), selectivity similarly similarly and described describedaiming by to Tucciimproveby Tucci and theand co-workers yield, co-workers the inreaction a in closely a closely was related repeated related in thein the presence presence of NaOHof NaOH (1.1 (1.1 equiv), equiv), similarly similarly described described by byTucci Tucci and and co-workers co-workers in ain closely a closely related related in the in presence the presence of NaOH of NaOH (1.1 equiv), (1.1 equiv), similarly similarly described described by Tucci by Tucciand co-workers and co-workers in a closely in a closely related related

Molecules 2017, 22, 327 5 of 10

Then, phenylacetylene 1a (1.0 mmol) was added and the mixture was stirred under N2 at the same temperature for an additional 5 h, affording the desired divinyl telluride 4a in 40% yield (Z,Z-isomer, only).Molecules Interested2017, 22, 327 in the excellent selectivity and aiming to improve the yield, the reaction5 wasof 10 Molecules 2017, 22, 327 5 of 10 repeated in the presence of NaOH (1.1 equiv), similarly described by Tucci and co-workers in a closely ◦ relatedreactionreaction reaction [24],[24], affordingaffording [24], affording productproduct product 4a4a inin 4a82%82%in 82%yieldyield yield afterafter after 55 hh 5atat h 6060 at 60°C.°C. C.ByBy By usingusing using thethe the samesame same strategy,strategy, strategy, bis(3,5-dimethoxystyryl)bis(3,5-dimethoxystyryl) telluridetelluride 4b4b waswas obtained obtained in in 83% 83% yield yield from from 3,5-dimethoxyphenylacetylene 3,5-dimethoxyphenylacetylene ◦ 1f1f afterafter 55 hh atat 9090 °C°CC (Scheme(Scheme2 2).2).).

Scheme 2. Synthesis of divinyl tellurides by hydrotelluration of aryl alkynes. Scheme 2. Synthesis of divinyl tellurides by hydrotelluration of aryl alkynes.

InIn orderorderorder to demonstratetoto demonstratedemonstrate the synthetic thethe syntheticsynthetic versatility versativersati of divinyllitylity selenides,ofof divinyldivinyl the selenides, Fe-catalyzedselenides, thethe cross-coupling Fe-catalyzedFe-catalyzedof bis(3,5-dimethoxystyryl)cross-couplingcross-coupling ofof bis(3,5-dimethoxystyryl)bis(3,5-dimethoxystyryl) selenide 3f with (4-methoxyphenyl)magnesium selenideselenide 3f3f withwith (4-methoxyphenyl)magnesium(4-methoxyphenyl)magnesium bromide 5 was investigated bromidebromide for55 waswas the investigatedinvestigated synthesis of for resveratrolfor thethe synthesissynthesis trimethyl ofof resveratrolresveratrol ether 6. Following trimethyltrimethyl the etherether synthesis 66.. FollowingFollowing and purification thethe synthesissynthesis of 3f andand, it purification of 3f, it was reacted with Grignard’s reagent 5 in the presence of catalytic Fe(acac)3 at room waspurification reacted of with 3f, it Grignard’s was reacted reagent with Grignard’s5 in the presence reagent of5 in catalytic the presence Fe(acac) of 3catalyticat room Fe(acac) temperature3 at room to afford,temperaturetemperature after toto 4 h,afford,afford, the expected afterafter 44 h,h, resveratrolthethe expectedexpected trimethyl resveratrolresveratrol ether trimethyltrimethyl6 in 57% etherether yield 66 inin (Scheme57%57% yieldyield3 ). (Scheme(Scheme The reaction 3).3). TheThe wasreactionreaction stereoconservative, waswas stereoconserstereoconservative,vative, with compound withwith compoundcompound6 being 66 beingbeing obtained obtainedobtained asa asasZ a/a EZZ//mixtureEE mixturemixture (Z ((Z:ZE::EEratio ratioratio ofofof 73:27).73:27). TheThe sequencesequence shownshown inin SchemeScheme 3 33 is isis a aa straightforward straightforwstraightforwardard waywayway to toto polymethoxylated polymethoxylatedpolymethoxylated stilbenes,stilbenes,stilbenes, whichwhichwhich areareare themselvesthemselves biologicallybiologically activeactive andand pharmaceuticallypharmaceutically relevantrelevantrelevant precursorsprecursorsprecursors (Scheme(Scheme(Scheme3 3).).3).

