Unprecedented Multifunctionality of Grubbs And

catalysts

Article Unprecedented Multifunctionality of Grubbs and Hoveyda–Grubbs Catalysts: Competitive Isomerization, Hydrogenation, Silylation and Metathesis Occurring in Solution and on Solid Phase

Maitena Martinez-Amezaga 1, Carina M. L. Delpiccolo 1, Luciana Méndez 1, Ileana Dragutan 2,*, Valerian Dragutan 2 and Ernesto G. Mata 1,*

1 Instituto de Química Rosario (CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina; [email protected] (M.M.-A.); [email protected] (C.M.L.D.); [email protected] (L.M.) 2 Institute of Organic Chemistry, Romanian Academy, 202B Spl. Independentei, P.O. Box 35-108, 060023 Bucharest, Romania; [email protected] * Correspondence: [email protected] (I.D.); [email protected] (E.G.M.); Tel.: +40-21-316-7900 (I.D.); +54-9-341-4370477 (E.G.M.)

Academic Editor: Keith Hohn Received: 28 February 2017; Accepted: 6 April 2017; Published: 9 April 2017

Abstract: This contribution showcases the interplay of several non-metathetic reactions (isomerization, silylation and “hydrogen-free” reduction) with metathesis in systems comprising a functionalized olefin and a soluble or resin-immobilized silane. These competing, one-pot reactions occur under activation by second-generation Ru-alkylidene catalysts. Different olefinic substrates were used to study the influence of the substitution pattern on the reaction outcome. Emphasis is placed upon the rarely reported yet important transformations implying a solid phase-supported silane reagent. Catalytic species involved in and reaction pathways accounting for these concurrent processes are evidenced. An unexpected result of this research was the clearly proved partial binding of the olefin to the resin, thereby removing it from the reacting ensemble.

Keywords: cross-metathesis; reduction; silylation; isomerization; solid-phase; oleﬁns; ruthenium catalyst

1. Introduction Ruthenium metathesis catalysts have long been known to also promote, in homogeneous or heterogeneous phase, different chemical processes [1–3] such as olefin isomerization [4–8], hydrogenation [9], oxidation [10] and oxidative dehydrogenation [11], atom transfer radical addition [12,13], cyclization [14] and polymerization [15], cyclopropanation [16–19], cycloisomerization [20], etc. These mechanistically distinct reactions might compete with metathesis, even to a large extent, producing undesired secondary products, thus diminishing the efficiency of olefin metathesis. Various physical or chemicals methods have been implemented in order to suppress such problematic side reactions (notably isomerization). Thus, with the 2nd generation Grubbs catalyst (1), isomerization induced by in situ generated ruthenium-hydride complexes [4–8,21,22] is negatively influencing the yield and product selectivity, creating difficulties in product separation and purification. Olefin isomerization has been decreased by the addition of electron-deficient benzoquinones (e.g., 1,4-benzoquinones, 10 mol %), tricyclohexylphosphine oxide (0.5 mol %) or phenylphosphoric acid (5 mol %), as well as quinone-containing Hoveyda-type complexes [23–27]. Also proved was that for other 2nd

Catalysts 2017, 7, 111; doi:10.3390/catal7040111 www.mdpi.com/journal/catalysts Catalysts 2017, 7, 111 2 of 13 Catalysts 2017, 7, 111 2 of 14 Also proved was that for other 2nd generation Ru metathesis catalysts, the contribution of the isomerizationgeneration Ru pathway metathesis hinges catalysts, on the thecatalyst contribution loading [28]. of the isomerization pathway hinges on the catalystNevertheless, loading [28 non]. ‐metathetic reactions initiated by ruthenium alkylidene catalysts can provide an expedientNevertheless, entry non-metatheticinto otherwise reactionsinaccessible initiated interesting by ruthenium compounds. alkylidene In particular, catalysts isomerization can provide andan expedient hydrogenation entry into have otherwise industrial inaccessible relevance interesting being used compounds. to convert Inlow particular,‐value coal isomerization‐ or petroleum and‐ basedhydrogenation by‐products have (e.g., industrial lower relevancealpha olefins) being or used olefins to convert from renewable low-value oil coal- feedstocks or petroleum-based into useful startingby-products materials (e.g., for lower the production alpha olefins) of surfactants, or olefins from detergents, renewable lubricants, oil feedstocks cosmetics, into etc. useful [29]. starting materialsWhereas for the the production aforementioned of surfactants, homogeneous detergents, non‐metathetic lubricants, reactions cosmetics, with etc. Grubbs [29]. catalysts are very wellWhereas documented, the aforementioned occasionally homogeneouseven by the pairwise non-metathetic use of metathesis/non reactions with‐metathesis Grubbs protocols catalysts [30],are very there well are some documented, aspects about occasionally the competitive even by reactions the pairwise that useare still of metathesis/non-metathesis unclear. In heterogeneous phase,protocols named [30 ],solid there‐phase are organic some aspectssynthesis, about we have the carried competitive out pioneering reactions work that on are the still application unclear. ofIn a heterogeneous combination of phase, ruthenium named‐catalyzed solid-phase cross organic‐metathesis synthesis, and reduction we have carried to perform out pioneering a formal alkane work metathesison the application to build of C asp combination3–Csp3 linkages of ruthenium-catalyzed [31,32]. Solid‐phase organic cross-metathesis synthesis and (SPOS), reduction initially to performused in peptidea formal chemistry, alkane metathesis is now broadly to build applied Csp3–Csp to3 linkagesthe preparation [31,32]. Solid-phaseof a range of organic biologically synthesis interesting (SPOS), structuresinitially used [33–35]. in peptide chemistry, is now broadly applied to the preparation of a range of biologically interestingApart from structures our work, [33–35 very]. few studies have been published on heterogeneous non‐metathetic reactionsApart with from Grubbs our work, catalysts very [36]; few however, studies have no report been publishedrelated to the on use heterogeneous of solid‐phase non-metathetic reagents has beenreactions disclosed with Grubbsso far. Utilization catalysts [36 of]; reagents however, bound no report to a related solid support to the use has of a solid-phase number of reagentsadvantages has [37]:been (i) disclosed alike traditional so far. Utilization SPOS, purification of reagents boundis achieved to a solid by filtration; support has(ii) areactions number ofcan advantages be monitored [37]: by(i) alikestandard traditional organic SPOS, techniques purification such isas achievedthin‐layer by chromatography filtration; (ii) reactions since starting can be monitoredmaterial and by productstandard are organic in solution techniques phase; such as(iii) thin-layer toxic, explosive chromatography or odorous since startingreagents material become and safe product after immobilization;are in solution phase; and (iv), (iii) perhaps toxic, explosive the most or important odorous reagents present‐ becomeday feature, safe aftersolid immobilization;‐phase reagents andare especially(iv), perhaps suitable the most for flow important chemistry present-day [38]. feature, solid-phase reagents are especially suitable for flowIn chemistry this contribution, [38]. we delve into the different competing pathways for metathesis and non‐ metathesisIn this reactions contribution, that we happen delve intoduring the differentruthenium competing‐catalyzed pathwaysdouble‐bond for metathesisreduction andof functionalizednon-metathesis olefins, reactions under that the happen action of during triethylsilane ruthenium-catalyzed or the unexplored double-bond solid‐phase reduction reagent, 4 of‐ (diethylsilylbutyl)functionalized olefins, polystyrene under resin. the action of triethylsilane or the unexplored solid-phase reagent, 4-(diethylsilylbutyl) polystyrene resin. 2. Results and Discussion 2. ResultsReactions and of Discussion mono‐ or disubstituted alkenes were carried out either homogeneously or with resin‐Reactionssupported of silanes, mono- in or the disubstituted presence of alkenesthe Grubbs were (1 carried) or Hoveyda–Grubbs out either homogeneously (2) initiators or(Figure with 1).resin-supported silanes, in the presence of the Grubbs (1) or Hoveyda–Grubbs (2) initiators (Figure1).

MesN NMes MesN NMes Cl Cl Ru Ru Cl Cl Ph O PCy3

1 2 2nd. Generation 2nd. Generation Grubbs Catalyst Hoveyda-Grubbs Catalyst Mes= mesityl

FigureFigure 1. 1. 2nd2nd generation generation Grubbs Grubbs and and Hoveyda–Grubbs Hoveyda–Grubbs catalysts. catalysts.

