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
2
*
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.) 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
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Also proved was that for other 2nd generation Ru metathesis catalysts, the contribution of the isomerization pathway hinges on the catalyst loading [28]. generation Ru metathesis catalysts, the contribution of the isomerization pathway hinges on the Nevertheless, non‐metathetic reactions initiated by ruthenium alkylidene catalysts can provide catalyst loading [28]. an expedient entry into otherwise inaccessible interesting compounds. In particular, isomerization Nevertheless, non-metathetic reactions initiated by ruthenium alkylidene catalysts can provide and hydrogenation have industrial relevance being used to convert low‐value coal‐ or petroleum‐ an expedient entry into otherwise inaccessible interesting compounds. In particular, isomerization and based by‐products lower relevance alpha olefins) olefins from renewable feedstocks into useful hydrogenation have(e.g., industrial beingor used to convert low-valueoil coalor petroleum-based starting materials for the production of surfactants, detergents, lubricants, cosmetics, etc. [29]. by-products (e.g., lower alpha olefins) or olefins from renewable oil feedstocks into useful starting Whereas the aforementioned homogeneous non‐metathetic reactions with Grubbs catalysts are materials for the production of surfactants, detergents, lubricants, cosmetics, etc. [29]. very well documented, occasionally even by the pairwise use of metathesis/non‐metathesis protocols Whereas the aforementioned homogeneous non-metathetic reactions with Grubbs catalysts [30], there are some aspects about the competitive reactions that are still unclear. In heterogeneous are very well documented, occasionally even by the pairwise use of metathesis/non-metathesis phase, named solid‐phase organic synthesis, we have carried out pioneering work on the application protocols [30], there are some aspects about the competitive reactions that are still unclear. of a combination of ruthenium‐catalyzed cross‐metathesis and reduction to perform a formal alkane In heterogeneous phase, named solid-phase organic synthesis, we have carried out pioneering work 3–Csp3 linkages [31,32]. Solid‐phase organic synthesis (SPOS), initially used in metathesis to build Csp on the application of a combination of ruthenium-catalyzed cross-metathesis and reduction to perform peptide chemistry, is now broadly applied to the preparation of a range of biologically interesting a formal alkane metathesis to build Csp3 –Csp3 linkages [31,32]. Solid-phase organic synthesis (SPOS), structures [33–35]. initially used in peptide chemistry, is now broadly applied to the preparation of a range of biologically Apart from our work, very few studies have been published on heterogeneous non‐metathetic interesting structures [33–35]. reactions with Grubbs catalysts [36]; however, no report related to the use of solid‐phase reagents has Apart from our work, very few studies have been published on heterogeneous non-metathetic been disclosed so far. Utilization of reagents bound to a solid support has a number of advantages reactions with Grubbs catalysts [36]; however, no report related to the use of solid-phase reagents has [37]: (i) alike traditional SPOS, purification is achieved by filtration; (ii) reactions can be monitored been disclosed so far. Utilization of reagents bound to a solid support has a number of advantages [37]: by standard organic techniques such is as achieved thin‐layer since starting material and (i) alike traditional SPOS, purification bychromatography filtration; (ii) reactions can be monitored by product are in solution phase; (iii) toxic, explosive or odorous reagents become safe after standard organic techniques such as thin-layer chromatography since starting material and product immobilization; and (iv), perhaps the most important present‐day feature, solid‐phase reagents are are in solution phase; (iii) toxic, explosive or odorous reagents become safe after immobilization; and especially suitable for flow chemistry [38]. (iv), perhaps the most important present-day feature, solid-phase reagents are especially suitable for flowIn this contribution, we delve into the different competing pathways for metathesis and non‐ chemistry [38]. metathesis that wehappen during ruthenium‐catalyzed double‐bond reduction and of In this reactions contribution, delve into the different competing pathways for metathesis functionalized olefins, under the action of triethylsilane or the unexplored solid‐phase reagent, non-metathesis reactions that happen during ruthenium-catalyzed double-bond reduction 4‐ of (diethylsilylbutyl) polystyrene resin. functionalized olefins, under the action of triethylsilane or the unexplored solid-phase reagent, 4-(diethylsilylbutyl) polystyrene resin. 2. Results and Discussion 2. Results and of Discussion Reactions mono‐ or disubstituted alkenes were carried out either homogeneously or with
resin‐supported silanes, in the presence of the Grubbs (1) or Hoveyda–Grubbs (2) initiators (Figure Reactions of mono- or disubstituted alkenes were carried out either homogeneously or with 1). resin-supported silanes, in the presence of the Grubbs (1) or Hoveyda–Grubbs (2) initiators (Figure 1).
MesN Cl Cl
NMes Ru PCy 3
Ph
MesN Cl Cl
NMes Ru O
2
1
2nd. Generation Hoveyda-Grubbs Catalyst Mes= mesityl
2nd. Generation Grubbs Catalyst
Figure 1. 2nd generation Grubbs and Hoveyda–Grubbs catalysts. Figure 1. 2nd generation Grubbs and Hoveyda–Grubbs 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
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shown in Table 1. Along with the desired reduction product (4), an unexpected silylated compound, Table 1. Along with the desired reduction product (4), an unexpected silylated compound, the benzyl the benzyl (4‐triethylsilyl)‐trans‐crotonate (5), was formed. (4-triethylsilyl)-trans-crotonate (5), was formed. Table 1. Reduction of trans‐benzyl crotonate (3) with triethylsilane catalyzed by 2 Table 1. Reduction of trans-benzyl crotonate (3) with triethylsilane catalyzed by 2 aa.. O O
catalyst 2 (5 mol%) Et3SiH DCM anh MW, 150 ºC
3
O
O SiEt3
O
O 4
+
5
+
3
b
Entry 1 2 3 4
Entry Et3 SiH (equiv.) Et3SiH (equiv.) 1 2 3 4
0.5 1.0 2.5 5.0
0.5 1.0 2.5 5.0
Products (3/4/5) Products (3/4/5) b Molar Ratio Percentage (%) Molar Ratio Percentage (%) 10.5/1.0/1.4 10.5/1.0/1.4 81/8/11 81/8/11 4.4/1.0/0.4 76/17/7 76/17/7 4.4/1.0/0.4 0.9/1.0/0.3 41/46/13 41/46/13 0.9/1.0/0.3 0/1.0/0.1 0/91/9 0/91/9 0/1.0/0.1
a Conditions: olefin 3, Hoveyda–Grubbs catalyst (2; 5 mol %), microwave reactor (maximum power; Conditions: olefin 3, Hoveyda–Grubbs catalyst (2; 5 mol %), microwave reactor (maximum power; 150 ◦ C), a
b Determined from the 150 C), reaction time 30 min, in anhydrous dichloromethane (DCM); H‐NMR reaction time 30 min, in anhydrous dichloromethane (DCM); b Determined from the 1 H-NMR (nuclear1magnetic resonance) of the crude product. (nuclear magnetic resonance) 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 (Table 1, 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 Et3 SiH activated by Grubbs carbenes is a well-known catalytic process, its mechanism is still not very 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 Et3 SiH to the Ru carbene to form an active Ru-hydride species (A) 1) [9]. Then, species A would give B or C by insertion of 3 into the Ru–H bond. Lastly, B (or C) would (Scheme 1) [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 Et3 SiH [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 Et3 SiH in the presence of Lewis acids [42]. At the beginning, considered, since formation of free radicals 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 (Scheme 2).
