Atom Efficient Preparation of Zinc Selenates for the Synthesis Of

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Article Atom Efﬁcient Preparation of Zinc Selenates for the Synthesis of Selenol Esters under “On Water” Conditions

Luca Sancineto 1, Jaqueline Pinto Vargas 2, Bonifacio Monti 1, Massimiliano Arca 3, Vito Lippolis 3, Gelson Perin 4, Eder Joao Lenardao 4,* and Claudio Santi 1,*

1 Catalysis and Organic Green Chemistry Group, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06100 Perugia, Italy; [email protected] (L.S.); [email protected] (B.M.) 2 Universidade Federal do Pampa—Unipampa, Av. Pedro Anunciação, 111, Caçapava do Sul-RS 96570-000, Brazil; [email protected] 3 Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, S.S. 554 bivio per Sestu, 09042 Monserrato, Cagliari, Italy; [email protected] (M.A.); [email protected] (V.L.) 4 Laboratório de Síntese Orgânica Limpa-LASOL-CCQFA, Universidade Federal de Pelotas-UFPel, P.O. Box 354, Pelotas-RS 96010-900, Brazil; [email protected] * Correspondence: [email protected] (E.J.L.); [email protected] (C.S.); Tel.: +55-53-3275-7533 (E.J.L.); +39-075-585-5112 (C.S.)

Academic Editor: Derek J. McPhee Received: 11 May 2017; Accepted: 3 June 2017; Published: 8 June 2017

Abstract: We describe here an atom efﬁcient procedure to prepare selenol esters in good to excellent yields by reacting [(PhSe)2Zn] or [(PhSe)2Zn]TMEDA with acyl chlorides under “on water” conditions. The method is applicable to a series of aromatic and aliphatic acyl chlorides and tolerates the presence of other functionalities in the starting material.

Keywords: selenium; selenol esters; zinc; TMEDA; water

1. Introduction Selenol esters are versatile tools in organic synthesis, once they can be easily converted to a sort of more complex molecules, acting as acyl-transfers, and in other important functional groups modiﬁcations [1]. Aromatic selenol esters, such as I, are stable liquid crystals with a large nematic mesophase range [2–4]. In contrast to their sulfur analogues, selenol esters only recently have attracted the attention to their pharmacological potential; the thiazolidine-4-carboselenoate II is a potent antioxidant [5], while the polyfunctionalized selenol esters III and IV presented high cytotoxic and antiproliferative activities against MCF-7 human cancer cells [6,7] (Figure1). The synthetic usefulness of selenol esters goes far beyond the transfer of acyl group [8], or its use as a protecting group for selenium compounds [9]. Selenol esters were explored in the total synthesis of several complex molecules [10–14], such as the marine alkaloid amphimedime [10], apparicine [11], (+)-geissoschizine [12], ciguatoxin CTX3C7d [13] and the peach moth (Carposia niponensis) pheromone [14]. More recently, selenol esters have gained even more importance, after the discovery that they can be used in native chemical ligation (NCL) reactions where the traditional thioester ligation chemistry is prohibitive [15,16].

Molecules 2017, 22, 953; doi:10.3390/molecules22060953 www.mdpi.com/journal/molecules Molecules 2017, 22, 953 2 of 13

Molecules 2017, 22, 953 2 of 13

Figure 1. Examples of molecules bearing the selenol ester moiety. Figure 1. Examples of molecules bearing the selenol ester moiety. As a consequence of the increasing demand for selenol esters, the number of methods to prepare As a consequencethis class of compounds of the has increasing been increased demand along the years for selenol[1,17–43] Among esters, the the strategies number to prepare of methods to prepare thisselenol class esters of compounds there are the reactions has been of nucleophil increasedic selenium along the reagents years with [1,17 an– acyl43] group Among source, the strategies such as N-acyl benzotriazoles [17,18] activated carboxylic acids (using DCC [3] or PBu3 [4,5,19,20]), to prepareenol selenol esters esters[21], anhydrides there are [22–24 the], esters reactions [25], carbon of nucleophilic monoxide [26,27], selenium aldehydes reagents[28,29] or acyl with an acyl group source,chlorides such [2,7,30–43]. as N-acyl Other benzotriazoles approaches to selenol [17 esters,18] involve activated the alkylation carboxylic of selenocarboxylate acids (using DCC [3] anions with alkyl halides [6,44–46] or the acidic hydration of selenoalkynes [47,48]. The acyl or PBu3 [4,5,19,20]), enol esters [21], anhydrides [22–24], esters [25], carbon monoxide [26,27], substitution of acyl chlorides is by far the most explored method to access selenol esters, mainly aldehydesbecause [28,29] of or its acylversatility, chlorides since the [2 ,diversity7,30–43 of]. acyl Other chlorides approaches that can be toprepared selenol is practically esters involve the alkylationendless. of selenocarboxylate The pivotal step in this anions reaction with is the alkylgeneration halides of the nucleophilic [6,44–46] selenium or the species acidic and hydration a of selenoalkynesrange [ 47of ,reagents48]. The have acyl been substitutionused for this purpose, of acyl including chlorides Se°/ArMgBr is by [2], far (NH the2)2 mostC=Se/Et explored3N [30], method to access selenolSe°/NaBH esters,4 [6], InI/(PhSe) mainly2 because[31,39,40], ofSe°/LiAlH its versatility,4 [32,37], (RSe) since2/Zn/AlCl the diversity3 [33], Ph(NH of2)C=Se acyl [34], chlorides that (Bu3Sn)2/(PhSe)2/hv [35,36], Se°/R2C=CZrCp2Cl [38], (RSe)2/Zn°/[bmim]PF6 [41], (PhSe)2/Hg°/dioxane [42] can be preparedand (PhSe) is2/SnCl practically2/CuBr2/[bmim]BF endless.4 [43]. The Despite pivotal these stepreaction in syst thisems reaction afforded a is range the of generation selenol of the nucleophilicesters, selenium they suffer species from one and or more a range of the followin of reagentsg drawbacks: have use been of VOCs used as forsolvent, this strong purpose, bases, including ◦ strong and moisture sensible reducing agents,◦ expensive reagents and low atom-economy. ◦ Se /ArMgBr [2], (NH2)2C=Se/Et3N[30], Se /NaBH4 [6], InI/(PhSe)2 [31,39,40], Se /LiAlH4 [32,37], Significant progress towards the greenness of the synthesis of selenol esters has◦ been recently (RSe)2/Zn/AlCldescribed3 [ 33[49,50].], Ph(NH Braga and2)C=Se co-workers [34], described (Bu3Sn) the2/(PhSe) solvent-free2/hv, microwave [35,36], accelerated Se /R2C=CZrCp reaction 2Cl [38], ◦ ◦ (RSe)2/Zn of/[bmim]PF diorganyl diselenides6 [41], (PhSe) with 2acyl/Hg chlorides;/dioxane good [ 42yields] and of (PhSe)selenol 2esters/SnCl were2/CuBr obtained2/[bmim]BF after 4 [43]. Despite theseirradiation reaction at 80 systems °C for only afforded 2 min [49]. a rangeIn the same of selenol year, some esters, of us theydescribed suffer the use from of the one bench or more of the following drawbacks:stable nucleophilic use species, of VOCs PhSeZnX as solvent, (X=Br, Cl), strong in the synthesis bases, strong of a range and of selenol moisture esters sensible in good reducing yields at room temperature and using water as medium [50]. It was observed that the reaction was agents, expensiveaccelerated reagents when it andwas performed low atom-economy. under “on water” conditions and, in addition, the water was Signiﬁcantreused progressfor subsequent towards cycles of the reactions. greenness of the synthesis of selenol esters has been recently described [49,50Nine]. Braga years andago, we co-workers introduced describeda simple method the solvent-free, to prepare in microwavesitu nucleophilic accelerated sulfur and reaction of selenium reagents by reducing dichalcogenides with elemental zinc in an acidic biphasic system [51]. diorganyl diselenidesThis protocol withhas been acyl more chlorides; recently used good by us yields and others of selenol to effect estersa series wereof selenylation obtained reactions after irradiation ◦ at 80 C forinvolving only 2 nucleophilic min [49]. substitutions, In the same ring year, opening some and ofhydrochalcogenations us described the [51–53] use and ofthe it was bench stable nucleophilicadopted species, by Flemer PhSeZnX in the (X=Br, synthesis Cl), of peptides in the synthesis[54,55]. of a range of selenol esters in good yields at room temperatureThe actual and using reactive water specie asin mediumthis protocol [50 was]. Itsupposed was observed to be a zinc that bis-selenate the reaction [(PhSe) was2Zn] accelerated probably in equilibrium with the corresponding selenol. Considering that [(PhSe)2Zn] is when it wascharacterized performed by a under higher “onatom water”economy conditionsrespect to the and, PhSeZn-halides in addition, in the the insertion water of wasPhSe reused for subsequentgroups, cycles the of possibility reactions. to obtain it in a bench stable form is desirable. It could improve the versatility Nine yearsof its synthetic ago, we application introduced (avoiding a the simple strong methodacidic conditions to prepare of the biphasic in situ system), nucleophilic controlling sulfur and or preventing undesired side reactions like those observed when it was prepared and used in situ in selenium reagentsthe presence by of reducing THF [56]. dichalcogenides with elemental zinc in an acidic biphasic system [51]. This protocol has been more recently used by us and others to effect a series of selenylation reactions involving nucleophilic substitutions, ring opening and hydrochalcogenations [51–53] and it was adopted by Flemer in the synthesis of peptides [54,55]. The actual reactive specie in this protocol was supposed to be a zinc bis-selenate [(PhSe)2Zn] probably in equilibrium with the corresponding selenol. Considering that [(PhSe)2Zn] is characterized by a higher atom economy respect to the PhSeZn-halides in the insertion of PhSe groups, the possibility to obtain it in a bench stable form is desirable. It could improve the versatility of its synthetic application (avoiding the strong acidic conditions of the biphasic system), controlling or preventing undesired side reactions like those observed when it was prepared and used in situ in the presence of THF [56]. Molecules 2017, 22, 953 3 of 13 Molecules 2017, 22, 953 3 of 13