Scheme 3. Synthesis of resveratrol trimethyl ether 6. Scheme 3.3. Synthesis of resveratrol trimethyltrimethyl etherether 66.. 3. Materials and Methods 3.3. Materials and Methods 3.1. General Information 3.1.3.1. General Information The reactions were monitored by thin layer chromatography (TLC), which were performed using TheThe reactionsreactions werewere monitoredmonitored byby thinthin layerlayer chromatographychromatography (TLC),(TLC), whichwhich werewere performedperformed usingusing Merck (Merck, Darmstadt, Germany) silica gel (60 F254), with a 0.25 mm thickness. For visualization, MerckMerck (Merck,(Merck, Darmstadt,Darmstadt, Germany)Germany) silicasilica gelgel (60(60 FF254254),), with a 0.250.25 mmmm thickness.thickness. ForFor visualization,visualization, TLC plates were either exposed to UV light, or stained with iodine vapor or in a 5% vanillin solution in TLCTLC platesplates were either exposed to to UV UV light, light, or or staine stainedd with with iodine iodine vapor vapor or or in in a 5% a 5% vanillin vanillin solution solution in 10% aqueous H2SO4 and heat. Column chromatography was performed using Merck Silica Gel in10% 10% aqueous aqueous H H2SO2SO4 and4 and heat. heat. Column Column chromatography chromatography was was performed performed using using Merck Silica GelGel (230–400(230–400 mesh).mesh). High-resolutionHigh-resolution massmass spectraspectra (HRMS)(HRMS) werewere recordedrecorded inin positivepositive ionion modemode (ESI)(ESI) usingusing aa BrukerBruker microQTOFmicroQTOF spectrometerspectrometer (Bruker,(Bruker, Billerica,Billerica, MA,MA, USA).USA). Low-Low-resolutionresolution massmass spectraspectra werewere obtainedobtained withwith aa ShimadzuShimadzu GC-MS-QP2010GC-MS-QP2010 massmass spectrometerspectrometer (Shimadzu(Shimadzu Corporation,Corporation, Kyoto,Kyoto, Japan).Japan). NMR spectra were recorded with Bruker DPX (Bruker). (1H-NMR = 400 and 500 MHz; 13C-NMR = NMR spectra were recorded with Bruker DPX (Bruker). (1H-NMR = 400 and 500 MHz; 13C-NMR = 100 and 126 MHz) instruments using CDCl3 as solvent and calibrated using tetramethylsilane (TMS) 100 and 126 MHz) instruments using CDCl3 as solvent and calibrated using tetramethylsilane (TMS) asas internalinternal standard.standard. CouplingCoupling constantsconstants ((J)J) werewere reportedreported inin HertzHertz andand chemicalchemical shiftsshifts ((δδ)) inin ppm.ppm.

Molecules 2017, 22, 327 6 of 10

(230–400 mesh). High-resolution mass spectra (HRMS) were recorded in positive mode (ESI) using a Bruker microQTOF spectrometer (Bruker, Billerica, MA, USA). Low-resolution mass spectra were obtained with a Shimadzu GC-MS-QP2010 mass spectrometer (Shimadzu Corporation, Kyoto, Japan). NMR spectra were recorded with Bruker DPX (Bruker). (1H-NMR = 400 and 500 MHz; 13C-NMR = 100 and 126 MHz) instruments using CDCl3 as solvent and calibrated using tetramethylsilane (TMS) as internal standard. Coupling constants (J) were reported in Hertz and chemical shifts (δ) in ppm. The NMR spectra are found in the Supplementary Materials. The reagents (substituted alkynes, sodium tetrahydroborate, elemental chalcogen) and PEG-400 were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO, USA).

3.2. General Procedure for the Preparation of Divinyl Selenides 3a–f In a two necked round bottomed flask under nitrogen atmosphere, sodium selenide was generated by reaction of elemental selenium (Se0, 0.5 mmol) with sodium tetrahydroborate (0.8 mmol, 0.030 g) in PEG-400 (3.0 mL) at 60 ◦C. After 30 min, a colorless solution was obtained and the corresponding alkyne was added (1.0 mmol). After stirring for 5 h at 60 or 90 ◦C, the reaction mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (3 × 15.0 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel eluting with hexanes to yield the products as an inseparable mixture of isomers. All compounds were properly characterized by MS, 1H-NMR, and 13C-NMR, and the isomers ratios were determined by GC and NMR.