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O O O
H H H Et SiSiEt Et Et333SiSiEt SiSiEt333
BnO BnO BnO
Et SiH Et Et333SiH SiH
Ru CH Ru Ru CH CH222
H H H 444 Et SiH Et Et333SiH SiH
H H H Ru Ru Ru
O O O BnO BnO BnO Et Si Et Et333Si Si
H H H Ru Ru Ru C C C
SiEt SiEt SiEt333 A A A
O O O
O O O
BnO BnO BnO B B B
H H H
BnO BnO BnO
Ru Ru Ru
333
SiEt SiEt SiEt333
Scheme 1. Proposed mechanism Et of 3 by 1 Scheme mechanism forfor Et3 SiH-reduction of olefin 3 activated by catalysts 1 or 2, according Scheme 1. 1. Proposed Proposed mechanism for Et333SiH‐reduction SiH‐reduction of olefin olefin 3 activated activated by catalysts catalysts 1 or or 2, 2, according to Cossy et al. [9]. to Cossy et al. [9]. according to Cossy et al. [9].
O O O O
O O 66
DCM DCM anh anh MW, MW, 150 150 ºC ºC
33
O O
isomerization isomerization
catalyst catalyst 22
O O
Et SiH Et333SiH
SiEt SiEt333
O O
77 isomerization isomerization O O
SiEt SiEt333
O O 55
Scheme 2. Formation of the silylated derivative 5. Scheme 2. Formation of the silylated derivative 5. Scheme 2. Formation of the silylated derivative 5.
An allylic mechanism, by intermediacy of allyl‐Ru complexes, might also be considered in the An allylic mechanism, by intermediacy of allyl‐Ru complexes, might also be considered in the An allylic mechanism, by intermediacy of allyl-Ru complexes, might also be considered in the generation of 5 from the internal (3) and terminal olefin (6) when the disilane Et SiSiEt generation of 5 from the internal (3) and terminal olefin (6) when the disilane Et SiSiEt3333 would be would be generation of 5 from the internal (3) and terminal olefin (6) when the disilane Et3333SiSiEt would be present in the reacting system (Scheme 3). present in the reacting system (Scheme 3). present in the reacting system (Scheme 3). O O BnO BnO
O O
Si Si
BnO BnO
55 LLnnnRu Ru
LL
33
O O BnO BnO 6 6
O O
O O BnO BnO
BnO BnO
LLnnnRu Ru
LLn-1 Ru SiEt n-1 n-1 Ru SiEt333
Et Et333Si Si LL
Et Et333SiSiEt SiSiEt333
Scheme 3. Possible allylic mechanism for the silylation of olefins 3 and 6 to the allylsilane 5. Scheme 3. Possible allylic mechanism for the silylation of olefins 3 and 6 to the allylsilane 5. Scheme 3. Possible allylic mechanism for the silylation of olefins 3 and 6 to the allylsilane 5.
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As mentioned in the Introduction, solid‐phase reagents are gaining popularity in synthesis due As mentioned in the Introduction, solid-phase reagents are gaining popularity in synthesis to some comparative advantages especially useful for flow chemistry. Particularly, to the best of our due to some comparative advantages especially useful for flow chemistry. Particularly, to the best knowledge, silanes silanes immobilized on solid phase have not non‐metathetic of our knowledge, immobilized on solid phase have notbeen beenapplied applied to to non-metathetic hydrogenations. Using high‐loading Merrifield resin, we prepared 4‐(diethylsilylbutyl) polystyrene hydrogenations. Using high-loading Merrifield resin, we prepared 4-(diethylsilylbutyl) polystyrene resin (8) in two steps according to literature [44] (Table 2). Upon reacting benzyl trans‐crotonate (3) resin (8) in two steps according to literature [44] (Table 2). Upon reacting benzyl trans-crotonate (3) with 8 in presence of catalyst 1 or 2, a different outcome has been attained. Concerned are both the with 8 in presence of catalyst 1 or 2, a different outcome has been attained. Concerned are both the nature of the products and a more intricate pattern of the reactions routes, this time also involving nature of the products and a more intricate pattern of the reactions routes, this time also involving metathesis (Table 2). metathesis (Table 2). Table 2. Reduction of benzyl trans‐crotonate (3) using resin‐immobilized silane (8) or triethylsilane, Table 2. Reduction of benzyl trans-crotonate (3) using resin-immobilized silane (8) or triethylsilane, in presence of catalyst 1 or 2. in presence of catalyst 1 or 2.
