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Article (Z,Z)-Selanediylbis(2-propenamides): Novel Class of Organoselenium Compounds with High Glutathione Peroxidase-Like Activity. Regio- and Stereoselective Reaction of with 3-Trimethylsilyl-2-propynamides

Mikhail V. Andreev, Vladimir A. Potapov * , Maxim V. Musalov and Svetlana V. Amosova

A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of The Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia; [email protected] (M.V.A.); [email protected] (M.V.M.); [email protected] (S.V.A.) * Correspondence: [email protected]

Academic Editor: Derek J. McPhee   Received: 3 December 2020; Accepted: 14 December 2020; Published: 15 December 2020

Abstract: The efficient regio- and stereoselective synthesis of (Z,Z)-3,30-selanediylbis(2-propenamides) in 76–93% yields was developed based on the reaction of sodium selenide with 3-trimethylsilyl-2- propynamides. (Z,Z)-3,30-Selanediylbis(2-propenamides) are a novel class of organoselenium compounds. To date, not a single representative of 3,30-selanediylbis(2-propenamides) has been described in the literature. Studying glutathione peroxidase-like properties by a model reaction showed that the activity of the obtained products significantly varies depending on the organic moieties in the amide group. Divinyl selenide, which contains two lipophilic cyclohexyl substituents in the amide group, exhibits very high glutathione peroxidase-like activity and this compound is considerably superior to other products in this respect.

Keywords: (Z,Z)-3,30-selanediylbis(2-propenamides); 3-trimethylsilyl-2-propynamides; sodium selenide; glutathione peroxidase-like activity; regioselective reactions; stereoselective reactions; desilylation

1. Introduction Vinyl are important intermediates for organic synthesis [1–9]. These compounds have been used for the preparation of a number of valuable products [4–9]. Vinyl selenides have found application in the synthesis of functionalized ketones, (Z)-allyl alcohols, and unsaturated aldehydes [4]. The cross-coupling of vinyl selenides with terminal alkynes in the presence of a nickel/CuI catalyst at room temperature proceeded with of retention of stereochemical configuration leading to (Z)- and (E)-enyne derivatives in good yields [5]. The coupling reaction of vinyl selenides with Grignard reagents provided corresponding functionalized alkenes [6,7]. The synthesis of and its methoxylated analogues—well known compounds due to their anti-inflammatory, anticancer, antibacterial, and neuroprotective activity, has been proposed based on vinyl selenides [8]. An efficient method for preparation of α-phenylselanyl lactones has been developed from α-(phenylseleno)vinyl tozylates [9]. Some vinyl selenides exhibit antioxidant [10], antinociceptive [11], and hepatoprotective activity [12].

Molecules 2020, 25, 5940; doi:10.3390/molecules25245940 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 15 Molecules 2020, 25, 5940 2 of 15 The main methods for the preparation of vinyl selenides include a transition metal catalyzed couplingThe mainof vinyl methods halides for with the diselenides preparation or of selenols vinylselenides [13–16], reactions include aof transition thiols or chalcogenolates metal catalyzed couplingwith selenoalkynes of vinyl halides [14,17,18], with diselenides and addition or selenolsof -centered [13–16], reactions nucleophiles of thiols orto chalcogenolatesacetylenes [8,14,19– with selenoalkynes23]. [14,17,18], and addition of selenium-centered nucleophiles to acetylenes [8,14,19–23]. OneOne ofof thethe mostmost usefuluseful andand atom-economicatom-economic method methodss is is based based on on addition addition reactions reactions of of selenoles selenoles oror selenolateselenolate anionsanions withwith acetylenesacetylenes [[8,14,19–22].8,14,19–22]. Examples Examples of of these these reactions reactions refer refer mainly mainly to to vinyl vinyl selenidesselenides containingcontaining aliphaticaliphatic or aromatic substituents at at the the ββ-carbon-carbon atom atom of of the the double double bond. bond. ExamplesExamples ofof thethe synthesissynthesis ofof vinylvinyl selenidesselenides bearin bearingg electron-withdrawing groups groups are are scarce scarce in in the the literature.literature. TheThe synthesis synthesis of of (Z,Z (Z,Z)-bis(2-acylvinyl))-bis(2-acylvinyl) selenides selenides by the by addition the addition reaction reaction of sodium of sodium selenide selenide with organyl ethynyl ketones was developed [23]. with organyl ethynyl ketones was developed [23]. There are only a few representatives of vinyl selenides containing the amide group [24–27]. The There are only a few representatives of vinyl selenides containing the amide group [24–27]. Pd-catalyzed four-component reaction between sulfonamide, alkyne, diphenyl diselenide, and The Pd-catalyzed four-component reaction between sulfonamide, alkyne, diphenyl diselenide, and carbon carbon monoxide afforded substituted 3-(phenylselanyl)propenamides in 65–90% yields [24]. monoxide afforded substituted 3-(phenylselanyl)propenamides in 65–90% yields [24]. Functionalized Functionalized 3-(phenylselanyl)propenamides were obtained in 57–89% yields based on 3- 3-(phenylselanyl)propenamides were obtained in 57–89% yields based on 3-(phenylselanyl)acrylic (phenylselanyl)acrylic acid which was synthesized in 65% yield from diphenyl diselenide and ethyl which was synthesized in 65% yield from diphenyl diselenide and ethyl propiolate [25]. The reaction propiolate [25]. The reaction of carbamoselenoate, PhSeC(O)NMe2, with 1-octyne in the presence of of carbamoselenoate, PhSeC(O)NMe2, with 1-octyne in the presence of Pd(PPh3)4 gave 3-hexyl-3- Pd(PPh3)4 gave 3-hexyl-3-(phenylselanyl)propenamide in 40% yield [26]. (phenylselanyl)propenamide in 40% yield [26]. There are no data in the literature about the biological activity of 3-selanylpropenamides. There are no data in the literature about the biological activity of 3-selanylpropenamides. However, However, it is known that vinyl sulfides bearing the amide group in the β-position exhibit anticancer it is known that vinyl sulfides bearing the amide group in the β-position exhibit anticancer [28] and [28] and antifungal [29] activity (Figure 1). Containing the 2-amidovinylsulfonyl group antifungal [29] activity (Figure1). Containing the 2-amidovinylsulfonyl group methylgerambullone methylgerambullone (isolated from Glycosmis angustifolia) acts as the agonist of acetylcholine Glycosmis angustifolia (isolatedreceptors from [30]. Phenoxyquinolines) actsbearing as the a 2-amidov agonist ofinylsulfonyl acetylcholine moiety receptors shows [30]. the Phenoxyquinolines properties of c- bearingMet kinase a 2-amidovinylsulfonyl inhibitors [31] (Figuremoiety 1). Taking shows theinto properties account the of c-Metindicated kinase biological inhibitors properties [31] (Figure of 3-1). Takingsulfanylpropenamides, into account the indicatedit can be assumed biological that properties selenium of analogs 3-sulfanylpropenamides, of these compounds it can can also be assumeddisplay thatsome selenium kinds of analogs biological of theseactivity. compounds Moreover, can the also vinyla displaymide some group, kinds itself, of is biological an important activity. part Moreover, of some thebiologically vinylamide active group, natural itself, iscompounds an important and part phar of somemaceuticals, biologically which active exhibit natural antitumor, compounds anti- and pharmaceuticals,tuberculosis, andwhich anticonvulsant exhibit antitumor, activity [32–36]. anti-tuberculosis, and anticonvulsant activity [32–36].

Me Me O O N S N S Me O Me Me Me O O O Me O

Antifungal activity Methylgerambullone (agonist of acetylcholine receptors)

Me F Me O O N S N S Me Me Me O Me N Me O NNO 2 O O O MeO HO O Anticancer activity c-Met kinase inhibitor OH N O N N Me FigureFigure 1.1. Known biologically biologically active active derivatives derivatives of of vinyl vinyl sulfides sulfides containing containing the the amide amide group group (anticancer(anticancer [ [28],28], antifungalantifungal [[29],29], agonistagonist of acetylcholine receptors [30], [30], c-Met kinase kinase inhibitor inhibitor [31]). [31]).