We first examined the reduction of trans‐benzyl crotonate (3) with triethylsilane as reducing We ﬁrst examined the reduction of trans-benzyl crotonate (3) with triethylsilane as reducing agent, agent, in homogeneous phase, in presence of catalyst (2) and under microwave(MW)‐enhanced in homogeneous phase, in presence of catalyst (2) and under microwave(MW)-enhanced heating. heating. Detailed analysis of the crude product at different reaction times showed that, in most cases, Detailed analysis of the crude product at different reaction times showed that, in most cases, some some unreacted (3) was found, even for excess of silane (up to 5 equiv.). A summary of the study is unreacted (3) was found, even for excess of silane (up to 5 equiv.). A summary of the study is shown in

Catalysts 2017, 7, 111 3 of 14 Catalysts 2017, 7, 111 3 of 13

Tableshown1. in Along Table with 1. Along the desired with the reduction desired product reduction ( 4 ),product an unexpected (4), an unexpected silylated compound, silylated compound, the benzyl (4-triethylsilyl)-the benzyl (4‐triethylsilyl)trans-crotonate‐trans (‐5crotonate), was formed. (5), was formed.

Table 1. Reduction of transtrans-benzyl‐benzyl crotonate ((33)) withwith triethylsilanetriethylsilane catalyzedcatalyzed byby 22 aa.

O O O catalyst 2 (5 mol%) SiEt3 Et3SiH O O O DCM anh 4 + 5 + 3 3 MW, 150 ºC b Products (3/4/5) b Entry Et3SiH (equiv.) Products (3/4/5) Entry Et3SiH (equiv.) MolarMolar Ratio Ratio PercentagePercentage (%) (%) 1 10.5 0.5 10.5/1.0/1.410.5/1.0/1.4 81/8/11 81/8/11 2 21.0 1.0 4.4/1.0/0.44.4/1.0/0.4 76/17/7 76/17/7 3 32.5 2.5 0.9/1.0/0.30.9/1.0/0.3 41/46/1341/46/13 4 45.0 5.0 0/1.0/0.10/1.0/0.1 0/91/9 0/91/9 a a Conditions: olefinolefin3 ,3 Hoveyda–Grubbs, Hoveyda–Grubbs catalyst catalyst (2; 5 (2 mol; 5 mol %), microwave%), microwave reactor reactor (maximum (maximum power; 150power;◦C), reaction150 C), time reaction 30 min, time in anhydrous30 min, in dichloromethaneanhydrous dichloromethane (DCM); b Determined (DCM); from b Determined the 1H-NMR from (nuclear the 1 magneticH‐NMR resonance)(nuclear magnetic of the crude resonance) product. of the crude product. At low concentration of triethylsilane (0.5 equiv., Entry 1) the allylsilane 5 overpassed 4 in the At low concentration of triethylsilane (0.5 equiv., Entry 1) the allylsilane 5 overpassed 4 in the reaction output, whereas at higher concentrations of triethylsilane, the reduction compound 4 was reaction output, whereas at higher concentrations of triethylsilane, the reduction compound 4 was predominant (Table 1, Entries 3 and 4). The underlying rationale is that the increased availability of the predominant (Table1, Entries 3 and 4). The underlying rationale is that the increased availability hydrogen source at high triethylsilane content raises the concentration of Ru hydride species of the hydrogen source at high triethylsilane content raises the concentration of Ru hydride species responsible for the hydrogenation pathway, favouring reduction over hydrosilylation. Thus, an responsible for the hydrogenation pathway, favouring reduction over hydrosilylation. Thus, an interplay between two non‐metathetical reactions—reduction and isomerization—is unmasked in the interplay between two non-metathetical reactions—reduction and isomerization—is unmasked in the present study. Intervention of isomerization was to be expected, especially because we operated at high present study. Intervention of isomerization was to be expected, especially because we operated at high temperature (150 °C) using the 2nd generation Grubbs catalyst known to be isomerization‐prone. The temperature (150 ◦C) using the 2nd generation Grubbs catalyst known to be isomerization-prone. The reduction product 4 may arise either directly from 3 or from its isomerized counterpart 6 (vide infra). reduction product 4 may arise either directly from 3 or from its isomerized counterpart 6 (vide infra). Interestingly, we have previously reported that, under conditions similar to Entry 4 but using Interestingly, we have previously reported that, under conditions similar to Entry 4 but using the the Grubbs catalyst (1), a nearly quantitative yield of 4 was obtained, without formation of any Grubbs catalyst (1), a nearly quantitative yield of 4 was obtained, without formation of any silylated silylated compound [31]. compound [31]. Though olefin reduction with Et3SiH activated by Grubbs carbenes is a well‐known catalytic Though olefin reduction with Et SiH activated by Grubbs carbenes is a well-known catalytic process, its mechanism is still not very3 clear [2,9,39,40]. Cossy et al. have proposed a mechanism that process, its mechanism is still not very clear [2,9,39,40]. Cossy et al. have proposed a mechanism involves the addition of Et3SiH to the Ru carbene to form an active Ru‐hydride species (A) (Scheme that involves the addition of Et SiH to the Ru carbene to form an active Ru-hydride species (A) 1) [9]. Then, species A would give3 B or C by insertion of 3 into the Ru–H bond. Lastly, B (or C) would (Scheme1)[ 9]. Then, species A would give B or C by insertion of 3 into the Ru–H bond. Lastly, suffer an elimination reaction regenerating the ruthenium carbene. In our case, hexaethyldisiloxane B (or C) would suffer an elimination reaction regenerating the ruthenium carbene. In our case, was detected in the final crude mixture. Formation of disiloxanes was also reported by Cossy et al. in hexaethyldisiloxane was detected in the final crude mixture. Formation of disiloxanes was also the same publication [9]. Silanes have weak Si‐H bonds and formation of hexaethyldisiloxane can be reported by Cossy et al. in the same publication [9]. Silanes have weak Si-H bonds and formation of explained by an oxidation of Et3SiH [41]. It is known that alkyldisiloxanes can be obtained by air hexaethyldisiloxane can be explained by an oxidation of Et3SiH [41]. It is known that alkyldisiloxanes oxidation from Et3SiH in the presence of Lewis acids [42]. At the beginning, a radical pathway was can be obtained by air oxidation from Et SiH in the presence of Lewis acids [42]. At the beginning, considered, since formation of free radicals3 by changing oxidation state from +2 to +3 in some carbene‐ a radical pathway was considered, since formation of free radicals by changing oxidation state from ruthenium complexes had been reported [43]. Nevertheless, reaction was unaffected by addition of a +2 to +3 in some carbene-ruthenium complexes had been reported [43]. Nevertheless, reaction was radical inhibitor such as di‐tert‐butyl nitroxide (DTBN), consequently a radical mechanism was ruled unaffected by addition of a radical inhibitor such as di-tert-butyl nitroxide (DTBN), consequently a out. radical mechanism was ruled out. Formation of the other reaction product, the silylated compound 5, may occur through the Formation of the other reaction product, the silylated compound 5, may occur through the following sequential steps: (i) isomerization of the internal olefin 3 into the terminal olefin 6; (ii) direct following sequential steps: (i) isomerization of the internal olefin 3 into the terminal olefin 6; (ii) direct silylation of the latter to the corresponding vinylsilane (7); (iii) finally, a second isomerization of 7 to silylation of the latter to the corresponding vinylsilane (7); (iii) finally, a second isomerization of 7 to the allylsilane 5 (Scheme 2). the allylsilane 5 (Scheme2).

Catalysts 2017, 7, 111 4 of 14 CatalystsCatalysts 20172017,,, 77,,, 111111 44 ofof 1313

O OO HH

Et33SiSiEt33 Et 3SiH BnOBnO Et3SiSiEt3 Et33SiH Ru CH2 Ru CH22 HH 44

EtEt33SiHSiH 3 HH SiEt 3 SiEt33 RuRu AA OO OO O BnO OO BnO HH BnO Ru BnOBnO BnO Ru RuRu BnO EtEt33SiSi 3 HH 33 SiEt 3 CC BB SiEt33

SchemeScheme 1.1.1. ProposedProposedProposed mechanism mechanismmechanism for forforfor Et3 SiH-reductionEtEt333SiHSiH‐‐‐reductionreduction of oleﬁn ofof olefinolefin3 activated 33 activatedactivated by catalysts byby catalystscatalysts1 or 2, according 11 oror 22,,, accordingtoaccording Cossy et tototo al. CossyCossy [9]. etet al.al. [9].[9].[9].

O O O isomerizationisomerization O OO O catalyst 2 isomerization catalyst 2 EtEt3SiHSiH SiEtSiEt3 O 3 O 3 OO O O DCM anh 7 DCM anh 66 7 33 MW,MW, 150 150 ºC ºC

isomerizationisomerizationisomerization

OO SiEt SiEt33 OO 5 55

SchemeScheme 2. 2. FormationFormation ofof thethethe silylatedsilylated derivative derivative 55...

AnAn allylic allylic mechanism, mechanism, byby intermediacyintermediacy intermediacy ofof allyl allyl-Ruallyl‐‐RuRu complexes,complexes, mightmight alsoalso bebe considered considered ininin thethe the generation of 5 from thethe internalinternal (3) and terminalterminal olefin (6) when thethe disilane Et33SiSiEt33 would be generation of 5 fromfrom thethe internalinternal ((33)) andand terminalterminal oleﬁnolefin ((66)) whenwhen thethe disilanedisilane EtEt33SiSiEtSiSiEt33 would be presentpresent in inin the thethe reacting reacting system system (Scheme (Scheme3 3).3).).