SiEt 2H O O 3
Entry Entry 1 2 3 4 5 6 7
1 2
Olefin
Olefin
3 3 3 3 3 3 3 3 3 3 3 Resin from Entry 6
8 catalyst (5 mol %) DCM anh MW, 150 ºC, 30 min
O O 4
Reaction Conditions Reaction Conditions a a Silane Catalyst Silane (Equivalents) Catalyst (5 mol %) Ratio 4:3 b Temp. Time (h) Ratio 4:3 b (Equivalents) Temp. (◦ C) (°C) Time (h) (5 mol %) 2 8 c, 3.0 Reflux 24 1:19 c 3.0 2 8 Reflux 1:19 2 8 ,c, 2.5 55 (sealed system) 24 16 1:5.6 c 55 (sealed 2 150 (MW) d 16 0.5 1:0.3 e 2 88c , , 2.5 2.5 1:5.6 system) 2 ‐f 150 (MW) d 0.5 1:0.3 e c , 2.5 e d 2 8 0.5 1:0.3 c 150 (MW) d 1 8 , 2.5 150 (MW) 0.75 1:3.2 e e f d 2 1:0.3 150 (MW) 2 8 c-, 0.75 150 (MW) d 0.5 0.5 ND g c e d 1 , 2.5 1:3.2 150 (MW) 2 150 (MW) d 0.75 0.5 1:0.6 h Et83SiH (2.5)
3 4 5 c , 0.75 3 0.5 ND g 150 (MW) d a 6In anhydrous dichloromethane; b 2 Estimated 8 from 1H‐NMR of the crude reaction mixture; hc 7 Resin from Entry 6 2 Et3 SiH (2.5) 0.5 150 (MW) d 1:0.6
Synthesized resin, loading 2.8 mmol/g (theoretical loading calculated from the initial loading level of a In anhydrous dichloromethane; b Estimated from 1 H-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)); d MW = microwave heating; e The 1 H-NMR spectrum of the crude reaction mixture showed a by-product, reaction mixture showed a by‐product, subsequently identified as 11 (see Supplementary Materials, f The crude from Entry 3 was filtered and, after adding a supplementary amount of subsequently identified as 11 (see Supplementary Materials, Figures S15–S17); f The crude from Entry 3 was Figures S15–S17); filtered and, after adding a supplementary amount of catalyst 2 (5 mol %), heating was repeated; g The product catalyst 2 (5 mol %), heating was repeated; g The product composition was not determined (ND), the composition was not determined (ND), the filtered resin was used in a subsequent experiment (Entry 7; see also h The 1H‐NMR spectrum filtered resin was used in a subsequent experiment (Entry 7; see also text); text); h The 1 H-NMR spectrum of the crude reaction mixture showed a by-product, identified by NMR techniques as 5 (see Scheme 1 and Supplementary Materials, Figures S1–S9). of the crude reaction mixture showed a by‐product, identified by NMR techniques as 5 (see Scheme 1 and Supplementary Materials, Figures S1–S9).
Only low conversions to the reduced product 4 could be attained in refluxing dichloromethane, Only low conversions to the reduced product 4 could be attained in refluxing dichloromethane, even at reaction times andand withwith excess of silane. (Table 2, Entries and 2). 1 Switching microwave even at long long reaction times excess of silane. (Table 2, 1Entries and 2). to Switching to heating greatly improved conversion. Under best conditions (Entry 3), approximately one-quarter of microwave heating greatly improved conversion. Under best conditions (Entry 3), approximately the starting material (3) was still present after reaction. Moreover, the IR spectrum of the resin recovered one‐quarter of the starting material (3) was still present after reaction. Moreover, the IR spectrum of from a typical experiment showed an intense signal at 2100 cm−1 (Si–H stretching), indicating that −1 (Si–H stretching), the resin recovered from a typical experiment showed an intense signal at 2100 cm the resin still preserved some of its reducing ability. Consequently, in a further attempt to enhance indicating that the resin still preserved some of its reducing ability. Consequently, in a further attempt production of 4 a supplementary amount of catalyst 2 (5 mol %) was added to the filtered crude to enhance production of 4 a supplementary amount of catalyst 2 (5 mol %) was added to the filtered product from Entry 3 and the mixture heated (MW) for another half hour (Entry 4), but to no avail. crude product from Entry 3 and the mixture heated (MW) for another half hour (Entry 4), but to no avail. Whenever conversion to 4 has reached higher values (Entries 3 and 4), formation of a secondary product (11) was apparent from the additional signal observed in the NMR spectrum of the crude Whenever conversion to 4 has reached higher values (Entries 3 and 4), formation of a secondary reaction mixture. Catalysis by 1 (Entry 5) resulted in lesser production of 4, while also the secondary product (11) was apparent from the additional signal observed in the NMR spectrum of the crude product 11 could be evidenced by NMR. reaction mixture. Catalysis by 1 (Entry 5) resulted in lesser production of 4, while also the secondary At this point some conclusions became obvious: (i) always approximately one-quarter of the product 11 could be evidenced by NMR. starting material not react; (ii) catalyst is more (i) active thanapproximately 1, in agreement with its stability At this point does some conclusions became 2obvious: always one‐quarter of the under the rather harsh conditions (high temperature) employed; (iii) MW-assisted heating leads to starting material does not react; (ii) catalyst 2 is more active than 1, in agreement with its stability better yields than refluxing in dichloromethane; (iv) additional silane has no positive effect. under the rather harsh conditions (high temperature) employed; (iii) MW‐assisted heating leads to better yields than refluxing in dichloromethane; (iv) additional silane has no positive effect.