ToTo date,date, considerableconsiderable eeffortffort hashas beenbeen devoted to the discovery of of compounds compounds that that mimic mimic the the actionaction ofof selenium-containingselenium-containing glutathioneglutathione peroxidase enzymes [37–47]. [37–47]. The The presence presence of of selenium selenium in in thesethese enzymes enzymes largelylargely determinesdetermines the glutathione pe peroxidaseroxidase activity. activity. In In particular, particular, organoselenium organoselenium compoundscompounds bearing bearing amide amide groups groups have have been been shown show to ben to good be catalystsgood catalysts for the reductionfor the reduction of peroxides of andperoxides hydroperoxides and hydroperoxides with thiols with (Figure thiols2). (Figure 2).

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O O O O O 2 O N R N N N Se N R1 N Se Se Se Se Se

Ebselen (antiinflammatory, neuroprotective and GPx-like activity) Ethaselen Propylselen 1,2-Selenazolan-3-ones

Me O O Me Se Se 2 O O R HO Se N HO OH N O R1 O HO OH Se R Me N Se C N O O N C H H Me O O

1,2-Benzoselenazin-3-ones Camphor derived selenenamide Benzoselenazolinones Seleninic acid anhydride derivative FigureFigure 2.2. ContainingContaining amide amide group group organoselenium compounds, compounds, which which exhibit exhibit glutathione glutathione peroxidase-likeperoxidase-like activity. activity.

Ebselen,Ebselen, whichwhich containscontains thethe selenenamideselenenamide functi functionon in in the the cycle, cycle, and and its its analog analog ethaselen ethaselen and and propylselenpropylselen showshow highhigh glutathioneglutathione peroxidaseperoxidase mimeticmimetic propertiesproperties [[37–41].37–41]. Additionally, Additionally, ebselen ebselen exhibitsexhibits anti-inflammatory anti-inflammatory andand neuroprotectiveneuroprotective activity.activity. These properties properties combined combined with with glutathione glutathione peroxidase-likeperoxidase-like activityactivity and relatively relatively low low toxicity toxicity of ofebselen ebselen has has led ledto therapeutic to therapeutic application application of this of thiscompound, compound, which which has hasundergone undergone evaluation evaluation in clinical in clinical trials trialsas an asanti-inflammatory an anti-inflammatory agent agent[42]. This [42 ]. Thiscompound compound is also is also used used for forthe the treatment treatment and and prev preventionention of ofcardiovascular cardiovascular diseases diseases and and ischemic ischemic strokestroke [ 41[41].]. TheThe rangerange ofof bearingbearing amideamide groupgroup organoseleniumorganoselenium compounds, which which exhibit exhibit glutathione glutathione peroxidaseperoxidase activity, activity, comprises comprises 1,2-benzoselenazin-3-ones 1,2-benzoselenazin-3-ones (including (including the homologuethe homologue of ebselen, of ebselen, 2-phenyl- 2- 1,2-benzoselenazin-3-one),phenyl-1,2-benzoselenazin-3-one), 1,2-selenazolan-3-ones, 1,2-selenazolan-3-ones, benzoselenazolinones, benzoselenazolinones, and seleninic and acidseleninic anhydride acid (whichanhydride has been (which synthesized has been based synthe onsized salicylic based acid on amide salicylic and acid selenium amide tetrachloride) and selenium [41 tetrachloride)–44] (Figure2). [41–44]Camphor-derived (Figure 2). selenenamide was synthesized by action of bromine on corresponding camphor diselenide,Camphor-derived which was obtainedselenenamide based was on synthesized the reaction by of action camphor of bromine enolate withon corresponding selenium [42 ]. Thecamphor glutathione diselenide, peroxidase which mimetic was obtained property based of the on camphor the reaction derived of camphor selenenamide enolate was with studied selenium using a[42]. model The reaction glutathione of benzenemethanethiol peroxidase mimetic property oxidation of by thetert camphor-butyl hydroperoxide derived selenenamide in the presence was studied of the selenenamideusing a model as reaction a catalyst of benzenemethanethiol (10% mol) in dichloromethane oxidation by or tert deuterochloroform-butyl hydroperoxide at room in the temperature. presence Aof similar the selenenamide model reaction as a of catalyst benzenemethanethiol (10% mol) in dichloromethane oxidation by hydrogen or deuterochloroform peroxide was applied at room to examinetemperature. the glutathione A similar model peroxidase-like reaction of activitybenzenem ofethanethiol containing hydroxyoxidation group by hydrogen divinyl peroxide selenides was as a catalystsapplied (10%to examine mol) [ 45the]. Theglutathione progress peroxidase-lik of the reactione wasactivity monitored of containing by 1H NMRhydroxy spectroscopy. group divinyl 1 selenidesPreviously as a catalysts we developed (10% emol)fficient [45]. syntheses The progress of vinyl of and the divinylreaction selenides was monitored based on by the H addition NMR ofspectroscopy. selenium-containing reagents, including sodium selenide, to the triple bond of acetylene and its Previously we developed efficient syntheses of vinyl and divinyl selenides based on the addition derivatives [23,27,48–57]. of selenium-containing reagents, including sodium selenide, to the triple bond of acetylene and its To date, the reactions of sodium selenide with neither 2-propynamides nor 3-(triorganylsilyl)- derivatives [23,27,48–57]. 2-propynamides have yet been described in the literature. It is known that the introduction of To date, the reactions of sodium selenide with neither 2-propynamides nor 3-(triorganylsilyl)-2- electron-donating triorganylsilyl group at the triple bond changes the reactivity of acetylene derivatives propynamides have yet been described in the literature. It is known that the introduction of electron- and deactivates the triple bond toward nucleophilic addition [58]. donating triorganylsilyl group at the triple bond changes the reactivity of acetylene derivatives and In order to develop the method for preparation of previously unknown divinyl selenides containing deactivates the triple bond toward nucleophilic addition [58]. amide groups we studied the reaction of sodium selenide with 3-(trimethylsilyl)-2-propynamides and In order to develop the method for preparation of previously unknown divinyl selenides found the conditions for regio- and stereoselective addition. The obtained results are described in the containing amide groups we studied the reaction of sodium selenide with 3-(trimethylsilyl)-2- present work. propynamides and found the conditions for regio- and stereoselective addition. The obtained results 2.are Results described and in Discussion the present work.

2. ResultsRecently and weDiscussion realized the addition of sodium benzeneselenolate to 3-(trimethylsilyl)-2- propynamides containing morpholine and phenylamide moieties (Scheme1)[ 27]. The reaction was Recently we realized the addition of sodium benzeneselenolate to 3-(trimethylsilyl)-2- propynamides containing morpholine and phenylamide moieties (Scheme 1) [27]. The reaction was

Molecules 2020, 25, 5940 4 of 15 Molecules 2020, 25, x FOR PEER REVIEW 4 of 15 carriedcarried out out by by addition addition of sodium of sodium borohydride borohydride to a stirred to solutiona stirred of 3-trimethylsilyl-2-propynamidessolution of 3-trimethylsilyl-2- andpropynamides diphenyl diselenide and diphenyl in a THF–waterdiselenide in (4 /1)a THF–water system at room (4/1) temperaturesystem at room and accompaniedtemperature and by desilylation.accompanied The by desilylation. generation of The sodium generation benzeneselenolate of sodium benzeneselenolate occurred in situ followedoccurred byin situ nucleophilic followed additionby nucleophilic of this highly addition reactive of this intermediate highly reactive to the intermediate triple bond. to the triple bond.