1 Bis-(Z,Z)-styryl selenide 3a: Yield: 0.132 g (92%) [13]; Orange solid; H-NMR (CDCl3, 500 MHz) δ (ppm): 7.20–7.38 (m, 10H), 6.92 (d, J = 10.4 Hz, 2H), 6.64 (d, J = 10.4 Hz, 2H). MS: m/z (rel. int.) 286 (M+, 22.2), 1 205 (100), 102 (36.7), 91 (42.8), 77 (50.4). Z,E-3a:[13] H-NMR (CDCl3, 500 MHz) δ (ppm): 7.14 (d, J = 10.4 Hz, 1H), 7.08 (d, J = 15.4 Hz, 1H), 6.85 (d, J = 15.4 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), other peaks were overlapped with those of Z,Z-3a. MS: m/z (rel. int.) 286 (M+, 25.0), 205 (100), 102 (35.3), 13 91 (41.4), 77 (44.1). C-NMR (125 MHz, CDCl3) δ (ppm): (Z,Z + Z,E) 137.0, 136.7, 134.7, 134.1, 130.5, 130.2, 128.61, 128.57, 128.4, 128.2, 127.9, 127.6, 127.3, 126.3, 125.9, 123.4, 121.3, 119.5. HRMS (ESI): m/z + calcd. for C16H14Se [M + H] : 287.0339, found: 287.0328. 1 Bis-(Z,Z)-4-methylstyryl selenide 3b: Yield: 0.129 g (82%); Orange solid; H-NMR (CDCl3, 400 MHz) δ (ppm): 7.10–7.50 (m, 8H), 6.91 (d, J = 10.4 Hz, 2H), 6.60 (d, J = 10.4 Hz, 2H), 2.34 (s, 6H). MS: m/z + 1 (rel. int.) 314 (M , 38.8), 219 (100), 204 (25.9), 102 (20.4), 91 (32.4), 77 (6.6). Z,E-3b: H-NMR (CDCl3, 400 MHz) δ (ppm): 6.96 (d, J = 10.3 Hz, 1H), 6.86 (d, J = 15.6 Hz, 1H), 6.76 (d, J = 15.6 Hz, 1H), 6.69 (d, J = 10.3 Hz, 1H), other peaks were overlapped with those of E,E and Z,Z-3b. MS: m/z (rel. + 1 int.) 314 (M , 32.6), 219 (100), 204 (23.7), 102 (18.6), 91 (28.0), 77 (6.2). E,E-3b:[15] H-NMR (CDCl3, 400 MHz) δ (ppm): 7.04 (d, J = 15.8 Hz, 2H), 6.84 (d, J = 15.8 Hz, 2H), other peaks were overlapped with those of Z,E and Z,Z-3b. MS: m/z (rel. int.) 314 (M+, 39.3), 219 (100), 204 (25.0), 102 (17.4), 91 13 (29.4), 77 (7.0). C-NMR (CDCl3, 100 MHz) δ (ppm): (Z,Z + Z,E + E,E) 138.0, 137.5, 137.13, 137.11, 134.31, 134.29, 134.25, 130.4, 130.1, 129.34, 129.3, 129.1, 128.22, 128.17, 127.2, 126.5, 126.3, 126.1, 125.91, + 125.87, 122.5, 120.5, 118.2, 116.6, 21.3, 21.2. HRMS (ESI): m/z calcd. for C18H18Se [M + H] : 315.0652, found: 315.0648.

1 Bis-(Z,Z)-4-methoxystyryl selenide 3c: Yield: 0.133 g (77%); Orange solid; H-NMR (CDCl3, 500 MHz) δ (ppm): 6.72–7.34 (m, 10H), 6.52 (d, J = 9.9 Hz, 2H), 3.80 (s, 6H). MS: m/z (rel. int.) 346 (M+, 13.9), 266 1 (100), 235 (36.7), 77 (10.2). Z,E-3c: H-NMR (CDCl3, 500 MHz) δ (ppm): 6.61 (d, J = 10.2 Hz, 1H), 3.78 (s, 6H), other peaks were overlapped with those of Z,Z-3c. MS: m/z (rel. int.) 346 (M+, 14.8), 266 (100), 13 235 (35.6), 77 (10.7). C-NMR (CDCl3, 100 MHz) δ (ppm): (Z,Z + Z,E) 159.2, 158.7, 134.6, 134.2, 129.9, 129.8, 129.7, 129.63, 129.6, 127.2, 127.1, 121.0, 119.2, 116.5, 114.2, 114.0, 113.8, 113.7, 55.2. HRMS (ESI): + m/z calcd. for C18H18O2Se [M + H] : 347.0550, found: 347.0545. Molecules 2017, 22, 327 7 of 10