O O OO SiSi BnO BnO BnOBnO 5 55 33 OO L Ru LLnnRuRu LL BnOBnO 66

O OO OO BnO BnOBnO BnOBnO

L Ru SiEt LLnRuRu Ln-1n-1Ru SiEt33 n

Et Si L Et SiSiEt Et33Si L Et33SiSiEt33

SchemeScheme 3.3. PossiblePossible allylicallylic mechanismmechanism forforfor thethethe silylationsilylation ofof olefinsolefins oleﬁns 33 andand 66 tototo thethe the allylsilane allylsilane 55...

Catalysts 2017, 7, 111 5 of 14 Catalysts 2017, 7, 111 5 of 13

As mentioned mentioned in in the the Introduction, Introduction, solid solid-phase‐phase reagents reagents are are gaining gaining popularity popularity in synthesis in synthesis due todue some to some comparative comparative advantages advantages especially especially useful useful for flow for chemistry. ﬂow chemistry. Particularly, Particularly, to the best to the of bestour knowledge,of our knowledge, silanes silanesimmobilized immobilized on solid on solid phase phase have have not not been been applied applied to to non-metatheticnon‐metathetic hydrogenations. Using high high-loading‐loading Merrifield Merriﬁeld resin, we prepared 4-(diethylsilylbutyl)4‐(diethylsilylbutyl) polystyrene resin ( 8) in two steps according to literature [44] [44] (Table 2 2).). UponUpon reactingreacting benzylbenzyl trans‐-crotonatecrotonate ( (33)) with 8 in presence of catalystcatalyst 1 oror 22,, a differentdifferent outcomeoutcome has beenbeen attained.attained. Concerned are both the nature of the products and a more intricate pattern of the reactions routes, this time also involving metathesis (Table 2 2).).

Table 2.2. ReductionReduction ofof benzyl benzyltrans trans-crotonate‐crotonate ( 3()3) using using resin-immobilized resin‐immobilized silane silane (8 )(8 or) or triethylsilane, triethylsilane, in inpresence presence of catalystof catalyst1 or 1 or2. 2.

SiEt2H O O 8 O catalyst (5 mol %) O DCM anh 3 4 MW, 150 ºC, 30 min

Reaction Conditionsa a Entry Olefin Catalyst (5 Catalystmol %) SilaneSilane (Equivalents) Reaction Conditions Ratio 4:3 b Entry Olefin Temp. (°C) Time (h) Ratio 4:3 b (5 mol %) (Equivalents) Temp. (◦C) Time (h) 1 3 2 8 c, 3.0 Reflux 24 1:19 c 2 1 3 32 2 88 ,c, 3.0 2.5 Reflux55 (sealed system) 2416 1:191:5.6 c 55 (sealed d e 3 2 3 32 2 88c,, 2.5 2.5 150 (MW) 160.5 1:5.61:0.3 4 3 2 ‐ f system)150 (MW) d 0.5 1:0.3 e c d e 5 3 3 31 2 88 ,c, 2.5 2.5 150 (MW)150 (MW) d 0.50.75 1:0.31:3.2 e f d e 6 4 3 32 2 8 c-, 0.75 150 (MW)150 (MW) d 0.50.5 1:0.3ND g c d e 7 5 Resin from Entry3 6 2 1Et 83SiH, 2.5 (2.5) 150 (MW)150 (MW) d 0.750.5 1:3.21:0.6 h 3 2 8 c d g a 6In anhydrous dichloromethane; b Estimated from, 0.75 1H‐NMR150 (MW)of the crude reaction0.5 mixture; ND c 7 Resin from Entry 6 2 Et SiH (2.5) 150 (MW) d 0.5 1:0.6 h Synthesized resin, loading 2.8 mmol/g (theoretical3 loading calculated from the initial loading level of a In anhydrous dichloromethane; b Estimated from 1H-NMR of the crude reaction mixture; c Synthesized resin, Merrifield resin (3.8 mmol/g)); d MW=microwave heating; e The 1H‐NMR spectrum of the crude loading 2.8 mmol/g (theoretical loading calculated from the initial loading level of Merrifield resin (3.8 mmol/g)); reactiond MW = mixture microwave showed heating; a bye The‐product,1H-NMR subsequently spectrum of identified the crude as reaction 11 (see mixture Supplementary showed a by-product,Materials, Figuressubsequently S15–S17); identified f The as crude11 (see from Supplementary Entry 3 was Materials, filtered and, Figures after S15–S17); adding af Thesupplementary crude from Entry amount 3 was of g catalystfiltered and, 2 (5 after mol adding%), heating a supplementary was repeated; amount g The of product catalyst 2 composition(5 mol %), heating was wasnot determined repeated; The (ND), product the composition was not determined (ND), the filtered resin was used in a subsequent experiment (Entry 7; see also h 1 filteredtext); h The resin1H-NMR was used spectrum in a ofsubsequent the crude reaction experiment mixture (Entry showed 7; asee by-product, also text); identified The H by‐NMR NMR techniquesspectrum ofas 5the(see crude Scheme reaction1 and Supplementary mixture showed Materials, a by‐product, Figures S1–S9). identified by NMR techniques as 5 (see Scheme 1 and Supplementary Materials, Figures S1–S9). Only low conversions to the reduced product 4 couldcould be be attained attained in in refluxing refluxing dichloromethane, dichloromethane, even atat long long reaction reaction times times and and with with excess excess of silane. of silane. (Table 2(Table, Entries 2, 1 Entries and 2). Switching1 and 2). toSwitching microwave to microwaveheating greatly heating improved greatly conversion. improved Underconversion. best conditions Under best (Entry conditions 3), approximately (Entry 3), approximately one-quarter of onethe starting‐quarter material of the starting (3) was material still present (3) was after still reaction. present Moreover, after reaction. the IR spectrum Moreover, of the the IR resin spectrum recovered of −1 thefrom resin a typical recovered experiment from a typical showed experiment an intense showed signal at an 2100 intense cm signal(Si–H at 2100 stretching), cm−1 (Si–H indicating stretching), that indicatingthe resin still that preserved the resin still some preserved of its reducing some of ability. its reducing Consequently, ability. Consequently, in a further attemptin a further to enhance attempt toproduction enhance production of 4 a supplementary of 4 a supplementary amount of amount catalyst of2 catalyst(5 mol 2 %) (5 wasmol %) added was toadded the filteredto the filtered crude crudeproduct product from Entry from 3Entry and the3 and mixture the mixture heated heated (MW) for (MW) another for another half hour half (Entry hour 4), (Entry but to 4), no but avail. to no avail.Whenever conversion to 4 has reached higher values (Entries 3 and 4), formation of a secondary productWhenever (11) was conversion apparent to from 4 has the reached additional higher signal values observed (Entries in 3 theand NMR 4), formation spectrum of ofa secondary the crude productreaction mixture.(11) was Catalysisapparent byfrom1 (Entry the additional 5) resulted signal in lesser observed production in the ofNMR4, while spectrum also the of secondarythe crude reactionproduct 11mixture.could beCatalysis evidenced by 1 by (Entry NMR. 5) resulted in lesser production of 4, while also the secondary productAt this11 could point be some evidenced conclusions by NMR. became obvious: (i) always approximately one-quarter of the startingAt this material point does some not conclusions react; (ii) catalystbecame 2obvious:is more (i) active always than approximately1, in agreement one with‐quarter its stability of the startingunder the material rather harshdoes not conditions react; (ii) (high catalyst temperature) 2 is more employed;active than (iii) 1, in MW-assisted agreement with heating its stability leads to underbetter yieldsthe rather than harsh refluxing conditions in dichloromethane; (high temperature) (iv) additional employed; silane (iii) has MW no‐assisted positive heating effect. leads to better yields than refluxing in dichloromethane; (iv) additional silane has no positive effect.