NaBH4/THF/H2O Ph2Se2 2 PhSeNa

O NR1R2 Se Se NaBH4/THF/H2O NaBH4/THF/H2O O Ph Se O 1 2 2 2 1 2 NR R = NHPh NR R = N(C2H4)2O N HN SiMe3 O

NR1R2 = NHPh, N(C H ) O 2 4 2 SchemeScheme 1.1. Synthesis of containing the the am amideide group group vinyl vinyl selenides selenides from from diphenyl diphenyl diselenide diselenide and and 3- 3-(trimethylsilyl)-2-propynamides.(trimethylsilyl)-2-propynamides.

TheThe reactionreaction proceededproceeded inin stereo-stereo- andand regioselectiveregioselective mannersmanners aaffordingffording ((ZZ)-)-NN-phenyl-3--phenyl-3- (phenylselanyl)prop-2-enamide(phenylselanyl)prop-2-enamide (72% (72% yield) yield) andand ((ZZ)-1-morpholino-3-(phenylselanyl)prop-2-en-1-one)-1-morpholino-3-(phenylselanyl)prop-2-en-1-one (70%(70% yield), yield), which which were were isolated isolated as colorless as colorless crystalline crystalline compounds compounds [27]. To the[27]. best To of the our best knowledge, of our theseknowledge, are first these examples are first of theexamples addition of ofthe organylselenolates addition of organylselenolates to 3-silyl-2-propynamides. to 3-silyl-2-propynamides. TheThe commonlycommonly usedused conditionsconditions forfor generationgeneration ofof organylselenolatesorganylselenolates fromfrom correspondingcorresponding diselenidesdiselenides andand sodiumsodium selenideselenide fromfrom elementalelemental seleniumselenium consistconsist inin thethe applicationapplication ofof sodiumsodium borohydrideborohydride asas aa reducingreducing agentagent andand carryingcarrying outout thethe reactionreaction inin alcoholsalcohols [59[59].]. However,However, whenwhen thethe reactionsreactions ofof sodiumsodium benzeneselenolatebenzeneselenolate oror sodiumsodium selenide selenide with with 3-(trimethylsilyl)-2-propynamides 3-(trimethylsilyl)-2-propynamides proceededproceeded inin methanolmethanol oror ethanol,ethanol, thethe formationformation ofof 3-alkoxy-2-propenamides3-alkoxy-2-propenamides asas by-productsby-products waswas observed.observed. The possibility of thethe formationformation ofof 3-alkoxy-2-propenamides3-alkoxy-2-propenamides fromfrom 3-(trimethylsilyl)-2-3-(trimethylsilyl)-2- propynamidespropynamides in in reactions reactions with with alcohols alcohols has has been been previously previously described described [ 60[60].]. WeWe foundfound thatthat thethe THF–waterTHF–water systemsystem isis preferablepreferablein inaddition additionreactions reactionsof ofselenium-centered selenium-centered nucleophilesnucleophiles with with 3-(trimethylsilyl)-2-propynamides 3-(trimethylsilyl)-2-propynamides compared compared to commonly to commonly used alcohol used conditions. alcohol Theconditions. yields of The the targetyields products of the target are higher products and are 3-alkoxy-2-propenamides higher and 3-alkoxy-2-propenamides are not formed asare by-products. not formed as by-products.The addition reactions of selenide anion with propynamides and 3-silyl-2-propynamides have not yet beenThe described addition inreactions the literature. of selenide In order anion to obtain with previouslypropynamides unknown and 3-silyl-2-propynamides divinyl selenides containing have amidenot yet groups been wedescribed studied in the the addition literature. of sodium In orde selenider to obtain to 3-(trimethylsilyl)-2-propynamides previously unknown divinyl selenides bearing variouscontaining groups amide (phenyl, groups alkyl, we cyclohexyl, studied morpholinethe addition and of piperidine) sodium selenide in the amide to moieties3-(trimethylsilyl)-2- (Scheme2). Sodiumpropynamides selenide bearing was effi variousciently generatedgroups (phenyl, from elemental alkyl, cyclohexyl, selenium morpholine and sodium and borohydride piperidine) in waterin the andamide used moieties without (Scheme isolation 2). in Sodium further selenide nucleophilic was additionefficiently reactions. generated from elemental selenium and sodiumThe borohydride conditions for in the water regio- and and used stereoselective without isolation reaction in further of 3-trimethylsilyl-2-propynamides nucleophilic addition reactions.1a–i with sodiumThe conditions selenide for were the regio- found. and The stereoselectiv reaction proceedede reaction in of the3-trimethylsilyl-2-propynamides THF–water system under argon 1a– aiff withording sodium (Z,Z)-3,3 selenide0-selanediylbis(2-propynamides) were found. The reaction proceeded2a–i in 76-93% in the yields THF–water (Scheme system2). under argon affording (Z,Z)-3,3′-selanediylbis(2-propynamides) 2a–i in 76-93% yields (Scheme 2).

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Se + 2 NaBH4 Na2Se H2O

Na Se O 2 Se

Me3Si H O−THF, r.t., 4 h 2 R1R2N O O NR1R2 NR1R2 or reflux, 10 min −[ 1a-i (Me3Si)2O] 2a-i 25−93%[a] 76−91%[b] 50−73%[c]

Se Se Se

H N O O NH MeHN O O NHMe N O O N 2 2 H H [a] [c] [b] [c] 2c, 85% , 69% 2a, 91%[b], 72%[c] 2b, 80% , 71%

Se Se Se Me N O O N Me N O O N Me2N O O NMe2 Me Me 2d, 86%[a], 70%[c] 2e, 86%[a], 72%[c]

2f, 25%[a], 76%[b], 66%[c]

Se Se Se N O O N N O O N N O O N O O

[a] [c] 2g, 77%[b], 50%[c] 2h, 93%[a], 73%[c] 2i, 89% , 65%

Scheme 2. Synthesis of divinyl selenides 2a–i from 3-(trimethylsilyl)-2-propynamides 1a–i, elemental Schemeselenium, 2. andSynthesis sodium of borohydride.divinyl selenides Sodium 2a–i selenide from 3-(trimethylsilyl)-2-propynamides was obtained by addition of an aqueous 1a–i, elemental solution selenium,of sodium and borohydride sodium borohydride. to a hot mixture Sodium of selenium selenide and was water obtained (Methods by additionA and B ).of[a] anMethod aqueousA : solutionTHF/water~1:3. of sodium A borohydride solution of 3-(trimethylsilyl)-2-propynamide to a hot mixture of selenium and water in THF (Methods was added A and toa B hot). [a] aqueousMethod Asolution: THF/water~1:3. of sodium A selenide solutionand of 3-(trimethylsilyl the mixture was)-2-propynamide refluxed for 10 min.in THF Yields: was added 25–93%. to a[b] hotMethod aqueousB : solutionTHF/water~3:1. of sodium A solutionselenide ofand 3-(trimethylsilyl)-2-propynamide the mixture was refluxed for 10 in min. THF Yields: was added 25–93%. to a[b] hot Method aqueous B: THF/water~3:1.solution of sodium A solution selenide of and 3-(trimethylsilyl)-2-propynamide the mixture was refluxed for 10 in min. THF Yields: was added 76–91%. to a [c]hotMethod aqueousC : solutionsodium borohydrideof sodium selenide was added and portionwise the mixture to was a mixture refluxed of 3-(trimethylsilyl)-2-propynamide, for 10 min. Yields: 76–91%. [c] Method selenium, C: sodiumTHF and borohydride water and the was mixture added was portionwise stirred at room to a temperature mixture of for 3-(trimethylsilyl)-2-propynamide, 4 h (10 h for 2g). Yields: 50–73%. selenium, THF and water and the mixture was stirred at room temperature for 4 h (10 h for 2g). Yields: 50–73%.Water is necessary for generating sodium selenide and reacting Na2Se with propynamides 1a–i which are soluble in THF. The ratio of the solvents in the THF–water system was varied from 1/3

