Ketone and Vinyl Grignard Reagents: C- Versus O-Alkylation—Part

molecules

Article Regioselectivity in Reactions between Bis(2-benzothiazolyl)ketone and Vinyl GrignardGrignard Reagents: CC-- versus versus O-alkylation—Part III †

1, 1 1 1, 2 Carla Boga 1,** SilviaID , Silvia Bordoni Bordoni , Lucia1, Lucia Casarin Casarin , Gabriele1, Gabriele Micheletti Micheletti * and1,* Magda and Magda Monari Monari 2 1 1 DepartmentDepartment of of Industrial Industrial Chemistry Chemistry ‘Toso ‘Toso Montanari’ Montanari’,, Alma Alma Mater Mater Studiorum–Università Studiorum–Università didi Bologna Bologna Viale DelDel Risorgimento Risorgimento 4, 4, 40136 40136 Bologna, Bologna, Italy; Italy; silvia.bor [email protected]@unibo.it (S.B.); (S.B.); luciac [email protected]@yahoo.it (L.C.) (L.C.) 2 2 DepartmentDepartment of of Chemistry Chemistry ‘Giacomo ‘Giacomo Ciamician’, Ciamician’, Alma Alma Mater Mater Studiorum–Università Studiorum–Università didi Bologna Bologna Via Via Selmi Selmi 2, 2, 4012640126 Bologna, Bologna, Italy; Italy; [email protected] [email protected] * Correspondence:Correspondence: carla [email protected]@unibo.it (C.B.); (C.B.); [email protected] [email protected] (G.M.); (G.M.); Tel.:Tel.: +39-051-209-3616 +39-051-209-3616 (C.B.) (C.B.) † Parts Parts 1 1and and 2 2are are references references 10 10 and and 12, 12, respectively. respectively.

Received: 20 December 2017; Accepted: 12 January 2018; Published: 15 January 2018

Abstract: The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave th thee product derived from attack on the carbonylic carbon- and/or oxygen-atom. oxygen-atom. The The regioselectivity regioselectivity of of the the attack attack depends depends on on th thee kind of substituents bound to thethe vinylicvinylic carboncarbon atomsatoms andand onon theirtheir relativerelative position.position. The reaction between vinylmagnesium bromide and 2-methyl-1-propenylmagnesium2-methyl-1-propenylmagnesium bromide bromide was carried out under different experimental conditions and in the presencepresence of radical scavengers. The results indicate a plausible mechanisticmechanistic pathway pathway involving involving radical radical intermediates intermediates in thein the case case of O -alkylation,of O-alkylation, but a but polar a polarones inones the in case the of case classic of classicC-alkylation. C-alkylation. This agreesThis agrees with with our previous our previous reports reports indicating indicating a key a rolekey playedrole played by the by delocalizationthe delocalization ability ability of the of substituentsthe substituents bound bound to the to carbonylthe carbonyl group group in driving in driving the theregioselectivity regioselectivity of the of vinylmagnesiumthe vinylmagnesium bromide bromide attack attack towards towardsO-alkylation. O-alkylation. Further Further support support of this wasof this obtained was obtained by diffractometric by diffractometric analysis analysis of four of distinct four distinct bis(heteroaryl)ketones. bis(heteroaryl)ketones.

Keywords: bis(2-benzothiazolyl)ketone; Grignard Grignard reagents; reagents; vinylmagnesium bromide; C-alkylation; O-alkylation

1. Introduction Traditionally, GrignardGrignard reagents reagents [1 ][1] are are considered considered as potentialas potential anions anions able toable easily to easily react toreact hetero to heterodouble double bonds. bonds. The most The important most important reaction reaction is the nucleophilic is the nucleophilic 1,2-addition 1,2-addition to the carbonylic to the carbonylic carbon carbonatom that atom gives that access gives toaccess a plethora to a plethora of alcohol of alcohol derivatives derivatives (Scheme (Scheme1). 1).

O OMgX OH + + R''MgX H3O R R' R R" R R" R' R' R, R' = H, alkyl, aryl R'' = alkyl, aryl

Scheme 1. Classic pathway of the addition of Grig Grignardnard reagents to carbonyl compounds.

Depending on the structure of Grignard reagents, substrates or the nature of solvents, alternative Depending on the structure of Grignard reagents, substrates or the nature of solvents, alternative reactions can take place [2]. For example, benzophenone reacts with cyclohexyl or isobutyl Grignard reactions can take place [2]. For example, benzophenone reacts with cyclohexyl or isobutyl Grignard reagents forming alcohols [3] or bimolecular reduction to pinacol by using neopentylmagnesium reagents forming alcohols [3] or bimolecular reduction to pinacol by using neopentylmagnesium halides; both the classic 1,2-addition and the conjugate addition on the phenyl ring can occur with tert-butyl Grignard reagents. O-alkylation by Grignard reagents [2] to carbonylic oxygen atom is rarely Molecules 2018, 23, 171; doi:doi:10.3390/molecules2301017110.3390/molecules23010171 www.mdpi.com/journal/moleculeswww.mdpi.com/journal/molecules Molecules 2018, 23, 171 2 of 14 halides; both the classic 1,2-addition and the conjugate addition on the phenyl ring can occur with tert-butyl Grignard reagents. O-alkylation by Grignard reagents [2] to carbonylic oxygen atom is rarely Molecules 2018, 23, 171 2 of 14 observed, although it occurred to a minor extent in the case of substrates such as orthoquinones [4], orthoquinolacetatesobserved, although [5 –it7 occurred], 9,10-phenanthraquinone to a minor extent in the [8], case and of benzil substrates [9]. such In our as orthoquinones previous studies, [4], we foundorthoquinolacetates unexpected reactivity [5–7], 9,10-phe of vinylmagnesiumnanthraquinone bromide [8], and (Schemebenzil [9].2 )In and our isoprevious-propenylmagnesium studies, we bromidefound with unexpected di(1,3-benzothiazol-2-yl)ketone reactivity of vinylmagnesium (1) which bromide gave (Scheme an exclusive 2) and attack iso-propenylmagnesium to the oxygen carbonyl atombromide [10]. By reactingwith di(1,3-ben1 and 2-methyl-1-propenylmagnesiumzothiazol-2-yl)ketone (1) which gave bromide, an exclusive mixtures attack of C to-and the Ooxygen-alkylation speciescarbonyl were atom obtained [10]. By in reacting almost equimolar1 and 2-methyl-1-propenylmagnesium amount. Conversely, alkyl, bromide, allyl, mixtures or alkynyl of C- Grignard and O-alkylation species were obtained in almost equimolar amount. Conversely, alkyl, allyl, or alkynyl reagents gave exclusively the expected carbinol [11]. O-alkylation and concomitant C-alkylation [12] Grignard reagents gave exclusively the expected carbinol [11]. O-alkylation and concomitant occurred with azaheteroaryl ketones such as di(thiazol-2-yl)ketone (5) or di(1,3-benzoxazol-2-yl)ketone (8). C-alkylation [12] occurred with azaheteroaryl ketones such as di(thiazol-2-yl)ketone (5) or di(1,3- Conversely,benzoxazol-2-yl)ketone di-[N-methyl-1,3-benzimidazol-2-yl]ketone (8). Conversely, di-[N-methyl-1,3-benzimidazol-2-yl]ketone (11) gave the carbinol as unique (11) gave compound the (see Schemecarbinol2 as). unique compound (see Scheme 2).

Scheme 2. C- and O-alkylation reactions between vinylmagnesium bromide and several azaheteroaryl Scheme 2. C- and O-alkylation reactions between vinylmagnesium bromide and several ketones. azaheteroaryl ketones. More recently, we discovered that phenyl lithium and phenyl Grignard reagents also produced Morea mixture recently, of C- weand discovered O-alkylation that species; phenyl the lithium relative andratio phenyl is dependent Grignard on the reagents substituent also producedon the a mixturephenyl of C ring- and [13].O-alkylation species; the relative ratio is dependent on the substituent on the phenyl ring [13]. Based on the above considerations, to verify the influence of the geometry and the nature of substituents bound to vinyl moiety to C- versus O-alkylation selectivity, we planned to run reactions Based on the above considerations, to verify the inﬂuence of the geometry and the nature of between 1 and a series of 1-alkenylmagnesium reagents. Further, we designed an investigation of substituents bound to vinyl moiety to C- versus O-alkylation selectivity, we planned to run reactions the crystal structure of the aza-heteroaryl ketones reported in Scheme 2, in order to try to rationalize betweentheir1 differentand a series behaviour of 1-alkenylmagnesium when they react with reagents.vinylmagnesium Further, bromide. we designed an investigation of the crystal structure of the aza-heteroaryl ketones reported in Scheme2, in order to try to rationalize their different behaviour when they react with vinylmagnesium bromide.