1 Bis-(Z,Z)-4-cyanostyryl selenide 3d: Yield: 0.124 g (74%); Orange solid; H-NMR (DMSO-d6, 400 MHz) δ 1 (ppm): 6.68–7.03 (m, 8H), 6.47 (d, J = 10.5 Hz, 2H), 6.30 (d, J = 10.5 Hz, 2H). Z,E-3d: H-NMR (DMSO-d6, 400 MHz) δ (ppm): 6.57 (d, J = 10.5 Hz, 1H), 6.52 (d, J = 15.1 Hz, 1H), 6.45 (d, J = 15.1 Hz, 1H), 6.19 (d, J = 10.5 Hz, 1H), other peaks were overlapped with those of E,E and Z,E-3d. E,E-3d: 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 6.08 (d, J = 15.6 Hz, 2H), other peaks were overlapped with those of Z,Z 13 and Z,E-3d. C-NMR (DMSO-d6, 100 MHz) δ (ppm): (Z,Z + Z,E + E,E) 141.1, 141.0, 140.6, 132.8, 132.4, 132.33, 132.26, 130.7, 130.5, 128.9, 128.8, 128.7, 128.4, 127.2, 127.1, 126.8, 126.42, 126.36, 125.7, 125.5, 118.5, 118.4, 110.2, 109.9, 109.6, 109.4, 109.38. MS: m/z (rel. int.) 336 (M+, 19.0), 207 (100), 191 (13.8), 127 + (40.4), 102 (9.0), 77 (11.6). HRMS (ESI): m/z calcd. for C18H12N2Se [M] : 336.0166, found: 336.0150. Bis-(Z,Z)-3,4-dichlorostyryl selenide 3e: Yield: 0.196 g (93%). Yellowish solid; m.p.: 152–155 ◦C. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 7.43–7.45 (m, 4H), 7.21 (dd, J = 8.2 and 2.1 Hz, 2H), 6.86 (d, J = 10.4 Hz, 13 2H), 6.73 (d, J = 10.4 Hz, 2H). C-NMR (CDCl3, 100 MHz) δ (ppm): δ 136.8, 132.7, 131.4, 130.5, 130.1, 128.6, 127.2, 124.9. MS: m/z (rel. int.) 422 (M+, 6.2), 207 (83.8), 40 (100). HRMS (ESI): m/z calcd. for + C16H10Cl4Se [M + H] : 422.8780, found: 422.8758. 1 Bis-(Z,Z)-3,5-dimethoxystyryl selenide 3f: Yield: 0.158 g (78%); Yellowish solid; H-NMR (CDCl3, 500 MHz) δ (ppm): 6.88 (d, J = 10.3 Hz, 2H), 6.67 (d, J = 10.3 Hz, 2H), 6.54 (d, J = 2.3 Hz, 4H), 13 6.38 (t, J = 2.3 Hz, 2H), 3.79 (s, 12H). C-NMR (CDCl3, 125 MHz) δ (ppm): 160.7, 138.8, 130.2, 124.0, 1 106.1, 100.0, 55.3. Z,E-3f: H-NMR (CDCl3, 500 MHz) δ (ppm): 7.11 (d, J = 15.7 Hz, 1H), 6.93 (d, J = 10.3 Hz, 1H), 6.79 (d, J = 15.7 Hz, 1H), 6.77 (d, J = 10.3 Hz, 1H), 6.48 (d, J = 2.3 Hz, 4H), 6.34–6.35 (m, 2H), 3.81 (s, 12H). MS: m/z (rel. int.) 406 (M+, 2.8), 325 (100), 207 (45.9), 77 (15.0). HRMS (ESI): m/z + calcd. for C20H22O4Se [M + H] : 407.0762, found: 407.0740.