2. Results To betterbetter understandunderstand andand preventprevent thethe sideside reactionreaction observedobserved in the presence of THF [[56],56], DFT calculationscalculations werewere performed performed comparing comparing [(PhCh) [(PhCh)2Zn]2 (Ch=S,Zn] (Ch=S, Se) with Se) the with previously the previously reported PhChZnXreported (Ch=S,PhChZnX Se; X=Cl,(Ch=S, Br) Se; [57X=Cl,]. Br) [57]. DFT-optimized geometriesgeometries ofof thethe (PhCh)(PhCh)22Zn species (Ch=S,(Ch=S, Se) show a nearly linear coordination at the ZnZn center.center. ThisThis geometrygeometry hashas beenbeen observedobserved inin thethe gasgas phasephase forfor ZnHZnH22 andand ZnClZnCl22,,[ [58]58] although severalseveral examplesexamples areare reportedreported ofof structurallystructurally characterizedcharacterized zinc(II)zinc(II) compoundscompounds featuringfeaturing discretediscrete linearlinear E–Zn–E moieties moieties with with E=O E=O [58–60], [58–60], S S[61,62], [61,62 ],or or Se Se [63]. [63 ].On On passing passing from from Ch=S Ch=S to Ch=Se, to Ch=Se, the thenatural natural charge charge polarization polarization of ofthe the Ch–Zn Ch–Zn bond bond decreases decreases (1.233 (1.233 and and 1.093 1.093 e efor for Ch=S Ch=S and and Se, respectively),respectively), suggestingsuggesting a higherhigher reactivityreactivity ofof (PhS)(PhS)22Zn in all conditions as compared to (PhSe)2Zn. TheThe solvatedsolvated speciesspecies (PhCh)(PhCh)22ZnZn·2solv·2solv (solv=THF, H 22O)O) were also successfullysuccessfully optimized.optimized. For bothboth solvents,solvents, solvated species show a distortiondistortion of thethe Ch–Zn–ChCh–Zn–Ch moietymoiety towardstowards thethe usuallyusually encounteredencountered tetrahedraltetrahedral coordinationcoordination of thethe ZnZn center.center. A SecondSecond Order Perturbation Theory Analysis of Fock Matrix inin NBO NBO Basis Basis allows allows evaluating evaluating the the interaction interaction energies energies between between the Zn the center Zn andcenter each and solvent each −1 moleculesolvent molecule by about 50,by 58,about 48, and 50, 5558, kcal 48,·mol and for55 (PhS)kcal·mol2Zn·2THF,–1 for (PhS)(PhS)22ZnZn·2THF,·2H2O, (PhSe)(PhS)22Zn·2HZn·2THF,2O, and(PhSe) (PhSe)2Zn·2THF,2Zn·2H and2O, respectively.(PhSe)2Zn·2H Such2O, respectively. interactions ariseSuch frominteractions the electron arise densityfrom the donation electron from density the oxygendonation LP from of the the solvent oxygen units LP of to the the solvent antibonding units to empty the antibonding Zn atomic empty orbitals Zn (Figure atomic2 )orbitals and, to (Figure a minor 2) extent,and, to toa minor the Zn-Ch extent, antibonding to the Zn-Ch NBOs, antibonding and result NBOs in an overall, and result electron in an transfer overall of electron 0.095, 0.105, transfer 0.133, of and0.095, 0.104 0.105, e for (PhS)0.133,2 Znand·2THF, 0.104 (PhS) e 2Znfor· 2H(PhS)2O, (PhSe)2Zn·2THF,2Zn· 2THF,(PhS) and2Zn·2H (PhSe)2O, 2Zn(PhSe)·2H2Zn·2THF,O, respectively. and Notably,(PhSe)2Zn·2H the interactions2O, respectively. between Notably, (PhCh) the2Zn interactions species and between the solvent (PhCh) units2Zn are species remarkably and the stronger solvent thanunits those are remarkably calculated betweenstronger PhChZnXthan those (Ch=S, calculated Se; X=Cl, between Br and PhChZnX I) and the (Ch=S, same Se; solvents, X=Cl, Br which and I) were and calculatedthe same solvents, in about which 18 kcal were·mol −calculated1 at the same in about level 18 of theory.kcal·mol–1 at the same level of theory.