(methodWaterA )is to necessary 3/1(method for Bgenerating). In the method sodiumA selenideand B, aand solution reacting of silylpropynamidesNa2Se with propynamides in THF 1a was–i whichadded are to asoluble hot aqueous in THF. solution The ratio of sodium of the solvents selenide, in which the THF–water was obtained system from was elemental varied seleniumfrom 1/3 (methodand sodium A) to borohydride, 3/1(method andB). In the the mixture method was A refluxedand B, a forsolution 10 min. of Insilylpropynamides the case of method inC THF, sodium was addedborohydride to a hot was aqueous added solution portionwise of sodium to a mixture selenide, of which propynamides was obtained1b– dfrom,f–i and elemental selenium selenium in the andTHF–water sodium systemborohydride, (the ratio and of the the mixture solvents was 4/1) re andfluxed the for mixture 10 min. was In stirred the case at of room method temperature C, sodium for borohydride4 h (10 h for 2gwas). added portionwise to a mixture of propynamides 1b–d,f–i and selenium in the THF–water system (the ratio of the solvents 4/1) and the mixture was stirred at room temperature for 4 h (10 h for 2g). Best yields of the products were obtained when the reaction mixtures were refluxed for 10 min in the THF–water system. When reaction was carried out at room temperature, the yields dropped

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despite increasing the reaction duration. The divinyl selenides 2b–d,f–i were obtained in 50–73% yields with 4 h stirring at room temperature under argon (Scheme 2, method C). Surprisingly, neither unconverted 3-(trimethylsilyl)-2-propynamides 1b–d,f–i nor desilylated propynamides were

Moleculesdetected2020 in, 25the, 5940 reaction mixture in these cases after completion of the reaction (method C). However,6 of 15 the yields of the target products 2b–d,f–i were lower than in the methods A and B. The reaction of sodium selenide with propynamide 1f bearing two phenyl substituents in the amideBest group yields under of the the products conditions were of obtainedmethod A when led to the a mixture reaction containing mixtures weredivinyl refluxed selenide for 2f 10 in min 25% inyield, the THF–water unconverted system. silylpropynamide When reaction 1f (31% was carriedconversion) out atand room the temperature,desilylated amide, the yields N,N-diphenyl- dropped despite2-propynamide increasing (1%). the reactionThe reaction duration. of sodium The divinyl selenide selenides with silylpropynamide2b–d,f–i were obtained 1g containing in 50–73% two yieldscyclohexyl with 4moieties h stirring in at the room amide temperature group also under gave argonsimilar (Scheme poor results.2, method We supposedC). Surprisingly, that the neither reason unconvertedof the insufficient 3-(trimethylsilyl)-2-propynamides yield of selenides 2f,g and 1blow–d ,conversionf–i nor desilylated of starting propynamides amides 1f,g were may detected be poor insolubility the reaction of propyneamides mixture in these 1f cases,g in the after mixture completion water–THF of the reaction (3/1, method (method A) dueC). However,to lipophilic the organic yields ofmoieties the target of productsthe amide2b group.–d,f–i Thewere silylpropynamides lower than in the methods1f,g are insolubleA and B. in water but soluble in THF. Indeed,The when reaction the ofmethod sodium B (THF–water selenide with 3/1) propynamide was applied,1f productsbearing 2f two,g were phenyl obtained substituents in 76–77% in theyields. amide The group method under A was the found conditions to provide of method high yieldsA led of to products a mixture 2c– containinge,h,i (85–93%) divinyl derived selenide from 2fsilylpropynamidesin 25% yield, unconverted 1c–e,h,i containing silylpropynamide monophenyl,1f (31%dialkyl, conversion) morpholine, and and the piperidine desilylated moieties amide, in Nthe,N -diphenyl-2-propynamideamide group. (1%). The reaction of sodium selenide with silylpropynamide 1g containingThe possible two cyclohexyl pathway moieties for the in formation the amide of group products also gave 2a–i similar can include poor results. both the We addition— supposed thatdesilylation the reason processes of the insu andfficient the yield sequential of selenides desily2flation—addition,g and low conversion reactions of starting via the amides generation1f,g may of beintermediate poor solubility propynamides of propyneamides 3a–i (Scheme1f,g in the3). The mixture addition water–THF of sodium (3/1, selenide method toA) the due triple to lipophilic bond of organicsilylpropynamides moieties of the 1a amide–i is accompanied group. Thesilylpropynamides by the formation 1fof, gsodiumare insoluble hydroxide, in water which but acts soluble as the in THF.catalyst Indeed, for whenthe desilylation the method reaction.B (THF–water We suppose 3/1) was applied,that the productsdesilylation2f,g wereprocess obtained can proceed in 76–77% on yields.different The stages method of theA was reaction found including to provide various high yieldsintermediate of products species2c –(Schemee,h,i (85–93%) 3). derived from silylpropynamidesThe formation1c of–e intermediate,h,i containing 2-propynamides monophenyl, dialkyl, 3a–i in morpholine,very small amounts and piperidine (before the moieties isolation in theof the amide reaction group. products 2a–i) was registered in the reaction mixture by NMR. The NMR data of the intermediateThe possible propynamides pathway for the3a– formationi coincide ofwith products the spectral2a–i can characteristics include both theof the addition—desilylation previously obtained processessamples of and these the compounds, sequential desilylation—additionwhich were synthesized reactions by desilylation via the of generationsilylpropynamides of intermediate 1a–i [60]. propynamidesThe formation3a–i (Scheme of propynamides3). The addition 3a–i ofin sodiumthe reaction selenide (Scheme to the triple2) indicates bond of the silylpropynamides possibility of the 1areaction–i is accompanied pathway byvia the desilylation formation ofof sodium silylpropynamides hydroxide, which 1a–i. acts It was as the previously catalyst for established the desilylation that reaction.silylpropynamides We suppose 1a– thati can the be desilylation desilylated processby the canaction proceed of various on di reagentsfferent stages (potassium of the reactionfluoride, includingalkali metal various hydroxides intermediate and other species bases) (Scheme and converted3). to corresponding propynamides 3a–i [60].

SiMe3 H O H H O H SeNa NaOH 2 SeNa Na2Se Me3Si H2O 1 2 NR R 1 2 1 2 R R N O Catalyst of R R N O 1a−i desilylation

H2O NaOH H H H H H O Na2Se H Se H SeNa 1 2 1 2 1 2 NR R H2O R R N O O NR R R1R2N O 3a−i 2a−i

SchemeScheme 3. 3.The The possible possible reaction reaction pathways pathways for for the the formation formation of of products products2a 2a–i–.i.