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By virtue of the starting benzyl crotonate (3) not being entirely consumed in all experiments with By virtue of the starting benzyl crotonate (3) not being entirely consumed in all experiments with By virtue of the starting benzyl crotonate (3) not being entirely consumed in all experiments with By virtue of the starting benzyl crotonate (3) not being entirely consumed in all experiments with resin‐supported silane 8, a reasonable assumption would be that crotonate 3 partially binds to the resin‐supported silane 8, a reasonable assumption would be that crotonate 3 partially binds to the resin-supported silane 8, a reasonable assumption would be that crotonate 3 partially binds to the resin‐supported silane 8, a reasonable assumption would be that crotonate 3 partially binds to the resin. To verify this hypothesis, a reaction was carried out (Table 2, Entry 6) using only about one‐ resin. To verify this hypothesis, a reaction was carried out (Table 2, Entry 6) using only about one‐ resin. To verify this hypothesis, a reaction was carried out (Table 2, Entry 6) using only about one-third resin. To verify this hypothesis, a reaction was carried out (Table 2, Entry 6) using only about one‐ third (0.75 equiv.) of the usual amount of silane. After 0.5 h, the resin was filtered and an IR spectrum third (0.75 equiv.) of the usual amount of silane. After 0.5 h, the resin was filtered and an IR spectrum (0.75 equiv.) of the usual amount of silane. After 0.5 h, the resin was filtered and an IR spectrum was third (0.75 equiv.) of the usual amount of silane. After 0.5 h, the resin was filtered and an IR spectrum −1 (C=O bond stretching) characteristic for a carboxyl was showing run, showing showing an absorption absorption at 1716 cm−1 −1 cm was an 1716 (C=O bond characteristic for run, an absorption at 1716at cm characteristic for a carboxyl moiety. was run, run, showing an absorption at 1716 (C=O cm−1 bond (C=O stretching) bond stretching) stretching) characteristic for a a carboxyl carboxyl moiety. According to this result, the resin‐bound compound was proposed to have the structure 10 moiety. According to this result, the resin‐bound compound was proposed to have the structure 10 According to this result, the resin-bound compound was proposed to have the structure 10 indicating moiety. According to this result, the resin‐bound compound was proposed to have the structure 10 indicating the immobilization of the benzyl crotonate (Figure 2). Confirmation came from the further indicating the immobilization of the benzyl crotonate (Figure 2). Confirmation came from the further the immobilization of the benzyl crotonate (Figure 2). Confirmation came from the further treatment indicating the immobilization of the benzyl crotonate (Figure 2). Confirmation came from the further treatment of 10 with Et33SiH and catalyst 2 that allowed the catalytic cycle to continue, affording fresh SiH and catalyst 2 that allowed the catalytic cycle to continue, affording fresh treatment of 10 with Et of 10 with Et3 SiH and catalyst 2 that allowed the catalytic cycle to continue, affording fresh product 4 treatment of 10 with Et 3SiH and catalyst 2 that allowed the catalytic cycle to continue, affording fresh product 4 (Table 2, Entry 7; Scheme 4). product 4 (Table 2, Entry 7; Scheme 4). (Table 2, Entry 7; Scheme 4). product 4 (Table 2, Entry 7; Scheme 4).
Si Si Si2 Et Et Et22
O O O O O O
10 10 10
Figure 2. Crotonate 3 bound to the resin (10). Figure 2. Crotonate 3 bound to the resin (10). Figure 2. Crotonate 3 bound to the resin (10). Figure 2. Crotonate 3 bound to the resin (10). SiEt22H H SiEt SiEt 2H 88 8 (0.75 (0.75 eq) eq) (0.75 eq) catalyst 22 (5 (5 mol%) mol%) catalyst catalyst 2 (5 mol%) MW, 150ºC, 150ºC, 30 30 min i)i) MW, i) MW, 150ºC, 30 min min ii) f iltration iltration ii) f ii) f iltration soluble products products --- soluble soluble products
O O O O O O 33 3
Et33SiH SiH Et Et3mol%) SiH (5 22 (5 mol%) 2 (5 mol%) MW, 150ºC, 150ºC, 30 min min MW, MW, 150ºC, 30 30 min
10 10 10
O O O O O O
44 4
Scheme 4. Generation of the resin‐bound crotonate 10 and its further reduction to 4. Scheme 4. Generation of the resin‐bound crotonate 10 and its further reduction to 4. Scheme 4. Generation of the resin-bound crotonate 10 and its further reduction to 4. Scheme 4. Generation of the resin‐bound crotonate 10 and its further reduction to 4.
Under the best identified conditions for the “hydrogen‐free” reduction of 3 with resin 8 (Table Under the best identified conditions for the “hydrogen‐free” reduction of 3 with resin 8 (Table Under the best identified conditions for the “hydrogen‐free” reduction of 3 with resin 8 (Table Under the best identified conditions for the “hydrogen-free” reduction of 3 with resin 8 (Table 2, 2, Entries 3 and 5), we found as well a significant amount of a secondary product (11), formed along 2, Entries 3 and 5), we found as well a significant amount of a secondary product (11), formed along 2, Entries 3 and 5), we found as well a significant amount of a secondary product (11), formed along Entries 3 and 5), we found as well a significant amount of a secondary product (11), formed along with with the desired 4 (molar ration 4:11 = 1:0.3) (Scheme 5). Compound 11 was unequivocally deduced with the desired 4 (molar ration 4:11 = 1:0.3) (Scheme 5). Compound 11 was unequivocally deduced with the desired 4 (molar ration 4:11 = 1:0.3) (Scheme 5). Compound 11 was unequivocally deduced the desired 4 (molar ration 4:11 = 1:0.3) (Scheme 5). Compound 11 was unequivocally deduced by by NMR spectroscopy to be 1,5‐dibenzyl glutarate. by NMR spectroscopy to be 1,5‐dibenzyl glutarate. by NMR spectroscopy to be 1,5‐dibenzyl glutarate. NMR spectroscopy to be 1,5-dibenzyl glutarate. O O O O O O 33 3
88 8
SiEt2H H SiEt SiEt22H
catalyst 11 or or 22 (5 (5 mol%) mol%) catalyst catalyst 1 or150ºC 2 (5 mol%) MW, MW, 150ºC MW, DCM150ºC anh DCM anh DCM anh
O O O
O O O O O O
Ratio Ratio Ratio
44 4
= 11 = = 1
+ + +
:: :
O O O
O O O 11 11 11
O O O
0,3 0,3 0,3
Scheme 5. Reduction of 3 with immobilized silane (resin 8). Scheme 5. Reduction of 3 with immobilized silane (resin 8). Reduction of 3 with immobilized silane (resin 8). Scheme 5. Scheme 5. Reduction of 3 with immobilized silane (resin 8).