3.3. General Procedure for the Preparation of Divinyl Tellurides 4a,b In a two-necked round bottomed flask under nitrogen atmosphere, was generated by reaction of elemental tellurium (Te0, 0.5 mmol) with sodium tetrahydroborate (0.8 mmol, 0.030 g) and NaOH (0.55 mmol, 0.022 g) in PEG-400 (3.0 mL) at 60 ◦C. After 30 min, a violet solution was obtained and the corresponding alkyne was added (1.0 mmol). After stirring for 5 h at 60 or 90 ◦C, the reaction mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (3 × 15.0 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over silica gel eluting with hexanes to yield the products. All compounds were properly characterized by MS, 1H-NMR, and 13C-NMR. Bis-(Z,Z)-styryl telluride 4a: Yield: 0.138 g (82%); White solid; m.p.: 44–46 ◦C (Lit. [26]: 46–47 ◦C). 1 H-NMR (CDCl3, 400 MHz) δ (ppm): 7.43 (d, J = 10.6 Hz, 2H), 7.33–7.36 (m, 4H), 7.22–7.24 (m, 6H), 13 6.99 (d, J = 10.6 Hz, 2H). C-NMR (CDCl3, 100 MHz) δ (ppm): 138.8, 137.3, 128.4, 127.6, 127.4, 108.9. MS: m/z (rel. int.) 336 (M+, 17.2), 206 (100), 91 (71.4), 77(67.1). Bis-(Z,Z)-3,5-dimethoxystyryl telluride 4b: Yield: 0.189 g (83%); Orange solid; m.p.: 76–77 ◦C. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.45 (d, J = 10.5 Hz, 2H), 7.23 (d, J = 10.5 Hz, 2H), 6.42–6.47 (m, 6H), 13 3.76 (s, 12H). C-NMR (DMSO-d6, 100 MHz) δ (ppm): 160.6, 140.5, 136.9, 110.1, 105.0, 99.6, 55.2. MS: + + m/z (rel. int.) 456 (M , 13.7), 325 (100), 175 (34.0). HRMS (ESI): m/z calcd. for C20H22O4Te [M + H] : 457.0659, found: 457.0662.

3.4. Preparation of 3,4’,5-Trimethoxystilbene 6 To a two-necked 100 mL round bottomed flask under nitrogen, the dry solvent (NMP/THF 1:3, 20.0 mL), bis(3,5-dimethoxystyryl) selenide 3f (0.406 g, 1 mmol), Et3N (2.5 mL) and Fe(acac)3 (71 mg, 20 mol %) was added. The mixture was stirred at room temperature, and after 15 min a solution of the Grignard reagent from 1-bromo-4-methoxybenzene (5, 10 mmol; 10.0 mL of a 1 mol/L sol. in THF) was added dropwise. The reactions were monitored by TLC until total disappearance of the starting material 3f. After completion of the reaction, aqueous sat. NH4Cl (15.0 mL) was added and the reaction Molecules 2017, 22, 327 8 of 10 mixture was extracted with ethyl acetate (3 × 20.0 mL), the organic layer was washed with water and dried over MgSO4. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexanes, 10:90).

1 3,4’,5-Trimethoxystilbene 6: Yield: 0.155 g (57%) [42]; Whitish oil; Z-6: H-NMR (CDCl3, 400 MHz) δ (ppm): 7.11 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 12.0 Hz, 1H), 6.343 (d, J = 2.3 Hz, 2H), 6.337 (d, J = 12.0 Hz, 1H), 6.22 (t, J = 2.3 Hz, 1H), 3.66 (s, 3H), 3.56 (s, 6H). MS: m/z (rel. int.) 270 (M+, 100), 239 (23.6), 224 (15.6), 196 (7.9), 181 (4.9), 152 (7.8), 141 (4.7), 115 (6.0), 102 (1.2) 76 (2.9). 1 E-6: H-NMR (CDCl3, 400 MHz) δ (ppm): 7.33 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 16.2 Hz, 1H), 6.80 (d, J = 16.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 2.3 Hz, 2H), 6.28 (t, J = 2.3 Hz, 1H), 3.71 (s, 6H), 3.70 (s, 3H). MS: m/z (rel. int.) 270 (M+, 100), 239 (21.3), 224 (10.8), 196 (6.5), 181 (4.1), 152 (6.0), 141 (3.5), 13 115 (4.2), 102 (0.9) 76 (2.4). C-NMR (CDCl3, 100 MHz) δ (ppm): (Z + E) 160.9, 160.5, 159.3, 158.7, 139.6, 139.4, 130.2, 130.1, 129.8, 129.5, 128.65, 128.60, 127.7, 126.5, 114.1, 113.4, 106.5, 104.3, 99.8, 99.5, 55.22, 55.18, 55.1.