TheIt is formation worth noting of intermediate that the application 2-propynamides of 3-trimethylsilyl-2-propynamides3a–i in very small amounts (before 1a–i theas the isolation initial ofsubstrates the reaction in the products preparation2a–i) wasof the registered target vinyl in the selenides reaction is mixturepreferable by compared NMR. The to NMR 2-propynamides data of the intermediatewith the terminal propynamides triple bond.3a–i Thecoincide latter with compou the spectralnds are characteristicshardly available of the and previously the price obtainedfor these sampleschemicals of theseis very compounds, high. Their whichpreparation were synthesizedis usually based by desilylation on toxic and of skin-irritating silylpropynamides propynoic1a–i [acid.60]. The Thesilylpropynamides formation of propynamides 1a–i were synthesized3a–i in the in reactionthe present (Scheme work 2by) indicates the method the depicted possibility in Scheme of the reaction4 [61–63]. pathway Inexpensive via desilylation starting propargyl of silylpropynamides alcohol, good selectivity1a–i. It was of these previously reactions established and high thatyield silylpropynamidesof the target products1a–i allowecan bed desilylated to make silylpropynamides by the action of various 1a–i readily reagents available (potassium compounds fluoride, and alkali to metaluse them hydroxides in the synthesis and other of bases) valuable and products converted [64–66]. to corresponding propynamides 3a–i [60]. It is worth noting that the application of 3-trimethylsilyl-2-propynamides 1a–i as the initial substrates in the preparation of the target vinyl selenides is preferable compared to 2-propynamides with the terminal triple bond. The latter compounds are hardly available and the price for these chemicals is very high. Their preparation is usually based on toxic and skin-irritating propynoic Molecules 2020, 25, 5940 7 of 15 acid. The silylpropynamides 1a–i were synthesized in the present work by the method depicted in Scheme4[ 61–63]. Inexpensive starting propargyl alcohol, good selectivity of these reactions and high yield of the target products allowed to make silylpropynamides 1a–i readily available compounds and Moleculesto use them 2020, in25, thex FOR synthesis PEER REVIEW of valuable products [64–66]. 7 of 15

1) [Mg], THF, reflux, 9 h (Me3Si)2NH 2) 5% Me Si H H 3 80% OH OH saccharin (1 mol%), 98% OSiMe3 70°C, 30 min

1) (COCl)2, DMF (4 mol%), rt 1 2 O CrO3, H2SO4 O 2) HNR R (2 equiv.), Et2O Me Si Me3Si 3 − − ÷ − ° 1 2 aceton H2O, 25 30 C OH 1a−i NR R 55% 72−91%

R1 = H; R2 = H (a) 82%, Me (b) 72%, Ph (c) 84%

R1 = R2 = Me (d) 74%; Et (e) 82%; Ph (f) 91%; Cy (g) 81%

R1+ R2 = CH CH OCH CH (h) 87%; (CH ) (i) 81% 2 2 2 2 2 5 Scheme 4. TheThe method method for for the preparation of 3-trimethylsilyl-2-propynamides 1a–i.

The obtainedobtained selanediylbis(2-propynamides) selanediylbis(2-propynamides)2a– i 2aare–i a novelare a class novel oforganoselenium class of organoselenium compounds. compounds.Like ebselen andLike some ebselen organoselenium and some compounds, organosele whichnium exhibitcompounds, glutathione which peroxidase-like exhibit glutathione activity (Figureperoxidase-like2), products activity2a–i contain(Figure the2), amideproducts function, 2a–i contain and their the activity amide deserved function, to and be studied. their activity deservedWe studied to be studied. glutathione peroxidase-like activity of the obtained products 2a–i using the model reactionWe ofstudied benzenemethanethiol glutathione peroxidase-like oxidation [42 ,45activity] by tert of-butyl the obtained hydroperoxide products (TBHP) 2a–i inusing the presencethe model of 1 reactioncompounds of 2abenzenemethanethiol–i as catalysts and the oxidation progress of[42,45] this reaction by tert was-butyl monitored hydroperoxide by H NMR (TBHP) spectroscopy. in the presenceFirst experiments of compounds in the NMR2a–i as tubes catalysts (TBHP, and BnSH, the progress 0.1 mmol, of deuterochloroform)this reaction was monitored at room temperatureby 1H NMR spectroscopy.showed that the First reactions experiments proceeded in the too NMR fast tubes when (TBHP, 10% mol BnSH, of the 0.1 catalysts mmol, weredeuterochloroform) used. In order toat 1 roomrealize temperature the H NMR showed monitoring, that the the reactions amounts procee of theded catalysts too fast were when decreased 10% mol to of 0.5% the mol.catalysts Diphenyl were used.diselenide In order was to used realize as the the standard 1H NMR compoundmonitoring, (this the compoundamounts of isthe often catalysts used aswere the decreased standard catalystto 0.5% mol.for in Diphenyl these experiments diselenide [42 was–47 used]). as the standard compound (this compound is often used as the standardIt was catalyst found for that in thethese activity experiments of the obtained[42–47]). products 2a–i varies significantly depending on the organicIt was found moieties that in the the activity amide of group. the obtained The results products of studying 2a–i varies the significantly compounds depending2d,f,g,h,i, whichon the organicoutperform moieties diphenyl in the diselenide amide group. in the glutathione The results peroxidase-like of studying the activity, compounds are presented 2d,f,g, inh,i Figure, which3 (aoutperform 24 h scale) diphenyl and Figure diselenide4 (a 90 in min the scale).glutathione In the peroxidase-like control experiment, activity, under are presented the same in reactionFigure 3 (aconditions 24 h scale) but and in the Figure absence 4 (a of the90 min catalyst, scale). the In conversion the control of phenylmethanethiolexperiment, under wasthe same only aboutreaction 4% 1 conditionsafter 24 h according but in the to absenceH NMR of data.the catalyst, the conversion of phenylmethanethiol was only about 4% afterProduct 24 h 2gaccordingcontaining to 1H two NMR lipophilic data. cyclohexyl substituents in the amide group shows highest glutathioneProduct peroxidase-like 2g containing two properties lipophilic (Figures cyclohexyl4 and 5substituents). This compound in the amide is significantly group shows superior highest to glutathioneother products peroxidase-like in activity. Theproperties second (Figures most active 4 and product 5). This is compound compound is2i significantly(Figure4) bearing superior the to piperidineother products moieties in activity. in the amide The second function most and theactive third product is product is compound2d (the activity 2i (Figure of which 4) isbearing presented the piperidinein both Figures moieties3 and 4in). Compoundsthe amide function2f,h containing and the thethird morpholine is product and 2d phenyl (the activity moieties of also which exhibit is presentedhigher activity in both compared Figures to3 and diphenyl 4). Compounds diselenide. 2f,h containing the morpholine and phenyl moieties also exhibitThe obtained higher resultsactivity are compared very promising. to diphenyl However, diselenide. the interpretation of the influence of organic moietiesThe onobtained the catalytic results activity are very and promising. discussion However, on possible the intermediates interpretation of of the the catalytic influence cycle of requiresorganic moietiesadditional on data the and catalytic further activity research. and discussion on possible intermediates of the catalytic cycle requires additional data and further research.

MoleculesMolecules2020 2020, 25,, 25 5940, x FOR PEER REVIEW 8 of8 of 15 15 Molecules 2020, 25, x FOR PEER REVIEW 8 of 15 100 2d Molecules100 902020, 25, x FOR PEER REVIEW 8 of 15 2d 2h 90 80 2h 2f 100 80 70 2d 2f PhSeSePh 90 70 60 2h PhSeSePhControl 80 2f Control 60 50 70 PhSeSePh

50(%) Conversion 4060 Control

Conversion (%) Conversion 40 3050

30 20(%) Conversion 40

20 1030

20 10 0 10 3 6 9 12 15 18 21 24 0 Reaction Time (h) 0 3 6 9 12 15 18 21 24 3 6 9Reaction 12 Time (h) 15 18 21 24 Figure 3. Studying glutathione peroxidase-likeReaction Time activity (h) of compounds 2d,f,h by 1H NMR monitoring

Figurewith 3. the StudyingStudying use of Ph glutathione 2Se2 as the peroxidase-like standard compound activity (TBHP, of compounds BnSH, 0.1 2d mmol,,f,h by deuterochloroform, 1H NMR monitoring 0.5% Figure 3. Studying glutathione peroxidase-like activity of compounds 2d,f,h by 1H NMR monitoring withmol thethe of useuse studied ofof Ph PhSe2 Secompounds).2 asasthe the standard standard The compound controlcompound experiment (TBHP, (TBHP, BnSH, BnwasSH, 0.1 carried 0.1 mmol, mmol, out deuterochloroform, deuterochloroform,in the absence 0.5%of 0.5%studied mol with the use of2 Ph22Se2 as the standard compound (TBHP, BnSH, 0.1 mmol, deuterochloroform, 0.5% compounds. molof studied ofmol studied of compounds). studied compounds). compounds). The control The The control experimentcontrol experimentexperiment was carried waswas outcarried carried in the out out absence in inthe the ofabsence studiedabsence of compounds.studied of studied compounds.compounds. 100 2g 100 90100 2g 2g 90 90 80 2i 80 2i 80 70 2i 70 70 60 2d 60 2d 2d 60 50 50 50 40 Conversion (%) 40 Conversion (%) 40 Conversion (%) 3030