Catalysts 2017, 7, 111 6 of 14 Catalysts 2017,, 7,, 111 6 of 13 Catalysts 2017, 7, 111 6 of 13 By virtue of the starting benzyl crotonate (3) not being entirely consumed in all experiments with ByBy virtuevirtue ofof thethe startingstarting benzylbenzyl crotonatecrotonate ((33))) notnot beingbeing entirelyentirely consumedconsumed ininin allall experimentsexperiments withwith resin‐supported silane 8, a reasonable assumption would be that crotonate 3 partially binds to the resin-supportedresinresin‐‐supportedsupported silanesilane 88,, aa reasonablereasonablereasonable assumptionassumption wouldwould bebe thatthatthat crotonatecrotonate 33 partiallypartially bindsbinds toto thethethe resin. To verify this hypothesis, a reaction was carried out (Table 2, Entry 6) using only about one‐ resin.resin.resin. ToTo verify verify this thisthis hypothesis, hypothesis, a reactiona reactionreaction was was carried carried out out (Table (Table(Table2, Entry 2, Entry 6) using 6) using only aboutonly about one-third one‐‐ third (0.75 equiv.) of the usual amount of silane. After 0.5 h, the resin was filtered and an IR spectrum (0.75thirdthird equiv.) (0.75(0.75 equiv.) of the of usual thethe usual amount amount of silane. of silane.silane. After After 0.5 h, 0.5 the h, resin thethe resinresin was ﬁltered was filteredfiltered and an and IR an spectrum IRIR spectrumspectrum was was run, showing an absorption at 1716− cm−1 (C=O bond stretching) characteristic for a carboxyl run,was showingrun,run, showingshowing an absorption an absorption at 1716 at cm 17161 (C=O cm −1 bond(C=O(C=O stretching)bond stretching)stretching) characteristic characteristic for a carboxyl forfor a carboxyl moiety. moiety. According to this result, the resin‐bound compound was proposed to have the structure 10 Accordingmoiety. According to this result, toto thisthis the result,result, resin-bound thethe resinresin compound‐‐bound compound was proposed was proposed to have the toto structure have thethe10 structurestructureindicating 10 indicating the immobilization of the benzyl crotonate (Figure 2). Confirmation came from the further theindicatingindicating immobilization thethe immobilizationimmobilization of the benzyl of thethe crotonate benzyl (Figure crotonate2). Conﬁrmation(Figure(Figure 2). Confirmation came from came the further fromfrom thethe treatment furtherfurther treatment of 10 with Et3SiH and catalyst 2 that allowed the catalytic cycle to continue, affording fresh oftreatment10 with Etof3 10SiH with and Et catalyst3SiH and2 thatcatalyst allowed 2 that the allowed catalytic the cycle catalytic to continue, cycle to affording continue, fresh affording product fresh4 product 4 (Table 2, Entry 7; Scheme 4). (Tableproduct2, Entry 4 (Table(Table 7; Scheme 2, Entry4 ).7; Scheme 4).

O Si O Si Et2 Et2 O 2 O 10 10 FigureFigure 2.2. Crotonate 33 boundbound toto thethe resinresin ((1010).). Figure 2. Crotonate 3 bound toto thethe resinresin ((10).).

SiEt H SiEt2H SiEt2H 8 8 (0.75 eq) (0.75(0.75 eq) eq) catalyst 2 (5 mol%) catalyst 2 (5(5 mol%) mol%) O i)MW,150ºC,30min Et SiH O O i)MW,150ºC,30min Et3SiH O ii)i)MW,150ºC,30min filtration 2 (5Et3 mol%)SiH O ii) filtration 2 (5(5 mol%) mol%) O ii) filtration 10 O O - soluble products 10 MW, 150ºC, 30 min O - soluble products MW, 150ºC, 30 min 3 - soluble products 4 3 4 Scheme 4. Generation of the resin‐bound crotonate 10 and its further reduction to 4. SchemeScheme 4.4. Generation ofof thethe resin-boundresinresin‐‐bound crotonatecrotonate 1010 andand itsitsits furtherfurtherfurther reductionreductionreduction to toto 4 4...

Under the best identified conditions for the “hydrogen‐free” reduction of 3 with resin 8 (Table UnderUnder thethe bestbest identiﬁed identified conditions conditions for for the the “hydrogen-free” “hydrogen‐free” reduction reduction of of3 with3 with resin resin8 (Table8 (Table2, 2, Entries 3 and 5), we found as well a significant amount of a secondary product (11), formed along Entries2, Entries 3 and 3 and 5), we5), we found found as well as well a signiﬁcant a significant amount amount of a secondaryof a secondary product product (11), formed(11), formed along along with with the desired 4 (molar ration 4::11 = 1:0.3) (Scheme 5). Compound 11 was unequivocally deduced thewith desired the desired4 (molar 4 (molar ration ration4:11 =4: 1:0.3)11 = 1:0.3) (Scheme (Scheme5). Compound 5). Compound11 was 11 was unequivocally unequivocally deduced deduced by by NMR spectroscopy to be 1,5‐dibenzyl glutarate. NMRby NMR spectroscopy spectroscopy to be to 1,5-dibenzyl be 1,5‐dibenzyl glutarate. glutarate.

SiEt H SiEt2H SiEt2H O O O O O 8 O O O 8 O O O + O O O O + O O 3 catalyst 1 or 2 (5(5 mol%) mol%) 4 11 3 catalyst 1 or 2 (5 mol%) 4 11 3 MW, 150ºC 4 11 MW,DCM 150ºC anh DCM anh Ratio = 1 : 0,3 Ratio = 1 : 0,3

Scheme 5. Reduction of 3 with immobilized silane (resin 8). Scheme 5. Reduction of 3 with immobilized silane (resin 8). Scheme 5. Reduction of 3 with immobilizedimmobilized silanesilane (resin(resin 8).). We assume that diester 11 arises by several successive transformations. First, isomerization species, We assume that diester 11 arises by several successive transformations. First, isomerization formedWe in assume situ from thatthat the diester catalyst, 11 triggerarises by double-bond severalseveral successivesuccessive migration transformations.transformations. in 3 [23,45,46] toFirst, give isomerizationisomerization the terminal species, formed in situ from the catalyst, trigger double‐bond migration in 3 [23,45,46] to give the olefinspecies,species,6 andformedformed a trans inin situ-situcis isomerizationfromfrom thethe catalyst, to olefin triggertrigger12 double[23] (Scheme‐‐bond 6migration). Then, cross-metathesis inin 3 [23,45,46][23,45,46] toto between give thethe terminal olefin 6 and a trans‐cis isomerization to olefin 12 [23] (Scheme 6). Then, cross‐metathesis olefinterminalterminal3 (or olefin12) and6 and6, a promoted transtrans‐‐ciscis isomerizationisomerization by the ruthenium toto olefin alkylidenes 12 [23][23] (Scheme originated(Scheme 6). from Then,1 orcross2,‐ leads‐metathesis to 13 between olefin 3 (or 12) and 6, promoted by the ruthenium alkylidenes originated from 1 or 2, leads (betweentrans and olefincis). 3 Finally, (or(or 12)) saturated and 6,, promoted diester 11by isthethe formed rutheniumruthenium by hydrogenation alkylidenes originated of 13, under fromfrom activation 1 or 2,, leadsleads by to 13 (trans and cis). Finally, saturated diester 11 is formed by hydrogenation of 13, under activation by short-livedtoto 13 ((transtrans and Ru-hydride ciscis).). Finally, species saturatedsaturated arising diester from the 11 is catalyst.is formedformed These by hydrogenation species transfer of 13 hydrogen,, under activation atoms from by short‐lived Ru‐hydride species arising from the catalyst. These species transfer hydrogen atoms from theshortshort immobilized‐‐livedlived Ru‐‐hydride silane speciesspecies moieties arising to the fromfrom C–C thethe double catalyst. bond. These Formation speciesspecies transfer oftransfer13 was hydrogen not detected atoms under fromfrom the immobilized silane moieties to the C–C double bond. Formation of 13 was not detected under homogenousthethe immobilizedimmobilized phase. silanesilane This moieties could be toto attributed thethe C–C double to a faster bond. reduction Formation under of triethylsilane,13 was not detected as compared under homogenous phase. This could be attributed to a faster reduction under triethylsilane, as compared withhomogenous supported phase. silane This8, and could therefore be attributed reduction toto a of fasterfaster3 prevents reductionreduction any furtherunder triethylsilane,triethylsilane, cross-metathesis as compared reaction. with supported silane 8, and therefore reduction of 3 prevents any further cross‐metathesis reaction. with supportedsupported silanesilane 8,, and thereforetherefore reductionreduction of 3 prevents any furtherfurther cross‐‐metathesis reaction.reaction.