4. Conclusions An efficient methodology to prepare divinyl selenides from elemental selenium and arylalkynes was developed. The nucleophilic species of selenium was generated in situ from elemental selenium ◦ and NaBH4/PEG-400. The reactions proceeded at a gentle heating of 60 C for only 5 h, affording the corresponding divinyl selenides in good to excellent yields with high selectivity to the Z,Z-isomer. The same strategy was used to prepare (Z,Z)-divinyl tellurides analogues from elemental tellurium, but good results were obtained only when NaOH was present in the reaction media. Divinyl selenides with the appropriate substitution pattern was used in a Fe-catalyzed cross-coupling reaction with a Grignard reagent to afford 3,4’,5-trimethoxystilbene in moderate yield. Thus, this procedure could be used to access valuable polymethoxylated stilbenes.

Supplementary Materials: NMR spectra of synthesized compounds are available online. Acknowledgments: The authors thank FAPERGS, CNPq, and CAPES for financial support. CNPq is also acknowledged for the fellowship for G.P., R.G.J., and E.J.L. This manuscript is part of the scientific activity of the international multidisciplinary “SeS Redox and Catalysis” network. Author Contributions: G.P., R.G.J., and E.J.L. conceived and designed the experiments; A.M.B., E.Q.L., and E.L.B. performed the experiments; A.M.B., E.Q.L., G.P., E.J.L., L.S., and C.S. analyzed the data; G.P., E.J.L., and C.S. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Zeni, G.; Lüdtke, D.S.; Panatieri, R.B.; Braga, A.L. Vinylic Tellurides: From Preparation to Their Applicability in Organic Synthesis. Chem. Rev. 2006, 106, 1032–1076. [CrossRef][PubMed] 2. Perin, G.; Lenardão, E.J.; Jacob, R.G.; Panatieri, R.B. Synthesis of Vinyl Selenides. Chem Rev. 2009, 109, 1277–1301. [CrossRef][PubMed] 3. Menezes, P.H.; Zeni, G. Vinyl Selenides in Patai’s Chemistry of Functional Groups; John Wiley & Sons: New York, NY, USA, 2011. 4. Alonso, F.; Beletskaya, I.P.; Yus, M. Transition-Metal-Catalyzed Addition of Heteroatom-Hydrogen Bonds to Alkynes. Chem. Rev. 2004, 104, 3079–3159. [CrossRef][PubMed] 5. Freudendahl, D.M.; Shahzad, S.A.; Wirth, T. Recent Advances in . Eur. J. Org. Chem. 2009, 2009, 1649–1664. [CrossRef] 6. Silveira, C.C.; Mendes, S.R.; Wolf, L. Iron-Catalyzed Coupling Reactions of Vinylic Chalcogenides with Grignard Reagents. J. Braz. Chem. Soc. 2010, 21, 2138–2145. [CrossRef] 7. Silveira, C.C.; Braga, A.L.; Vieira, A.S.; Zeni, G. Stereoselective Synthesis of Enynes by Nickel-Catalyzed Cross-Coupling of Divinylic Chalcogenides with Alkynes. J. Org. Chem. 2003, 68, 662–665. [CrossRef] [PubMed] Molecules 2017, 22, 327 9 of 10