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Results might2.Results Results direct and and and Discussionthe Discussion Discussion regioselectivity of the vinyl Grignard reagent attack towards the carbonylic oxygen- that mightForFor thedirect thesake thesake of regioselectivity simplicity,of simplicity, this ofthis part the part wasvinyl was divided Grignard divided in reagent sub-headings,in sub-headings, attack towardsexamining examining the separatelycar separatelybonylic the oxygen thefactors factors- thator might carbonForFor direct-theatom. thesake thesake of regioselectivitysimplicity,of simplicity, this this part part of was the was divided vinyl divided Grignardin sub-headings,in sub-headings, reagent examining examining attack separately towards separately the thefactors carbonylic factors orthat carbonthat FormightFor Formight -theatom. the direct thesake sake directsake of ofthe simplicity, ofsimplicity, the regioselectisimplicity, regioselecti this this vitythis part partvity partof was wastheof was divided thedividedvinyl divided vinyl Grignardin in Grignardsub-headings, insub-headings, sub-headings, reagent reagent examiningexaminingattack examining attack towards separatelytowards separately separately the the carbonylicthe the carbonylic thefactors factors factors oxygen-thatthat ormight carbon-atom.might direct direct the the regioselecti regioselectivityvity of ofthe the vinyl vinyl Grignard Grignard reagent reagent attack attack towards towards the thecarbonylic carbonylic oxygen-thatthatthatoxygen- mightmight might or carbon-atom. ordirectdirect carbon-atom.direct thethe the regioselectiregioselecti regioselecti vityvityvity ofof ofthethe the vinylvinyl vinyl GrignardGrignard Grignard reagentreagent reagent attackattack attack towardstowards towards thethe the carbonyliccarbonylic carbonylic 2.1oxygen-. Influenceoxygen- or carbon-atom.ofor thecarbon-atom. Stereochemistry of Methyl Substituents on Vinyl Moiety 2.1.2.1 Inﬂuenceoxygen-oxygen-. Influenceoxygen- or or of carbon-atom.of or thecarbon-atom. thecarbon-atom. Stereochemistry Stereochemistry of Methyl Methyl Substituents Substituents on onVinyl Vinyl Moiety Moiety 2.1.2.1. TheInfluence Influence reaction of the of between theStereochemistry Stereochemistry di(1,3-benzothiazol of Methyl of Methyl Substituents-2 -Substituentsyl)ketone on (1 )Vinylon and Vinyl Moietyvinyl Moiety m agnesium reagents bearing 2.1.2.1. TheInfluence Influence reaction of the of between theStereochemistry Stereochemistry di(1,3-benzothiazol of Methyl of Methyl Substituents-2 -Substituentsyl)ketone on (1 )Vinylon and Vinyl Moietyvinyl Moiety m agnesium reagents bearing different2.1.The2.1.2.1. Influence Influence reaction Influence substituents of of betweenthe ofthe theStereochemistry Stereochemistry onStereochemistry di(1,3-benzothiazol-2-yl)ketonethe vinyl of of moietyMethyl ofMethyl Methyl Substituents(Scheme Substituents Substituents 3) on wason Vinylon Vinyl ( 1carriedVinyl) andMoiety Moiety Moiety vinyl out at magnesium −70 °C by adding reagents the bearing differentThe Thesubstituents reaction reaction between betweenon the di(1,3 vinyldi(1,3-benzothiazol-2-yl)ketone -benzothiazol-2-yl)ketone moiety (Scheme 3) was (1) ( carriedand1) and vinyl vinyl out magnesium at magnesium −70 °C reagentsby reagents adding bearing thebearing differentGrignardThe substituentsThe reagent reaction reaction to between a onsolutionbetween the di(1,3 vinyl ofdi(1,3 ketone-benzothiazol-2-yl)ketone-benzothiazol-2-yl)ketone moiety in anhydrous (Scheme tetrahydrofuran3) was(1) (and1) carried and vinyl vinyl. Grignard magnesium out magnesium at reagents−70 reagents ◦reagentsC 2a by– cbearing were adding bearing the GrignarddifferentdifferentTheTheThe reagent reactionsubstituentsreaction reactionsubstituents to between betweena solutionbetween on on the di(1,3di(1,3 ofthe di(1,3vinyl ketone-benzothiazol-2-yl)ketone -benzothiazol-2-yl)ketonevinyl-benzothiazol-2-yl)ketone mo inmoiety anhydrousiety (Scheme (Scheme tetrahydrofuran 3) was3) (1( 1) was )( and1andcarried) and carried vinylvinyl vinyl. Grignardout magnesium magnesiumout magnesiumat −at70 reagents− 70°C reagents reagents°Cby reagents by adding2a – addingc bearing bearingwere bearing the the Grignardcommerciallydifferentdifferent reagent substituents substituents available to a solution on whereas onthe the vinyl of vinyl2 ketoned –moh moietywereiety in (Scheme anhydroussynthesized (Scheme 3) was3) tetrahydrofuran. fromwas carried carried the outsuitable out at −at 70 Grignardvinylbromide− 70°C °Cby byadding reagentsadding and the the 2a –c commerciallyGrignarddifferentdifferentdifferentGrignard substituentsreagentsubstituents substituentsreagent available to a to solution onaon whereas solution on thethe the vinylofvinyl ketone vinyl2ofd –ketone mohmo mo ietywereiniety anhydrous ietyin (Scheme (Schemeanhydroussynthesized (Scheme 3)tetrahydrofuran.3) was3)tetrahydrofuran.was fromwas carriedcarried carried the outsuitable outGrignard out Grignardatat −at− 7070 vinylbromide− reagents70 °C°C reagents °C byby by adding adding2a adding– 2a c andwere– c the thewere the magnesiumGrignardGrignard reagent turning reagent tos and ato solution a titrated solution of prior ketoneof ketone the inuse. anhydrousin After anhydrous 15 min tetrahydrofuran. tetrahydrofuran.from the addition Grignard Grignard of the reagentsGrignard reagents 2a reagent– 2ac were–c were, weremagnesiumcommerciallyGrignardGrignard commerciallyGrignardcommercially reagent reagentturning reagent available availabletoavailables to and a toa solution solution a titrated solutionwhereas whereas of priorof ketone ofketone2d ketone the–2dh2d in–use. in–wereh h anhydrous inanhydrous wereAfterwere anhydrous synthesized 15synthesized synthesized min tetrahydrofuran. tetrahydrofuran. tetrahydrofuran.from from thefrom from additionthe the Grignard thesuitableGrignard Grignard suitableof suitable the reagentsGrignardvinylbromide reagents reagentsvinylbromide vinylbromide 2a reagent2a– 2a–cc were –wereandc were, and and thecommercially reactioncommercially was availablequenched available whereaswith whereas water 2d and–2dh –, werehafter were fastsynthesized synthesizedwork-up (seefrom fromexperimental) the the suitable suitable the vinylbromide react vinylbromideion mixture and and magnesiumthemagnesiumcommerciallycommercially reactioncommerciallymagnesium turnings was turnings availablequenchedturnings1available available and and titrated andwhereaswith whereas titratedwhereas titrated water prior 2dprior2d and – the2dprior–hh –, the wereh use.afterwere the wereuse. Afterfast synthesizeduse.synthesized After synthesizedwork 15After min-15up 15min (see from from min fromfromexperimental) thethefromthe the addition suitable suitablethe additionsuitable addition the ofvinylbromide vinylbromidereact theofvinylbromide theofion Grignard the Grignardmixture Grignard andand reagent, and wasmagnesium magnesiumanalysed byturnings turningsH-NMR and andspectroscopy titrated titrated prior priorand the relative the use. use. Aftermolar After 15 C /O15min- alkylationmin from from the ratio the addition wasaddition inferred of ofthe the fromGrignard Grignard the thewas reactionreagent,magnesiummagnesium magnesiumreagent,analysed the was the reaction byturningsturnings quenched reactionturnings1H-NMR was andand was andspectroscopy withquenched titrated titratedquenched titrated water priorwithprior and,priorwithand water thethe relative afterwaterthe use. use.and, use. fast and, Aftermolar Afterafter After work-up after 15 fastC15 / O15 minfast minwork-up- alkylationmin (seework-up fromfrom from experimental) (see thethe ratio (seethe experimental) additionaddition experimental)wasaddition inferred of theof theofthe reactionthe the from Grignardthe Grignardreaction Grignard reactionthe mixture spectrumreagent,reagent,. theThe the reaction procedure reaction was haswas quenched been quenched developed with with water sincewater and, it and, is after known after fast fast thatwork-up work-up the O -(seealk (seeylation experimental) experimental) species thecan the reaction easily reaction wasspectrummixturereagent, analysedreagent,reagent,mixture . wasthe Thethe bywasthe reaction reactionanalysedprocedure1 reaction H-NMRanalysed was was by haswas quenched spectroscopyby1quenchedH-NMR been quenched1H-NMR developed spectroscopywith with spectroscopywith water andwater sincewater relative and, and, andit and, is andafter afterknownrelative after molar relative fast fast fast thatwork-up molarwork-upC work-up/ molartheO -alkylationC O/ O -(see Calk(see-alkylation/ O(seeylation experimental)-alkylation experimental) experimental) ratio species ratio ratio was was the canthe was inferredthe reaction inferredeasilyreaction reactioninferred from undergomixturemixture airwas- oxidationwas analysed analysed of by benzy by1H-NMR 1H-NMRlic CH spectroscopy group spectroscopy forming and and arelative hemiketal relative molar molar which C/O C -alkylationdecompose/O-alkylation ratios toratio 1was and was inferred vinyl inferred undergofrommixturemixturemixturefrom the air wasthespectrum.was- oxidation wasspectrum. analysed analysed analysed The of Theby by procedurebenzy by1 H-NMR1procedureH-NMR 1H-NMRlic CH hasspectroscopy spectroscopy group has spectroscopybeen been developedforming developed and and and arelative relativehemiketalsince relative since it molar molaris it molarknown whichis knownC C/O /OC -alkylationthatdecompose/-alkylationO -alkylationthat the theO-alkylation ratio Osratio -alkylation toratio 1was wasand was inferred speciesinferredvinyl inferredspecies thealco spectrum.fromhfromol the that thespectrum. The immediatelyspectrum. procedure The The procedure collapse procedure has been tohas thehas been developed aldehydebeen developed developed sincetautomeric since itsince isit knownis formit known is known. A that similarthat that the the thebehaviourOO-alkylation-alkylation O-alkylation was species speciesalso species can alcocanfromfromhfromcan oleasily the the thateasily thespectrum. spectrum.undergo immediatelyspectrum. undergo The air-oxidationThe Theair-oxidation procedure procedurecollapse procedure of tohas has benzylic of thehas been benzylicbeen aldehydebeen developed developedCH developed CH group tautomeric group since sinceforming since forming it it is formisit known aisknown hemiketal knowna. Ahemiketal similarthat that that the whichthe thebehaviourwhichO O-alkylation -alkylation Odecomposes-alkylation decomposes was species species also speciesto 1to 1 easilyobservedcan undergocan easily easily for undergo bis(2air-oxidation undergo-benzothiazolyl)methane air-oxidation air-oxidation of benzylic of benzylicof benzylic CH that CH group spontaneously CH group group forming forming forming undergoes a hemiketala hemiketal a hemiketal oxidation which which which to decomposesdecomposes 1 decomposes [14]. Every to to 1to 1 1and observedandcancancanand easily vinyleasily easily vinyl for undergoalcohol undergo bis(2 undergoalcohol-benzothiazolyl)methane that air-oxidation air-oxidation that air-oxidationimmediately immediately of of benzylic ofcollapsebenzylic benzyliccollapse that CH to CH spontaneously CHthe togroup group the aldehydegroup aldehyde forming forming forming undergoestautomeric a tautomerica hemiketal hemiketala hemiketal oxidation form. form.which which whichA similartoA decomposes decomposes similar1 decomposes [1 4]behaviour. Everybehaviour to to 1 to1 1 vinylreactionand alcoholand vinyl betweenvinyl thatalcohol alcoholimmediately 1 andthat that theimmediately immediatelyselected collapse vinyl collapse collapse toGrignard the to aldehyde theto wasthe aldehyde aldehyde repeated tautomeric tautomeric tautomericthree times form. form. form.and A A similarthe similarA rasimilartio behaviourreported behaviour was reactionwasandandandwas alsovinyl vinyl betweenalsovinyl observed alcohol alcohol observed alcohol 1 andthat forthat thatfor bis(2-benzothiazolyl)metha theimmediately immediately bis(2-benzothiazolyl)metha immediatelyselected vinyl collapse collapse collapse Grignard to to the netothe wasthe nethataldehyde aldehyde that aldehyderepeatedspontaneously spontaneously tautomeric tautomeric tautomericthree undergoestimes form. undergoesform. form.and A A the oxidation similar Asimilar oxidationrasimilartio behaviourreported behaviourto behaviour 1to [14]. 1 [14]. alsoinwas observedTablewas also 1also isobserved the forobserved average bis(2-benzothiazolyl)methane for for bis(2-benzothiazolyl)methaof thebis(2-benzothiazolyl)metha three measurements. neC thatompounds nethat that spontaneouslyspontaneously spontaneously 4a–g resulted undergoes undergoes undergoes to be stable oxidation oxidation oxidation enough to 1toto [14]. be to1 [14].1 [14 ]. inEverywas wasTablewasEvery also also reaction 1also is observed reactionobserved the observed average between betweenfor for for bis(2-benzothiazolyl)metha ofbis(2-benzothiazolyl)metha the1bis(2-benzothiazolyl)metha and 1three and the measurements.the selected selected vinyl vinyl neCne Grignardompounds nethat that Grignard that spontaneously spontaneously spontaneously was 4 awas– grepeated resulted repeated undergoes undergoes undergoes threeto bethree stabletimes oxidation oxidation times oxidation enoughand and tothe to 1to tothe 1 ratio[14]. be[14].1 ratio [14]. EverypurifiedEvery reactionEvery reaction by reaction columnbetween between between chromatography1 1and and 1 and the the theselected selected selected on silicavinyl vinyl Grignard gel Grignard Grignard and was stored was was repeated repeatedrepeated for at three least three three times two times times andmonths and the and the ratio theat ratio ratio purifiedreportedEveryEveryEveryreported reaction reaction by inreaction Tablein column Tablebetween between 1between is 1 chromatography theis 1 the1average and and1 averageand the the ofthe selected selected theof selected on thethree silicathreevinyl vinyl measurements.vinyl measurements.Grignard gelGrignard Grignard and was storedwas Compounds was Compoundsrepeated repeated repeated for at three 4athree least – three4ag –resultedtimes gtimes two resultedtimes and andmonths to and bethe tothe thebestable ratio ratio atstable ratio −18reported °Creported. Howev in Tableiner Table, it decomposes1 is 1 theis theaverage average as above of theof indicated the three three measurements. within measurements. 2 days whenCompounds Compounds dissolved 4a –in4ag deute–resultedg resultedrochloroform to beto bestable stable reported−18enoughreportedreported °Creportedenough. H in owevto in Table in be to Table inTable erpurifiedbe Table,1 it purified isdecomposes1 1 is theis1 the byisthe average thebycolumnaverage average columnaverage as above chromatographyof ofof chromatographythe of the indicated thethree three three three measurements. measurements. within measurements.measurements. on onsilica 2 dayssilica gel whenCompounds gelCompoundsand Compounds and storeddissolved Compounds stored for4a 4a –forin4a–atgg deute–resulted leastresultedatg resultedleast4a rochloroformtwo– gtwoto tomonthsresulted be tobe months bestable stable stableat to at be solventenoughenough. to beto bepurified purified by bycolumn column chromatography chromatography on onsilica silica gel geland and stored stored for forat leastat least two two months months at at stablesolvent−enoughenough18 enoughenough− °C.18. °C.However, to to However, be tobe to bepurified purified be purifiedit puriﬁeddecomposes it decomposesby by bycolumn column bycolumn as column chromatography aboveaschromatography chromatographyabove indicated chromatography indicated within on on within onsilica silica 2silica days gel 2gel days on gel and whenand silica andwhen stored stored dissolved stored geldissolved for for and forat atin least at storeddeuterochloroform leastin least deuterochloroform two two two for months months atmonths least at at at two −18− °C.18 °C.However, However,◦ it decomposes it decomposes as aboveas above indicated indicated within within 2 days 2 days when when dissolved dissolved in deuterochloroform in deuterochloroform monthssolvent.−−1818−solvent. °C.18 at°C. °C.However,− However,18 However, C. it However,it decomposes decomposesit decomposes it as decomposesas above asabove above indicated indicated indicated as abovewithin within within 2 indicated2 days days 2 days when when when withindissolved dissolved dissolved 2 in daysin deuterochloroform indeuterochloroform deuterochloroform when dissolved in solvent.solvent. deuterochloroformsolvent.solvent.solvent. solvent.

Scheme 3. Reactions between 1 and different vinylmagnesium bromides.

Scheme 3. Reactions between 1 and different vinylmagnesium bromides. SchemeScheme 3. Reactions 3. Reactions between between 1 and 1 and different different vinylm vinylmagnesiumagnesium bromides. bromides. Results obtainedScheme areScheme gathered 3. Reactions 3. Reactions in Table between between 1. For 1 andthe 1 and sakedifferent different of comparison, vinylm vinylmagnesiumagnesium previous bromides. bromides. data [10] obtained by reactingResults 1 with obtained vinylmagnesiumSchemeScheme areScheme gathered 3. 3. Reactions Reactions3. Reactions bromides in Table between between between 1 .2a For –1 c1 and theareand 1 and sakedifferent alsodifferent different ofreported. comparison, vinylm vinylm vinylm agnesiumagnesiumagnesium previous bromides. bromides. bromides. data [10] obtained by reactingResults 1Results with obtained vinylmagnesiumScheme obtained are 3. aregatheredReactions gathered bromides in between Tablein Table 2a 1.–1 cFor 1. andare For the also different thesake reported. sake of vinylmagnesium comparison,of comparison, previous previous bromides. data data [10] [10] obtained obtained ResultsResults obtained obtained are aregathered gathered in Tablein Table 1. For 1. For the the sake sake of comparison,of comparison, previous previous data data [10] [10] obtained obtained by byreactingResults ResultsreactingResults 1 obtained obtainedwith 1 obtained with vinylmagnesium arevinylmagnesium Tableare aregathered gathered 1.gathered Reaction in in bromides Table in Tableof bromides Table1 with 1. 1. For 1.2aFor vinyl For– 2athe cthe are –Grignardthe csake sakeare also sake alsoof ofreported. comparison, reagentsofcomparison, reported. comparison, 2a– h previous. previousa. previous data data data [10] [10] [10] obtained obtained obtained by byreacting reacting 1 with 1 with vinylmagnesium vinylmagnesium bromides bromides 2a– 2ac are–c are also also reported. reported. a byby byreacting reacting reacting 1 1 with with1 with vinylmagnesium vinylmagnesium TablevinylmagnesiumTable 1.1. Reaction bromides bromides of bromides of 1 1withwith 2a vinyl2a– vinyl2a–cc are –Grignardarec are Grignardalso also also reported. reported. reagents reported. reagents 2a – h2a. a.– h. Entry GrignardTableTable Reagent 1. Reaction 1. Reaction C of-Alkylation 1 of with 1 with vinyl vinylProduct Grignard Grignard (%) reagentsO reagents-Alkylation 2a– 2ah. –a .hProduct . a. (%) Entry GrignardTableTable Reagent 1. Reaction 1. Reaction C of-Alkylation 1 of with 1 with vinyl vinylProduct Grignard Grignard (%) reagentsO reagents-Alkylation 2a– 2ah. –a .hProduct . a. (%) Entry GrignardTableTableTable Reagent 1. 1. Reaction Reaction1. Reaction ofC of-Alkylation 1 of1 with with 1 with vinyl vinyl vinyl Product Grignard Grignard Grignard (%) reagents reagents reagentsO-Alkylation 2a 2a– –2ahh. –.a .ha . . a. Product (%) EntryEntry GrignardGrignard Reagent Reagent C-AlkylationC-Alkylation Product Product (%) (%)O-AlkylationO-Alkylation Product Product (%) (%) Entry1 Entry GrignardGrignard Reagent Reagent C-AlkylationC-Alkylationb,c Productd Product (%) (%)O-AlkylationO-Alkylationb Productc Product (%) (%) EntryEntryEntry GrignardGrignardGrignard Reagent Reagent Reagent CC-Alkylation-AlkylationC-Alkylation3a n.d. Product Product Product (%) (%) (%)OO-Alkylation-AlkylationO-Alkylation4a > 97 Product Product Product (%) (%) (%) 11 1 1 b,c d b c 1 1 33aa3a b,cb,c 3an.d. n.d. b,c n.d. d d 4a4a >b4a4a >97 b97b > c97 c b,c b,c d d b b c c 11 1 3a 3a n.d. n.d. 4a 4a > 97 > 97 3a3a b,c 3ab,c n.d. n.d.b,c n.d. d d d 4a4a b 4a b> > 97b 97 > c 97 c c Molecules 2018, 23, 171 4 of 15 2 2 Molecules 2018, 232 2, 171 2 (2b)(2b) 3b b,c3b n.d. b,c n.d. d d 4b b4b > 97b > c97 c 4 of 15 2 b,cb,cb,c b,cd d d b b bb c c c 2 2 MgBrMgBr(2b)(2b) 33bb3b 3b n.d. n.d. n.d. 4b4b 4b>4b >97 97 > 97 2 2 b,cb,c b,c dd d b b b c c c (2b)(2b) 3b3bb,c 3b n.d. n.d. dn.d. 4b4bb 4b > > 97 97 c> 97 MgBrMgBr (2b) 3b n.d. 4b > 97 MgBrMgBrMgBr