Figure 2. Drawings of the NBOs involved in the second order interaction between (PhSe)2Zn and the Figure 2. Drawings of the NBOs involved in the second order interaction between (PhSe)2Zn and the THF fragments in the compound (PhSe)2Zn·2THF at the DFT-optimized geometry (energy difference THF fragments in the compound (PhSe)2Zn·2THF at the DFT-optimized geometry (energy difference –1 0.74650.7465 a.u.;a.u.; interactioninteraction energyenergy 25.7725.77 kcalkcal·mol·mol−1).). LeftLeft: :filled ﬁlled NBO NBO LP LP localized localized on the oxygenoxygen donordonor atomatom ofof oneone THFTHF solventsolvent fragmentfragment (NBO(NBO #127,#127, 34.45%34.45% ss andand 65.54%65.54% pp character).character). RightRight:: virtualvirtual NBONBO LP* localizedlocalized onon thethe ZnZn centercenter (NBO(NBO #124,#124, 9.51%9.51% ss andand 90.35%90.35% pp character).character). CutoffCutoff value:value: 0.10.1 |e|.|e|. Hydrogen atoms have been omittedomitted for clarity.clarity. (Grey(Grey == Carbon;Carbon; Red == Oxygen; Yellow == Selenium; VioletViolet == Zinc).Zinc)

All (PhCh)2Zn species and the corresponding solvated forms show their HOMOs largely All (PhCh)2Zn species and the corresponding solvated forms show their HOMOs largely localized on the negatively charged Ch atoms (QS = −0.315, −0.377, and −0.367 |e| for (PhSe)2Zn, localized on the negatively charged Ch atoms (QS = −0.315, −0.377, and −0.367 |e| for (PhSe)2Zn, (PhCh)2Zn·2THF, and (PhCh)2Zn·2H2O; QSe = −0.236, −0.305, and −0.274 |e| for (PhSe)2Zn, (PhCh)2Zn·2THF, and (PhCh)2Zn·2H2O; QSe = −0.236, −0.305, and −0.274 |e| for (PhSe)2Zn, (PhCh)2Zn·2THF, and (PhCh)2Zn·2H2O, respectively). (PhCh)2Zn·2THF, and (PhCh)2Zn·2H2O, respectively). The LUMOs of (PhCh)2Zn species are antibonding MOs displaying a remarkable contribution The LUMOs of (PhCh)2Zn species are antibonding MOs displaying a remarkable contribution from the zinc atomic orbitals. About solvated species, it is worth noting that both (PhS)2Zn·2THF and from the zinc atomic orbitals. About solvated species, it is worth noting that both (PhS)2Zn·2THF (PhSe)2Zn·2H2O feature empty molecular orbitals with large contributions from the virtual molecular and (PhSe)2Zn·2H2O feature empty molecular orbitals with large contributions from the virtual orbitals of the solvent molecules, which are therefore sensibly stabilized. In particular, the LUMO+4 molecular orbitals of the solvent molecules, which are therefore sensibly stabilized. In particular, the MO calculated for THF shows an antibonding character with respect to the C–O bonds Kohn-Sham LUMO+4 MO calculated for THF shows an antibonding character with respect to the C–O bonds (KS) eigenvalue ε = +0.1389 Hartree). This orbital contributes to the LUMO+14 and LUMO+15 of Kohn-Sham (KS) eigenvalue ε = +0.1389 Hartree). This orbital contributes to the LUMO+14 and (PhS)2Zn·2THF and (PhSe)2Zn·2THF, respectively, which are stabilized in energy by 0.887 eV (ε = +0.1063 Hartree for both virtual MOs). The strength of the interaction between THF and

Molecules 2017, 22, 953 4 of 13

LUMO+15Molecules 2017 of, 22 (PhS), 953 2Zn·2THF and (PhSe)2Zn·2THF, respectively, which are stabilized in energy4 of by 13 0.887 eV (ε = +0.1063 Hartree for both virtual MOs). The strength of the interaction between THF and(PhCh) (PhCh)2Zn 2accompaniedZn accompanied by a by low-lying a low-lying MO MO with with remarkable remarkable C–O C–O antibonding antibonding character partly localizedlocalized onon thethe coordinatedcoordinated THFTHF unitsunits maymay accountaccount forfor thethe ringring openingopening reactionsreactions ofof coordinatedcoordinated solventssolvents observedobserved experimentallyexperimentally [[56].56].

Therefore,MoleculesTherefore, 2017, wewe22, 953 investigatedinvestigated the possibilitypossibility to prepareprepare anan isolableisolable zinczinc bis-selenatebis-selenate to bebe4 of usedused 13 inin thethe synthesissynthesis ofof chalcogenolchalcogenol estersesters avoidingavoiding thethe presencepresence of THFTHF duringduring thethe reactionreaction withwith thethe acylacyl chlorides.chlorides.(PhCh) Different2Zn accompanied conditions by fora low-lying the oxidativeoxidative MO with insertioninse remarkablertion of the C–O zinczinc antibonding inin thethe Se-SeSe-Se character bondbond startingstarting partly fromfrom thethe commerciallycommerciallylocalized on the availableavailable coordinated diphenyldiphenyl THF units diselenidediselenide may accoun wereweret exploredexplored for the ring (Table(Table opening1 1).). The The reactions reduction reduction of coordinated of of diselenides diselenides inin organicorganicsolvents solventssolvents observed cancan experimentally bebe unequivocallyunequivocally [56]. evidencedevidenced byby thethe discolorationdiscoloration ofof thethe originallyoriginally yellowyellow solutionsolution andandTherefore, itit waswas we observedobserved investigated thatthat the bothboth possibility thethe presencepresen to preparce of catalyticcatalytice an isolable amount zinc bis-selenate of TFA (10(10 to molmol be used %)%) andand in thethe the synthesis of chalcogenol esters avoiding the presence of THF during the reaction with the acyl THFTHF (or(or aa 1:1 THF/water mixture) mixture) are are mandatory mandatory for for the the reduction reduction at at reflux reﬂux (Table (Table 1,1 ,entries entries 4 4 and and 5 chlorides. Different conditions for the oxidative insertion of the zinc in the Se-Se bond starting from 5 respectively). Interestingly, the insertion did not occur in reﬂuxing THF for 2 h (Table1, entry 2) respectively).the commercially Interestingly, available the diphenyl insertion diselenide did not were occur explored in refluxing (Table 1). THFThe reduction for 2 h (Tableof diselenides 1, entry 2) neitherneitherin organic inin waterwater solvents suspensionsuspension can be at unequivocally the same temperature evidenced (Table(Tbyable the 1 discoloration1,, entryentry 1),1), asas of wellwell the asoriginallyas in in the the presence presenceyellow of of TFATFA (10solution(10 molmol %)and%) (Table (Tableit was1 ,observed1, entry entry 3). 3).that both the presence of catalytic amount of TFA (10 mol %) and the THF (or a 1:1 THF/water mixture) are mandatory for the reduction at reflux (Table 1, entries 4 and 5 respectively). Interestingly, the insertionTable 1.1. SynthesisSynthesisdid not occur ofof compoundcompound in refluxing 11.. THF for 2 h (Table 1, entry 2) neither in water suspension at the same temperature (Table 1, entry 1), as well as in the presence of TFA (10 mol %) (Table 1, entry 3).