8. Uemura, S.; Takahashi, H.; Ohe, K. Styryl coupling vs. styryl acetate formation in reactions of styryl tellurides with palladium(II) salts. J. Organomet. Chem. 1992, 423, C9–Cl2. [CrossRef] 9. Amosova, S.V.; Penzik, M.V.; Albanov, A.I.; Potapov, V.A. The reaction of selenium dichloride with divinyl sulfide. J. Organomet. Chem. 2009, 694, 3369–3372. [CrossRef] 10. Amosova, S.V.; Penzik, M.V.; Albanov, A.I.; Potapov, V.A. Addition of selenium dibromide to divinyl sulfide: Spontaneous rearrangement of 2,6-dibromo-1,4-thiaselenane to 5-bromo-2-bromomethyl-1,3-thiaselenolane. Tetrahedron Lett. 2009, 50, 306–308. [CrossRef] 11. Potapov, V.A.; Kurkutov, E.O.; Musalov, M.V.; Amosova, S.V. Reactions of selenium dichloride and dibromide with divinyl sulfone: Synthesis of novel four- and five-membered selenium heterocycles. Tetrahedron Lett. 2010, 51, 5258–5261. [CrossRef] 12. Potapov, V.A.; Amosova, S.V.; Volkova, K.A.; Penzik, M.V.; Albanov, A.I. Reactions of selenium dichloride and dibromide with divinyl selenide: Synthesis of novel selenium heterocycles and rearrangement of 2,6-dihalo-1,4-diselenanes. Tetrahedron Lett. 2010, 51, 89–92. [CrossRef] 13. Testaferri, L.; Tiecco, M.; Tingoli, U.; Chianelli, D. Stereospecific synthesis of divinyl selenides nucleophilic substitutions of unactivated vinyl halides by vinyl selenide anions. Tetrahedron 1986, 42, 63–69. [CrossRef] 14. Comasseto, J.V.; Petragnani, N. The reaction of selenophosphonates with carbonyl compounds. Vinylic selenides. J. Organomet. Chem. 1978, 152, 295–304. [CrossRef] 15. Silveira, C.C.; Santos, P.C.S.; Braga, A.L. Preparation and nickel-catalyzed coupling reactions of divinylic selenides. Tetrahedron Lett. 2002, 43, 7517–7520. [CrossRef] 16. Silveira, C.C.; Rinaldi, F.; Guadagnin, R.C. Preparation and Reactivity of Chalcogenyl Phosphonates and Phosphane Oxides. Eur. J. Org. Chem. 2007, 2007, 4935–4939. [CrossRef] 17. Sheldon, R.A. The E Factor: Fifteen years on. Green Chem. 2007, 9, 1273–1283. [CrossRef] 18. Braverman, S.; Cherkinsky, M.; Jana, R.; Kalendar, Y.; Sprecher, M. Reaction of selenium and tellurium halides with propargyl alcohols. The regio- and stereoselectivity of addition to the triple bond. J. Phys. Org. Chem. 2010, 23, 1114–1120. [CrossRef] 19. Potapov, V.A.; Khuriganova, O.I.; Musalov, M.V.; Larina, L.I.; Amosova, S.V. Stereospecific Synthesis of E,E-Bis(2-chlorovinyl)selenide. Russ. J. Gen. Chem. 2010, 80, 541–542. [CrossRef] 20. Potapov, V.A.; Musalov, M.V.; Khuriganova, O.I.; Larina, L.I.; Amosova, S.V. Reactions of Stereoselective Addition of Selenium Dibromide and Monobromide to Acetylene. Russ. J. Org. Chem. 2010, 46, 753–754. [CrossRef] 21. Braverman, S.; Pechenick-Azizi, T.; Gottlieb, H.E.; Sprecher, M. Synthesis and Reactivity of Divinylselenium Dichlorides and Dibromides. Synthesis 2011, 2011, 577–584. [CrossRef] 22. Musalova, M.V.; Potapov, V.A.; Amosova, S.V. Synthesis of Novel E-2-Chlorovinyltellurium Compounds Based on the Stereospecific Anti-addition of Tellurium Tetrachloride to Acetylene. Molecules 2012, 17, 5770–5779. [CrossRef][PubMed] 23. Potapov, V.A.; Elokhina, V.N.; Larina, L.I.; Yaroshenko, T.I.; Tatarinova, A.A.; Amosova, S.V. Reactions of sodium selenide with ethynyl and bromoethynyl ketones: Stereo- and regioselective synthesis of functionalized divinyl selenides and 1,3-diselenetanes. J. Organomet. Chem. 2009, 694, 3679–3682. [CrossRef] 24. Tucci, F.C.; Chieffi, A.; Comasseto, J.V. Tellurium in Organic Synthesis. Preparation of Z-Vinylic Cuprates from Z-Vinylic Tellurides and Their Reaction with Enones and Epoxides. J. Org. Chem. 1996, 61, 4975–4989. [CrossRef] 25. Barros, S.M.; Comasseto, J.V.; Berriel, J. Vinyllithiums from butyl-vinyl tellurides and bis-vinyl tellurides. Tetrahedron Lett. 1989, 30, 7353–7356. [CrossRef] 26. Barros, S.M.; Dabdoub, M.J.; Dabdoub, V.M.B.; Comasseto, J.V. Hydrotelluration of Acetylenes: Synthesis of Vinylic Tellurides, Divinyl Tellurides, and l-(Organyltelluro)-l,3-butadienes. Organometallics 1989, 8, 1661–1665. [CrossRef]

27. Trofimov, B.A.; Amosova, S.V.; Gurasova, N.K.; Musorin, G.K. Reactions of triads Se8-KOH-DMSO, Se8-KOH-DMSO, Te-KOH-HMPA with acetylenes. Tetrahedron 1982, 38, 713–718. [CrossRef] 28. Kerton, F.M.; Marriott, R. RSC Green Chemistry Book Series—Alternative Solvents for Green Chemistry, 2nd ed.; RSC Publishing: Cambridge, UK, 2013. 29. Reichardt, C.; Welton, T. Solvents and Solvent Effects in Organic Chemistry, 4th ed.; WILEY-VCH: Weinheim, Germany, 2011. Molecules 2017, 22, 327 10 of 10