Catalysts 2017, 7, 111 7 of 14 Catalysts 2017, 7, 111 7 of 13 Catalysts 2017, 7, 111 7 of 13

1 or 2 (5 mol%) O 1MW,or 2 (5 150ºC mol%) O O O MW,DCM 150ºC anh O O O DCM anh O + O + 3 O O + O + 3 3 12 3 6 6 12 1 or 2 (5 mol%) 1MW,or 2 (5 150ºC mol%) O O MW,DCM 150ºC anh O O 6 DCM anh O O 6 3 or 12 O O 3 or 12 13 13

SiEt2H O O SiEt2H O O 8 13 O O 8 13 O O 1 or 2 (5 mol%) 11 1MW,or 2 (5 150ºC mol%) 11 MW,DCM 150ºC anh DCM anh SchemeScheme 6. 6. CrossCross-metathesis‐metathesis pathway pathway yielding yielding product product 1111.. Scheme 6. Cross‐metathesis pathway yielding product 11. Intriguingly however, homometathesis of 3 (Scheme 7, path b) seems not to intervene, likely Intriguingly however, homometathesis of 3 (Scheme 77,, pathpath b)b) seemsseems notnot toto intervene, intervene, likelylikely because of steric reasons (internal double bond). Indeed, product E (that would have been formed because of steric reasons (internal double bond). Indeed, product E (that would have been formed through path b and c) has not been detected among the reaction products. through path b and c) has not been detected amongamong thethe reactionreaction products.products.

a reduction O a reduction O O O 4 4 O O Grubbs catalyst (1 or 2) O Grubbs catalyst (1 or 2) O SiEt2H SiEt H 8 2 3 8 3 O O O O O O O b homometathesis D O b homometathesis D c c SiEt2H reduction SiEt2H reduction 8 8

O O O O O O E O E O Scheme 7. Hypothetical formation of compound E by tandem homometathesis and reduction. Scheme 7. Hypothetical formation of compound E by tandem homometathesis and reduction. Scheme 7. Hypothetical formation of compound E by tandem homometathesis and reduction. In this intricate catalytic process, the metathesis catalysts (1 or 2) generate prevailingly Ru In this intricate catalytic process, the metathesis catalysts (1 or 2) generate prevailingly Ru species for isomerization and hydrogenation, leaving, however, some of the initial catalyst to speciesIn thisfor intricateisomerization catalytic and process, hydrogenation, the metathesis leaving, catalysts however, (1 or 2) generatesome of prevailinglythe initial catalyst Ru species to promote cross‐metathesis of 3 (or 12) with 6. The validity of this interpretation is confirmed by the forpromote isomerization cross‐metathesis and hydrogenation, of 3 (or 12) with leaving, 6. The however, validity of some this interpretation of the initial catalystis confirmed to promote by the preponderance of compound 4 among the reaction products. cross-metathesispreponderance of ofcompound3 (or 12 )4 among with 6 .the The reaction validity products. of this interpretation is confirmed by the Inasmuch as olefin 3 has a disubstituted double bond, we next chose, for comparison, the mono‐ preponderanceInasmuch as of olefin compound 3 has 4a disubstitutedamong the reaction double products. bond, we next chose, for comparison, the mono‐ substituted olefin 14 (acetyleugenol) as starting material. Interestingly, on reacting 14 with substitutedInasmuch olefin as olefin14 (acetyleugenol)3 has a disubstituted as starting double material. bond, weInterestingly, next chose, on for reacting comparison, 14 with the triethylsilane in solution under the usual conditions, the isomerized compound 15 was obtained as mono-substitutedtriethylsilane in solution olefin 14under(acetyleugenol) the usual conditions, as starting the material. isomerized Interestingly, compound on 15 reactingwas obtained14 with as the only product (Scheme 8). the only product (Scheme 8).

Catalysts 2017, 7, 111 8 of 14

triethylsilaneCatalysts 2017, 7 in, 111 solution under the usual conditions, the isomerized compound 15 was obtained as8 theof 13 CatalystsCatalysts 2017 2017, 7, ,7 111, 111 8 8of of 13 13 only product (Scheme8).

Et SiH EtEt3SiHSiH 2 (533 mol%) O 22(5(5 mol%) mol%) O OO OOO OO OO DCM anh O DCM anh OO Reflux or MW, 150 ºC O 14 Reflux or MW, 150 ºC OO 15 14 15

Scheme 8. Isomerization of acetyleugenol (14) with Et3SiH and catalyst 2. 3 SchemeScheme 8. 8. Isomerization Isomerization of of acetyleugenol acetyleugenol ((14 (14)) with) with Et Et33SiHSiH and and catalyst catalyst 2 .2 .

Anew, thisthis result gives evidence thatthat double‐bond migration from thethe terminalterminal toto thethe internalinternal Anew, thisthis resultresult givesgives evidenceevidence thatthat double-bonddouble‐bond migration from the terminal to the internal olefin isis takingtaking place [9] (as already seen for isomerizationisomerization of 3 toto 6). A plausible mechanism for olefin oleﬁnolefin is taking place [[9]9] (as already seen for isomerization of 3 to 6). A plausible mechanism for olefin oleﬁn isomerization,isomerization, as shown inin Scheme 9, involvesinvolves a cyclic pathway, throughthrough thethe intermediacyintermediacy of species isomerization, as shown in Scheme 9 9,, involvesinvolves aa cycliccyclic pathway,pathway, through through the the intermediacy intermediacy of of species species II–IV, similarly toto an earlier proposal by Schmidt [4]. II–IV, similarlysimilarly toto anan earlierearlier proposalproposal byby SchmidtSchmidt [ [4].4].

Ru CH2 RuRu CHCH22

R R Ru H R RR RuRu H H I I I R RR

R R Ru H Ru H RuRu H H RuRu H H IV II IVIV IIII

R H RR HH Ru RuRu IIIIII III Scheme 9. Plausible mechanism for isomerization of terminal olefins to internal olefins (adapted from SchemeScheme 9. 9. Plausible Plausible mechanism mechanism for for isomerization isomerization of of terminal terminal olefins oleﬁns olefins to to internal internal olefins oleﬁns olefins (adapted (adapted from from ref. [4]). ref.ref. [[4]). 4[4]).]).

Additional results have been obtained for reduction with resin 8, of a further substrate, the AdditionalAdditional results results results have have have been been been obtained obtained obtained for reductionfor for reduction reduction with resinwith with 8resin ,resin of a further8 8, ,of of a a substrate,further further substrate, substrate, the dimethyl the the dimethyl itaconate (16) bearing two carbonyl groups and a 1,1‐disubstituted olefin (Scheme 10). itaconatedimethyldimethyl (itaconate 16itaconate) bearing ( 16(16 two) )bearing bearing carbonyl two two groupscarbonyl carbonyl and groups groups a 1,1-disubstituted and and a a 1,1 1,1‐disubstituted‐disubstituted oleﬁn (Scheme olefin olefin 10 (Scheme (Scheme). 10). 10).

SiEt2H SiEtSiEt2H2H 8 (2,5(2,5 eq) eq) O 88 (2,5 eq) OO O catalyst 2 (5 mol %) O O catalystcatalyst22(5(5 mol mol %) %) O OO OO + 16 + byproducts O DCM anh O ++ 1616 ++ byproductsbyproducts O DCMDCM anh anh O O MW, 150 ºC, 30 min O OO MW,MW, 150 150 ºC, ºC, 30 30 min min OO 16 17 1616 17 SchemeScheme 10. 10.Reduction Reduction of of dimethyl dimethyl itaconate itaconate ( 16(16)) with with immobilized immobilized silane silane ( 8(8)) and and catalyst catalyst2 .2. SchemeScheme 10. 10. Reduction Reduction of of dimethyl dimethyl itaconate itaconate ( 16(16) )with with immobilized immobilized silane silane ( 8()8 )and and catalyst catalyst 2 .2 .

After filtering the resin, removing the solvent and drying the product under reduced pressure, AfterAfter filteringfiltering filtering the the resin, resin, removing removing the the solvent solvent and and drying drying the the product product under under reduced reduced pressure, pressure, we recovered only 27% of the feed (starting materials + catalyst).1 1H‐NMR analysis of the crude wewe recoveredrecovered recovered onlyonly only 27%27% 27% ofof of thethe the feedfeed feed (starting(starting (starting materialsmaterials materials ++ + catalyst).catalyst). catalyst). 1 HH-NMR1H‐NMR‐NMR analysis analysis of of the the crude crude product testified to the presence of the starting 16, the reduced compound 17, as well as of several productproduct testifiedtestified testified to to the the presence presence of of the the starting starting 16 16,, , thethe the reducedreduced reduced compound compound 17 17, , as as well well as as of of several several unidentified by‐products. IR spectrum of the resin recovered after the reaction revealed an intense unidentifiedunidentifiedunidentified by-products.by by‐products.‐products. IR IR IR spectrum spectrum of of the the resin resin recovered recovered after after the the reaction reaction revealed revealed an an intense intense bifid absorption at 1718 and 1735 cm−1, corresponding to C=O stretching of the two carbonyls from bifidbifid absorption absorption at at 1718 1718 and and 1735 1735 cm cm−1−,1 ,corresponding corresponding to to C=O C=O stretching stretching of of the the two two carbonyls carbonyls from from the dimethyl itaconate. This result supports our assumption that in the catalytic cycle, a C–Si bond thethe dimethyl dimethyl itaconate. itaconate. This This result result supports supports our our assumption assumption that that in in the the catalytic catalytic cycle, cycle, a a C–Si C–Si bond bond (analogous to 10) is formed between the silane and 16. Consequently, in case of immobilized silanes, (analogous(analogous to to 10 10) )is is formed formed between between the the silane silane and and 16 16. .Consequently, Consequently, in in case case of of immobilized immobilized silanes, silanes, some of the starting material ends up anchored to the solid phase, causing a decrease in the yield. somesome of of the the starting starting material material ends ends up up anchored anchored to to the the solid solid phase, phase, causing causing a a decrease decrease in in the the yield. yield.