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4e 30 c,e 3e 70 c,e 4e 30 c,e 6 6 3e 70 c,e

3f 53f 5 4f 954f c95 c 6 6 7 7

c 3f 5 4f 95 c 3f 5 4f 95 3g 903g c90 c 4g 104g c10 c

7 7 8 8

f f d d 3h 53h 5 4h n.d.4h cn.d. c 4g 10 c 3g 90 c 4g 10 a Reactionsa Reactions were were carried carried out outin tetrahydrofuranein tetrahydrofurane3g (THF)90 (THF) at − at70 − °C70 with°C with an equimolaran equimolar reactants reactants ratio ratio withinwithin 15 min;15 min; b Data b Data from from reference reference 10; 10;c Relative c Relative ratio ratio calculated calculated from from 1H-NMR 1H-NMR of crudeof crude reaction reaction mixture;mixture; d n.d. d n.d. means means not notdetected; detected; e In e thisIn this case case (entry (entry 5), due5), due to the to thereaction reaction with with 2f, produced2f, produced by by 8 isomerizationisomerization8 during during the theGrignard Grignard preparation, preparation, crude crude reaction reaction mixture mixture contains contains carbinol carbinol 3f and3f and f f vinylvinyl ether ether 4f (in4f (inabout about 40% 40% relative relative molar molar ratio ratio with with respect respect to theto themixture mixture of 3eof and3e and 4e ); 4e In); thisIn this

case,case, the thecrude crude reaction reaction mixture mixture contains contains mostly mostly3 theh 5 thefalcohol alcohol 3g, 3gcoming, coming from4 hfrom n.d.2g, 2gind ,turn in turn formed formed by by 3h 5 f 4h n.d. d a isomerizationReactionsisomerization were during carried during Grignard out Grignard in tetrahydrofuranepreparation. preparation. (THF) at −70 °C with an equimolar reactants ratio a Reactions were carried out in tetrahydrofurane (THF) at −70 °C with an equimolar reactants ratio within 15 min; b Data from reference 10; c Relative ratio calculated from 1H-NMR of crude reaction within 15 min; b Data from reference 10; c Relative ratio calculated from 1H-NMR of crude reaction 2.1.1.2.1.1.mixture Methyl Methyl; d Substituentsn.d. Substituents means not in detected βin-Position β-Position; e In this case (entry 5), due to the reaction with 2f, produced by mixture; d n.d. means not detected; e In this case (entry 5), due to the reaction with 2f, produced by isomerization during the Grignard preparation, crude reaction mixture contains carbinol 3f and vinyl isomerizationTheThe regioselectivity regioselectivity during the of Grignard theof thereaction reaction preparation, between between crude 1 and 1 reaction and vinylmagnesium vinylmagnesium mixture contains reagents reagentscarbinol bearing 3fbearing and onevinyl one methyl methyl ether 4f (in about 40% relative molar ratio with respect to the mixture of 3e and 4e); f In this case, the groupgroupether in 4f βin-position (in β-position about with40% with relativerespect respect molar to theto ratio theC–Mg C–Mg with bond respect bond result resultto theed stronglyedmixture strongly of influenced 3e influenced and 4e )by; f In bythe this thestereogeometry case stereogeometry, the crude reaction mixture contains mostly the alcohol 3g, coming from 2g, in turn formed by andandcrude by bythe reaction the electronic electronic mixture feature feature contains of theof the mostlysubstituent substituent the alcohol which which 3bothg, bothcoming affect affect the from the alkene 2g alkene, in stability. turn stability. formed In theIn bythe case case of of isomerization during Grignard preparation. thethe isomerizationGrignard Grignard Z-isomer duringZ-isomer Grignard(compound (compound preparation 2e, 2eTable, Table. 1, entry1, entry 5) the5) the carbinol carbinol 3e and3e and the the vinyl vinyl ether ether 4e were4e were 2.1.formed1.formed Methyl in 70/30in Substituents 70/30 relative relative molarin βmolar-Position ratio ratio whereas whereas almost almost complete complete O-alkylation O-alkylation was was observed observed with with the the 2.1.E-isomer1.E Methyl-isomer (compound Substituents(compound 2f, 2fTablein, βTable-Position 1, entry 1, entry 6). 6). The regioselectivity of the reaction between 1 and vinylmagnesium reagents bearing one methyl TheWhen Whenregioselectivity the theβ-dimethyl β-dimethyl of thesubstituted substitutedreaction Grignardbetween Grignard 1reagent and reagent vinylmagnesium 2c was2c was used used (Table reagents (Table 1, entry1, bearing entry 3) a 3)one 57/43 a 57/43methyl molar molar group in β-position with respect to the C–Mg bond resulted strongly influenced by the stereogeometry groupratioratio ofin the βof-position theC/O C-alkylated/O -alkylatedwith respect products products to the was Cwas obtained–Mg obtained bond thus resulted thus suggesting suggesting strong thely theinfluenceprevalence prevalenced by of the of theester steric eeo stericgeometry hindrance hindrance and by the electronic feature of the substituent which both affect the alkene stability. In the case of andeffect effectby (comparethe (compare electronic entries entries feature 3, 5,3, andof5, andthe 6 in substituent6 Tablein Table 1). 1). Thiswhich This was bothwas further furtheraffect confirmed the confirmed alkene by stabilitybythe theexperiment experiment. In the casewith with of 2g 2g the Grignard Z-isomer (compound 2e, Table 1, entry 5) the carbinol 3e and the vinyl ether 4e were thewhich Grignardwhich gave gave Z90:10- isomer90:10 C-alkylation: C(compound-alkylation:O-alkylation O2e-alkylation, Table ratio1, entryratio indicating indicating5) the carbinol that that the 3e theeffect and effect thedue duevinyl to theto ether theβ-substituent β4e-substituent were formed in 70/30 relative molar ratio whereas almost complete O-alkylation was observed with the E- formedprevailsprevails in over70/30 over the re l theaαtive-substituent α -substituentmolar ratio (compare whereas(compare entry almost entry 7 withcomplete7 with entry entry O 2-alkylation in2 Tablein Table 1).was 1).To observed Tofurther further withconfirm confirm the Ethe- the isomer (compound 2f, Table 1, entry 6). isomerinfluenceinfluence (compound of theof thestability 2f stability, Table of 1, theof entry thealkene 6).alkene (mainly (mainly due due to theto thesubstituent substituent electronic electronic effect) effect) and and of hisof his When the β-dimethyl substituted Grignard reagent 2c was used (Table 1, entry 3) a 57/43 molar ratio geometrygeometryWhen inthe driving in β- drivingdimethyl the theregioselectivity substituted regioselectivity Grignard of the of theattack reagent attack to 2cthe to was thecarbonyl usedcarbonyl ( Tablegroup group 1, of entry 1 of we 1 3 weattempted) a 57/43attempted molar to prepare to ratio prepare of the C/O-alkylated products was obtained thus suggesting the prevalence of the e steric hindrance effect ofcompound thecompound C/O-alkylated 2h 2hfrom fromproducts which which waswe we expectedobtained expected thusto recoverto suggesting recover almost almost the exclusivelyprevalence exclusively ofthe the theO e-alkylation stericO-alkylation hindrance product product effect 4h . 4h. (compare entries 3, 5, and 6 in Table 1). This was further confirmed by the experiment with 2g which gave (compareUnfortunately,Unfortunately, entries presence3, 5,presence and 6of in the ofTable thelatter 1)latter. Thiswas was wasnot not detectedfurther detected confirmed but but the thetwo by two thecarbinols carbinolsexperiment 3g and3g with and 3h 2g3hin which 95:5in 95:5 relative gave relative 90:10 C-alkylation:O-alkylation ratio indicating that the effect due to the β-substituent prevails over the α- 90:10molarmolar C- ratioalkylatio ratio were weren: Orecovered-alkylation recovered ascribed ratio ascribed indicating to the to therelevant thatrelevant the isomerization effect isomerization due to occurred the occurred β-substituent during during the prevails thepreparation preparation over the of αthe of- the substituent (compare entry 7 with entry 2 in Table 1). To further confirm the influence of the stability of substitueorganometallicorganometallicnt (compare reagent reagent entry [15]. 7[15]. with entry 2 in Table 1). To further confirm the influence of the stability of the alkene (mainly due to the substituent electronic effect) and of his geometry in driving the

regioselectiv2.1.2.2.1.2. Effect Effectity of of theof the the Substituent attack Substituent to the in carbonyl αin-Position α-Position group of 1 we attempted to prepare compound 2h from which

ConcerningConcerning the the influence influence of theof the substituent substituent in αin-position α-position with with respect respect to Mgto Mg atom atom of vinylof vinyl GrignardGrignard reagents reagents which which rules rules the the regi regioselectivityoselectivity of theof the attack attack towards towards C- Cor- orO-alkylation, O-alkylation, we we comparedcompared the the results results reported reported in entriesin entries 1, 2,1, and2, and 4 of 4 Tableof Table 1. Vinylmagnesium1. Vinylmagnesium bromide bromide (2a )( 2aand) and 1-propenylmagnesium1-propenylmagnesium bromide bromide (2b ()2b reacted) reacted with with 1 giving1 giving exclusively exclusively O -alkylation,O-alkylation, whereas whereas

MoleculesMolecules 2018 2018, 23,, 17123, 171 4 of4 15 of 15 MoleculesMolecules 2018 2018, 23,, 17123, 171 4 of 415 of 15 MoleculesMolecules 2018 2018, 23,, 17123, 171 4 of 415 of 15

Molecules 2018, 23, 171 4 of 15 3 3 3c 573c b57,c b,c 4c b4 43c b c43 c 3 b,c b c 3 3c 57 b,c,c 4c 43b c 3 3 3c 57 4c 43 3c 573c b57,c b,c 4c b4 43c b c43 c