We assume that diester 11 arises by several successive transformations. First, isomerization species, We inassume assume that diester 11 trigger arises by by several successive successive transformations. First, isomerization We that diester 11 several transformations. First, formed situ from the catalyst, double-bond migration in 3 [23,45,46] to giveisomerization the terminal We assume that diester 11 arises arises by several successive transformations. First, isomerization species, formed in situ from the catalyst, trigger double‐bond migration in 3 [23,45,46] to give the species, formed in situ from the catalyst, trigger double‐bond migration in 3 [23,45,46] to give the olefin 6 and a trans-cis isomerization to olefin 12 [23] (Scheme 6). Then, cross-metathesis between species, formed in situ from the catalyst, trigger double‐bond migration in 3 [23,45,46] to give the terminal olefin 6 and and a trans‐cis isomerization isomerization to olefin olefin 12 [23] [23] originated (Scheme 6). 6). from Then, cross‐metathesis terminal olefin 6 trans‐cis to 12 Then, cross‐metathesis olefin 3 (or 12) and 6, a promoted by the ruthenium alkylidenes 1 or 2, leads to 13 terminal olefin 6 and a trans‐cis isomerization to olefin 12 [23] (Scheme (Scheme 6). Then, cross‐metathesis between olefin 3 (or 12) and 6, promoted by the ruthenium alkylidenes originated from 1 or 2, leads between olefin 3 (or 12) and 6, promoted by the ruthenium alkylidenes originated from 1 or 2, leads (trans and cis). Finally, saturated diester 11 is formed by hydrogenation of 13, under activation by between olefin 3 (or 12) and 6, promoted by the ruthenium alkylidenes originated from 1 or 2, leads to 13 (trans and cis). Finally, saturated diester 11 is formed by hydrogenation of 13, under activation by to 13 (trans and cis). Finally, saturated diester 11 is formed by hydrogenation of 13, under activation by short-lived Ru-hydride species arising from the catalyst. These species transfer hydrogen atoms from to 13 (trans and cis). Finally, saturated diester 11 is formed by hydrogenation of 13, under activation by short‐lived Ru‐hydride species arising from the catalyst. These species transfer hydrogen atoms from short‐lived Ru‐hydride species arising from the catalyst. These species transfer hydrogen atoms from the immobilized silane moieties to the C–C double bond. Formation of 13 was not detected under short‐lived Ru‐hydride species arising from the catalyst. These species transfer hydrogen atoms from the immobilized silane moieties to attributed the C–C C–C double bond. Formation of triethylsilane, 13 was was not detected detected under the immobilized silane moieties to bond. Formation of under homogenous phase. This could be to a faster reduction under as compared the immobilized silane moieties to the the C–C double double bond. Formation of 13 13 was not not detected under homogenous phase. This could be attributed to a faster reduction under triethylsilane, as compared homogenous phase. This could be attributed to a faster reduction under triethylsilane, as compared with supported silane 8, and therefore reduction of 3 prevents any further cross-metathesis reaction. homogenous phase. This could be attributed to a faster reduction under triethylsilane, as compared with supported silane 8, and therefore reduction of 3 prevents any further cross‐metathesis reaction. with supported silane 8, and therefore reduction of 3 prevents any further cross‐metathesis reaction. with supported silane 8, and therefore reduction of 3 prevents any further cross‐metathesis reaction.
Catalysts 2017, 7, 111 Catalysts 2017, 7, 111 Catalysts 2017, 7, 111
7 of 14 7 of 13 7 of 13 O O
O O 3 3
6 6
13 13
1 or 2 (5 mol%) 1 MW, or 2 (5 mol%) 150ºC MW, DCM150ºC anh DCM anh
1 or 2 (5 mol%) 1 MW, or 2 (5 mol%) 150ºC MW, DCM150ºC anh DCM anh 3 or 12 3 or 12
O O O O
O O O O 12 12
+ +
6 6
O O
O O O O
SiEt 2H SiEt 2H 8 8 1 or 2 (5 mol%) 1 MW, or 2 (5 mol%) 150ºC MW, DCM150ºC anh DCM anh
O O
13 13 O O O O
+ 3 + 3
O O O O
11 11
Scheme 6. Cross‐metathesis pathway yielding product 11. Scheme 6. Cross-metathesis pathway yielding product 11. Scheme 6. Cross‐metathesis pathway yielding product 11.
Intriguingly however, not to intervene, likely Intriguingly however, homometathesis homometathesisof of 3 3 (Scheme (Scheme 7, 7, path path b) b) seems seems Intriguingly however, homometathesis of 3 (Scheme 7, path b) seems not not to to intervene, intervene, likely likely 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 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 among the reaction products. through path b and c) has not been detected among the reaction products. O O
a reduction a reduction
O O O O 3 3
O O
4 4
Grubbs catalyst (1 or 2) Grubbs catalyst (1 or 2) SiEt2 H SiEt2 H 8 8 O O O O b homometathesis b homometathesis
D D
c c reduction reduction
O O
8 8 O O
O O
O O
SiEt2 H SiEt2 H
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 intricate isomerization and hydrogenation, leaving, however, of the initial catalyst to In this catalytic process, the metathesis catalysts (1 or 2) some generate Ru species species for isomerization and hydrogenation, leaving, however, some of prevailingly the initial catalyst to promote cross‐metathesis of 3 (or 12) with 6. The validity of this interpretation is confirmed by the for isomerization and hydrogenation, leaving, however, some of the initial catalyst to promote promote cross‐metathesis of 3 (or 12) with 6. The validity of this interpretation is confirmed by the preponderance of compound 4 among the reaction products. cross-metathesis of 3 (or 12) with 6. The validity of this interpretation is confirmed by the preponderance of compound 4 among the reaction products. Inasmuch as olefin 3 has a disubstituted double bond, we next chose, for comparison, the mono‐ preponderance of compound 4 among the reaction products. Inasmuch as olefin 3 has a disubstituted double bond, we next chose, for comparison, the mono‐ substituted olefin 14 (acetyleugenol) as starting material. 14 with Inasmuch as olefin 3 has a disubstituted double bond, Interestingly, we next chose,on forreacting comparison, the substituted olefin 14 (acetyleugenol) as starting material. Interestingly, on reacting 14 with triethylsilane in solution under the usual conditions, the isomerized compound 15 was obtained as mono-substituted olefin 14 (acetyleugenol) as starting material. Interestingly, on reacting 14 with triethylsilane in solution under the usual conditions, the isomerized compound 15 was obtained as the only product (Scheme 8). the only product (Scheme 8).