Catalysts 2017, 7, 111 9 of 14 biﬁd absorption at 1718 and 1735 cm−1, corresponding to C=O stretching of the two carbonyls from the dimethyl itaconate. This result supports our assumption that in the catalytic cycle, a C–Si bond (analogous to 10) is formed between the silane and 16. Consequently, in case of immobilized silanes, some of the starting material ends up anchored to the solid phase, causing a decrease in the yield.

3. Materials and Methods

3.1. General Considerations Chemical reagents were purchased from commercial sources and were used without further puriﬁcation unless noted otherwise. Solvents were analytical grade or were puriﬁed by standard procedures prior to use. Resins were purchased from Aldrich. Reactions requiring inert atmosphere were carried out under a high-purity dry nitrogen atmosphere. Solvents from these reactions were transferred with syringe under high-purity dry nitrogen pressure. Reagents were transferred in that way or with Gilson micro-pipettes of 100–1000 µL or 20–200 µL.

3.2. Instrumental and Physical Data 1H-NMR spectra were recorded in a Bruker Avance spectrometer (Bruker Analytik GmbH, Karlsruhe, Germany) at 300 MHz, in CDCl3 with tetramethylsilane (TMS) as internal standard. 13 C-NMR spectra were recorded on the same apparatus at 75 MHz with CDCl3 as solvent and reference (76.9 ppm). Chemical shifts (δ) are reported in ppm upfield from TMS and coupling constants (J) are expressed in Hertz. In the preparation of the samples for 13C gel-phase NMR, 50–80 mg of resin is placed in a standard NMR tube and 0.5 mL of CDCl3 is slowly added in order to obtain a gel, which is homogenized by sonication. Spectra were run according to the literature [47]. Mass spectra were recorded on a Shimadzu QP2010 Plus apparatus (Shimadzu Corporation, Kyoto, Japan) at an ionization voltage of 70 eV equipped with a SPBTM-1 capillary column (internal diameter 0.25 mm, length 30 m). High-resolution mass spectra were obtained with a Bruker MicroTOF-Q II instrument (Bruker Daltonics, Billerica, MA, USA). Detection of the ions was performed in electrospray ionization, positive ion mode. Solid-phase reactions were carried out in polypropylene cartridges equipped with a frit (Supelco, Bellefonte, PA, USA), unless reflux or microwave conditions were required, in that case standard glassware was used. All solid-phase reaction mixtures were stirred at the slowest rate. The microwave-assisted chemical transformations were performed using a CEM Discover LabMate reactor (CEM Corporation, Matthews, NC, USA), using the standard heating program in which the operator chooses the final temperature and the equipment automatically adjusts the delivered power in order to maintain the final temperature constant. Infrared spectra were recorded on a Shimadzu FT-IR spectrometer model 8101 (Shimadzu Corporation, Kyoto, Japan). The resin samples were measured as dispersions in KBr discs, made by compression of a mixture finely powdered in an agate mortar, the approximate composition being 3 mg of sample in 100 mg of KBr.

3.3. Synthetic Procedures

3.3.1. Synthesis of 4-(Diethylsilylbutyl) Polystyrene Resin (8) Merrifield resin (3.8 mmol/g, 1.9 mmol, 0.5 g) was swelled under gentle stirring in anhydrous toluene (20 mL). Allylmagnesium chloride (2M in tetrahydrofuran [THF], commercial solution) was added (2.6 equiv, 4.92 mmol, 2.5 mL). The mixture was stirred at 60 ◦C for 12 h. After filtration, the resin was washed with THF, 20 mL of a THF/HCl 1N solution (3/1) were added, and the mixture was stirred for 12 h at 45 ◦C. After filtration, the resin was sequentially washed with THF (3 × 10 mL), MeOH (3 × 10 mL), CH2Cl2 (3 × 10 mL) and finally dried under high vacuum. The resin was analyzed Catalysts 2017, 7, 111 10 of 14 by IR and 13C gel-phase NMR in order to confirm formation of the intermediate compound and then the second stage of synthesis was carried out: A solution of Wilkinson catalyst [RhCl(PPh3)3] (0.4 mol %, 8 × 10−3 mmol, 8 mg) in 20 mL of anhydrous toluene was added to the resin and the mixture was stirred for several minutes. The mixture was then treated with excess of Et2SiH2 (2 equiv., 4 mmol, 0.5 mL) and left to stir for 2 h at r.t. After that, the resin was filtered and washed with toluene (4Catalysts× 15 mL),2017, 7 THF, 111 (4 × 15 mL), DCM (4 × 15 mL) and finally dried under high vacuum. IR spectroscopy10 of 13 13 andCatalystsC 2017 gel-phase, 7, 111 NMR were performed to corroborate if the expected resin 8 was obtained [4410]. of 13 3.3.2. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane Catalysts3.3.2. General 2017, 7, 111 Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane10 of 13 3.3.2. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane The corresponding olefin and Et3SiH were added to a microwave tube equipped with stirrer and 3.3.2.The General corresponding Procedure olefinfor Olefin and Reduction Et3SiH were in addedthe Presence to a microwave of Grubbs tube Catalysts equipped and Triethylsilane with stirrer and purgedThe for corresponding a few minutes olefin with andN2. Then,Et3SiH 3 weremL of added anhydrous to a microwave DCM and tube5 mol equipped % of the Grubbswith stirrer catalyst and purgedwere added. for a fewThe minutes tube was with capped N2. Then, and the 3 mL reaction of anhydrous mixture DCM was subjected and 5 mol to % microwave of the Grubbs heating catalyst at purgedThe for corresponding a few minutes olefin with and N2. Then,Et3SiH 3 were mL of added anhydrous to a microwave DCM and tube 5 mol equipped % of the withGrubbs stirrer catalyst and were150 °C added. (maximum The tube power was = 120 capped W) for and the the corresponding reaction mixture time was in each subjected case. After to microwave heating, the heating reaction at purgedwere added. for a fewThe minutes tube was with capped N2. Then, and the 3 mL reaction of anhydrous mixture DCM was subjectedand 5 mol to% microwaveof the Grubbs heating catalyst at 150 ◦C (maximum power = 120 W) for the corresponding time in each case. After heating, the reaction were150crude °C added. was (maximum concentrated The tube power was and = 120capped dried W) for underand the the highcorresponding reaction vacuum. mixture time was in each subjected case. After to microwave heating, the heating reaction at crude was concentrated and dried under high vacuum. 150crude °C was(maximum concentrated power and = 120 dried W) forunder the correspondinghigh vacuum. time in each case. After heating, the reaction 3.3.3. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ crude3.3.3. Generalwas concentrated Procedure and for Olefindried under Reduction high invacuum. the Presence of Grubbs Catalysts and Resin-Immobilized3.3.3.Immobilized General Silane Procedure Silane(8) for (8 )Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ 3.3.3.Immobilized General Silane Procedure (8) for Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ The corresponding olefin olefin and the 4-(diethylsilylbutyl)4‐(diethylsilylbutyl) polystyrene resin ( 8) were added to a ImmobilizedmicrowaveThe corresponding tube Silane with (8 )stirrer olefin and and purged the 4 for‐(diethylsilylbutyl) a few minutes with polystyrene N2. Then, resin 3 mL ( 8of) wereanhydrous added DCM to a microwave tube with stirrer and purged for a few minutes with N2. Then, 3 mL of anhydrous DCM andmicrowave 5The mol corresponding % tube of the with Grubbs stirrer olefin catalyst and and purged werethe 4 added.for‐(diethylsilylbutyl) a few The minutes tube was with polystyrene capped N2. Then, and resin 3 the mL reaction( 8of) wereanhydrous mixture added DCM to was a heated at 150 ◦°C (maximum power = 120 W). After the time set for each case, the reaction crude was microwaveheatedand 5 mol at 150 % tube ofC the with (maximum Grubbs stirrer catalyst powerand purged =were 120 foradded. W). a After few The minutes the tube time was with set capped for N2 each. Then, and case, 3the mL the reaction of reaction anhydrous mixture crude DCM was andfilteredheatedfiltered 5 mol at throughthrough 150 % of °C the a (maximum sintereda Grubbssintered glass catalyst powerglass filter =werefilter and 120 the added.W).and liquid After the The was liquidthe tube collectedtime waswas set capped for incollected a each round-bottom and case, in the athe reactionround reaction flask,‐bottom concentratedmixture crude flask, was heatedandconcentratedfiltered then at through dried150 and°C under (maximum athen sintered high dried vacuum. powerunderglass =highfilter 120 vacuum.W).and After the theliquid time was set forcollected each case, in athe round reaction‐bottom crude flask, was In the case of the reaction with dimethyl itaconate (16), the 1H‐NMR spectrum of the reaction filteredconcentratedIn thethrough case and of athen the sintered reactiondried underglass with highfilter dimethyl vacuum.and itaconatethe liquid ( 16was), the collected1H-NMR in spectrum a round of‐bottom the reaction flask, crude was analyzed and compared to the starting material spectrum.1 It was verified that product 17 concentratedcrudeIn was the analyzedcase and of then the and driedreaction compared under with high todimethyl the vacuum. starting itaconate material (16), spectrum. the H‐NMR It was spectrum verified of that the productreaction was obtained since the characteristic signal at 0.97 ppm of the three protons of methyl group was 17crudewasIn was obtainedthe analyzedcase of since the and thereaction compared characteristic with to dimethyl the signal starting atitaconate 0.97 material ppm (16 ofspectrum.), thethe three1H‐NMR It protons was spectrum verified of methyl thatof the product group reaction was 17 evidenced. Nevertheless, the reaction resulted in the formation of many by‐products and there was crudeevidenced.was obtained was analyzed Nevertheless, since theand characteristic compared the reaction to signalthe resulted starting at in0.97 thematerial ppm formation of spectrum. the ofthree many Itprotons was by-products verified of methyl that and productgroup there was 17 still some starting material 16 in the crude. wasstillevidenced. someobtained starting Nevertheless, since material the characteristic the16 reactionin the crude. signalresulted at in0.97 the ppm formation of the ofthree many protons by‐products of methyl and group there was evidenced.still some starting Nevertheless, material the 16 reaction in the crude. resulted in the formation of many by‐products and there was 3.4. Analytical Data still3.4. Analyticalsome starting Data material 16 in the crude. 3.4. Analytical Data 3.4. Analytical Data