3 3c 57 b,c 4c b 43 c Molecules 2018, 23, 1714 4 4 of 14 Molecules 2018, 23, 171 3d 703d c70 c 4d 304d c30 c 4 of 14 Molecules 2018, 23, 4171 c c 4 of 14 4 3d 70 c 4d 30 c Molecules 2018, 234, 171 4 3d 70 4d 30 4 of 14 4 3d 703d c70 c 4d 304d c30 c Molecules 2018, 23, 171 3d 70 c 4d 30 c 4 of 14 4 Table 1. Cont. 3d 70 c 4d 30 c 4 3d 70 c 4d 30 c 4 5 5 c c Entry4 Grignard Reagent C-Alkylation3d 70 Product (%) O-Alkylation4d 30 Product (%) 5 c c 4 5 3d 70 4d 30 3d 70 c 4d4e 30340e c c 3,e0 c,e 5 5 c,e c,e 3e 730e 70 c,e 4e 30 c,e c,e 4e 30 3e 70 c,e 5 55 5 3e 70 4e 340e c3,e 0 c,e 5 c,e c,e 3e 730ec,e c,e 7 0 c,e c,e 5 3e 70 4e 304e c,e 3e 70c,e 4c,eec 303,e0 5 3e 70 c,e 4e4 e30 3 0 3e 730ec,e c 7,e 0 c,e 3e 70 4e 30 6 6 3e 70 c,e 4e 30 c,e 6 6 6 6 6 66 6 3f 53 f 5 4f 954f c95 c c 66 6 3f 5 4f 95 c 3f 5 4f 95 c 3f 5 3f 5 4f 95 4c f 95 c 3f 5 4fc c95 c 3f3 f5 5 3 f 5 4f4 f95 954 f 95 3f 5 4f 95 c 3f 53 f 5 4f 954f c 95 c 77 7 7 7 7 7 7 77 7 3g 90 c 4g 10 c c c c c 3g 90 c c 4g4 g10 104 g 10 3g 903gc 90 c 3g 90 c 4g 10 c c 7 7 3g 90 c 4g 104g 10 c 3g3g 90 90 c c 4g 104 gc 10 3g 90 c c c c 4g 104g 10 8 3g 903g 90 c c 8 3gc 90 c 4g 104g 10 88 8 3g 90 8 8 3h 5 f 4h n.d. d 8 8 3h 5 f 4h n.d. d a Reactions8 were8 carried out in tetrahydrofurane 3h(THF) 5 f at −70 °C with an equimolar4h n.d. d reactants ratio a f f f dd d Reactions wereb carried out in tetrahydrofurane c (THF)3h3h 5 5 3 hf at 5 − 70 °C with an1 equimolar4h4h n.d. n.d.4h n.d. reactants d ratio withina 15 min; Data from reference 10; Relative3h ratio5 calculated from H-NMR4h n.d.of crude reaction Reactions were8 carried out in tetrahydrofurane (THF)f at −70 °C with an equimolard reactants ratio a a a 8 b c 3h 5 f 1 4h n.d. d a within Reactions Reactions Reactions 15 dmin; were were wereData carried carried carriedfrom out out reference inout in tetrahydrofurane tetrahydrofuranein etetrahydrofurane 10; Relative (THF) (THF)ratio 3(THF)h calculatedat 5◦a t − −70a7t0 °C− °7C0 with fromwith°C with an anH-NMR equimolar equimolaran equimolar4h of n.d. crudereactants r eactants r eactants reaction ratio ratio ratio Reactionsmixture; were n.d. carried meansb out not in detected; tetrahydrofurane In thisc (THF)case (entry at −70f 5),Cf due with to anthe equimolar reaction1 with reactants 2fd , producedd ratio within by 15 min; withina 15d min; Data from referencee 10; Relative3 hratio 53 h 5calculated from H-NMR4h n.d.4h n.d.of crude reaction b mixture; Reactionsa n.d. were meansb b carriedb notc detected;out in tetrahydrofurane In thisc c casec (entry (THF)1 5), a duet −70 to ° Cthe with reaction an1 1 equimolar 1with 2f, producedreactantsd ratioby Dataisomerizationwithinwithin fromwithin Reactions 15 15 referenced min; min15 minduring ; were Data Data 10;; Data carriedfromthe Relativefrom Grignardfrom reference referenceout ratioreference in etetrahydrofuranepreparation, calculated 10;10 ; 10Relative Relative; Relative from crude ratio ratio (THF)H-NMR ratio reactioncalculated calculated acalculatedt of− 7 0mixture crude °from Cfrom with from reaction H-NMRcontainsH an -NMRH equimolar-NMR mixture; of ofcarbinol crude crudeof crudereactants n.d.reaction reaction3f andreaction means ratio not mixture;a a n.d. meansb not detected; In thisc case (entry 5),f due to the reaction1 with 2f, producedd by isomerizationwithin Reactions Reactionse 15dd min were dduring; were Datacarriedb carriedthe from Grignardout referenceout in tetrahydrofuranein etetrahydrofuranepreparation,e 10e ; Relativec crude 3(THF)h ratio 5 3(THF) hf reaction5 a calculatedt − a7t0 − ° 7Cmixture0 with° Cfrom with an containsH equimolaran4-hNMR1 equimolarn.d.4h n.d. carbinolofd cruder eactants reactants 3freaction and ratio ratio detected;vinylmixture;mixturemixturewithin etherIn ; thisn.d. n.d.154f; (in min casen.d.means means about; means (entry Data not not 40% detected; 5),notfromdetected relative duedetected reference to ; theInmolar In; this reactionthisIn 10 ratiothiscase; case Relative case (entrywith (entry (entry respect2f 5),ratio 5),, produceddue due5), calculated to dueto to the the theto bymixture reaction thereaction isomerizationfrom reaction of Hwith with -3eNMR with and2f 2f, during ,produced of 4e2fproduced crude,); produced f In the thisreaction by Grignardby by isomerizationd duringb b the Grignard epreparation,c c crude reaction mixture 1contains1 carbinol 3f and preparation,vinylamixturewithinwithina etherReactions 15 crude; 4fmin15n.d. d (inmin reaction; weremeans aboutData; Datacarried mixturenotfrom40% fromdetected relative referenceout containsreference in ;tetrahydrofurane molar In10carbinol ethis; 10 ratioRelative; case Relative 3fwith (entryand ratio (THF)respect vinylratio 5), calculated due a ethercalculated tto − 7tothe04f the° Cmixturefrom(in withreaction from about H an - ofNMRH 40% equimolar with3e-NMR and relativeof 2f crude ,of 4eproduced );crudereactants molarf Inreaction thisreaction ratio by ratio with isomerizationisomerization Reactionsisomerizationmixture ;were duringn.d.during carriedduring means the the outGrignardGrignardnot Grignard indetected tetrahydrofurane preparation, preparation, preparation,; In this crudecase crude(THF) crude (entry reaction reactiona reactiont −5),70 mixture due°C mixture mixturewith to the contains an reactioncontains equimolar carbinol with carbinolcarbinol reactants 2f 3f, andproduced 3ff 3f and vinylandratio vinyl by case,vinyl theether cruded 4fd (in reaction about mixture40% relativef contains emolare mostly ratio thewith alcohol respect 3g to, coming the mixture from of2g 3e, in and turn 4e formed); In this by respectcase,isomerizationmixture to withinmixturethe the crude;mixture 15n.d.; min n.d.reactionduring meansb of; means3eb Data theand notmixture Grignard notfrom4edetected); detected Incontainsreference this ;preparation, In case,; thismostly In10c thethis; casec Relative crude crudecasethe (entry alcohol reaction(entry reaction ratio 5), due5),3g calculated mixture ,mixturedue comingto theto contains thereaction containsfrom 1reaction 12g mostlyH with ,-carbinol NMRin with turn f2f the ,of fproduced2f alcoholformed3fcrude, producedandf vinyl reaction3gby by, coming by isomerizationvinylwithinetheretherisomerization ether 4f 15 (in 4f min4f (inabout during(in; about Dataabout during40% Grignard40% fromrelative 40% the relative reference relativeGrignard preparation.molar molar molarratio 10preparation, ;ratio with Relative ratio with respect with respectcruderatio respect to calculated reactionthe to the mixtureto themixture mixture frommixture of 3e of Hcontains and3e- NMRof and 3e4e ) ;and4eofcarbinol In )crude; 4ethis In); this 3fcase reactionIn and casethis, the vinyl, the fromcase,isomerization2g,isomerization inthe turn crude formedd duringreaction during by the isomerization mixture theGrignard Grignard contains preparation, during preparation,e mostly Grignard crude the crude alcohol preparation. reaction reaction 3g mixture, coming mixture contains from contains 2g carbinol, in carbinol fturn 3fformed and 3f and vinyl by vinyl isomerizationcase,mixturecrudeethercrudemixtureether the 4f reaction ;crude(in d4f reactionn.d. ;about(in during n.d. reactionabout means mixture 40% means mixtureGrignard 40% notrelative mixture containsnotrelativedetected contains detectedpreparation. molar contains molar; mostlye ratio In;mostly this ratioInmostly with this the case with the respect casealcoholthe (entry respect alcohol alcohol(entry to5),3 gthe to ,due5), 33g coming gthemixture ,due, tocomingcoming mixture the to fromtheofreaction from3e fromofreaction and 2g3e 2g , andwith2g 4e,in in, ) with ; 4e in turnturn2f In ),; turn producedf2fthis Informed formed, produced this case formed case, by theby , the byby isomerizationetherether 4f (in 4f about(in during about 40% Grignard40% relative relative preparation.molar molar ratio ratio with with respect respect to the to themixture mixture of 3e of and3e and 4e) ;4e f In); fthis In this case case, the, the 2.1.1.isomerization isomerizationMethylcrudeisomerizationisomerizationcrude reaction Substituents reaction during during mixture during mixture Grignard theGrignard in the Grignard containsβ-Position Grignard contains preparation. preparation preparationpreparation, mostly preparation, mostly . the . the crude alcohol crude alcohol reaction 3 reactiong , 3comingg ,mixture coming mixture from contains from contains 2g , 2gcarbinolin, carbinol turnin turn 3f formed and 3f formed and vinyl by vinyl by crudecrude reaction reaction mixture mixture contains contains mostly mostly the the alcohol alcohol 3g , 3comingg, coming from from 2g , 2gin, turnin turnf formed formed by by 2.1.1.Results Methyletherisomerizationetherisomerization obtained 4f Substituents(in 4f about(in during about are during40% gathered 40%Grignard inrelative Grignardβ relative-Position molar preparation in molar Tablepreparation ratio ratio1 with.. For with. respect the respect sake to the to of themixture comparison, mixture of 3e of and3e previousand 4e) ;4e f In); this In data this case case [, the10, ] the obtained 2.1.1.The isomerizationMethyl isomerizationregioselectivity Substituents during during of Grignard in the Grignard β -Positionreaction preparation preparation between. . 1 and vinylmagnesium reagents bearing one methyl by reacting2.1.1.2.1.2.1.1.The crudeMethyl Methyl1. 1cruderegioselectivity Methylwith reaction Substituents Substituentsreaction vinylmagnesium Substituents mixture mixtureof in thein containsβ βin-Positionreaction -Position contains β-Position bromides mostly between mostly the2a the1 alcohol –andc alcoholare vinylmagnesium also3g , 3comingg reported., coming from reagents from 2g , 2gin, bearing turnin turn formed one formed methyl by by group2.1.2.1.1.Theisomerization inMethyl1. isomerizationβ regioselectivityMethyl-position Substituents Substituents during with during respect ofGrignard inthe Grignard β in -reaction Positionto β preparation-thePosition preparation C–Mg between bond. . 1 resultand vinylmagnesiumed strongly influenced reagents by bearingthe stereogeometry one methyl group2.1.1.The Thein Methyl βTheregioselectivity -positionregioselectivity regioselectivity Substituents with respectof of inthe theof β thereaction- toPositionreaction the reaction C–Mg between between between bond 1 1 resultand and 1 andvinylmagnesium edvinylmagnesium stronglyvinylmagnesium influenced reagents reagents reagents by thebearing bearing stereogeometrybearing one one onemethyl methyl methyl andgroup 2.1.by in 1.the βMethyl-position electronic Substituents with feature respectβ of in to theβ -thePosition substituent C–Mg bond which result bothed strongly affect the influenced alkene stability. by the stereogeometry In the case of 2.1.1.andgroupgroup Methyl groupbyThe in thein Theβ βregioselectivity-positionin Substituentselectronic-position βregioselectivity-position with with feature with respect inrespectof therespect ofof-Position the thetoreaction to the reactionthesubstituentto C–Mgthe C –between MgC –between Mgbond bond which bond 1 result resultedand 1 resultedbothand edvinylmagnesium stronglyvinylmagnesium strongaffect strong lythe influenced influencely alkene influence reagents reagents stability.d by byd the bearingbythe stereogeometrythebearing sterIn sterthe eoonegeometryeo caseone methylgeometry methylof theand2.1. Grignard2.1. 1.byThe Methyl 1.theThe Methylregioselectivity electronic regioselectivity Z-isomerSubstituents Substituents feature (compound of in theof βofin - the Positionreaction theβ- Positionreaction 2esubstituent, Table between between 1, entrywhich 1 and 1 5) andboth vinylmagnesium the vinylmagnesium affectcarbinol the 3e alkene andreagents reagents the stability. vinyl bearing bearing etherIn theone 4e onecase methyl were methyl of theandandgroup Grignardand groupby by in the bythe βin -theelectronic position electronic βZ-isomer- positionelectronic with feature feature (compoundwith respectfeature respect of of the totheof the2etothesubstituent substituent, theCTable substituent– MgC– Mg 1,bond entry whichbondwhich resultedwhich 5) resultedboth boththe both strongcarbinolaffect affect strong affect lythe the influence3ely thealkene alkene influenceand alkene the dstability. stability by vinyld stability theby the sterether .In I n stereo.the theI ngeometry4eeo thecase casegeometrywere case of of of formedthegroupThe groupGrignard regioselectivity inin β in70/30-position β Z-isomer-position relative with ofwith(compound molarrespect the respect reaction ratio to theto2e whereas , the CTable between– MgC–Mg bond1,almost entrybond1 resultedand complete5)resulted vinylmagnesiumthe strong carbinol strong O-alkylationly influence ly3e influence and reagents thewasd by dvinyl observedbythe thebearingster ether stereo geometrywith eo4egeometry onewere the methyl formedthetheand theGrignardand Grignard byThe inGrignard bytheThe regioselectivity70/30 the electronic regioselectivityZ-isomer Z electronic -relative isomerZ-isomer feature (compound (compound molar offeature (compound theof of theratioreaction theof reaction 2e thewhereas2esubstituent, ,Table 2esubstituentTablebetween, Tablebetween 1,almost 1, entry entrywhich11, and entrywhich1 complete 5) and5) vinylmagnesiumboth the the5) vinylmagnesiumboth thecarbinol affectcarbinol O affectcarbinol-alkylation the 3e 3e thealkene and reagents3eand alkene reagentsand wasthe thestability thevinyl observedstabilityvinylbearing vinylbearing .ether etherIn . one etherthe Iwithn 4e one4e thecasemethyl were 4ewere themethylcase wereof of groupEformedand-isomer inand byβ-position inbythe (compound 70/30 the electronic electronic relative with 2f feature respect, Table molarfeature of1, toratio entrytheof the the substituentwhereas C–Mg 6). substituent bondalmost which resultedwhich complete both both affect strongly Oaffect-alkylation the the influencedalkene alkene was stability stabilityobserved by the. In. stereogeometrytheI nwith the case thecase of of Eformedgroupformedthe-isomerformedgroupthe Grignard in Grignardin in(compound β in 70/30- 70/30inposition β 70/30-Zposition - relativeisomerre Zl- areisomerwith tive2fla ,with tive Table(compound molarrespect (compoundmolarrespect 1, ratio entryto ratio theto 2ewhereaswhereas the6).C, whereas2eTable– MgC, Table–Mg bond almost almost1, bondalmostentry 1, resulted entry complete complete resulted5) complete the5) strong the carbinol strongO O carbinol- alkylation-alkylationOly- alkylationinfluencely 3e influence and3e wasand dwasthe wasby dobservedthe vinylobservedtheby observed vinyl thester ether stereo withether geometrywitheo with4egeometry the were4e the the Ewere - E- andE bythe-isomerthe GrignardWhen Grignard electronic (compound the Zβ--dimethylisomer Z- featureisomer 2f , (compoundTable substituted (compound ofthe 1, entry substituent 2e Grignard , 6). 2eTable , Table 1, whichreagent entry1, entry both5) 2c the5) was affectthe carbinol used carbinol the (Table 3e alkene and3e 1,and theentry stability. the vinyl 3)vinyl aether 57/43 In ether the 4e molar casewere4e were of the Eandisomerformed-isomerisomerandformedWhen by (compoundbythein (compound the (compound70/30 the inelectronic 70/30β electronic-dimethyl rel a re2ftive 2f l,featurea 2fTable,tive Table molar, feature substitutedTable molar 1, of1, ratioentry 1, theentryof ratioentry the whereassubstituent Grignard6). 6). whereassubstituent 6). almost reagent almostwhich which complete 2c bothcomplete wasboth affect Oused affect-alkylation O the- alkylation(Table the alkene alkene 1,was entrystability was observed stability observed3) a. I57/43n. withtheIn withthe molarcase the case theEof - Eof- Grignardratioformedformed Whenof Z-isomer the in C 70/30thein/O 70/30 -alkylatedβ -dimethyl (compoundrel aretivelative productsmolar substituted molar2e ratio, was Tableratio whereas obtainedGrignard 1whereas, entry almost thus reagent 5)almost thesuggesting complete carbinolcomplete2c was O theused- alkylation3eO prevalence-alkylation and(Table the was1, of vinyl entrywas the observed eobserved ether3) steric a 57/43 4ewithhindrance werewith molar the the E formed - E- ratiotheisomerthe isomerofGrignardWhenWhen the Grignard(compoundWhen C (compoundthe /theO -alkylated Zthe β--dimethyl-isomer diZ β-methyl- isomerdi2fmethyl, 2fTable products(compound, substitutedTable (compound substituted1, entry 1, was entry 2e obtained6).GrignardGrignard, 2eTable Grignard6)., Table 1,thus reagentreagent entry 1, reagent suggestingentry 5)2c 2c thewas2c5) was wasthe carbinol used the used carbinolused prevalence (Table (Table (3eTable and3e1, entry1, and1, of the entry the the3vinyl) e a 33)steric vinyl57/43) a aether 57/4357/43 hindrance ethermolar 4emolar molar were 4eratio wereratio effectratioisomerisomer of (compare the (compound C(compound/O-alkylated entries 2f , 3, 2fTable products5,, Table and 1, entry 61, wasin entry Table 6). obtained 6). 1). This thus was suggesting further theconfirmed prevalence by theof the experiment e steric hindrance with 2g in 70/30effectratioformedof theofformed of(compareWhen relativethe C the/ inWhenO C - C/70/30alkylated Ointhe/O- alkylated70/30 -alkylated molar theentriesβ -redi βlmethyl a-re diproductstive ratiolmethyl3,a productstive products5,molar substitutedand whereasmolar wassubstituted ratio6 was inwasobtained ratio Tablewhereasobtained almostGrignardobtained whereas Grignard 1).thus Thisalmostthus complete thusreagentsuggesting almost reagentsuggestingwas suggesting complete 2cfurther completeO was 2cthe-alkylation was theused prevalence confirmedOthe -prevalenceusedalkylation O prevalence (-Tablealkylation (Table was of by1, the entryofwas observed1,the of the entryewas thestericobservedexperiment 3 e) stericeaobserved 3 steric57/43 )hindrance a with 57/43 hindrance withmolarhindrance with thewithmolar the effect ratioE2g the -isomereffectE ratio - E- whicheffect When (comparegaveWhen the90:10 theβentries-di βCmethyl--alkylation:di methyl3, 5, substituted and substitutedO 6-alkylation in Table Grignard Grignard 1).ratio This reagent indicating reagentwas 2cfurther was2c thatwas used confirmed usedthe (Table effect (Table 1,by entrydue 1,the entry to experiment3) athe 3 57/43) a β57/43-substituent molar with molar ratio 2g ratio (compoundwhicheffectisomer(compareof the(compareisomerof (compare thegaveC /(compoundO2f C entries- alkylated/(compound,O90:10 Table entries-alkylated entries 3,C1 5,-alkylation: , 3,2fproducts entryand 5,, 3, 2fTableproducts and 5,,6 Table in 6).and 6 Table 1,wasinO entry -alkylation 6 Table1,was obtainedin entry1) Table.obtained 6).This1). 6).This wasthus1). ratio wasthusThis further suggesting indicating further suggestingwas confirmed further confirmed the that theprevalence confirmed bytheprevalence theby effect the experiment of byexperiment duethe of the thee to stericexperiment e with thesteric withhindrance β2g-substituent hindrance which2g withwhich effect gave 2g effectgave prevailswhichof theof theCgave /overO C-/alkylated O90:10 -thealkylated αC-substituent -alkylation:products products was O(compare was-alkylation obtained obtained entry thus ratio thus suggesting7 indicating withsuggesting entry the that the prevalence2 in prevalencethe Table effect of1). the dueof To thee sterictofurther e stericthe hindrance β confirmhindrance-substituent effect the effect prevailswhich90:10(compareWhen90:10(compareWhen Cgave -overalkylatio WhentheC entries-alkylatio the 90:10 βentriesthe the-dimethylβ-n 3,di α: OβC -substituentmethyl5,n- -alkylation:-3,di:alkylation Oand methyl5,-alkylation and 6 substituted in substituted 6 Tablesubstituted in Oratio(compare Table-alkylation ratio 1) indicating. Grignard This 1)indicating. GrignardThisentry was ratio wasthat furtherreagent7 thatindicating withfurtherthereagent reagent the effectconfirmed 2centry effect confirmedwas 2c due thatwas 2used2c due toin byusedwasthe the toTable( theTableby the βeffect ( the-Tableusedexperimentsubstituent β 1).1,- experimentsubstituent entry due 1,To (Table entry furtherto 3 ) withprevails athe 13 57/43 ),prevailswith a entry2g β57/43confirm-substituent which molar2gover whichmolarover 3) the gaveratiothe a the α 57/43gave ratio - α- influenceprevails(compare(compare overof entries the entriesthe stability 3,α 5,-substituent 3, and 5, and 6of in 6the Table in (compareTablealkene 1). This1) (mainly. This entrywas was further 7due furtherwith to confirmed entrythe confirmed substituent 2 inby Tabletheby theexperiment electronic 1).experiment To further witheffect) with 2g confirmand which2g which of gavethehis gave molarinfluenceprevailsofsubstitue90:10 the ratiosubstitueof90:10 CtheC- / alkylatiooverO CofntC--/alkylated alkylatio O(comparethent -thealkylated (compare stabilitynC :αO/-substituentn -Oproductsalkylation: Oentry-alkylated -productsalkylation entryof 7the withwas 7 ratio (comparewith alkenewas obtainedratioentry products indicating obtainedentry indicating (mainly2 inentry thus2 Tablein wasthusthat Table suggestingdue7 that 1) thewithsuggesting obtained. 1)toTo theeffect. Totheentryfurther effect the furtherduesubstituent the thusprevalence 2due confirmtoin prevalence the confirmtoTable suggesting theβ- substituenttheelectronic β of1).- substituentthe theinfluence of To influencethee steric thefurther e effect)prevails steric of prevalenceprevailshindrance the of confirmhindranceand the overstability stabilityoverof the effect histhe of theeffectαof - the ofα- e geometryinfluence90:1090:10 C-alkylatio Cinof-alkylatio drivingthe nstability:O nthe-alkylation:O -regioselectivityalkylation of the ratio alkene ratio indicating ofindicating (mainly the attack that duethat theto the toeffect theeffectcarbonyl due substituent due to groupthe to theβ- substituent ofβelectronic- substituent1 we attempted prevailseffect) prevails andto over prepare overof the his the α - α- stericgeometryinfluence(comparethesubstitue hindrancethe (comparesubstitue alkene alkene innt ofentries driving (comparent (the mainlyentries effect(compare ( mainly stability3, 5,the 3, anddue (compareentry 5,regioselectivity dueand entry 6ofto in7 6the with toTable the in7 with theTablealkene entries substituententry 1) substituent.entry ofThis1) 2.(mainlythe This 3,in was2 attack 5,Table in was electronic andfurtherTable due electronic 1)furtherto. 6 theTo1)to inconfirmed. Tofurthercarbonyl effectthe Tableconfirmed further effectsubstituent) 1confirm and ).)by group andconfirm This theby of theexperiment ofthe hiselectronic was experiment 1 histheinfluence we geometry furtherinfluence geometryattempted witheffect) of with in confirmed the2gof in drivingandto which 2gthestability preparedriving which stabilityof gave his the ofbygave the of the compoundgeometrysubstituesubstitue ntin 2h (comparedrivingnt from(compare thewhich entry regioselectivity entry 7we with 7expected with entry entry of 2 thetoin 2 recover Tableattackin Table 1) to .almost To1)the. Tofurther carbonyl furtherexclusively confirm group confirm thethe of the1influenceO we-alkylation influence attempted of the ofproduct thetostability prepare stability 4h of. of compoundgeometry90:10regioselectivtheregioselectiv 90:10the alkene C - alkenealkylatio Cin -2halkylatio driving (itymainly from ityof (mainlyn :the Oof nthe- which alkylation:the dueattackO - regioselectivityalkylation attackdue towe to tothethe toratioexpected the carbonyl substituentratio indicating carbonylsubstituent ofindicating tothe group recover attack group electronicthat of electronicthat the 1to ofalmost we theeffect1 weattempted effecteffectcarbonyl attempted exclusivelydue effect) due to and) grouptheto to and prepare ofto theβ - thepreparesubstituent ofhis ofβ - substituent 1 hisO geometrycompoundwe-alkylation geometrycompound attempted prevails prevails in 2hproduct indriving from2h toover drivingpreparefrom over whichthe 4h which the theα. - the α- experimentUnfortunately,compoundthe the alkene alkene with 2h (mainly 2gpresencefrom (mainlywhich whichdue ofdue gave tothe we tothelatter 90:10expected thesubstituent wassubstituentC-alkylation: notto recoverdetected electronic electronic Oalmost but-alkylation effect the effectexclusively two) and) carbinols ratioand of the of his indicating his3gO geometry-alkylation and geometry 3h that in in 95:5product thein driving drivingrelative effect 4h the .due the to Unfortunately,compoundsubstitue regioselectiv substitueregioselectivnt 2h(comparentity presence from(compare ofity the of which theattackentry of attackentry the 7towe with latter the 7 toexpected with thecarbonyl entry was carbonyl entry 2 not toin group 2 recoverTabledetectedin group Table of 1) 1 of. almost weTobut1) 1. weattemptedTofurther the attemptedfurtherexclusively two confirm carbinols toconfirm prepare to preparethe 3gtheinfluenceO compound -alkylation andinfluence compound 3h ofin 2h the of95:5product from 2hthestability relative from stability which 4h which of. of the βmolarUnfortunately,regioselectiv-substituentregioselectiv ratio wereity presenceprevails ofity recovered the of theattack ofattack over ascribedthe to the thelatterto thecarbonylα to -substituentwascarbonyl the notrelevant group detected group of isomerization (compare 1 of we but1 weattempted the attempted entrytwo occurred carbinolsto 7 prepare to with prepare during entry3g compound and compoundthe 2 3hpreparation in in Table 2h 95:5 from2h1 fromrelative). ofwhich To the which further molarUnfortunately,the alkeneratio were (mainly presence recovered due of ascribed tothe thelatter substituent to was the relevantnot detected electronic isomerization but effect the two) occurred and carbinols of during his 3g geometry and the preparation3h in in 95:5 driving relative of the the confirmorganometallicmolar the ratio influence were reagent recovered of the[15]. stabilityascribed to of the the relevant alkene isomerization (mainly due occurred to the substituent during the preparation electronic of effect) the and organometallicmolarregioselectiv ratio wereity reagent of recovered the attack [15]. ascribed to the carbonyl to the relevant group of isomerization 1 we attempted occurred to prepare during compound the preparation 2h from ofwhich the of hisorganometallic geometry in reagent driving [15]. the regioselectivity of the attack to the carbonyl group of 1 we attempted 2.1.2.organometallic Effect of thereagent Substituent [15]. in α-Position to prepare2.1.2. Effect compound of the Substituent2h from in which α-Position we expected to recover almost exclusively the O-alkylation 2.1.2. Effect of the Substituent in α-Position productConcerning4h. Unfortunately, the influence presence of the of substituent the latter wasin α not-position detected with but respect the twoto Mg carbinols atom of3g vinyland 3h in 2.1.2.Concerning Effect of the the Substituent influence in of α the-Position substituent in α-position with respect to Mg atom of vinyl 95:5Grignard relativeConcerning molarreagents ratiothe which influence were rules recovered of the the regi substituentoselectivity ascribed in to ofα the -positionthe relevant attack with towards isomerization respect C -to or Mg O occurred-alkylation, atom of vinyl during we the GrignardConcerning reagents the which influence rules ofthe the regi substituentoselectivity in of α -positionthe attack with towards respect C- toor MgO-alkylation, atom of vinyl we comparedGrignard reagentsthe results which reported rules in the entries regi oselectivity1, 2, and 4 ofof Tablethe attack 1. Vinylmagnesium towards C- or bromideO-alkylation, (2a) andwe preparationcomparedGrignard of reagentsthe the results organometallic which reported rules in the reagententries regi oselectivity1, [ 152, ].and 4 ofof Tablethe attack 1. Vinylmagnesium towards C- or bromide O-alkylation, (2a) and we 1-propenylmagnesiumcompared the results reported bromide in (entries2b) reacted 1, 2, and with 4 of1 Tablegiving 1. Vinylmagnesiumexclusively O-alkylation, bromide whereas(2a) and 1-propenylmagnesiumcompared the results reported bromide in (entries2b) reacted 1, 2, andwith 4 of1 Tablegiving 1. exclusivelyVinylmagnesium O-alkylation, bromide whereas(2a) and 1-propenylmagnesium bromideα (2b) reacted with 1 giving exclusively O-alkylation, whereas 2.1.2. 1-propenylmagnesium Effect of the Substituent bromide in -Position(2b) reacted with 1 giving exclusively O-alkylation, whereas