30 2020

20 1010

10 0 0 10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90 0 Reaction Time (min) Reaction Time (min) 10 20 30 40 50 60 70 80 90 Reaction Time (min) FigureFigure 4. Studying 4. Studying glutathione glutathione peroxidase-like peroxidase-like activity of of compounds compounds 2d,2dg,i, (TBHP,g,i (TBHP, BnSH, BnSH, 0.1 mmol, 0.1 mmol, Figure 4. Studying glutathione peroxidase-like activity1 of compounds 2d,g,i (TBHP, BnSH, 0.1 mmol, deuterochloroform,deuterochloroform, 0.5% 0.5% mol mol of of studied studied compounds) compounds) by 1HH NMR NMR monitoring. monitoring. Figuredeuterochloroform, 4. Studying glutathione 0.5% mol peroxidase-like of studied compounds) activity of by compounds 1H NMR monitoring. 2d,g,i (TBHP, BnSH, 0.1 mmol, deuterochloroform, 0.5% mol of studied compounds) by 1H NMR monitoring. Se Se Se N O Se O N N O OSe N Me N O O SeNMe N SeO O N N SeO O N 2 2 Me N SeO O NMe N O O N N O O N 2 2 2g 2i 2d Me2N O O NMe2

2g 2i 2d 2g 2i Se 2d Se N O O N N O O N Se O Se O Se Se N O O N N O 2h O N 2f N O O N O N O O N O Figure 5. CompoundsO 2d,f,g,h,i exhibitingO higher glutathione peroxidase-like activity compared to 2h 2f Ph2Se2 (the compounds are arranged in the decreasing order of the activity). 2h 2f

Molecules 2020, 25, 5940 9 of 15

3. Experimental Section

3.1. General Information The 1H (400.1 MHz), 13C (100.6 MHz) and 77Se (76.3 MHz) NMR spectra (Supplementary Materials) were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) 1 13 77 in CDCl3 and d6-DMSO 5–10% solutions and referred to TMS ( H, C) and dimethyl selenide ( Se). The IR spectra were taken on a Bruker IFS-25 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany). Mass spectra were recorded on a Shimadzu GCMS-QP5050A (Shimadzu Corporation, Kyoto, Japan) with electron impact (EI) ionization (70 eV). Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A apparatus (Wagner & Munz GmbH, München, Germany). The organic solvents were dried and distilled according to standard procedures. Silica gel (Alfa Aesar, 0.06–0.20 mm (70–230 mesh)) and ethyl acetat–methanol (10:1) as an eluent were used for column chromatography.

3.2. Method A (Preparation of Compounds 2c–f,h,i) A mixture of elemental selenium (19 mg, 0.24 mmol) and degassed water (4.0 mL) was heated on a water bath (90–95 ◦C) and a solution of NaBH4 (40 mg, 1.05 mmol) in degassed water (0.5 mL) was added under argon. After dissolution of selenium and the formation of colorless mixture, a solution of 3-trimethylsilyl-2-propynamide (0.48 mmol) in THF (1.5 mL) was added to a hot aqueous solution of the sodium selenide and the mixture was refluxed for 10 min (5 h for 1g) under argon. The mixture was cooled by cold water bath and extracted with CH Cl (3 7.0 mL). The organic phase was dried 2 2 × over Na2SO4 and the solvent was removed under reduced pressure. General yields: 85–93%.

3.3. Method B (Preparation of Compounds 2a,b,f,g) A mixture of elemental selenium (19 mg, 0.24 mmol) and degassed water (2.0 mL) was heated on a water bath (90–95 ◦C) and a solution of NaBH4 (40 mg, 1.05 mmol) in degassed water (0.4 mL) was added under argon. After dissolution of selenium and the formation of colorless mixture, a solution of 3-trimethylsilyl-2-propynamide (0.48 mmol) in THF (7.0 mL) was added to a hot aqueous solution of the sodium selenide and the mixture was refluxed for 10 min (5 h for 1g) under argon. The mixture was cooled by cold water bath and THF was removed by a rotary evaporator. The residue was extracted with CH Cl (3 7.0 mL). The organic phase was dried over Na SO and the solvent was removed 2 2 × 2 4 under reduced pressure. General yields: 76–91%.

3.4. Method C (Preparation of Compounds 2a–i)

NaBH4 (30 mg, 0.79 mmol) was added portionwise to a stirred mixture of selenium (19 mg, 0.24 mmol), 3-trimethylsilyl-2-propynamide (0.48 mmol), degassed water (0.5 mL) and THF (2.0 mL). The mixture was stirred at room temperature for 5 h under argon and degassed water (2 mL) was added. The mixture was extracted with CH Cl (3 7.0 mL). The organic phase was dried over Na SO 2 2 × 2 4 and the solvent was removed under reduced pressure. General yields: 50–74%.

3.5. Compounds 2a–i (Z)-3-[(Z)-3-amino-3-oxo-1-propenyl]selanyl-2-propenamide (2a) was prepared by the method B (91% yield) and the method C (72% yield). After refluxing for 10 min, the solvent was removed under reduced pressure and product 2a was extracted from the residue by boiling acetone. The solvent was removed under reduced pressure giving 2a (48 mg, 91%, method B); (38 mg, 72%, method C); yellowish powder; 1 3 mp 183–184 ◦C. H NMR (400 MHz, d6-DMSO): δ 6.38 (d, J = 9.5 Hz, 2H, =CHCO), 7.10 (s, 2H, NH2), 3 13 7.50 (s, 2H, NH2), 7.65 (d, J = 9.5 Hz, 2H, SeCH=). C NMR (100 MHz, d6-DMSO): δ 120.6 (=CCO), 1 77 145.3 (SeC=, JSe–C = 128.2 Hz), 168.1 (C=O). Se NMR (76 MHz, d6-DMSO): δ 507.4. IR (KBr): 3430, Molecules 2020, 25, 5940 10 of 15