4‐(Diethylsilylbutyl) polystyrene resin (8). IR (KBr) νmax (cm−1 ) 3024; 2916; 2848; 1637; 1600; 1560; 1490; −1 4-(Diethylsilylbutyl)13 polystyrene resin (8). IR (KBr) νmax (cm ) 3024; 2916; 2848; 1637; 1600; 1560; 41448;‐(Diethylsilylbutyl) 906; 756; 592. Cpolystyrene gel‐phase NMR resin ((CDCl8). IR 3(KBr), 75 MHz): νmax (cm δ =− 1145.6, ) 3024; 138.6, 2916; 128.2, 2848; 125.9,1637; 1600; 115.0, 1560; 46.4, 1490; 44.2, 1490; 1448; 906; 756; 592. 13C gel-phase NMR (CDCl , 75 MHz): δ = 145.6, 138.6, 128.2, 125.9, 115.0, 40. 7, 35.9, 53.3. 13 3 41448;‐(Diethylsilylbutyl) 906; 756; 592. Cpolystyrene gel‐phase NMR resin ((CDCl8). IR (KBr)3, 75 MHz): νmax (cm δ =− 1145.6,) 3024; 138.6, 2916; 128.2, 2848; 1637;125.9, 1600; 115.0, 1560; 46.4, 1490; 44.2, 46.4, 44.2, 40. 7, 35.9, 53.3. 1448;40. 7, 906;35.9, 756; 53.3. 592. 13C gel‐phase NMR (CDCl3, 75 MHz): δ = 145.6, 138.6, 128.2, 125.9, 115.0, 46.4, 44.2, 40. 7, 35.9, 53.3.

Benzyl butyrate (4). 1H‐NMR (CDCl3, 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), 13 1.87Benzyl (m, butyrate 2H), 0.94 (4 (t,). 1 HJ =‐NMR 7.4 Hz, (CDCl 3H).3 , 300C‐NMR MHz): (CDCl δ = 7.353, 75 (m, MHz): 5H), δ 5.12= 173.5, (s, 2H), 136.2, 2.34 128.5, (t, J = 128.2,7.4 Hz, 128.1, 2H), 1 Benzyl butyrate (4). H-NMR (CDCl , 300 MHz): δ = 7.35 (m, 5H),+ 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), 128.1,1.87 (m, 66.0, 2H), 36.21, 0.94 18.5,(t,1 J =13.7. 7.4 Hz,GC ‐3H).MS 3(EI, 13C ‐70NMR eV): (CDCl m/z (%)3, 75 = 178MHz): [M δ ] (15),= 173.5, 160 136.2,(1), 108 128.5, (94), 128.2, 91 (100), 128.1, 71 Benzyl butyrate (4). H‐NMR (CDCl313, 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), 1.87(35), (m,65 (26). 2H), 0.94 (t, J = 7.4 Hz, 3H). C-NMR (CDCl3, 75 MHz):+ δ = 173.5, 136.2, 128.5, 128.2, 128.1, 1.87128.1, (m, 66.0, 2H), 36.21, 0.94 18.5,(t, J =13.7. 7.4 Hz,GC ‐3H).MS (EI, 13C ‐70NMR eV): (CDCl m/z (%)3, 75 = 178MHz): [M δ ] (15),= 173.5, 160 136.2,(1), 108 128.5, (94), 128.2, 91 (100), 128.1, 71 128.1, 66.0, 36.21, 18.5, 13.7. GC-MS (EI, 70 eV): m/z (%) = 178 [M+] (15), 160 (1), 108 (94), 91 (100), 71 128.1,(35), 65 66.0, (26). 36.21, 18.5, 13.7. GC‐MS (EI, 70 eV):MeO m/z (%) = 178 [M+] (15), 160 (1), 108 (94), 91 (100), 71 (35), 65 (26). (35), 65 (26). MeOAcO 15 MeOAcO 15 Acetyl isoeugenol (15). 1H‐NMR (CDCl3, 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, AcO 1315 Acetyl1H), 3.83 isoeugenol (s, 3H), 2.30 (15 (s,). 1 3H),H‐NMR 1.88 (CDCl(d, J = 36.5, 300 Hz, MHz): 3H). δ C=‐ NMR6.93 (m, (CDCl 5H),3, 6.3775 MHz): (d, J=15.7 δ = 169.2, Hz, 1H), 151.0, 6.20 138.6, (m, 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4.13 Acetyl1H), 3.83 isoeugenol (s, 3H), 2.30 (15 (s,). 1 3H),H‐NMR 1.88 (CDCl (d, J = 36.5, 300 Hz, MHz): 3H). δ C=‐ NMR6.93 (m, (CDCl 5H),3, 6.3775 MHz): (d, J=15.7 δ = 169.2, Hz, 1H), 151.0, 6.20 138.6, (m, 1H),137.1, 3.83 130.5, (s, 3H), 126.1, 2.30 122.7, (s, 3H), 118.4, 1.88 109.6, (d, J 55.8,= 6.5 20.7,Hz, 3H). 18.4. 13 C‐NMR (CDCl3, 75 MHz): δ = 169.2, 151.0, 138.6, 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4.

1,5‐Dibenzyl glutarate (11). 1H‐NMR (CDCl3, 300 MHz): δ = 7.34 (m, 10H), 5.11 (s, 4H), 2.43 (t, J = 7.4 13 1,5Hz,‐Dibenzyl 4H), 1.99 glutarate(q, J = 7.4 (Hz,11). 2H).1H‐NMR C‐NMR (CDCl (CDCl3, 3003 MHz):, 75 MHz): δ = 7.34 δ = 172.7,(m, 10H), 135.9, 5.11 128.6, (s, 4H), 128.3, 2.43 128.2, (t, J =66.2, 7.4 33.3, 20.1. 13 1,5Hz,‐Dibenzyl 4H), 1.99 glutarate(q, J = 7.4 ( Hz,11). 2H).1H‐NMR C‐NMR (CDCl (CDCl3, 300 3MHz):, 75 MHz): δ = 7.34 δ = 172.7,(m, 10H), 135.9, 5.11 128.6, (s, 4H), 128.3, 2.43 128.2, (t, J =66.2, 7.4 Hz,33.3, 4H), 20.1. 1.99 (q, J = 7.4 Hz, 2H). 13C‐NMR (CDCl3, 75 MHz): δ = 172.7, 135.9, 128.6, 128.3, 128.2, 66.2, 33.3, 20.1.

Catalysts 2017, 7, 111 10 of 13 Catalysts 2017, 7, 111 10 of 13

3.3.2. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane

The corresponding olefin and Et3SiH were added to a microwave tube equipped with stirrer and The corresponding olefin and Et3SiH were added to a microwave tube equipped with stirrer and purged for a few minutes with N2. Then, 3 mL of anhydrous DCM and 5 mol % of the Grubbs catalyst purged for a few minutes with N2. Then, 3 mL of anhydrous DCM and 5 mol % of the Grubbs catalyst were added. The tube was capped and the reaction mixture was subjected to microwave heating at 150 °C (maximum power = 120 W) for the corresponding time in each case. After heating, the reaction crude was concentrated and dried under high vacuum.