Table 1. Synthesis of compound 1. Entry Solvent Additive Time T (◦C) Discoloration Entry Solvent Additive Time T (°C) Discoloration 1 1H2O H2Onone none2 h 2 h 7070 No No 2 THF none 2 h reflux No 2 THF none 2 h reflux No 3 H2O TFA 10 mol % 1 h 70 No 3 H2O TFA 10 mol % 1 h 70 No Entry 4Solvent THF Additive TFA 10 mol % Time 20 min reflux T (°C) DiscolorationYes 4 THF TFA 10 mol % 20 min reflux Yes 1 5 H2HO2 O/THF TFAnone 10 mol %2 20h min 7070 Yes No 5 2 H2O/THFTHF TFA 10 none mol % 20 2 hmin reflux 70 No Yes 3 H2O TFA 10 mol % 1 h 70 No 4 THF TFA 10 mol % 20 min reflux Yes UsingUsing the the conditions conditions depicted depicted in inTable Table 1, entry1, entry 4, after 4, afterthe discoloration, the discoloration, the THF the was THF removed was 5 H2O/THF TFA 10 mol % 20 min 70 Yes removedunder-reduced under-reduced pressure, pressure, giving a givingwhitish a whitishamorphous amorphous and, unfortunately, and, unfortunately, relatively relatively unstable unstable solid, which was used without further purification. The supposed formation of a polymeric form of the solid, whichUsing was the conditions used without depicted further in Table purification. 1, entry 4, after The the supposeddiscoloration, formation the THF was of removed a polymeric 77 formreagentunder-reduced of 1 the was reagent confirmed pressure,1 was by giving the confirmed presence a whitish by of amorphous thea broad presence signaland, unfortunately, of at a−41 broad ppm signalrelain thetively atSe unstable− NMR.41 ppm solid,Similarly, in the 77startingSe NMR.which from was Similarly, diphenyl used without starting disulf furtheride, from the purification. diphenylzinc bis-thiolate disulfide,The supposed 2 was the formed formation zinc bis-thiolate in situof a (Figurepolymeric2 was 3). formIn formed this of case,the in situ the (Figurestartingreagent3 ).material In 1 was this is confirmed case,colorless the by startingand the the presence materialreduction of a is broadtime colorless wassignal arbitrarily andat −41 the ppm reductionchosen in the according77Se time NMR. was Similarly,to arbitrarilythat of the chosenreductionstarting according of fromdiphenyl diphenyl to thatdiselenide disulf of theide, to the reduction afford zinc bis-thiolate1. A of monomeric diphenyl 2 was formed diselenideand more in situ stable to(Figure afford zinc 3). In1selenate. this A case, monomeric (3 )the can be 1 1 andprepared morestarting according stable material zinc to is the selenatecolorless literature and (3) using canthe reduction be the prepared bidentate time accordingwas TMEDA( arbitrarilyN,N,N to thechosen,N literature-tetramethyl-ethylendiamine) according using to that the of bidentate the reduction of diphenyl diselenide to afford 1. A monomeric and more stable zinc selenate (3) can be TMEDA(for the stabilizationN,N,N1,N1 -tetramethyl-ethylendiamine)of the complex 3, with TMEDA for in thethe stabilizationplace of THF of [64]. the complex 3, with TMEDA prepared according to the literature using the bidentate TMEDA(N,N,N1,N1-tetramethyl-ethylendiamine) in thefor place the stabilization of THF [64 of]. the complex 3, with TMEDA in the place of THF [64].

Figure 3. Reagents investigated in the present work. FigureFigure 3. 3.Reagents Reagentsinvestigated investigated in in the the present present work. work. The reactivity of 1,3 and 2 with benzoyl chloride (4a) for the formation of the selenol ester 5a or thiol esterThe 6a ,reactivity was evaluated of 1,3 and in 2“on with water” benzoyl conditions chloride ( 4a(Tab) forle the 2, entriesformation 10–12) of the and selenol these ester results 5a or were Thethiol reactivityester 6a, was of evaluated1,3 and 2 inwith “on benzoyl water” conditions chloride ((Tab4a)le for 2, theentries formation 10–12) and of thethese selenol results ester were 5a or compared with some data recently reported using other zinc selenates, as well as different reaction thiolcompared ester 6a, was with evaluated some data inrecently “on water” reported conditions using other (Table zinc 2selenates,, entries as 10–12) well as and different these resultsreaction were conditions (Table 2, entries 1–3, 5–9). The bis-phenylselenate (1) showed an interesting reactivity comparedconditions with (Table some 2, data entries recently 1–3, 5–9). reported The bis-phenylselenate using other zinc selenates,(1) showedas an well interesting as different reactivity reaction affording, after 30 min, the formation of 5a in 83% yield (Table 2, entry 10). This result confirms that conditionsaffording, (Table after2 ,30 entries min, the 1–3, formation 5–9). Theof 5a bis-phenylselenate in 83% yield (Table 2, ( entry1) showed 10). This an result interesting confirms reactivity that zinc selenates, as previously reported, are efficient selenenylating reagents for the on-water acyl affording,zinc selenates, after 30 as min, previously the formation reported, of are5a efficiin 83%ent selenenylating yield (Table2 ,reagents entry 10). for Thisthe on-water result conﬁrms acyl substitution.substitution. In addition, In addition, the the use use of of water water as as mediummedium for for the the reaction reaction with with the the acyl acyl chloride chloride prevents prevents the undesiredthe undesired ring ring opening opening of of THF THF [56], [56], affordingaffording diphenyldiphenyl diselenide diselenide and and benzoic benzoic acid acidas side as side organicorganic products products of residualof residual decomposition, decomposition, and TMEDATMEDA when when 3 was3 was used. used. Reasonably Reasonably the zincthe zinc derivativesderivatives are areremoved removed during during the the workup workup duedue to theirtheir water water solubility. solubility. We We also also observed observed that thethat the

Molecules 2017, 22, 953 5 of 13 that zinc selenates, as previously reported, are efﬁcient selenenylating reagents for the on-water acyl substitution. In addition, the use of water as medium for the reaction with the acyl chloride prevents the undesired ring opening of THF [56], affording diphenyl diselenide and benzoic acid as side organic productsMolecules 2017 of, residual 22, 953 decomposition, and TMEDA when 3 was used. Reasonably the zinc derivatives5 of 13 are removed during the workup due to their water solubility. We also observed that the reactivity ofreactivity1 in THF of depends 1 in THF on depends the acid on used the as acid catalyst used inas thecatalyst oxidative in the zinc oxidative insertion zinc into insertion the Se-Se into bond the (TableSe-Se 2bond, entries (Table 3 and 2, entries 4) and that3 and the 4) bestand resultsthat the were best obtainedresults were using obtained TFA. When using the TFA. reaction When was the performedreaction was using performed the TMEDA-stabilized using the TMEDA-stabilized zinc selenate 3zinc, we selenate observed 3, onlywe observed a decrease only of thea decrease reactivity, of obtainingthe reactivity, a good obtaining conversion a good of 4a conversioninto 5a (71%) of 4a in into 30 min 5a (Table(71%) 2in, entry30 min 11). (Table Interestingly, 2, entry the11). sulfur-containingInterestingly, the sulfur-containing reagent 2 afforded reagent only 50% 2 afforded of conversion only 50% (Table of conversion2, entry 12) (Table and this 2, entry is consistent 12) and withthis is DFT consistent calculations, with DFT that calculations, evidenced a higherthat eviden reactivityced a ofhigher the sulfur reactivity reagents. of the This sulfur aspect, reagents. probably, This representsaspect, probably, a problem represents for the stabilitya problem of thefor zincthe thiolatestability duringof the thezinc solvent thiolate evaporation during the or solvent in the presenceevaporation of water, or in the leading presence to a fasterof water, decomposition leading to a offaster the reactant.decomposition of the reactant. FromFrom thethe results reported in Table2 2,, it it appearsappears clearclear thatthat zinc-bis-chalcogenateszinc-bis-chalcogenates areare considerablyconsiderably moremore atom-efﬁcientatom-efficient respect respect other other similar similar reagents reagents (compare (compare entries entries 10,11 10,11 vs. vs. 7,8; 7,8; and and 12 vs. 12 9)vs. and 9) thisand isthis an is important an important parameter parameter to be to evaluated be evaluated in terms in terms of “greenness” of “greenness“ of a syntheticof a synthetic process. process.

Table 2.2. ZincZinc chalcogenateschalcogenates 11––33 inin thethe preparationpreparation ofof chalcogenolchalcogenol esters.esters.