30. Perin, G.; Alves, D.; Jacob, R.G.; Barcellos, A.M.; Soares, L.K.; Lenardão, E.J. Synthesis of Organochalcogen Compounds using Non-Conventional Reaction Media. Chem. Sel. 2016, 2, 205–258. [CrossRef] 31. Perin, G.; Borges, E.L.; Alves, D. Highly stereoselective method to prepare bis-phenylchalcogen alkenes via addition of chalcogenolate to phenylseleno alkynes. Tetrahedron Lett. 2012, 53, 2066–2069. [CrossRef] 32. Perin, G.; Borges, E.L.; Rosa, P.C.; Carvalho, P.N.; Lenardão, E.J. Simple cleavage of diorganyl diselenides

with NaBH4/PEG-400 and direct Michael addition to electron-deficient alkenes. Tetrahedron Lett. 2013, 54, 1718–1721. [CrossRef] 33. Perin, G.; Borges, E.L.; Peglow, T.J.; Lenardão, E.J. Direct Michael addition to electron-deficient alkenes using

diorganyl dichalcogenides (Te/S) and NaBH4/PEG-400. Tetrahedron Lett. 2014, 55, 5652–5655. [CrossRef] 34. Silva, P.C.; Borges, E.L.; Lima, D.B.; Jacob, R.G.; Lenardão, E.J.; Perin, G.; Silva, M.S. A simple and non-conventional method for the synthesis of selected β-arylalkylchalcogeno substituted alcohols, amines and carboxylic . ARKIVOC 2016, V, 376–389. 35. Neves, A.R.; Lúcio, M.; Lima, J.L.C.; Reis, S. Resveratrol in Medicinal Chemistry: A Critical Review of its Pharmacokinetics, Drug-Delivery, and Membrane Interactions. Curr. Med. Chem. 2012, 19, 1663–1681. [CrossRef][PubMed] 36. Liu, P.-L.; Chong, I.-W.; Lee, Y.-C.; Tsai, J.-R.; Wang, H.-M.; Hsieh, C.-C.; Kuo, H.-F.; Liu, W.-L.; Chen, Y.-H.; Chen, H.-L. Anti-inflammatory Effects of Resveratrol on Hypoxia/Reoxygenation-Induced Alveolar Epithelial Cell Dysfunction. J. Agric. Food Chem. 2015, 63, 9480–9487. [CrossRef][PubMed] 37. Hong, T.; Jiang, W.; Dong, H.-M.; Qiu, S.-X.; Lu, Y. Synthesis and cytotoxic activities of E-resveratrol derivatives. Chin. J. Nat. Med. 2015, 13, 375–382. [CrossRef] 38. Park, S.; Cha, S.-H.; Cho, I.; Park, S.; Park, Y.; Cho, S.; Park, Y. Antibacterial nanocarriers of resveratrol with gold and silver nanoparticles. Mater. Sci. Eng. C 2016, 58, 1160–1169. [CrossRef][PubMed] 39. Hong, J.-H.; Lee, H.; Lee, S.-R. Protective effect of resveratrol against neuronal damage following transient global cerebral ischemia in mice. J. Nutr. Biochem. 2016, 27, 146–152. [CrossRef][PubMed] 40. Guiso, M.; Marra, C.; Farina, A. A new efficient resveratrol synthesis. Tetrahedron Lett. 2002, 43, 597–598. [CrossRef] 41. Botella, L.; Nájera, C. Synthesis of methylated resveratrol and analogues by Heck reactions in organic and aqueous solvents. Tetrahedron 2004, 60, 5563–5570. [CrossRef] 42. Lara-Ochoa, F.; Sandoval-Minero, L.C.; Espinosa-Pérez, G. A new synthesis of resveratrol. Tetrahedron Lett. 2015, 56, 5977–5979. [CrossRef] 43. Brown, J.W.; Jarenwattananon, N.N.; Otto, T.; Wang, J.L.; Glöggler, S.; Bouchard, L.-S. Heterogeneous Heck coupling in multivariate metal–organic frameworks for enhanced selectivity. Catal. Commun. 2015, 65, 105–107. [CrossRef]

Sample Availability: Samples of the compounds 3, 4 and 6 are available from the authors.

© 2017 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).