3.3.3. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ Immobilized Silane (8) The corresponding olefin and the 4‐(diethylsilylbutyl) polystyrene resin (8) were added to a microwave tube with stirrer and purged for a few minutes with N2. Then, 3 mL of anhydrous DCM microwave tube with stirrer and purged for a few minutes with N2. Then, 3 mL of anhydrous DCM and 5 mol % of the Grubbs catalyst were added. The tube was capped and the reaction mixture was heated at 150 °C (maximum power = 120 W). After the time set for each case, the reaction crude was filtered through a sintered glass filter and the liquid was collected in a round‐bottom flask, concentrated and then dried under high vacuum. 1 In the case of the reaction with dimethyl itaconate (16), the 1H‐NMR spectrum of the reaction crude was analyzed and compared to the starting material spectrum. It was verified that product 17 was obtained since the characteristic signal at 0.97 ppm of the three protons of methyl group was evidenced. Nevertheless, the reaction resulted in the formation of many by‐products and there was still some starting material 16 in the crude.

3.4. Analytical Data

4‐(Diethylsilylbutyl) polystyrene resin (8). IR (KBr) νmax (cm−1) 3024; 2916; 2848; 1637; 1600; 1560; 1490; 4‐(Diethylsilylbutyl) polystyrene resin (8). IR (KBr) νmax (cm−1) 3024; 2916; 2848; 1637; 1600; 1560; 1490; 1448; 906; 756; 592. 13C gel‐phase NMR (CDCl3, 75 MHz): δ = 145.6, 138.6, 128.2, 125.9, 115.0, 46.4, 44.2, 1448; 906; 756; 592. 13C gel‐phase NMR (CDCl3, 75 MHz): δ = 145.6, 138.6, 128.2, 125.9, 115.0, 46.4, 44.2, 40. 7, 35.9, 53.3.

Benzyl butyrate (4). 1H‐NMR (CDCl3, 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), Benzyl butyrate (4). 1H‐NMR (CDCl3, 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), 1.87 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C‐NMR (CDCl3, 75 MHz): δ = 173.5, 136.2, 128.5, 128.2, 128.1, 1.87 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C‐NMR (CDCl3, 75 MHz): δ = 173.5, 136.2, 128.5, 128.2, 128.1, + 128.1, 66.0, 36.21, 18.5, 13.7. GC‐MS (EI, 70 eV): m/z (%) = 178 [M+] (15), 160 (1), 108 (94), 91 (100), 71 (35), 65 (26). MeO Catalysts 2017, 7, 111 MeO 11 of 14

AcO AcO 15 15 1 Acetyl isoeugenol ((1515).). 1HH-NMR‐NMR (CDCl 3,, 300 300 MHz): δ δ == 6.93 6.93 (m, (m, 5H), 5H), 6.37 6.37 (d, (d, JJ=15.7=15.7 Hz, Hz, 1H), 1H), 6.20 6.20 (m, (m, Acetyl isoeugenol (15). 1H‐NMR (CDCl3, 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, 13 1H), 3.83 (s, (s, 3H), 3H), 2.30 2.30 (s, (s, 3H), 3H), 1.88 1.88 (d, (d, J =J 6.5= 6.5 Hz, Hz, 3H). 3H). 13C‐NMRC-NMR (CDCl (CDCl3, 75 3MHz):, 75 MHz): δ = 169.2,δ = 169.2,151.0, 138.6, 151.0, 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). 13C‐NMR (CDCl3, 75 MHz): δ = 169.2, 151.0, 138.6, 138.6, 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4. 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4.

1,5‐Dibenzyl glutarate (11). 1H1‐NMR (CDCl3, 300 MHz): δ = 7.34 (m, 10H), 5.11 (s, 4H), 2.43 (t, J = 7.4 1,5-Dibenzyl1,5‐Dibenzyl glutarate glutarate ( (1111).). 1H‐H-NMRNMR (CDCl (CDCl3, 3003, 300 MHz): MHz): δ = 7.34δ = (m, 7.34 10H), (m, 10H), 5.11 (s, 5.11 4H), (s, 2.43 4H), (t, 2.43 J = 7.4 (t, Hz, 4H), 1.99 (q, J = 7.4 Hz, 2H). 13C‐NMR13 (CDCl3, 75 MHz): δ = 172.7, 135.9, 128.6, 128.3, 128.2, 66.2, Hz,J = 7.4 4H), Hz, 1.99 4H), (q, 1.99 J = (q,7.4 JHz,= 7.4 2H). Hz, 13 2H).C‐NMRC-NMR (CDCl (CDCl3, 75 MHz):3, 75 MHz): δ = 172.7,δ = 135.9, 172.7, 135.9,128.6, 128.6,128.3, 128.3,128.2, 128.2, 66.2, 33.3,66.2, 20.1. 33.3, 20.1.

1 Benzyl (4-triethylsilyl)-trans-crotonate (5). H-NMR (CDCl3, 300 MHz): δ = 7.35 (m, 5H), 7.12 (dt, J = 15.3 Hz, J = 8.9 Hz, 1H), 5.73 (d, J = 15.4 Hz, 1H), 5.16 (s, 2H), 1.77 (d, J = 8.9 Hz, 2H), 0.95 (t, J = 7.9 13 Hz, 9H), 0.57 (q, J = 7.9 Hz, 6H). C-NMR (CDCl3, 75 MHz): δ = 166.7, 149.2, 136.4, 128.2, 128.1, 128.0, + 118.4, 65.7, 19.8, 3.2, 1.0. HRMS (ESI) m/z 313.15794 [(M + Na) ; calcd. for C17H26NaO2Si: 313.15943].

4. Conclusions In summary, this work focuses on the complex competition between metathesis and non-metathesis processes, here applied to both solution and solid-phase silane reagents. The reactions occur between different olefin substrates and silanes, in presence of the Grubbs or Hoveyda–Grubbs ruthenium catalysts 1 or 2. Catalysis of non-metathetic transformations (isomerization, “hydrogen-free” reduction, silylation) is being ascribed to clear-cut ruthenium species arising from promoters 1 and 2, under the experimental conditions. These transient catalytic species differ from the Ru-alkylidenes responsible for metathesis. Reaction pathways accounting for these simultaneous processes have been evidenced. An important finding of this research unveils the concurrent binding of the olefin to the silylated resin, bringing about an adverse effect on the overall yield of the reactions with a solid-phase silane reagent. Follow-up investigations on tandem metathetic/non-metathetic reactions of olefins, comparatively run in solution and solid-phase with ruthenium catalysts, are currently in progress.

Supplementary Materials: The following are available online at www.mdpi.com/2073-4344/7/4/111/s1, 1 13 Figure S1: H NMR of a mixture of compounds 4 and 5 in CDCl3, Figure S2: C NMR of a mixture of compounds 4 and 5 in CDCl3, Figure S3: HH-COSY NMR of a mixture of compounds 4 and 5 in CDCl3, Figure S4: HSQC NMR of a mixture of compounds 4 and 5 in CDCl3, Figure S5: HMBC NMR of a mixture of compounds 4 and 5 in CDCl3, Figure S6: TOCSY NMR of a mixture of compounds 4 and 5 in CDCl3, the experiment was carried out irradiating H-5 of compound 5, Figure S7: TOCSY NMR of a mixture of compounds 4 and 5 in CDCl3, the experiment was carried out irradiating H-4 of compound 5, Figure S8: Experimental HRMS of compound 5, 1 13 Figure S9: Simulated HRMS of compound 5, Figure S10: H NMR of compound 6 in CDCl3, Figure S11: C NMR 13 of compound 6 in CDCl3, Figure S12: HSQC NMR of compound 6 in CDCl3, Figure S13: C gel phase NMR of 1 resin 8 in CDCl3, Figure S14: IR of resin 8 in KBr pellet, Figure S15: H NMR of compound 11 in CDCl3, Figure 13 S16: C NMR of compound 11 in CDCl3, Figure S17: HSQC NMR of compound 11 in CDCl3. Acknowledgments: Support from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) and Universidad Nacional de Rosario from Argentina is gratefully acknowledged. Maitena Martinez-Amezaga thanks CONICET for fellowship. Ileana Dragutan and Valerian Dragutan gratefully acknowledge support from the “C.D. Nenitescu” Institute of Organic Chemistry of the Romanian Academy, Bucharest. Author Contributions: Carina M. L. Delpiccolo, Ileana Dragutan, Valerian Dragutan and Ernesto G. Mata conceived and designed the experiments; Carina M. L. Delpiccolo, Maitena Martinez-Amezaga and Luciana Méndez performed the experiments and analyzed the data; Maitena Martinez-Amezaga, Carina M. L. Delpiccolo, Ileana Dragutan, Valerian Dragutan and Ernesto G. Mata wrote the paper. Conflicts of Interest: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. Catalysts 2017, 7, 111 12 of 14

References and Notes

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