Entry Reagent Medium Time (h) Yield (%) a ae (%) b Reference Entry Reagent Medium Time (h) Yield (%) a ae (%) b Reference 11 PhSeZnClPhSeZnCl THF THF 24 24 25 2566 66[50] [50] 22 PhSeZnBrPhSeZnBr THF THF 24 24 30 3060 60[50] [50] c 33 [PhSeZnSePh][PhSeZnSePh]1 1 THFTHF 3 332 32c 79.679.6 [56] [56] 4 [PhSeZnSePh] 1 THF 3 d 79.6 – 4 [PhSeZnSePh] 1 THF 3 40 40d 79.6 – 5 PhSZnBr THF 24 86 54.6 [57] 5 PhSZnBr THF 24 86 54.6 [57] 6 [PhSeZnSePh/PhSeH] HClacq/Et2O 4 38 – [56] 6 [PhSeZnSePh/PhSeH] HClacq/Et2O 4 38 – [56] 7 PhSeZnCl H2O 3 60 66 [50] 7 PhSeZnCl H2O 3 60 66 [50] 8 PhSeZnBr H2O 3 70 60 [50] 98 PhSZnBrPhSeZnBr H H22OO 3 3 70 6560 54.6[50] [57] 109 [PhSeZnSePh]PhSZnBr 1 HH22OO 3 0.5 65 8354.6 79.6 [57] – 1110 [PhSeZnSePh]TMEDA[PhSeZnSePh] 1 3 HH22OO 0.5 0.5 83 6679.6 77– – 1211 [PhSeZnSePh]TMEDA [PhSZnSPh] 2 3 HH22OO 0.5 0.5 66 5077 76– – 12 [PhSZnSPh] 2 H2O 0.5 50 76 – a Conversion estimated by NMR; b Atom economy = m.w. of ﬁnal product × 100/Σ (m.w. reactants); c 1 was a b preparedConversion in the estimated presence of by 10 molNMR; % of TfOH.Atom Compoundeconomy =5a m.w.was formed of final together product with × 34%100/ PhC(O)O(CHΣ (m.w. reactants);2)4SePh c d and1 was 28% prepared PhC(O)O(CH in the2)4 O(CHpresence2)4SePh; of 101 molwas % prepared of TfOH. inthe Compound presence of 5a 10 was mol %formed of TFA. together Compound with5a 34%was formed together with 27% PhC(O)O(CH ) SePh and 5% PhC(O)O(CH ) Cl. PhC(O)O(CH2)4SePh and 28% PhC(O)O(CH2 4 2)4 O(CH2)4SePh;2 d4 1 was prepared in the presence of

10 mol % of TFA. Compound 5a was formed together with 27% PhC(O)O(CH2)4SePh and 5%

ThePhC(O)O(CH best conditions2)4 Cl. optimized for 1 and 3 were applied to a series of acyl chlorides 4a–h, affording the corresponding selenol esters 5a–h; the conversion rate as well as the isolate yields are reportedThe best in conditions Table3. All optimized the final products for 1 and were 3 fullywere characterizedapplied to a byseries GC-MS, of acyl1H- chlorides and 13C-NMR 4a–h, afteraffording purification the corresponding by flash chromatography selenol esters 5a (For–h; 1theH- conversion and 13C-NMR rate ofas thewell purified as the isolate compounds yields seeare Supplementaryreported in Table Materials). 3. All the final products were fully characterized by GC-MS, 1H- and 13C-NMR after purificationResults collectedby flash inchromatography Table3 indicate (For that the1H- reactionand 13C-NMR works wellof the with purified various compounds acyl chlorides see (Supplementary4a–h), including Materials). aromatic and aliphatic ones, with the only exception of cinnamic derivative 4g, that affordedResults collected only in in traces Table of 3 theindicate corresponding that the reaction selenol works ester well5g with(Table various3, entry acyl 7). chlorides In contrast (4a– toh), theincluding previously aromatic described and aliphatic biphasic systemones, with [56], the this only approach exception tolerates of cinnamic functional derivative groups sensitive4g, that toafforded reduction, only allowingin traces theof the preparation corresponding of selenol selenol ester ester4d 5g(R=3,5(NO (Table 3,2 )entry2C6H 37).) in In excellent contrast yieldsto the (Tablepreviously3, entry described 4). Noteworthily, biphasic itsystem can be [56], observed this approach that acyl chloridestolerates bearingfunctional electron-withdrawing groups sensitive to reduction, allowing the preparation of selenol ester 4d (R=3,5(NO2)2C6H3) in excellent yields (Table 3, entry 4). Noteworthily, it can be observed that acyl chlorides bearing electron-withdrawing groups gave better yields, probably because of the more pronounced electrophilic character of the carboxylic carbon.

Molecules 2017, 22, 953 6 of 13 groups gave better yields, probably because of the more pronounced electrophilic character of the carboxylicMolecules 2017 carbon., 22, 953 6 of 13 MoleculesMoleculesMolecules 2017 2017 2017,, , ,22 , 22 22,, , ,953 953, 953 953953 66 6of of of 13 13 13 MoleculesMolecules 20172017,, , 22 22,, , 953 953953 66 ofof 1313 Table 3.3. SynthesisSynthesis ofof selenolselenol estersesters 55.. TableTableTable 3. 3. 3. Synthesis SynthesisSynthesis Synthesis of ofof of selenol selenolselenol selenol esters estersesters esters 5 5 .5. . . TableTable 3.3. Synthesis SynthesisSynthesisSynthesis of ofofof selenol selenolselenolselenol esters estersestersesters 5 5... .

Conv, % of 4 in 5 Conv, % of 4 Entry Substrate 4 Product 5 Conv,Conv,Conv, % % % of of of 4 4 4in in in 5 5 5 Conv,Conv,Conv, % % % of of of 4 4 4 EntryEntryEntry Substrate Substrate Substrate 4 4 4 Product Product Product 5 5 5 (Yield,Conv,Conv,Conv, %)%% of of% 44 5of inin Using 545 in 5 1 Conv,Conv,in %Conv,% 5 ofof Using 44 % 3of 4 Entry EntryEntry Substrate Substrate Substrate 4 44 Product Product Product 5 55 (Yield,(Yield,(Yield,(Yield,(Yield, %) %) %) %)%) of of of ofof 5 5 5 5 5Using Using Using UsingUsing 1 1 1 1 1 ininininin 5 5 5 5 5Using Using Using UsingUsing 3 3 3 3 3 (Yield,(Yield,(Yield, %)%) %) ofof 5 5of UsingUsing 5 Using 11 1inin 55 UsingUsingin 5 3 3Using 3

11 1 848484 (80) (80) (80) 66 66 66 1 11 848484 (80)(80) (80) 66 66 66 1 84 (80) 66

4a4a4a 5a5a5a5a 4a4a 5a5a

4a 5a

2 22 2 81818181 (53) (53) (53) (53) 80 80 80 80 22 8181 (53)(53) 80 80

2 4b4b4b 5b5b5b 81 (53) 80 4b4b 5b5b

4b 5b 33 3 717171 (57) (57) (57) 40 40 40 3 33 717171 (57)(57) (57) 40 40 40

4c4c4c 5c5c5c 4c4c 5c5c 3 71 (57) 40

4c 5c 44 4 929292 (90) (90) (90) 80 80 80 4 44 929292 (90)(90) (90) 80 80 80

4d4d4d 5d5d5d 4d4d 5d5d 4 92 (90) 80 55 5 838383 (64) (64) (64) 62 62 62 5 55 838383 (64)(64) (64) 62 62 62

4e4e4e4e 5e5e5e5e 4d 4e4e 5d5e5e

6 666 6 8080808080 (65) (65) (65)(65) (65) 35 35 35 35 35 5 66 8080 (65)83(65) (64) 35 35 62

4f4f4f4f 5f5f5f5f 4e 4f4f 5e5f 5f

77 7 88 8 767676 7 77 88 87676 76 6 80 (65) 35

4g4g4g 5g5g5g 4g4g 5g5g 4f 5f 88 8 757575 (69) (69) (69) 80 80 80 88 7575 (69)(69) 80 80 8 75 (69) 80