3389, 3180, 2929, 1654 (C=O), 1575 (C=C), 1558 (C=C), 1397, 1282, 1162, 1111, 1050, 928, 802, 729, 632, 589, 524 cm–1. MS (EI), m/z (%): 220 [M]+, 218 (13), 152 (4), 150 (24), 148 (12), 134 (6), 133 (9), 106 (9), 88 (100), 71 (9), 70 (22), 55 (6), 44 (54), 43 (6). Anal. calcd for C6H8N2O2Se (219.10): C 32.89, H 3.68, N 12.79, Se 36.04%. Found: C 32.73, H 3.57, N 12.93, Se 35.89%. (Z)-N-methyl-3-[(Z)-3-(methylamino)-3-oxo-1-propenyl]selanyl-2-propenamide (2b) was prepared by the method B (80% yield) and the method C (71% yield). After addition of degassed water to the reaction mixture, the precipitate was filtered and dried in vacuum giving product 2b (47.5 mg, 80%, method 1 B); (42 mg, 71%, method C); white powder; mp 215–216 ◦C. H NMR (400 MHz, d6-DMSO): δ 2.64 3 3 3 (d, J = 4.4 Hz, 6H, CH3), 6.35 (d, J = 9.6 Hz, 2H, =CHCO), 7.59 (d, J = 9.6 Hz, 2H, SeCH=), 8.01 3 13 (q, J = 4.4 Hz, 2H, NH). C NMR (100 MHz, d6-DMSO): δ 25.5 (CH3), 120.4 (=CCO), 144.0 (SeC=, 1 77 JSe–C = 127.4 Hz), 166.8 (C=O). Se NMR (76 MHz, d6-DMSO): δ 502.7. IR (KBr): 3324, 3041, 2938, 1644 (C=O), 1580 (C=C), 1524 (C=C), 1413, 1240, 1184, 1057, 805, 725, 698, 653 cm–1. MS (EI), m/z (%): 248 (20) [M]+, 246 (9), 187 (6), 166 (9), 164 (43), 162 (30), 161 (25), 147 (92), 145 (45), 143 (22), 135 (9), 134 (15), 133 (10), 132 (7), 131 (7), 110 (11), 107 (13), 106 (15), 105 (8), 104 (9), 84 (100), 68 (17), 66 (7), 58 (96), 57 (7), 56 (15), 55 (15), 53 (13), 44 (14), 43 (9), 42 (19), 41 (10). Anal. calcd for C8H12N2O2Se (247.15): C 38.88, H 4.89, N 11.33, Se 31.95%. Found: C 38.91, H 4.86, N 11.57, Se 32.14%. (Z)-N-phenyl-3-[(Z)-3-anilino-3-oxo-1-propenyl]selanyl-2-propenamide (2c) was prepared by the method A (85% yield) and the method C (69% yield). After removing the solvent, the residue was dissolved in THF and precipitated with cold hexane giving product 2c which was dried in vacuum (76 mg, 85%, 1 method A); (61 mg, 69%, method C); beige powder; mp 219–220 ◦C. H NMR (400 MHz, d6-DMSO): δ 6.65 (d, 3J = 9.6 Hz, 2H, =CHCO), 7.06 (t, 3J = 7.7 Hz, 2H, Hp), 7.32 (dd, 3J = 7.7 Hz, 4H, Hm), 7.66 (d, 3J = 7.7 Hz, 4H, Ho), 7.94 (d, 3J = 9.6 Hz, 2H, SeCH=), 10.23 (s, 2H, NH). 13C NMR (100 MHz, o p m i 1 d6-DMSO): δ 119.0 (=CCO), 121.0 (C ), 123.4 (C ), 128.9 (C ), 139.1 (C ), 146.7 (SeC=, JSe–C = 129.0 Hz), 77 164.9 (C=O). Se NMR (76 MHz, d6-DMSO): δ 518.8. IR (KBr): 3266, 3129, 3039, 2929, 1636 (C=O), 1603 (C=C, Ph), 1544 (C=C, Ph), 1499 (C=C, Ph), 1439, 1365, 1302, 1247, 1201, 1159, 979, 796, 744, 689, 594, 505 cm–1. MS (EI), m/z (%): 372 (8) [M]+, 224 (15), 211 (9), 209 (47), 207 (23), 206 (9), 205 (9), 187 (6), 161 (18), 159 (11), 147 (13), 146 (100), 145 (12), 133 (8), 132 (31), 131 (6), 128 (9), 120 (8), 117 (14), 106 (8), 104 (12), 94 (11), 93 (79), 92 (29), 91 (9), 77 (37), 66 (11), 65 (34), 64 (7), 51 (11), 39 (17). Anal. calcd for C18H16N2O2Se (371.29): C 58.23, H 4.34, N 7.54, Se 21.27%. Found: C 58.50, H 4.29, N 7.48, 20.97%. (Z)-3-[(Z)-3-(dimethylamino)-3-oxo-1-propenyl]selanyl-N,N-dimethyl-2-propenamide (2d) was prepared by the method A (86% yield) and the method C (68% yield). After removing the solvent, the residue was dissolved in CHCl3 and precipitated with cold hexane giving product 2d, which was dried in vacuum 1 (57 mg, 86%, method A); (46 mg, 68%, method C); white powder; mp 181–182 ◦C. H NMR (400 MHz, 3 3 CDCl3): δ 3.01, 3.06 (s, 12H, CH3), 6.74 (d, J = 9.7 Hz, 2H, =CHCO), 7.52 (d, J = 9.7 Hz, 2H, SeCH=). 13 1 C NMR (100 MHz, CDCl3): δ 35.4, 37.2 (CH3), 116.8 (=CCO), 147.6 (SeC=, JSe–C = 132.6 Hz), 166.9 77 (C=O). Se NMR (76 MHz, CDCl3): δ 516.8. IR (KBr): 3024, 2925, 2861, 1624 (C=O), 1572 (C=C), 1492, 1 + 1403, 1324, 1261, 1146, 1065, 974, 868, 791, 649, 591, 523 cm− . MS (EI), m/z (%): 276 (8) [M] , 195 (10), 187 (8), 178 (25), 176 (12), 161 (7), 124 (8), 106 (6), 98 (71), 72 (100), 70 (9), 55 (9), 46 (12), 44 (29), 15 (42). Anal. calcd for C10H16N2O2Se (275.21): C 43.64, H 5.86, N 10.18, Se 28.69%. Found: C 43.71, H 5.63, N 10.29, Se 28.54%. (Z)-3-[(Z)-3-(diethylamino)-3-oxo-1-propenyl]selanyl-N,N-diethyl-2-propenamide (2e) was prepared by the method A (86% yield) and the method C (72% yield). After removing the solvent, residue was dissolved in CHCl3 and precipitated with cold hexane in a refrigerator ( 18 ◦C) giving product 2e which was − 1 dried in vacuum (68 mg, 86%, method A); (57 mg, 72%, method C); pale yellow solid; mp 56–57 ◦C. H 3 3 NMR (400 MHz, CDCl3): δ 1.12 (t, J = 6.8 Hz, 12H, CH3), 3.32, 3.38 (q, J = 6.8 Hz, 8H, CH2), 6.64 (d, 3 3 13 J = 9.7 Hz, 2H, =CHCO), 7.47 (d, J = 9.7 Hz, 2H, SeCH=). C NMR (100 MHz, CDCl3): δ 13.2, 14.8 1 77 (CH3), 40.6, 42.1 (CH2), 117.1 (=CCO), 147.5 (SeC=, JSe–C = 131.9 Hz), 166 (C=O). Se NMR (76 MHz, CDCl3): δ 519.4. IR (KBr): 3027, 2975, 2930, 2901, 2873, 1618 (C=O), 1566 (C=C), 1481, 1448, 1428, 1376, Molecules 2020, 25, 5940 11 of 15