Concerning the influence of the substituent in α-position with respect to Mg atom of vinyl Grignard reagents which rules the regioselectivity of the attack towards C- or O-alkylation, Molecules 2018, 23, 171 5 of 14 we compared the results reported in entries 1, 2, and 4 of Table1. Vinylmagnesium bromide ( 2a) and 1-propenylmagnesium bromide (2b) reacted with 1 giving exclusively O-alkylation, whereas 1-phenylmagnesium bromide gave the carbinol 3d and the vinyl ether 4d in 7/3 molar ratio. These findings might be explained by invoking competition between the C- and the O-attack reactions. FromMolecules the literature 2018, 23, 171 survey about effect of α-substituents to form and stabilize vinyl radicals5 of 14 from the corresponding bromides we found [16] that the configuration of vinyl radicals depends on the nature1-phenylmagnesium of the α-substituent. bromide Vinyl gave radicals the carbinol with an 3dα -hydrogen,and the vinyl -alkyl, ether -alkoxy,4d in 7/3 or-halogenmolar ratio. substituentThese havefindings a bent structure might be [explained17–20] while by invoking the cyano, competition carboxyl, between phenyl, the and C alkenyl- and the group O-attack are reactions.π-delocalized From the literature survey about effect of α-substituents to form and stabilize vinyl radicals from the and thought able to impose linearity on the radical center to effect maximum resonance stabilization, corresponding bromides we found [16] that the configuration of vinyl radicals depends on the nature of α as supportedthe α-substituent.by ESR Vinyl data [radicals21,22]. Thus,with an the α-hydrogen,-(phenyl)vinyl -alkyl, -alkoxy, radical or results-halogen more substituent stabilized have than a the α-methylbent structure and vinyl [17–20] analogues while the and cyano, this mightcarboxyl, explain phenyl, the and difference alkenyl group found are in π the-delocalized behavior and with 1. In otherthought words able, the to impose occurrence linearity of both on the the radicalO- and center the Cto-alkylation effect maximum with 2dresonance, and only stabilization, the O-alkylation as with supported2a and 2b bymight ESR data be explained [21,22]. Thus, by thethe factα-(phenyl)vinyl that the vinyl radical radical results from more2a stabilizedand 2b would than the be less stabilizedα-methyl and and then vinyl more analogues reactive and than this thatmight derived explain fromthe difference2d allowing found competition in the behavior between with 1. OIn- and C-alkylation.other words, the occurrence of both the O- and the C-alkylation with 2d, and only the O-alkylation with This2a and is 2b in might line with be explained the common by the opinionfact that the that vinyl anomalous radical from behaviour 2a and 2b of would Grignard be less reagents stabilized can be and then more reactive than that derived from 2d allowing competition between O- and C-alkylation. explained by invoking a single electron transfer (SET) mechanism [23,24]. It has been reported [2] This is in line with the common opinion that anomalous behaviour of Grignard reagents can be that the C–Mg bond dissociation energy is well related to the oxidation potential values of different explained by invoking a single electron transfer (SET) mechanism [23,24]. It has been reported [2] Grignardthat the reagents C–Mg bond (the C–Mgdissociation dissociation energy is energy well rela ofted 23 to Kcal/mol the oxidation corresponds potential anvalues oxidation of different potential differenceGrignard of 1.00reagents Volt (the [2]) C–Mg and thedissociation vinyl- and energy aryl-Grignard of 23 Kcal/mol reagents corresponds possess an oxidation the strongest potential among the C–Mgdifference dissociation of 1.00 Volt energies [2]) and the [2]. vinyl- Few and cases aryl-Grignard of O-alkylation reagents on possess alpha-dicarbonyl the strongest among substrates havethe been C–Mg reported, dissociation but theener reactiongies [2]. Few occurs cases with of O vinyl--alkylation and on phenyl-Grignard alpha-dicarbonyl reagentssubstrates onlyhave with 9,10-phenanthraquinonebeen reported, but the [8]. reaction The authors occurs hypothesized with vinyl- thatand thephenyl-Grignard nature of C-Mg reagents bond isonly an importantwith requisite9,10-phenanthraquinone to determine the fashion-mode [8]. The authors of hypothesized addition. that the nature of C-Mg bond is an important requisite to determine the fashion-mode of addition. 2.1.3. Effect of the Substituent in α-Position 2.1.3. Effect of the Substituent in α-Position It globally emerges from the reported data that the regioselectivity of the vinyl Grignard addition It globally emerges from the reported data that the regioselectivity of the vinyl Grignard to 1 cannot be exclusively attributed to both steric and electronic features of the vinyl moiety addition to 1 cannot be exclusively attributed to both steric and electronic features of the vinyl moiety substituentssubstituents but but also also to mechanisticto mechanistic path path effects.effects. In the context, context, di distinctstinct intermediate intermediate species species can be can be involvedinvolved in O in- andO- andC-alkylation C-alkylation deriving deriving by by single single electron electron transfer transfer (SET) (SET) or polar or polarmechanism. mechanism. Some of Some of themthem are are drawn drawn in in SchemeScheme 44..