4h4h4h 5h5h 4h4h 5h5h5h5h 7 5h5h 8 76 InIn orderorder toto clarifyclarify thethe naturenature ofof thethe speciesspecies thatthat areareare involvedinvolvedinvolved ininin thethethe reactionreactionreaction mechanismmechanismmechanism leadingleadingleading InInInIn order orderorderorder to tototo clarify clarifyclarifyclarify the thethethe nature naturenaturenature of ofofof the thethethe species speciesspeciesspecies that thatthatthat are areareare involved involved involvedinvolved in in inin the thethethe reaction reaction reactionreaction mechanism mechanismmechanismmechanism leading leading leadingleading tototototo 5a 5a5a,,, , , thethe thethethe possiblepossible possiblepossiblepossible4g 1:11:1 1:11:11:1 initialinitial initialinitialinitial intermediateintermediate intermediateintermediateintermediate modelmodel modelmodelmodel5g speciesspecies speciesspeciesspecies formedformed formedformedformed byby bybyby thethe thethethe interactioninteraction interactioninteractioninteraction betweenbetween betweenbetweenbetween (PhSe)(PhSe) (PhSe)(PhSe)(PhSe)2222Zn2ZnZn 1 11 In ordertoto 5a5a,, to thethe clarify possiblepossible the 1:11:1 nature initialinitial intermediateintermediate of the species modelmodel that speciesspecies are involved formedformed byby in thethe the interactioninteraction reaction betweenbetween mechanism (PhSe)(PhSe)22Zn leadingZn 11 to andandand PhCOClPhCOClPhCOCl 4a4a4a waswaswaswaswas optimized.optimized.optimized.optimized.optimized. TheTheTheTheThe onlyonlyonlyonlyonly optimizedoptimizedoptimizedoptimizedoptimized gegegegegeometryometryometry ofofof thethethe adductsadductsadducts showsshowsshows PhCOClPhCOClPhCOCl 5a, the possibleandand PhCOClPhCOCl 1:1 initial 4a4a waswas intermediate optimized.optimized. TheThe model onlyonly species optimizedoptimized formed gegeometryometry by the ofof the interactionthe adductsadducts shows betweenshows PhCOClPhCOCl (PhSe) Zn interactinginteractinginteractinginteractinginteracting withwith withwithwith thethe thethethe zinczinc zinczinczinc atomatom atomatomatom ofof ofofof (PhSe)(PhSe) (PhSe)(PhSe)(PhSe)2222Zn2ZnZn through throughthrough its itsits carbonyl carbonylcarbonyl group, group,group, thus thusthus distorting distortingdistorting the thethe Ch–Zn– Ch–Zn–Ch–Zn– 2 8 interactinginteracting withwith thethe zinczinc atomatom ofof (PhSe)(PhSe)22ZnZn throughthrough itsits carbonylcarbonyl group,group, thusthus75 (69)distortingdistorting thethe Ch–Zn–Ch–Zn– 80 1 and PhCOClChChCh groupgroupgroup4a towardstowardswastowards optimized. aaa roughlyroughlyroughly trigonaltrigonal Thetrigonal only geometry.geometry.geometry. optimized A AA naturalnaturalnatural geometry populationpopulationpopulation of the analysisanalysisanalysis adducts showsshowsshows shows thatthatthat thethe PhCOClthe ChCh groupgroup towardstowards aa roughly roughly trigonaltrigonal geometry.geometry. AA naturalnatural populationpopulation analysisanalysis showsshows thatthat thethe interactioninteractioninteractioninteraction results results4hresultsresults in ininin a aaa charge-transfer charge-transfercharge-transfercharge-transfer (CT) (CT)(CT)(CT) from fromfromfrom PhCOCl PhCOClPhCOClPhCOCl to tototo (PhSe) (PhSe)(PhSe)(PhSe)2222Zn,2Zn,Zn, whose whosewhose LUMO LUMOLUMO is isis partly partlypartly interactinginteractioninteractioninteraction with the resultsresultsresults zinc atom ininin aaa charge-transfercharge-transfer ofcharge-transfer (PhSe)2Zn through(CT)(CT)(CT) 5hfromfromfrom its PhCOClPhCOClPhCOCl carbonyl tototo (PhSe) group,(PhSe)(PhSe)22Zn,Zn, thus whosewhose distorting LUMOLUMO the isis partlypartly Ch–Zn–Ch localizedlocalizedlocalizedlocalized onon onon thethe thethe positivelypositively positivelypositively charged charged chargedcharged metalmetal metalmetal ion ion ionion (Q (Q (Q(QZnZnZnZn = = == +0.857).+0.857). +0.857).+0.857). TheThe TheThe CT-interactionCT-interaction CT-interactionCT-interaction results results resultsresults in in inin an an anan increaseincrease increaseincrease group towardslocalizedlocalizedlocalized a on roughlyonon the thethe positively positivelypositively trigonal charged chargedcharged geometry. metal metalmetal ion Aionionnatural (Q (Q(QZnZn = == +0.857). +0.857).+0.857). population The TheThe CT-interaction CT-interactionCT-interaction analysis shows results resultsresults that in inin an anan the increase increaseincrease interaction In order to clarify the nature of the species that are involved in the reaction mechanism leading results in a charge-transfer (CT) from PhCOCl to (PhSe)2Zn, whose LUMO is partly localized on the positivelyto 5a, the possible charged 1:1 metal initial ion intermediate (QZn = +0.857). model The species CT-interaction formed by results the interaction in an increase between in the(PhSe) positive2Zn 1 chargeand PhCOCl on the acyl4a was carbon optimized. and the polarizationThe only optimized of the C=O ge bondometry (|∆ QofCO the| =adducts 1.083, 1.177 shows for PhCOCl;PhCOCl interacting with the zinc atom of (PhSe)2Zn through its carbonyl group, thus distorting the Ch–Zn– Ch group towards a roughly trigonal geometry. A natural population analysis shows that the interaction results in a charge-transfer (CT) from PhCOCl to (PhSe)2Zn, whose LUMO is partly localized on the positively charged metal ion (QZn = +0.857). The CT-interaction results in an increase

Molecules 2017, 22, 953 7 of 13

Molecules 2017, 22, 953 7 of 13 and PhSeZnSePh·PhCOCl, respectively). Therefore, the activated carbonyl group in PhCOCl might be morein the suitable positive tocharge undergo on the a acyl nucleophilic carbon and attack the polarization by the chalcogen of the C=O donor bond of(|Δ aQ secondCO| = 1.083, molecule 1.177 of for PhCOCl; and PhSeZnSePh·PhCOCl, respectively). Therefore, the activated carbonyl group in (PhCh)2Zn. PhCOClThe TMEDA-stabilized might be more suitable reagent to undergo3 was investigated a nucleophilic using attack the by same the chalcogen set of acyl donor chlorides of a second4a–h and, molecule of (PhCh)2Zn. generally, it confirmed a slightly/moderate reduced reactivity with a superimposable trend respect to The TMEDA-stabilized reagent 3 was investigated using the same set of acyl chlorides 4a–h and, the nature of the substrate. The only exception was observed for acyl chloride 4g, that using TMEDA generally, it confirmed a slightly/moderate reduced reactivity with a superimposable trend respect affordedto the selenol nature esterof the5g substrate.in 80% yield The (Tableonly exception3, entry 7).was observed for acyl chloride 4g, that using TMEDAConsidering afforded that selenol the complex ester 5g3 inis 80% reported yield (Table in literature 3, entry as 7). particularly stable and it is sufficiently soluble inConsidering several organic that the solvents, complex 3 we is reported envisioned in literature the possibility as particularly to perform stable aand ”one-pot” it is sufficiently synthesis andsoluble chromatographic in several organic purification solvents, of we the envisioned selenol ester the possibility5a following to perform the setup a ”one-pot” reported synthesis in Figure 4. A pumpand chromatographic fluxes petroleum purification ether through of the aselenol Flash ester Pack 5a Jones following Chromatography the setup reported apparatus in Figure silica 4. gel columnA pump packed fluxes with petroleum 5 g of silica ether flashthrough (40–63 a Flashµm) Pack and, Jones at the Chromatography head of the column, apparatus was silica poured gel the reagentcolumn3 (0.25 packed mmol), with mixed 5 g of withsilica 500flash mg (40 of–63 the µm) same and, silica. at the Thehead column of the column, was conditioned was poured with the the solventreagent and 3 the (0.25 substrate mmol), mixed (0.5 mmol), with 500 dissolved mg of the in same DCM, silica. was The injected. column After was conditioned the column, with the the eluent wassolvent fractioned and andthe substrate the fractions (0.5 mmol), were isolateddissolved and in DCM, characterized was injected. by NMR. After the The column, selenol the ester eluent5a was was fractioned and the fractions were isolated and characterized by NMR. The selenol ester 5a was obtained as pure compound (separated from both, diphenyl diselenide and benzoic acid) in a yield obtained as pure compound (separated from both, diphenyl diselenide and benzoic acid) in a yield comparable to that observed in the bench condition (60%). This protocol allowed to bypass the workup comparable to that observed in the bench condition (60%). This protocol allowed to bypass the of the reaction saving a considerable amount of organic solvents (15 mL of EtOAc), brine solution (20 workup of the reaction saving a considerable amount of organic solvents (15 mL of EtOAc), brine mL) and Na SO reducing the production of wastes. solution 2(20 mL)4, and Na2SO4, reducing the production of wastes.