Catalysts 2017, 7, 111
8 of 14
triethylsilane in solution under the usual conditions, the isomerized compound 15 was obtained as8 of 13 the Catalysts 2017, 7, 111 Catalysts 2017, 7, 111 8 of 13 Catalysts 2017, 7, 111 8 of 13 only product (Scheme 8). Et SiH EtEt33SiH 3 SiH 22 (5 mol%) mol%) 2 (5(5mol%)
O OOO OO O OO
O O OO OO
DCM anh DCManh anh DCM Reflux or MW, 150 ºC Reflux or MW, 150ºC ºC Reflux or MW, 150
14 14 14
O OO
15 15 15
Scheme 8. Isomerization of acetyleugenol (14) with Et 3SiH and catalyst 2. Scheme 8. Isomerization of acetyleugenol (14) with Et 3SiH and catalyst 2. Scheme 8. Isomerization of acetyleugenol (14) with Et Scheme 8. Isomerization of acetyleugenol (14) with Et33SiH and catalyst 2. SiH and catalyst 2.
Anew, this result gives evidence that double‐bond migration from the terminal to the internal Anew, this result gives evidence that double‐bond migration from the terminal to the internal Anew, this result gives evidence that double‐bond migration from the terminal to the internal Anew, this result gives evidence that double-bond migration from the terminal to the internal olefin is taking place [9] (as already seen for isomerization of 3 to 6). A plausible mechanism for olefin olefin is taking place [9] (as already seen for isomerization of 3 to 6). A plausible mechanism for olefin olefin is taking place [9] (as already seen for isomerization of 3 to 6). A plausible mechanism for olefin olefin is taking place [9] (as already seen for isomerization of 3 to 6). A plausible mechanism for olefin isomerization, as shown in Scheme 9, involves a cyclic pathway, through the intermediacy of species isomerization, as shown in Scheme 9, involves a cyclic pathway, through the intermediacy of species isomerization, as shown in Scheme 9, involves a cyclic pathway, through the intermediacy of species isomerization, as shown in Scheme 9, involves a cyclic pathway, through the intermediacy of species II–IV, similarly to an earlier proposal by Schmidt [4]. II–IV, similarly to an earlier proposal by Schmidt [4]. II–IV, similarly to an earlier proposal by Schmidt [4]. II–IV, similarly to an earlier proposal by Schmidt [4]. Ru CH Ru CH CH222 Ru
R RR
R RR
Ru Ru HH H Ru II I R RR
R RR Ru H Ru HH Ru IV IVIV
Ru Ru HH H Ru IIII II R RR
Ru Ru Ru III IIIIII
H HH
Scheme 9. Plausible mechanism for isomerization of terminal olefins to internal olefins (adapted from Scheme 9. Plausible mechanism for isomerization of terminal olefins to internal olefins (adapted from Scheme 9. Plausible mechanism for isomerization of terminal olefins to internal olefins (adapted from Scheme 9. Plausible mechanism for isomerization of terminal olefins to internal olefins (adapted from ref. [4]). ref. [4]). ref. [4]). ref. [4]).
Additional results have been obtained for reduction with resin 8, of further substrate, the Additional results have been obtained for reduction reduction with resin 8, of of a a a substrate, further substrate, substrate, the Additional results have been obtained for with resin 8, further the Additional results have been obtained for reduction with resin 8, of a further the dimethyl dimethyl itaconate (16) bearing two carbonyl groups and a 1,1‐disubstituted olefin (Scheme 10). dimethyl itaconate (16) bearing two carbonyl groups and a 1,1‐disubstituted olefin (Scheme 10). dimethyl itaconate (16) bearing two carbonyl groups and a 1,1‐disubstituted olefin (Scheme 10). itaconate (16) bearing two carbonyl groups and a 1,1-disubstituted olefin (Scheme 10).
O OO
O OO O OO 16 16 16
O OO
SiEt 2H SiEt2H SiEt 2H (2,5 eq) 88 (2,5eq) eq) (2,5 8 O OO 2 catalyst (5 mol %) 2 catalyst2 (5(5mol mol%) %) catalyst O OO O DCM anh OO DCManh anh DCM O MW, 150 ºC, 30 min OO MW,150 150ºC, ºC,30 30min min MW, 17 17 17
+ 16 byproducts 16 ++ byproducts + byproducts ++ 16
Scheme 10. Reduction of dimethyl itaconate (16) with immobilized silane (8) and catalyst 2. Scheme 10. Reduction of dimethyl itaconate (16) with immobilized silane (8) and catalyst 2. Scheme 10. Reduction of dimethyl itaconate (16) with immobilized silane (8) and catalyst 2. Scheme 10. Reduction of dimethyl itaconate (16) with immobilized silane (8) and catalyst 2.