SchemeScheme 4. Possible 4. Possible reaction reaction pathways pathways of the cu currentlyrrently considered considered Grignard Grignard addition. addition.

Molecules 2018, 23, 171 6 of 14

To shed light on the mechanistic aspects of the reaction we planned to run some experiments and results obtained are reported in Table2. In particular, compound 1 was reacted with vinylmagnesium bromide (2a), and 2-methyl-1-propenylmagnesium bromide (2c) under different experimental conditions. We selected to run experiments by using these latter since they are representative of limit cases and exclude isomerization, thus avoiding further complications. Indeed, 2a gave only O-alkylation,Molecules 2018 while, 23, 171 both C- and O-alkylation occurred with 2c. 6 of 14 experimental conditions. We selected to run experiments by using these latter since they are Table 2. a representative of limitReactions cases and of 1 exclude with 2a isomerization, and 2c under different thus avoiding experimental further conditions.complications. Indeed, 2a gave only O-alkylation, while both C- and O-alkylation occurred with 2c. Vinyl Reaction Radical C-Alkylation O-Alkylation Entry Solvent Conversion% b Reagent Time (min) Scavenger Product (%) c Product (%) c Table 2. Reactions of 1 with 2a and 2c under different experimental conditions. a 1 2a THF 10 - 80 3a (n.d.) d 4a (pres.) e Vinyl Reaction Radical C-Alkylation O-Alkylation Entry Solvent Conversion% b Reagent Time (min) ScavengerTEMPO Product (%) c Product (%) c 2 2a THF 10 60 3a (n.d.) d 4a (pres.) e 1 2a THF 10 (1.0 - eq.) 80 3a (n.d.) d 4a (pres.) e TEMPO 3 2 2c 2a THFTHF 1010 -60 80 3a (n.d.)3c (67)d 4a (pres.)4c e(33) (1.0 eq.) 3 2c THF 10 TEMPO - 80 3c (67) 4c (33) 4 2c THF 10 50 3c (67) 4c (33) (0.5TEMPO eq.) 4 2c THF 10 50 3c (67) 4c (33) (0.5 eq.) TEMPO 2c TEMPO 3c e d 5 5 2c THFTHF 1010 3030 3c (pres.)(pres.) e 4c (n.d.)4c (n.d.) d (1.0(1.0 eq.) 6 6 2c 2c THFTHF 15–30–45–9015–30–45–90 - 80 80 3c (67)3c (67)c,f c,f 4c (33)4c c,f(33) c,f 7 2a Et2O 60 - 28 3a (50) 4a (50) 7 2a Et O 60 - 28 3a (50) 4a (50) a Reactions carried2 out at −70 °C with equimolar amount of reagents; b calculated with respect to 1; c a ◦ b c Reactionsrelative carried ratio outbetween at −70 C-C and with O equimolar-alkylation amount product of calculated reagents; fromcalculated 1H-NMR with of respect the crude to 1; reactionrelative ratio between C- and O-alkylation product calculated from 1H-NMR of the crude reaction mixture; d n.d. means not mixture; d n.d. means not detected; e Pres. means presence of the product; we selected to indicate detected; e Pres. means presence of the product; we selected to indicate ‘pres’. because the absence of carbinol does f not permit‘pres’. to because give 3:4 theratio absence value; fofThis carbinol relative does ratio not remained permit unchanged.to give 3:4 ratio value; This relative ratio remained unchanged.

FromFrom data data reported reported in in Table Table2 emerges2 emerges that that thethe conversionconversion of of 1 decreased1 decreased in the in thepresence presence of of 2,2,6,6-tetramethylpiperidinoxyl2,2,6,6-tetramethylpiperidinoxyl (TEMPO) (TEMPO) as radical scavenger scavenger (comparison (comparison between between entries entries 1 and 1 2); and 2); the recoverythe recovery of the of theO-alkylation O-alkylation product product even even inin the presence presence of of the the scavenger scavenger might might be due be dueto the to the couplingcoupling rate rate of the of the vinyl vinyl radical radical with with1 ,1, likely likely fasterfaster than than the the diffusion diffusion rate rate of the of thescavenger scavenger within within the solventthe solvent cage. cage. When When the the radical radical trapper was was present present in half in half equivalent equivalent amount amount with respect with to respect the to the reactantreactant amount,amount, the the reaction reaction between between 1 and1 and 2c 2c(Table(Table 2, 2entries, entries 3–5) 3–5) gives gives 3c:4c3c =: 4c2:1= in 2:1 minor in minor conversion, whereas only the carbinol 3c was detected when TEMPO was added in equimolar amount. conversion, whereas only the carbinol 3c was detected when TEMPO was added in equimolar amount. These results can be considered an indication that the O-alkylation involves the intervention of TheseC results-like radical can bespecies considered (Scheme an 4). indication The recovery that of the theO totally-alkylation deuterated involves species the 4a intervention from the crude of C -like radicalreaction species mixture (Scheme from4). 1 The and recovery 2a upon ofquenching the totally with deuterated D2O [12] supported species 4a thefrom above the speculation crude reaction mixture(Scheme from 5).1 and 2a upon quenching with D2O[12] supported the above speculation (Scheme5).

Scheme 5. Formation of 4a deuterated on the benzylic position upon quenching with D2O of the Scheme 5. Formation of 4a deuterated on the benzylic position upon quenching with D O of the reaction between 1 and 2a. 2 reaction between 1 and 2a. Finally, we made a further experiment aiming to support the hypothesis that the reaction Finally,between we1 and made vinyl a further Grignard experiment reagents aiming gives toC-alkylation support the through hypothesis a polar that mechanism the reaction while between 1 andO vinyl-alkylation Grignard proceeds reagents involving gives radicalC-alkylation species. throughAshby reported a polar fundamental mechanism whilestudiesO on-alkylation the proceedsmechanism involving of reaction radical of Grignard species. reagents Ashby with reported ketones. fundamental In particular, studies he reported on theexperiments mechanism in of which propenylmagnesium reagents having different cis/trans ratios were reacted with benzophenone reaction of Grignard reagents with ketones. In particular, he reported experiments in which excess [25,26]. The cis-propenylmagnesium bromide was selected as vinyl Grignard probe. If a free propenylmagnesium reagents having different cis/trans ratios were reacted with benzophenone radical would be formed during the reaction course, the cis-propenyl radical would isomerize to the excessthermodynamically [25,26]. The cis-propenylmagnesium stable trans-propenyl radical, bromide resulting was selected in a product as vinyl with Grignardtrans stereochemistry. probe. If a free The result [25] did not indicate isomerization of the propenyl group as evidenced by the fact that the starting Grignard reagent cis/trans ratio was exactly reflected in the reaction products. Thus, the retention

Molecules 2018, 23, 171 7 of 14 radical would be formed during the reaction course, the cis-propenyl radical would isomerize to the thermodynamically stable trans-propenyl radical, resulting in a product with trans stereochemistry. The result [25] did not indicate isomerization of the propenyl group as evidenced by the fact that the starting Grignard reagent cis/trans ratio was exactly reflected in the reaction products. Thus, the retention of configuration of the probe was considered an indication that the reaction is not proceeding via anMolecules SET mechanism. 2018, 23, 171 7 of 14 In line with these considerations, we prepared a THF solution of propenylmagnesium bromide by reactingof configurationcis-propenylbromide of the probe was with considered magnesium an indi turningscation that dividing the reaction it in two is not parts: proceeding one to via be reactedan SET mechanism. with benzophenone while the other with bis(2-benzothiazolyl)ketone (1). The 1H-NMR analysis of In line with these considerations, we prepared a THF solution of propenylmagnesium bromide the reactionby reacting mixture cis-propenylbromide with benzophenone with magnesium showed two turnings carbinol dividing signals it derived in two fromparts: theone addition to be of cis- andreactedtrans with-propenylmagnesium benzophenone while bromide the other to benzophenone.with bis(2-benzothiazolyl)ketone In agreement with (1).the The result 1H-NMR reported in Tableanalysis1, entry of the 5, reaction the cis :mixturetrans ratio with was benzopheno 1:2, indicatingne showed that two the carbinol isomerization signals derived occurs from in Grignard the formationaddition but of not cis during- and trans the-propenylmagnesium addition to the ketone. bromide to benzophenone. In agreement with the Inresult the reported case of reaction in Table with1, entry1, the5, the1H-NMR cis:trans spectrumratio was 1:2, exhibited indicating signals that the ascribed isomerization to carbinols occurs3e and 3f in relativein Grignard 1:2 molarformation ratio but and not of duringO-alkylated the addition products to the4e ketone.and 4f . These findings indicate that carbinols derive fromIn the a polar case of mechanism, reaction with as 1, in the the 1H-NMR case of spectrum the reaction exhibited with signals benzophenone. ascribed to Thecarbinols detection 3e of vinyland ethers 3f in suggests relative 1:2 the molar occurrence ratio and of of a O radical-alkylated mechanism products 4e when and 4f bis(2-benzothiazolyl)ketone. These findings indicate that was carbinols derive from a polar mechanism, as in the case of the reaction with benzophenone. The used as substrate. detection of vinyl ethers suggests the occurrence of a radical mechanism when bis(2- 2.2. Influencebenzothiazolyl)ketone of the Solvent was and used of the as Metal substrate. Bound to Vinyl Group It2.2. has Influence been reportedof the Solvent [9] thatand of the the reactionMetal Bound between to Vinyl benzil Group and phenylmagnesium bromide in THF gives O-alkylationIt has been (25% reported yield), [9] that whereas the reaction this reaction between occurred benzil and in phenylmagnesium negligible amount bromide in Et2O. in Therefore,THF additiongives of O2a-alkylationto a solution (25% of yield),1 in diethyl whereas ether this afforded reaction theoccurredC- and inO -alkylationnegligible amount in equimolar in Et2O. extent, althoughTherefore, the reaction addition is slowof 2a dueto a tosolution the low of solubility 1 in diethyl of 1etherin Et afforded2O confirming the C- aand strong O-alkylation influence in of the solventequimolar polarity extent, to the although regioselectivity. the reaction is slow due to the low solubility of 1 in Et2O confirming a Tostrong verify influence the role of the of thesolvent alkylating polarity agentto the regioselectivity. on the regioselectivity we run the reaction between 1 and vinylTo lithium, verify the prepared role of the in alkylating situ from agent tetravinylstannane on the regioselectivity and n -butyllithium.we run the reaction After between purification 1 and vinyl lithium, prepared in situ from tetravinylstannane and n-butyllithium. After purification by by silica gel chromatography the carbinol 3a in 25% yield was recovered and no O-alkylated product silica gel chromatography the carbinol 3a in 25% yield was recovered and no O-alkylated product was detected. This finding can be considered of synthetic interest since the vinyllithium offers an was detected. This finding can be considered of synthetic interest since the vinyllithium offers an alternativealternative synthetic synthetic path path to obtainto obtain the theC C-alkylation-alkylation product 3a3a (Scheme(Scheme 6).6 ).