FigureFigure 4. One-pot4. One-pot synthesis synthesis and and chromatographic chromatographic purification puriﬁcation of of the the selenol selenol ester ester 5a. 5a.

3. Materials and Methods 3. Materials and Methods Reactions were conducted in a round bottom flask and were stirred with Teflon-coated magnetic stirringReactions bars were at 800 conducted rpm. Solvents in a round and bottomreagentsﬂask were and used were as received stirred with unless Teﬂon-coated otherwise noted. magnetic stirringAnalytical bars atthin-laye 800 rpm.r chromatography Solvents and (TLC) reagents was performed were used on silica as receivedgel 60 F254 unless precoated otherwise aluminum noted. Analyticalfoil sheets thin-layer and visualized chromatography by UV irradiation (TLC) or was by KMnO performed4 staining. on silica Kieselgel gel 60 60 F254(70–230 precoated mesh) silica aluminum gel foil sheetswas used and for visualized column chromatography. by UV irradiation NMR or experime by KMnOnts4 staining.were conducted Kieselgel at 25 60 °C (70–230 with a DPX mesh) 200 silica gel wasspectrometer used for (Bruker, column Faellanden, chromatography. Switzerland).) NMR experimentsoperating at 200 were MHz conducted for 1H, 50.31 at 25 MHz◦C with for 13 aC DPX 200 spectrometerexperiments or (Bruker,with a Bruker Faellanden, DRX spectrometer Switzerland).) (Bruker, operating Faellanden, at 200 Switze MHzrland) for operating1H, 50.31 at MHz 400 for 13C experimentsMHz for 1H, 100.62 or with MHz a Bruker for 13C and DRX 76.31 spectrometer MHz for 77Se. (Bruker, Chemical Faellanden, shifts (δ) are Switzerland) reported in operatingparts per at 400 MHzmillion for (ppm),1H, 100.62 relative MHz to TMS for 13 (δC = and 0.0 ppm) 76.31 MHzand the for residual77Se. Chemical solvent peak shifts of ( δCDCl) are3 reported(δ = 7.26 inand parts 77.00 ppm in 1H- and 13C-NMR, respectively) and PhSeSePh δ = 464 ppm in 77Se. Data are reported as per million (ppm), relative to TMS (δ = 0.0 ppm) and the residual solvent peak of CDCl3 (δ = 7.26 and chemical shift (multiplicity, coupling constants where applicable, number of hydrogen atoms, and 77.00 ppm in 1H- and 13C-NMR, respectively) and PhSeSePh δ = 464 ppm in 77Se. Data are reported assignment where possible). Abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), quin as chemical shift (multiplicity, coupling constants where applicable, number of hydrogen atoms, and assignment where possible). Abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), quin Molecules 2017, 22, 953 8 of 13

(quintet), dd (doublet of doublet), dt (doublet of triplet), tt (triplet of triplet), m (multiplet), br. s (broad signal). Coupling constants (J) are quoted in Hertz (Hz) to the nearest 0.1 Hz. GC-MS analyses were carried out with an HP-6890 gas chromatography (dimethyl silicone column, 12.5 m) equipped with an HP-5973 mass-selective detector (Hewlett-Packard, Waldbronn, Germany). Acyl chlorides used for obtaining the selenol esters 5a, 5e, 5f and 5h are commercially available; acyl chlorides used for obtaining the selenol esters 5b, 5c, 5d and 5g were synthesized according to the literature [65]. Density Functional Theory (DFT) calculations were performed with the commercial suite of software Gaussian09 [66]. All calculations were carried out with the mPW1PW hybrid functional [67] and the full-electron Ahlrichs double-ζ basis sets with polarization functions (pVDZ) for all atomic species [67]. NBO populations [68–70] and Wiberg bond indices [71] were calculated at the optimized geometries, which were veriﬁed by harmonic frequency calculations. The results of the calculations were examined with GaussView 5 [72] and Molden 5.3 [73] programs.