1 1360, 1304, 1258, 1218, 1141, 1077, 949, 836, 791, 638, 592 cm− . Anal. calcd for C14H24N2O2Se (331.31): C 50.75, H 7.30, N 8.46, Se 23.83%. Found: C 50.56, H 7.10, N 8.31, Se 23.72%. (Z)-3-[(Z)-3-(diphenylamino)-3-oxo-1-propenyl]selanyl-N,N-diphenyl-2-propenamide (2f) was prepared by the method A (25% yield), the method B (76% yield) and the method C (66% yield). After removing the solvent, the residue was dissolved in CHCl3 and precipitated with cold hexane giving product 2f which was dried in vacuum (31 mg, 25%, method A); (96 mg, 76%, method B); (83 mg, 66%, method 1 3 C); beige powder; mp 201–203 ◦C. H NMR (400 MHz, CDCl3): δ 6.35 (d, J = 9.7 Hz, 2H, =CHCO), 7.23–7.30 (m, 12H, Ho,p), 7.32–7.40 (m, 8H, Hm), 7.48 (d, 3J = 9.7 Hz, 2H, SeCH=). 13C NMR (100 MHz, o,p m i 1 CDCl3): δ 119.6 (=CCO), 125.1–128.6 (C ), 129.2 (C ), 142.6 (C ), 149.2 (SeC=, JSe–C = 133.9 Hz), 166.3 77 (C=O). Se NMR (76 MHz, CDCl3): δ 533.3. IR (KBr): 2929, 1635 (C=O), 1552 (C=C, Ph), 1492, 1370, 1 + 1269, 1164, 1082, 1035, 782, 756, 695, 543 cm− . MS (EI), m/z (%): 523 (2) [M] , 303 (6), 222 (14), 209 (20), 208 (100), 196 (9), 180 (29), 170 (9), 169 (61), 168 (38), 167 (44), 166 (6), 77 (19). Anal. calcd for C30H24N2O2Se (523.48): C 68.83, H 4.62, N 5.35, Se 15.08%. Found: C 68.65, H 4.47, N 5.56, Se 15.04%. (Z)-3-[(Z)-3-(dicyclohexylamino)-3-oxo-1-propenyl]selanyl-N,N-dicyclohexyl-2-propenamide (2g) was prepared by the method B (refluxing for 5 h, 77% yield) and method C (stirring at room temperature for 10 h, 50% yield). After removing the solvent, the residue was recrystallized from benzene (101 mg, 77%, 1 method A); (66 mg, 50%, method C); white powder; mp 127–129 ◦C. H NMR (400 MHz, CDCl3): δ 1.03–1.38, 1.44–1.90 (m, 36H, H), 2.12–2.27 (m, 4H, H), 3.37–3.54 (m, 4H, H1), 6.70 (d, 3J = 9.7 Hz, 2H, 3 13 3,4,5 3,5 =CHCO), 7.39 (d, J = 9.7 Hz, 2H, SeCH=). C NMR (100 MHz, CDCl3): δ 24.4 (C ), 25.4 (C ), 2,6 1 1 77 29.4, 30.6, 31.0 (C ), 54.5, 56.0 (C ), 118.8 (=CCO), 145.0 (SeC=, JSe–C = 130.6 Hz), 165.4 (C=O). Se NMR (76 MHz, CDCl3): δ 508.7. IR (KBr): 2926, 2852, 2663, 1614 (C=O), 1559 (C=C), 1465, 1439, 1389, 1366, 1342, 1291, 1264, 1233, 1181, 1141, 1126, 1053, 996, 896, 779, 714, 637, 619, 595, 504. MS (EI), m/z (%): 549 (4) [M]+, 314 (20), 312 (10), 286 (6), 235 (19), 234 (89), 232 (9), 181 (8), 180 (44), 178 (6), 161 (10), 152 (47), 150 (19), 148 (7), 138 (19), 98 (69), 96 (11), 83 (49), 82 (9), 81 (18), 79 (8), 70 (12), 67 (9), 56 (21), 55 (100), 44 (10), 43 (8), 41 (42). Anal. calcd for C30H48N2O2Se (547.67): C 65.79, H 8.83, N 5.11, Se 14.42%. Found: C 65.63, H 8.82, N 4.96, Se 14.38%. (Z)-1-morpholino-3-[(Z)-3-morpholino-3-oxo-1-propenyl]selanyl-2-propen-1-one (2h) was prepared by the method A (93% yield) and the method C (73% yield). After removing the solvent, residue was dissolved in CHCl3 and precipitated with cold hexane (80 mg, 93%, method A); (63 mg, 73%, method C); white 1 3,5 3,5 powder; mp 196–197 ◦C. H NMR (400 MHz, CDCl3): δ 3.55 (br m, 4H, H ), 3.69 (br m, 12H, H , H2,6), 6.72 (d, 3J = 9.7 Hz, 2H, =CHCO), 7.59 (d, 3J = 9.7 Hz, 2H, SeCH=). 13C NMR (100.6 MHz, 3,5 2,6 1 77 CDCl3): δ 42.1, 46.0 (C ), 66.8 (C ), 116.0 (=CCO), 148.7 (SeC=, JSe–C = 132.2 Hz), 165.7 (C=O). Se NMR (76 MHz, CDCl3): δ 520.2. IR (KBr): 2957, 2910, 1616 (C=O), 1563 (C=C), 1437, 1235, 1112, 1035, 1 964, 786, 602, 572 cm− . Anal. calcd for C14H20N2O4Se (359.28): C 46.80, H 5.61, N 7.80, Se 21.98%. Found: C 46.96, H 5.39, 7.95, Se 21.60%. MS (EI), m/z (%): 549 (4) [M]+, 279 (11), 220 (27), 218 (13), 187 (14), 166 (11), 159 (15), 161 (26), 159 (14), 141 (11), 140 (100), 135 (9), 134 (9), 133 (10), 132 (7), 131 (8), 124 (6), 114 (79), 107 (7), 106 (8), 88 (17), 87 (16), 86 (99), 82 (13), 70 (77), 57 (17), 56 (55), 55 (30), 54 (9), 53 (9), 45 (8), 44 (6), 43 (6), 42 (40), 41 (10). (Z)-3-[(Z)-3-piperidino-3-oxo-1-propenyl]selanyl-1-piperidino-2-propen-1-one (2i) was prepared by the method A (89% yield) and the method C (65% yield). After removing the solvent, residue was dissolved in CHCl3 and precipitated with cold hexane (77 mg, 89%, method A); (55 mg, 65%, method 1 3,5 C); beige powder; mp 208–209 ◦C. H NMR (400 MHz, CDCl3): δ 1.53–1.61 (m, 8H, H ), 1.61–1.70 (m, 4H, H4), 3.49, 3.61 (br m, 8H, H2,6), 6.75 (d, 3J = 9.8 Hz, 2H, =CHCO), 7.49 (d, 3J = 9.8 Hz, 2H, 13 4 3,5 2,6 SeCH=). C NMR (100 MHz, CDCl3): δ 24.7 (C ), 25.6, 26.7 (C ), 42.9, 46.8 (C ), 117.0 (=CCO), 147.1 1 77 (SeC=, JSe–C = 131.0 Hz), 165.5 (C=O). Se NMR (76 MHz, CDCl3): δ 508.7. IR (KBr): ν 2931, 2853, 1 1608 (C=O), 1562 (C=C), 1442, 1347, 1243, 1225, 1128, 1012, 955, 788, 658, 631, 602, 538 cm− . MS (EI), m/z (%): 556 (4) [M]+, 218 (7), 161 (9), 138 (47), 112 (14), 84 (100), 69 (17), 56 (12), 55 (14), 42 (9), 41 (23). Molecules 2020, 25, 5940 12 of 15

Anal. calcd for C16H24N2O2Se (355.33): C 54.08, H 6.81, N 7.88, Se 22.22%. Found: C 53.81, H 6.82, N 7.91, Se 22.03%.

4. Conclusions The efficient regio- and stereoselective synthesis of a novel class of organoselenium compounds, (Z,Z)-3,30-selanediylbis(2-propenamides), based on the reaction of sodium selenide with 3-trimethylsilyl- 2-propynamides was developed. Not a single representative of 3,30-selanediylbis(2-propenamides) has yet been described in the literature. Studying their glutathione peroxidase-like properties by a model reaction showed that compounds 2g,i,d exhibit high activity. It was found that the glutathione peroxidase-like activity of the obtained products varies significantly depending on the organic moieties in the amide group. Containing two lipophilic cyclohexyl substituents in the amide group compound 2g is significantly superior to other products in activity. The second most active product is compound 2i bearing the piperidine moieties in the amide function. Containing the morpholine and diphenyl moieties compounds 2f,h also exhibit higher catalytic activity compared to diphenyl diselenide.

Supplementary Materials: The following are available online, the NMR spectra of the obtained compounds. Author Contributions: Research experiments: M.V.A.; methodology, conceptualization, and the paper preparation: V.A.P.; studying GPx-like activity: M.V.M.; data curation: S.V.A. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Russian Science Foundation, grant number 18-13-00372. Acknowledgments: The authors thank Baikal Analytical Center SB RAS for providing the instrumental equipment for structural investigations. Conflicts of Interest: The authors declare no conflict of interest.

References

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