Scheme 6. Synthesis of carbinol 3a. Scheme 6. Synthesis of carbinol 3a. 2.3. X-ray Diffraction Analysis of Azaheteroaryl Ketones Showing Different C-/O-Alkylation Regioselectivity 2.3. X-raytowards Diffraction Vinylmagnesium Analysis Bromide of Azaheteroaryl Ketones Showing Different C-/O-Alkylation Regioselectivity towards Vinylmagnesium Bromide It has been reported [10,12] that the reaction between 2a and a series of azaheteroaryl ketones Itexhibited has been O-vinylation reported [strongly10,12] that dependent the reaction on the betweengroups bound2a and to the aseries carbonyl of azaheteroarylmoiety. It occurred ketones exhibitedcompletelyO-vinylation only with strongly the ketone dependent 1, bearing on two the be groupsnzothiazolyl bound substituents to the carbonyl while the moiety. reaction It with occurred completelybis(2-thiazolyl)ketone only with the (5) ketone produced 1, bearingboth O-two and benzothiazolylC-alkylation products substituents in equimolar while theamount reaction with(Scheme bis(2-thiazolyl)ketone 2) evidencing the (5 )importance produced of both the benzO- andocondensation.C-alkylation The products presence inof equimolara benzene ring amount (Schemefused2) evidencingwith the heterocycle the importance might favor of the the benzocondensation. delocalization of a negative The presence charge of in a the benzene O-alkylated ring fused C-like intermediate (Scheme 4). Equimolar amount of two distinct O- and C products were obtained with the heterocycle might favor the delocalization of a negative charge in the O-alkylated C-like on bis(2-benzoxazolyl)ketone (8) substrate. Conversely, in the case of bis(1-methylbenzimidazolyl) O C intermediateketone (11) (Scheme the carbinol4). Equimolarspecies derived amount from the of twoclassic distinct Grignard addition- and wasproducts exclusively were obtained. obtained on These findings suggested us to investigate the structure of ketones 1, 5, 8, and 11 by diffractometric analysis. Suitable crystals for the purpose were obtained from acetone (1 and 11), methanol (8), or by the vapor diffusion technique (methanol/n-hexane) in the case of 6.

Molecules 2018, 23, 171 8 of 14 bis(2-benzoxazolyl)ketone (8) substrate. Conversely, in the case of bis(1-methylbenzimidazolyl)ketone (11) the carbinol species derived from the classic Grignard addition was exclusively obtained. These ﬁndings suggested us to investigate the structure of ketones 1, 5, 8, and 11 by diffractometric analysis. Suitable crystals for the purpose were obtained from acetone (1 and 11), methanol (8), or by the vapor Molecules 2018, 23, 171 8 of 14 diffusion technique (methanol/n-hexane) in the case of 6. X-rayX-ray study study showed showed distinct distinct stereogeometries stereogeometries characterized by by diffe differentrent dihedral dihedral angles angles (Table (Table 3) between3) between the planes the planes deﬁned defined by the by the two two carbonyl carbonyl substituents, substituents, asas shownshown in in Figure Figure 1.1 .

FigureFigure 1. 1.Molecular Molecular structuresstructures of of compounds compounds 1, 5 1(front-view),, 5 (front-view), 8, 11 (side-view)8, 11 (side-view) determined determined by X-ray by studies. X-ray studies. In compounds 1 and 5 in which the ketone group is bound to two benzothiazolyl and thiazolyl rings,In compounds respectively,1 andthe dihedral5 in which angles the are ketone 12.9(1)° group and 5.0(1)° is bound [8.3(1)°, to two for the benzothiazolyl second molecule and in thiazolyl 5]. rings,At respectively, a difference thewith dihedral the previously angles areobserved 12.9(1) values,◦ and 5.0(1)in 8 the◦ [8.3(1) dihedral◦, for angles the second formed molecule by the in 5]. At abenzoxazolyl difference withrings bound the previously to the carbonyl observed group values, are slightly in 8 widerthe dihedral being 22.76(7)° angles whereas formed the by the benzoxazolyllargest angle rings is found bound between to the the carbonyl methylbenzoimidazolyl group are slightly rings inwider 11 [39.76(7)°]. being This 22.76(7) latter◦ resultwhereas is the largestalso angle in agreement is found with between the analogous the methylbenzoimidazolyl dihedral angle between rings the in methylimidazole 11 [39.76(7)◦]. Thisrings latterin the result bis(1-methyl-2-imidazolyl)ketone that is even larger being 49.4(1)° [27]. is also in agreement with the analogous dihedral angle between the methylimidazole rings in the Although we are aware that conformations in the solid state◦ can differ from the ones in bis(1-methyl-2-imidazolyl)ketonesolution, by roughly comparing that the is structure even larger geometry being 49.4(1)of the benzocondensed[27]. azaheteroaryl ketonesAlthough 1, 8, we and are 11, aware it emerges that that conformations the attack at inthe the oxyge solidn atom state may can be differ sterically from impeded the ones by in the solution, by roughlypresence comparing of two N-methyl the structure groups in geometry the case of of 11 the. benzocondensed azaheteroaryl ketones 1, 8, and 11, it emergesA further that possible the attack explanation at the oxygen about the atom difference may be between sterically relative impeded C-and by O-alkylation the presence ratio of two N-methylpassing groups from 1 into the8 until case 11 of might11. reside in the distinct ability to delocalize a negative charge on the benzylicA further carbon possible atom. explanation In the case of about 11 the the presence difference of nitrogen between atoms relative makesC-and the imidazoleO-alkylation ring ratio passingmore from aromatic1 to thus8 until less11 pronemight to delocalize reside in the char distinctge within ability the to ring; delocalize when the a nitrogen negative is chargereplaced on the benzylicby the carbon oxygen atom. suchIn as the in 8 case this of feature11 the might presence be less of nitrogenimportant, atoms whereas makes the theintervention imidazole of ring the more sulfur d-orbitals in the case of 1 might likely favor the delocalization charge. aromatic thus less prone to delocalize the charge within the ring; when the nitrogen is replaced by the oxygen3. Materials such and as Methods in 8 this feature might be less important, whereas the intervention of the sulfur d-orbitals in the case of 1 might likely favor the delocalization charge. 3.1. General Methods

The 1H spectra were recorded with a Varian Gemini 300 (Varian, Palo Alto, CA, USA) spectrometer operating at 300 MHz for 1H-NMR and 75.56 MHz for 13C-NMR. Signal multiplicities were established by Distortionless Enhanced by Polarization Transfer (DEPT) experiments. Chemical shifts were measured in δ (ppm) with reference to the solvent (δ = 7.26 ppm and 77.00 ppm for

Molecules 2018, 23, 171 9 of 14

3. Materials and Methods

3.1. General Methods The 1H spectra were recorded with a Varian Gemini 300 (Varian, Palo Alto, CA, USA) spectrometer operating at 300 MHz for 1H-NMR and 75.56 MHz for 13C-NMR. Signal multiplicities were established by Distortionless Enhanced by Polarization Transfer (DEPT) experiments. Chemical shifts were measured in δ (ppm) with reference to the solvent (δ = 7.26 ppm and 77.00 ppm for CDCl3, for 1H-, and 13C-NMR, respectively). J values are given in Hz. MS analyses were performed with a gaschromatograph Agilent 6890 equipped with a (5%-phenyl)methyl-polysiloxane column (30 m length, 0.250 mm i.d., 0.25 µm thickness) interfaced to a quadrupole mass detector Agilent 5973N. Mass and HR-MS spectra were recorded on a VG 7070E instrument (VG Instruments, Inc., Stamford, CT, USA) at an ionization voltage of 70 eV in the EI mode. Electron spray ionization mass spectra (ESI-MS) were recorded with a WATERS 2Q 4000 instrument (Waters Corporation, Milford, MA, USA). IR spectra were recorded on a Perkin–Elmer model 1600 FT-IR spectrophotometer (Perkin Elmer, Waltham, MA, USA). Compounds 3a–h showed characteristic IR signals at 3650–3300 cm−1 (OH) and 4a–g (oils) at 1050–1300 cm−1 (O–C). Melting points were measured with a Büchi 535 apparatus and were not corrected. Chromatographic puriﬁcations (FC) were carried out on glass columns packed with silica gel (Merck grade 9385, 230–400 mesh particle size, 60 Å pore size) at medium pressure. Thin layer chromatography (TLC) was performed on silica gel 60 F254 coated aluminum foils (Fluka Chemie GmbH, Buchs, Switzerland). The solvents and reagents used are commercially available (Sigma-Aldrich (Milan, Italy) or Fluka Chemie GmbH, Buchs, Switzerland). THF and diethyl ether were distilled from sodium/benzophenone ketyl. Air- and moisture-sensitive solutions and reagents were handled in dried apparatus under an atmosphere of dry argon using standard Schlenk-type techniques. Compounds 1, 5, 8, and 11 are synthesized as previously reported [14] and their characterization data agreed with those reported. The Grignard reagents, if not commercially available, were prepared from the vinyl bromide precursor and their solution titrated immediately prior to use according to standard procedure [28].

3.2. Synthesis of 1,1-Di(1,3-benzothiazol-2-yl)-2-propen-1-ol (3a) In a three necked round bottom flask equipped with two drip funnels and with a neck settled with a sintered glass filter shut with a Teflon valve, under argon atmosphere and magnetic stirring, a solution of tetravinyltin (97% purity grade, 0.36 mL, 1.92 mmol) in anhydrous n-pentane (120 mL) was introduced. A solution of n-butyllithium 2.5 M in n-hexane (1.8 mL) was added dropwise and after 30 min the white solid obtained was separated by filtration from the liquid through the filter and washed with 2.0 mL of n-pentane. The solid remained within the flask was dissolved in anhydrous THF (5.0 mL) and the apparatus was cooled at −70 ◦C through immersion in a liquid nitrogen/acetone bath. After about 5 min, a solution of compound 1 (0.065, 0.22 mmol) in anhydrous THF (10 mL) was added dropwise. Immediately the pale yellow solution became red. The reaction course was monitored through TLC and after 2 h 10 mL of water was added; the crude was extracted with diethyl ether and the organic layer dried over anhydrous Na2SO4. Compound 3a was recovered in 20% yield after purification by column chromatography on silica gel (eluent: light petroleum/diethyl ether 75/25).

1 ◦ 1,1-Di(1,3-benzothiazol-2-yl)-2-propen-1-ol (3a): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.08–8.02 (m, 2H), 7.90–7.85 (m, 2H), 7.52–7.44 (m, 2H), 7.42–7.35 (m, 2H), 6.77 (dd, 1H, J = 17.0 Hz, J = 10.4 Hz), 5.77 13 ◦ (d, 1H, J = 17.0 Hz), 5.63 (bs, 1H, OH), 5.42 (d, 1H, J = 10.4 Hz); C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 173.7, 152.4, 139.2, 135.9, 126.1, 125.4, 123.3, 121.9, 116.1, 78.9; MS (m/z): 324 (M+, 76), 307 (25), 296 (25), 268 (27), 190 (38), 162 (100), 136 (41). HREIMS: m/z 324.0395 (calculated for C17H12N2OS2, 324.0391). Molecules 2018, 23, 171 10 of 14

3.3. Reactions between 1 and Vinylmagnesium Bromide Derivatives (2a–h)—General Procedure Vinylmagnesiumbromide derivative (0.41 mmol) in THF (3.0 mL) was added dropwise to a stirred solution of carbonyl compound (0.34 mmol) in THF (3.0 mL), cooled at −70 ◦C. After about 20 min. the reaction mixture was quenched with saturated aqueous (NH4)2SO4, stirred while being warmed to room temperature, and extracted with diethyl ether. The organic layers were washed with “brine”, dried over anhydrous Na2SO4, and concentrated “in vacuo” without warming. The time employed for this workup was about 15 min. The residue was analyzed by 1H-NMR and then the products were isolated by FC and fully characterized. The vinyl ethers, stored at −18 ◦C, are stable for several months. Reactions of 1 with 2a–c and related products have been reported in the literature [10]. Characterization data for new compounds are reported below and the relative 3:4 ratio is reported in Table1.