After filtering the resin, removing the solvent and drying the product under reduced pressure, After filtering the resin, removing the solvent and drying the product under reduced pressure, After filtering the resin, removing the solvent and drying the product under reduced pressure, After filtering the resin, removing the solvent and drying the product under reduced pressure, 1H‐NMR analysis of the crude 1 H-NMR we recovered only 27% of the feed (starting materials catalyst). we recovered of the feed (starting materials ++ + catalyst). ofof the 1H‐NMR analysis analysis of the crude crude we recovered recovered only only 27% 27% of the feed (starting materials + catalyst). 1H‐NMR analysis the crude we only 27% of the feed (starting materials catalyst). product testified to the presence of the starting 16, the reduced compound 17, as well as of several product testified to the presence of the starting 16, the reduced compound 17, as well as of several product testified to the presence of the starting 16, the reduced compound 17, as well as of several product testified to the presence of the starting 16, the reduced compound 17, as well as of several unidentified by‐products. IR spectrum of the resin recovered after the reaction revealed an intense unidentified by-products. IR spectrum of the resin recovered after the reaction revealed an intense unidentified by‐products. IR spectrum of the resin recovered after the reaction revealed an intense unidentified by‐products. IR spectrum of the resin recovered after the reaction revealed an intense −1, corresponding to C=O stretching of the two carbonyls from bifid absorption at 1718 and 1735 cm bifid absorption at 1718 and 1735 cm−1−1, corresponding to C=O stretching of the two carbonyls from , corresponding to C=O stretching of the two carbonyls from bifid absorption at 1718 and 1735 cm the dimethyl itaconate. This result supports our assumption that in the catalytic cycle, a C–Si bond the dimethyl itaconate. This result supports our assumption that in the catalytic cycle, a C–Si bond 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, (analogous to 10) is formed between the silane and 16. Consequently, in case of immobilized silanes, (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. some of the starting material ends up anchored to the solid phase, causing a decrease in the yield. some of the starting material ends up anchored to the solid phase, causing a decrease in the 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 1 H-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 CDCl as solvent and reference 3 (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 13 C 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), CH2 Cl2 (3 × 10 mL) and finally dried under high vacuum. The resin was analyzed
Catalysts 2017, 7, 111
10 of 14
by IR and 13 C 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 Et2 SiH2 (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 (4 × 15 mL), THF (4 × 15 mL), DCM (4 × 15 mL) and finally dried under high vacuum. IR spectroscopy Catalysts 2017, 7, 111 10 of 13 13 C gel-phase NMR were performed to corroborate if the expected resin 8 was obtained [44]. and Catalysts 2017, 7, 111 10 of 13 3.3.2. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane Catalysts 2017, 7, 111 10 of 13 3.3.2. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane 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 Et3 SiH were added to a microwave tube equipped with stirrer and 3.3.2. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Triethylsilane purged for a few minutes with N 2. Then, 3 mL of anhydrous DCM and 5 mol % of the Grubbs catalyst The corresponding olefin and Et 3SiH were added to a microwave tube equipped with stirrer and purged for a few minutes with N . 2 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 purged for a few minutes with N 2. Then, 3 mL of anhydrous DCM and 5 mol % of the Grubbs catalyst The corresponding olefin and Et 3SiH were added to a microwave tube equipped with stirrer and 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 were added. The tube was capped and the reaction mixture was subjected to microwave heating at purged for a few minutes with N 2. Then, 3 mL of anhydrous DCM and 5 mol % of the Grubbs catalyst ◦ C (maximum power = 120 W) 150 for the corresponding time in each case. After heating, the reaction crude was concentrated and dried under high vacuum. 150 °C (maximum power = 120 W) for the corresponding time in each case. After heating, the reaction were added. The tube was capped and the reaction mixture was subjected to microwave heating at crude was concentrated and dried under high vacuum. crude was concentrated and dried under high vacuum. 150 °C (maximum power = 120 W) for the corresponding time in each case. After heating, the reaction 3.3.3. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ crude was concentrated and dried under high vacuum. 3.3.3. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Immobilized Silane (8) 3.3.3. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ Resin-Immobilized Silane (8)
Immobilized Silane (8) 3.3.3. General Procedure for Olefin Reduction in the Presence of Grubbs Catalysts and Resin‐ The corresponding corresponding olefin and the the 4-(diethylsilylbutyl) 4‐(diethylsilylbutyl) polystyrene added to to aa The olefin and polystyrene resin resin (8) (8) were were added Immobilized Silane (8) microwave tube with stirrer and purged for a few minutes with N 2. Then, 3 mL of anhydrous DCM 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 and 5 mol % of the Grubbs catalyst were added. The tube was capped and the reaction mixture was microwave tube with stirrer and purged for a few minutes with N 2. Then, 3 mL of anhydrous DCM olefin and were the 4‐(diethylsilylbutyl) polystyrene (8) were mixture added to a and 5The molcorresponding % of the Grubbs catalyst added. The tube was capped andresin the reaction was heated at 150 °C (maximum power = 120 W). After the time set for each case, the reaction crude was ◦ and 5 mol % of the Grubbs catalyst were added. The tube was capped and the reaction mixture was microwave tube with stirrer and purged for a few minutes with N . Then, 3 mL of anhydrous DCM heated at 150 C (maximum power = 120 W). After the time set for2each case, the reaction crude was filtered through through a sintered glass filter and the liquid was collected in a round‐bottom flask, heated at 150 °C (maximum power = 120 W). After the time set for each case, the reaction crude was and 5 mol % of the Grubbs catalyst were added. The tube was capped and the reaction mixture was filtered a sintered glass filter and the liquid was collected in a round-bottom flask, concentrated concentrated and then dried under high vacuum. filtered a sintered glass filter and the liquid was collected in a round‐bottom flask, heated at 150 °C (maximum power = 120 W). After the time set for each case, the reaction crude was and thenthrough dried under high vacuum. 