General Procedure for the Synthesis of Selenol Esters 5a–h

To a water suspension of the zinc complexes 1 or 3 (0.5 mmol, 6 mL of H2O), acyl chloride 4 (1 mmol) was added at room temperature and under stirring. After 30 min, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), washed with brine (2 × 20 mL), dried with Na2SO4 and concentrated under vacuum to obtain a residue that was purified by flash chromatography. Se-Phenyl benzoselenoate (5a)[40] was purified eluting with 20% DCM in petroleum ether. Yellow solid. ◦ ◦ ◦ ◦ 1 m.p.: 39 –40 C (Lit.: [38] 37 –38 C). H-NMR (CDCl3, ppm) δ: 7.96–7.92 (m, 2H, H-Ar), 7.63–7.42 13 (m, 8H, H-Ar) ppm. C-NMR (CDCl3, ppm) δ: 193.5, 138.5, 136.4, 133.9, 129.4, 129.1, 128.9, 127.4, 125.8 ppm. CG-MS: m/z (%) = 262 (1) [M+], 157 (5), 105 (100), 77 (50), 51 (14). Se-Phenyl 2-bromobenzoselenoate (5b)[74] was purified eluting with 5% EtOAc in petroleum ether. 1 13 Yellow oil. H-NMR (CDCl3, ppm) δ: 7.72–7.6 (m, 4H, H-Ar), 7.45–7.34 (m, 5H, H-Ar) ppm. C-NMR 77 (CDCl3, ppm) δ: 194.4, 140.6, 135.8, 134.3, 132.6, 129.5, 129.2, 128.8, 127.3, 126.6, 118.0 ppm. Se-NMR + (CDCl3, ppm) δ: 662.1 ppm. CG-MS m/z (%) = 340 (1) [M ], 232 (3), 183 (100), 157 (54), 76 (16), 50 (9). Se-Phenyl 4-butylbenzoselenoate (5c)[50] was purified eluting with 20% DCM in petroleum ether. Yellow 1 oil. H-NMR (CDCl3, ppm) δ: 7.85 (d, J = 8.1 Hz, 2H, H-Ar), 7.61–7.57 (m, 2H, H-Ar), 7.44–7.41 (m, 3H, H-Ar), 7.31–7.26 (m, 2H, H-Ar), 2.67 (t, J = 7,8 Hz, 2H, CH2), 1.61 (quin, J = 8.15 Hz, 2H, CH2), 1.36 13 (sex, J = 7.6 Hz, 2H, CH2), 0.95 (t, J = 7.2 Hz, 3H, CH3) ppm. C-NMR (CDCl3, ppm) δ: 192.7, 149.8, 77 136.4, 136.2, 129.3, 129.0, 127.5, 126.0, 35.8, 33.1, 22.3, 13.9 ppm. Se-NMR (CDCl3, ppm) δ: 661.0 ppm. CG-MS m/z (%) = 318 [M+], 161 (100), 91 (30). Se-Phenyl-3,5-dinitrobenzoselenoate (5d)[50] was purified eluting with 5% EtOAc in petroleum ether. ◦ ◦ ◦ 1 Yellow solid. m.p.: 148–150 C (Lit.: [48] 148 –150 ). H-NMR (CDCl3, ppm) δ: 9.28 (t, J = 2.05 Hz, 1H, 13 H-Ar), 9.04 (d, J = 2.06 Hz, 2H, H-Ar), 7.7–7.4 (m, 5H, H-Ar) ppm. C-NMR (CDCl3, ppm) δ: 190.4, 77 148.9, 141.5, 136.1, 130.07, 129.9, 126,7, 124.1, 122.6 ppm. Se-NMR (CDCl3, ppm) δ: 662.3 ppm. Se-Phenyl 2-phenylethaneselenoate (5e)[75] was purified eluting with 20% DCM in petroleum ether. ◦ ◦ ◦ 1 Yellow solid. m.p.: 41–43 C (Lit.: [59] 41 –43 C). H-NMR (CDCl3, ppm) δ: 7.45–7.35 (m, 2H, H-Ar), 13 7.34–7.26 (m, 8H, H-Ar), 3.88 (s, 2H, CH2) ppm. C-NMR (CDCl3, ppm) δ: 198.9, 135.8, 132.6, 130.1, 129.3, 128.9, 128.8, 127.8, 126.6, 53.6 ppm. CG-MS m/z (%) = 276 [M+], 157 (22), 119 (26), 91 (100), 65 (26). Se-Phenyl thiophene-2-carboselenoate (5f)[22] was purified eluting with 5% EtOAc in petroleum ether. 1 Yellow oil. H-NMR (CDCl3, ppm) δ: 7.88 (dd, J = 1.2, 3.9 Hz, 1H, H-Ar), 7.71 (dd, J = 1.2, 4.96, Hz, 1H, H-Ar), 7.63–7.58 (m, 2H, H-Ar), 7.44–7.41 (m, 3H, H-Ar), 7.17 (dd, J = 3.9, 4.96 Hz, 1H, H-Ar) ppm. 13 C-NMR (CDCl3, ppm) δ: 183.6, 143.1, 136.3, 133.7, 132.0, 129.4, 129.2, 128.0, 125.5 ppm. CG-MS m/z (%) = 268 (1) [M+], 157 (16), 111 (100), 83 (20). Molecules 2017, 22, 953 9 of 13

(E)-Se-Phenyl 3-phenylprop-2-eneselenoate (5g)[65] was puriﬁed eluting with 5% EtOAc in petroleum ◦ ◦ ◦ 1 ether. Yellow solid. m.p.: 79–80 C (Lit.: [57] 81 –82 C). H-NMR (CDCl3, ppm) δ: 7.58–7.54 (m, 5H, 13 H-Ar), 7.43–7.40 (m, 6H, H-Ar), 6.78 (d, J = 15.0 Hz, 1H, CH) ppm. C-NMR (CDCl3, ppm) δ: 77 190.8, 141.1, 135.9, 133.9, 130.9, 129.4, 129.1, 129.0, 128.6, 128.1, 126.3 ppm. Se-NMR (CDCl3, ppm) δ: 663.6 ppm. CG-MS m/z (%) = 288 (1) [M+], 157 (14), 131 (100), 103 (55), 77 (36). Se-Phenyl dodecaneselenoate (5h)[76] was puriﬁed eluting with 20% DCM in petroleum ether. Yellow oil. 1 H-NMR (CDCl3, ppm) δ: 7.55–7.53 (m, 2H, H-Ar), 7.42–7.39 (m, 3H, H-Ar), 2.73 (t, J = 7.5 Hz, 2H, CH2C(O)), 1.73 (quin, J = 7.4 Hz; 2H, CH2), 1.4–1.3 (m, 16H, CH2), 0.94–0.90 (t, J = 6.5 Hz, 3H, CH3) ppm. 13 C-NMR (CDCl3, ppm) δ: 200.3, 135.7, 129.2, 128.7, 126.5, 47.5, 31.8, 29.5, 29.3, 29.26, 29.17, 28.8, 25.3, 22.6, 14.0 ppm. CG-MS m/z (%) = 340 (2) [M+], 183 (100), 157 (34), 109 (20), 85 (27), 71 (30), 57 (43).

4. Conclusions In conclusion, we report here that the side reactivity of zinc bis-selenates with the solvent (THF) during the reaction with acyl chlorides can be rationalized by DFT calculations demonstrating that the interactions between (PhSe)2Zn species and the solvent units are remarkably stronger than those calculated between PhSeZnCl and PhSeZnBr and THF. Even if water seems to be equally able to coordinate the Zn, it was not possible to perform the oxidative zinc insertion directly in “on water conditions”. Nevertheless, after the removal of THF, the solid product obtained by the reduction of PhSeSePh with Zn in the presence of a catalytic amount of TFA (formally [(PhSe)2Zn]) can be efficiently used for the synthesis of selenol esters starting from the corresponding acyl chlorides and using water as reaction medium. Furthermore, the complex [(PhSe)2Zn]-TMEDA, prepared according to literature, showed a similar reactivity in water having the additional advantage to be bench stable. To the best of our knowledge, this is the first example that report the use of [(PhSe)2Zn]-TMEDA as nucleophilic reagent and the possibility to use it in a one pot reaction-purification process is an intriguing aspect that is currently under deep investigation by some of us. It is important to underline that the reagents reported in the present work (1, 2, and 3) are more atom-efficient not only relative to the previously reported zinc-halo-selenates, but also among most of the alternative known methods for the synthesis of selenol esters. During the preparation of this manuscript a further synthesis of these compounds appeared starting from anhydrides, evidencing the current interest in this class of derivatives [24]. Nevertheless, in our opinion, both in terms of atom economy and general applicability, it can be claimed that the use of acyl chloride results largely preferable if compared to the anhydrides.

Supplementary Materials: Copies of the 1H and 13C-NMR spectra are available online. Optimized geometries in orthogonal Cartesian format, Mulliken and Natural charges, and thermochemical data for all investigated compounds are available from M.A. upon request. Acknowledgments: Financial support from the Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia “Fondo per il sostegno della Ricerca di Base 2014—Composti Organici ed Ibridi Inorgano-Organici del Selenio nella Sintesi Eco-Compatibile di Molecole Bioattive”. L.S. was fellow with a Regione Umbria, project “POR Umbria 2007–2013,”. Eder Joao Lenardao was Bolsista CAPES—Processo no. BEX 6391/14-1 and Mrs. Vargas was in CAPES Sandwich program with a Doctorate scholarship (PDSE process 99999.001342/2014-02). This research was undertaken as part of the scientific activity of the international multidisciplinary “SeS Redox and Catalysis” network. M.A. and V.L. thank the Università degli Studi di Cagliari for financial support. Author Contributions: C.S. and G.P. conceived and designed the experiments; J.P.V. and B.M. performed the experiments; C.S., L.S. and E.J.L. analyzed the data; V.L. and M.A. designed and executed DFT calculations; C.S., L.S., E.J.L., and V.L. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest and the founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

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Sample Availability: Original samples (due to their instability) are not available but can be provided upon request.

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