1 ◦ 1,1-Di(1,3-benzothiazol-2-yl)-2-phenyl-2-propen-1-ol (3d): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.03 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 7.4 Hz, 2H), 7.50–7.30 (m, 6H), 7.22–7.14 (m, 3H), 5.96 (bs, 1H, 13 ◦ OH, exchange with D2O), 5.56 (s, 1H), 5.47 (s, 1H); C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 173.8, 152.2, 150.6, 138.7, 136.1, 128.8, 127.8, 127.6, 126.1, 125.4, 123.4, 121.7, 120.1, 81.3; ESI-MS (m/z): + + 401 [M + H] , 423 [M + Na] ; HREIMS: m/z 400.0711 (calculated for C23H16N2OS2, 400.0704). 1 ◦ Z-1,1-Bis(2-benzothiazolyl)-2-buten-1-ol (3e): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.08–7.98 (m, 2H), 7.88–7.82 (m, 2H), 7.50–7.40 (m, 2H), 7.40–7.30 (m, 2H), 6.46 (dq, 1H, J = 11.2 Hz, J = 1.8 Hz), 13 6.05–5.90 (m, 1H), 5.73 (bs, 1H, OH), 1.76 (dd, 3H, J = 7.3 Hz, J = 1.8 Hz); C-NMR (CDCl3: 75.56 MHz, 25 ◦C): δ (ppm): 175.6, 152.4, 136.0, 132.8, 131.7, 126.1, 125.3, 123.3, 121.8, 78.3, 14.7; MS (m/z): 338 (M+), 321, 297, 281, 176, 136; HREIMS: m/z 338.0543 (calculated for C18H14N2OS2, 338.05475). 1 ◦ E-1,1-Bis(2-benzothiazolyl)-2-buten-1-ol (3f): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.10–7.95 (m, 2H), 7.90–7.80 (m, 2H), 7.55–7.42 (m, 2H), 7.42–7.35 (m, 2H), 6.40 (dq, J = 15.3 Hz, J = 1.5 Hz, 1H), 6.22–6.05 (m, 1H), 5.63 (br.s., 1H, OH, exchange with D2O), 1.78 (dd, J = 6.6 Hz, J = 1.5 Hz, 3H); 13 ◦ C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 174.5, 152.4, 135.9, 132.5, 128.2, 126.1, 125.3, 123.2, 121.8, 78.6, 17.6; MS (m/z): 338 (M+), 321, 297, 281, 176, 136; HREIMS: m/z 338.0546 (calculated for C18H14N2OS2, 338.05475). 1 ◦ Z-1,1-Bis(2-benzothiazolyl)-2-methyl-2-buten-1-ol (3g): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.05 (d, 2H, J = 7.4 Hz), 7.89 (d, 2H, J = 8.22 Hz), 7.53–7.35 (m, 4H), 5.81–5.77 (m, 1H), 5.62 (br.s., 1H, OH), 13 ◦ 1.85 (s, 3H), 1.47–1.43 (m, 3H); C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 175.1, 152.3, 136.6, 136.6, 136.0, 128.6, 126.1, 125.4, 123.4, 121.8, 80.4, 23.1, 15.0; MS (m/z): 352 (M+), 335, 320, 297, 190, 162; HREIMS: m/z 352.0707 (calculated for C19H16N2OS2, 352.0704). ◦ 1 E-1,1-Bis(2-benzothiazolyl)-2-methyl-2-buten-1-ol (3h): m.p.: 123–124 C. H-NMR (CDCl3, 300 MHz, 25 ◦C): δ (ppm): 8.05 (d, 2H, J = 8.1 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.50 (td, 2H, J = 8.1 Hz, J = 1.3 Hz), 7.40 (td, 2H, J = 8.4 Hz, J = 1.2 Hz), 5.70 (bs, 1H, OH), 5.70–5.55 (m, 1H), 1.80 (s, 3H), 1.70 (d, 3H, J = 6.8 Hz); 13 ◦ C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 174.1, 152.3, 137.8, 136.2, 126.1, 125.4, 125.3, 123.3, 121.8, 82.3, 13.9, 12.8; MS (m/z): 352 (M+), 335, 320, 297, 190, 162; HREIMS: m/z 352.0708 (calculated for C19H16N2OS2, 352.0704). 1 2-[1,3-Benzothiazol-2-yl((1-phenylvinyl)oxy)methyl]-1,3-benzothiazole (4d): H-NMR (CDCl3, 300 MHz, 25 ◦C): δ (ppm): 8.09 (d, 2H, J = 8.2 Hz), 7.88 (d, 2H, J = 8.0 Hz), 7.80–7.35 (m, 9H), 7.03 (s,1H), 4.91 (d, 1H, 13 ◦ J = 3.9 Hz), 4.62 (d, 1H, J = 4.0 Hz); C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 168.1, 157.6, 153.0, 135.2, 129.1, 128.4, 126.2, 125.6 (two signals overlapped), 123.9, 121.8, 87.6, 77.8; MS (m/z): 400 (M+), + 399 (M –1), 281; HREIMS: m/z 400.0709 (calculated for C23H16N2OS2, 400.0704). 1 ◦ Z-Bis-(2-benzothiazolyl)methyl 1-propenyl ether (4e): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.10–8.00 (m, 2H), 7.92–7.80 (m, 2H), 7.52–7.30 (m, 4H), 6.53 (s, 1H), 6.29 (dq, 1H, J = 6.1 Hz, J = 1.8 Hz), 13 4.72 (dq, 1H, J = 12.8 Hz, J = 6.9 Hz), 1.80 (dd, 3H, J = 6.9 Hz, J = 1.8 Hz); C-NMR (CDCl3: 75.56 MHz, 25 ◦C): δ (ppm): 168.3, 152.9, 142.8, 135.3, 126.2, 125.6, 123.8, 121.8, 106.3, 80.6, 9.6; MS (m/z): 400 (M+), + 338 (M ), 281, 162, 134; HREIMS: m/z 338.0543 (calculated for C18H14N2OS2, 338.05475). Molecules 2018, 23, 171 11 of 14

1 ◦ E-Bis-(2-benzothiazolyl)methyl 1-propenyl ether (4f): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.12–8.02 (m, 2H), 7.92–7.82 (m, 2H), 7.52–7.30 (m, 4H), 6.58 (s, 1H), 6.42 (dq, 1H, J = 12.4 Hz, J = 1.7 Hz), 5.22 (dq, 13 ◦ 1H, J = 12.4 Hz, J = 6.8 Hz), 1.54 (dd, 3H, J = 6.8 Hz, J = 1.6 Hz); C-NMR (CDCl3: 75.56 MHz, 25 C): δ (ppm): 168.3, 153.2, 143.7, 135.2, 126.2, 125.6, 123.8, 121.8, 105.2, 79.2, 12.4; MS (m/z): 338 (M+), 281, 162, 134; HREIMS: m/z 338.0541 (calculated for C18H14N2OS2, 338.05475). 1 ◦ Z-Bis(2-benzothiazolyl)methyl 2-butenyl ether (4g): H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm): 8.10–8.00 (m, 2H), 7.90–7.80 (m, 2H), 7.50–7.35 (m, 4H), 6.80 (s, 1H), 4.75–4.65 (m, 1H), 1.98–1.94 (m, 3H), 1.78–1.75 (m, 3H); REIMS: m/z 352.0700 (calculated for C19H16N2OS2, 352.0704).

3.4. Reactions of Propenylmagnesium Bromide with 1 or Benzophenone In a flame-dried apparatus and under argon atmosphere, a solution of cis-propenylbromide (0.425 mL, 0.005 mol) in anhydrous THF (30 mL) was added dropwise to magnesium turnings (0.005 mol) in THF (5.0 mL). After a gentle warming the Grignard formation was observed and the reaction was allowed until the magnesium was consumed. The resulting solution was withdrawn with a graduate syringe and a half amount was inserted in a dropping funnel and the other half in another one. Each funnel was connected with a flame-dried round-bottomed flask in which 0.00025 mol of ketone were dissolved in 5.0 mL of anhydrous THF and kept at −70 ◦C. After about 15 min from the addition of the Grignard solution, the reaction was quenched with aqueous (NH4)2SO4 and extracted with diethyl ether. The organic layer was dried over anhydrous Na2SO4, and the solvent was removed after filtration. The reaction mixture was analyzed through 1H-NMR spectroscopy. The reaction products were recognized by comparison with literature data in case of reaction with benzophenone [25] and with data obtained in experiments reported in Table1, entries 5 and 6.

3.5. X-ray Diffraction Data

Crystallographic Data Collection and Structure Determination The X-ray intensity data of 1, 5, 8, and 11 were measured with a Bruker Apex II CCD diffractometer. The cell dimensions and the orientation matrix were initially determined by a least squares refinement of reflections measured in three sets of 20 exposures, which were collected in three different ω regions, and eventually refined against all data. A full sphere of reciprocal space was scanned in 0.3◦ω steps. The SMART [29] software was used to collect frames of data, index reflections, and determine the lattice parameters. The collected frames were then processed for integration by the SAINT program, [29] and an empirical absorption correction was applied with SADABS [30]. The structures were solved by direct methods (SIR2004) [31] and subsequent Fourier syntheses and refined by full-matrix least-squares techniques on F2 (SHELXTL) [32] with anisotropic thermal parameters for all non-hydrogen atoms. All hydrogen atoms were added in calculated positions in the final stage of refinement and refined with U(H) = 1.2 Ueq(C) and allowed to ride on their carrier atoms. In the asymmetric unit of 5 there are two independent molecules. In 11.2H2O two water molecules are present in the asymmetric unit. Crystal data and details of the data collections for 1, 5, 8, and 11 are reported in Table3. CCDC 1587827 (for 1), 1587828 (for 5), 1587829 (for 8), and 1587830 (for 11) contain the Supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/, Tel.: +44 (0)1223 336408, Fax: +44 (0)1223 336033). Molecules 2018, 23, 171 12 of 14

Table 3. Crystal data and structure-reﬁnement details for 1, 5, 8, and 11.2H2O.

Compound 1 5 8 11.2H2O

Empirical formula C15H8N2OS2 C7H4N2OS2 C15H8N2O3 C17H14N4O.2H2O Formula. weight 296.35 196.24 264.23 326.35 Temperature 273(2) K 273(2) K 273(2) K 273(2) K Wavelength 0.71073 A 0.71073 A 0.71073 A 0.71073 A Crystal system orthorhombic Monoclinic Monoclinic Monoclinic Space group Pna21 Cc P21/c P21/n a,Å 18.3273(12) 3.7993(3) 13.1814(14) 7.3636(7) b,Å 16.2782(11) 29.361(2) 11.9694(13) 15.5117(14) c,Å 4.2718(3) 13.7502(10) 7.6380(8) 14.4556(13) α, ◦ 90 90 90 90 β, ◦ 90 91.769(1) 100.217(2) 103.544(1) γ , ◦ 90 90 90 90 Volume, Å3 1274.43(15) 1533.1(2) 1186.0(2) 1605.2(3) Z, Dc, Mg m−3 4, 1.545 8, 1.700 4, 1.480 4, 1.350 −1 µ(Mo-Kα), mm 0.412 0.636 0.106 0.095 F(000) 608 800 544 688 Crystal size, mm 0.28 × 0.15 × 0.15 0.20 ×0.15 × 0.12 0.35 × 0.30 × 0.20 0.20 × 0.15 × 0.10 θ limits, ◦ 1.67–28.62 1.39–28.66 1.57–27.989 1.96–26.24 Reflections collected 10765 6588 9953 12377 Unique obs. Reflections 3045 3461 2785 3230 [Fo > 4σ(Fo)] [R(int) = 0.0188] [R(int) = 0.0183] [R(int) = 0.0190] [R(int) = 0.0242] Goodness-of-fit on F2 1.076 1.037 0.993 1.090 a 2 R1 (F) , wR2 (F ) [I > 2σ(I)] 0.0255, 0.0681 0.0239, 0.0592 0.0348, 0.0883 0.0448, 0.1243 a 2 R1 (F) , wR2 (F ) (all data) 0.0279, 0.0691 0.0254, 0.0597 0.0473, 0.0947 0.0682, 0.1366 Largest diff. peak and hole, e. Å−3 0.291 and −0.155 0.339 and −0.337 0.165 and −0.134 0.355 and −0.195 a b 2 2 2 2 2 1/2 2 2 2 R1 = Σ||Fo| − |Fc||/Σ|Fo|; wR2 = [Σw(Fo − Fc ) /Σw(Fo ) ] where w = 1/[σ (Fo ) + (aP) + bP] where 2 2 P = (Fo + Fc )/3.

4. Conclusions The regioselectivity of the attack of vinyl Grignard reagents to bis(benzothiazolyl)ketone (1) strongly depends on the alkene geometry and on its substitution grade: the exclusive attack to the carbonylic oxygen atom occurring with vinyl Grignard reagents 2a and 2b indicates that the absence of substituents on the vinyl moiety or the presence of an alkyl substituent on the same carbon atom bound to the magnesium might play a key role in driving the regioselectivity of the attack towards the O-alkylation. In the presence of a methyl group bound to the carbon atom in β-position with respect to the Mg atom an almost complete O-alkylation was observed; the alkene was E stereoisomer. However, the Z-isomer undergoes both C-and O-alkylation. From the current data it emerges that the regioselectivity of the addition of vinyl Grignard reagents to 1 cannot be explained only by the steric effect or the geometry of the vinyl moiety but that it can be due to the concomitance of different effects on the mechanistic pathway. The latter was also investigated by reaction between 1 and vinylmagnesium bromide (and 2-methyl-1-propenylmagnesium bromide) under different experimental conditions and in the presence of radical scavengers: the results observed suggest a mechanistic pathway in the O-alkylation involving an intermediate bearing radical oxygen atom and negative charge in benzylic position. By comparing the results from the reaction between 2-propenylmagnesium bromide and benzophenone or bis(2-benzothiazolyl)ketone with the literature data we infer that a polar mechanism is likely involved in the formation of carbinols. The X-ray diffraction studies on four bis(heteroaryl)ketones, i.e., bis(benzothiazolyl)ketone (1), bis(2-thiazolyl)ketone (5), bis(2-benzoxazolyl)ketone (8), and bis(1-methylbenzimidazolyl)ketone (11) and comparison of the structural data supported the speculation that the ability in delocalizing the negative charge in the benzylic position of intermediate may play a key role in driving the attack of the vinyl Grignard reactant towards the O-alkylation.

Supplementary Materials: Supplementary materials are available online. Molecules 2018, 23, 171 13 of 14

Acknowledgments: Work supported by Alma Mater Studiorum—Università di Bologna (RFO funds). Authors thank Luca Zuppiroli for the mass spectra. Author Contributions: C.B. conceived and designed the experiments, analyzed the data and wrote the paper; G.M. and L.C. performed the experiments and analyzed the data; M.M. made crystallographic analyses and analyzed the relevant data; S.B. and M.M. contributed in writing the paper. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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