1H‐NMR spectrum of the reaction In the case of the reaction with dimethyl itaconate (16), the 1 H-NMR concentrated and then dried under high vacuum. filtered through sintered glass and itaconate the liquid was in spectrum a round‐bottom flask, In the case ofa the reaction withfilter dimethyl (16), thecollected of the reaction 1H‐NMR spectrum of the reaction crude was analyzed and compared to the starting material spectrum. It was verified that product 17 In the case of the reaction with dimethyl itaconate (16), the concentrated and then dried under high vacuum. crude was analyzed and compared to the starting material spectrum. It was verified that product was obtained since the characteristic signal at 0.97 ppm of the three protons of methyl group was 1H‐NMR spectrum of the reaction crude was analyzed and compared to the starting material spectrum. It was verified that product 17 In the case of the reaction with dimethyl itaconate (16), the 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 was obtained since the characteristic signal at 0.97 ppm of the three protons of methyl group was crude was analyzed and compared to the starting material spectrum. It was verified that product 17 evidenced. Nevertheless, the reaction resulted in the formation of many by-products and there was still some starting material 16 in the crude. evidenced. Nevertheless, the reaction resulted in the formation of many by‐products and there was was obtained since the characteristic signal at 0.97 ppm of the three protons of methyl group was still some starting material 16 in the crude. still some starting material 16 in the crude. evidenced. Nevertheless, the reaction resulted in the formation of many by‐products and there was 3.4. Analytical Data 3.4. Analytical Data still some starting 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 ) 3024; 2916; 2848; 1637; 1600; 1560; 4-(Diethylsilylbutyl) polystyrene resin (8). IR3, 75 MHz): δ = 145.6, 138.6, 128.2, 125.9, 115.0, 46.4, 44.2, (KBr) νmax (cm 1448; 906; 756; 592. 13C gel‐phase NMR (CDCl 4‐(Diethylsilylbutyl) polystyrene resin (8). IR (KBr) ν max (cm−1 ) 3024; 2916; 2848; 1637; 1600; 1560; 1490; 1490; 1448; 906; 756; 592. 13 C gel-phase NMR (CDCl3 , 75 MHz): δ = 145.6, 138.6, 128.2, 125.9, 115.0, 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. 1448; 906; 756; 592. 4‐(Diethylsilylbutyl) polystyrene resin (8). IR (KBr) ν max (cm−1) 3024; 2916; 2848; 1637; 1600; 1560; 1490; 46.4, 44.2, 40. 7, 35.9, 53.3. 40. 7, 35.9, 53.3. 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. 40. 7, 35.9, 53.3. Benzyl butyrate (4). H‐NMR (CDCl3, 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), 13 1.87 (m, 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, 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 H-NMR (CDCl , 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), Benzyl butyrate (4). +] (15), 160 (1), 108 (94), 91 (100), 71 3 13 128.1, 66.0, 36.21, 18.5, 13.7. GC‐MS (EI, 70 eV): m/z (%) = 178 [M 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). C‐NMR (CDCl3, 75 MHz): δ = 173.5, 136.2, 128.5, 128.2, 128.1, Benzyl butyrate (4). 13 C-NMR (CDCl , 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). 3 +] (15), 160 (1), 108 (94), 91 (100), 71 (35), 65 (26). 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 1.87 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). + ] (15), 160 (1), 108 (94), 91 (100), 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 (35), 65 (26). MeO 128.1, 66.0, 36.21, 18.5, 13.7. GC‐MS (EI, 70 eV): m/z (%) = 178 [M (35), 65 (26). MeO (35), 65 (26). AcO 15 MeO AcO 15 1 Acetyl isoeugenol (15). H‐NMR (CDCl3, 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, AcO 13 15C‐NMR (CDCl 1H‐NMR (CDCl3, 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). 3, 75 MHz): δ = 169.2, 151.0, 138.6, Acetyl isoeugenol (15). 13 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4. 1H‐NMR (CDCl3, 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). C‐NMR (CDCl3, 75 MHz): δ = 169.2, 151.0, 138.6, Acetyl isoeugenol (15). 13 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4. 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). C‐NMR (CDCl3, 75 MHz): δ = 169.2, 151.0, 138.6, 1
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 C‐NMR (CDCl 3, 75 MHz): δ = 172.7, 135.9, 128.6, 128.3, 128.2, 66.2, Hz, 4H), 1.99 (q, J = 7.4 Hz, 2H). 1,5‐Dibenzyl glutarate (11). H‐NMR (CDCl 3, 300 MHz): δ = 7.34 (m, 10H), 5.11 (s, 4H), 2.43 (t, J = 7.4
Benzyl butyrate (4). 11H‐NMR (CDCl H‐NMR (CDCl33, 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), , 300 MHz): δ = 7.35 (m, 5H), 5.12 (s, 2H), 2.34 (t, J = 7.4 Hz, 2H), Benzyl butyrate (4). 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). 13 1.87 (m, 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, ] (15), 160 (1), 108 (94), 91 (100), 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, 66.0, 36.21, 18.5, 13.7. GC‐MS (EI, 70 eV): m/z (%) = 178 [M (35), 65 (26). (35), 65 (26). MeO MeO
Catalysts 2017, 7, 111
AcO AcO
11 of 14 15 15
Acetyl isoeugenol (15). 1 H‐NMR (CDCl (CDCl , 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, , 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, Acetyl isoeugenol (15). Acetyl isoeugenol (15). H‐NMR (CDCl33, 300 MHz): δ = 6.93 (m, 5H), 6.37 (d, J=15.7 Hz, 1H), 6.20 (m, 13 C-NMR (CDCl , 75 MHz): δ = 169.2, 151.0, 13C‐NMR (CDCl 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). 3, 75 MHz): δ = 169.2, 151.0, 138.6, 3 13C‐NMR (CDCl 1H), 3.83 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 6.5 Hz, 3H). 3, 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. 137.1, 130.5, 126.1, 122.7, 118.4, 109.6, 55.8, 20.7, 18.4. 11 H-NMR
1,5‐Dibenzyl glutarate (11). H‐NMR (CDCl 3, 300 MHz): δ = 7.34 (m, 10H), 5.11 (s, 4H), 2.43 (t, J = 7.4 1 H-NMR (CDCl 1,5-Dibenzyl glutarate (11). H‐NMR (CDCl 1,5‐Dibenzyl glutarate (11). 3, 300 MHz): δ = 7.34 (m, 10H), 5.11 (s, 4H), 2.43 (t, J = 7.4 3 , 300 MHz): δ = 7.34 (m, 10H), 5.11 (s, 4H), 2.43 (t, 13C‐NMR (CDCl 3, 75 MHz): δ = 172.7, 135.9, 128.6, 128.3, 128.2, 66.2, Hz, 4H), 1.99 (q, J = 7.4 Hz, 2H). 13 J = 7.4 Hz, 4H), 1.99 (q, J = 7.4 Hz,132H). C-NMR (CDCl C‐NMR (CDCl 3, 75 MHz): δ = 172.7, 135.9, 128.6, 128.3, 128.2, 66.2, Hz, 4H), 1.99 (q, J = 7.4 Hz, 2H). 3 , 75 MHz): δ = 172.7, 135.9, 128.6, 128.3, 128.2, 33.3, 20.1. 66.2, 33.3, 20.1. 33.3, 20.1. 1 1
Benzyl (4-triethylsilyl)-trans-crotonate (5). 1 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 Hz, 9H), 0.57 (q, J = 7.9 Hz, 6H). 13 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 C17 H26 NaO2 Si: 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, Figure S1: 1 H NMR of a mixture of compounds 4 and 5 in CDCl3 , Figure S2: 13 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, Figure S9: Simulated HRMS of compound 5, Figure S10: 1 H NMR of compound 6 in CDCl3 , Figure S11: 13 C NMR of compound 6 in CDCl3 , Figure S12: HSQC NMR of compound 6 in CDCl3 , Figure S13: 13 C gel phase NMR of resin 8 in CDCl3 , Figure S14: IR of resin 8 in KBr pellet, Figure S15: 1 H NMR of compound 11 in CDCl3 , Figure S16: 13 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.
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22.
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