Research Article pubs.acs.org/acscatalysis
Cyclic Alkyl Amino Ruthenium ComplexesEfficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis Rafał Gawin,† Andrzej Tracz,† Michał Chwalba,† Anna Kozakiewicz,‡ Bartosz Trzaskowski,§ and Krzysztof Skowerski*,† †
Apeiron Synthesis SA ul., Duńska 9, 54-427 Wrocław, Poland Faculty of Chemistry, University of Nicolaus Copernicus, Gagarina 7, 87-100 Toruń, Poland § Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warszawa, Poland ‡
S Supporting Information *
ABSTRACT: The active species generated from ruthenium complexes bearing N-heterocyclic carbene (NHC) ligands exhibit limited stability under certain conditions (high dilution, high temperature) and in the presence of nitrile functionality. As a consequence, industrial implementation of metathesis for the production of important materials such as macrocyclic musks and polyamide 11 is uneconomical. Over the past decade, hundreds of ruthenium complexes bearing NHC ligands have been obtained. However, to this date, they have brought rather limited improvements in efficiency. In this paper, we report on cyclic alkyl amino carbene (CAAC) ruthenium complexes that promote highly challenging macrocyclization and cross metathesis (CM) with acrylonitrile reactions at loadings as low as 10−20 ppm. KEYWORDS: carbenes, metathesis, ruthenium, renewable resources, cross metathesis
O
changing the designs of NHC-based catalysts. It is worth mentioning that the above-mentioned TON values are far below the limits required for economic feasibility, thus prohibiting application of metathesis to the synthesis of polyamide. Unsustainable reaction conditions (0.05 M, 120 °C, 5 h) represented an additional obstacle. Macrocyclic scaffolds are very important for the pharmaceutical and fragrance industries.10 In particular, macrocyclic musks (e.g., Exaltolide, Scheme 1) are known for their outstanding fragrance properties.11 However, they are nowadays extracted from natural sources or synthesized with a tedious multistep synthesis.12 OM, which is a clean, catalytic method would be perfectly suited for the synthesis of musks via macrocyclization. Unfortunately, low stability of catalytically active species at high dilution and high temperatures leads to low TONs (usually in the range of 10−100).13The best TONs have been reported for the synthesis of 16-membered lactone by (i) Fogg et al. (TON 760, at 76% yield/76% conversion and TON 500 at >99% yield) in flow system with 1,14 (ii) our group (TON 3640 at 91% yield/95% conversion) with 9,15 and (iii) Kadyrov (TON 16 000, at 80% yield/92% conversion and TON 11 700 at 88% yield/100% conversion) with complex 5.16 TONs, especially those achieved at full conversion and close to quantitative yield, should be significantly higher to allow for
lefin metathesis (OM) allows for catalytic creation of new C−C double bonds.1 This method is now at the dawn of uptake in the manufacture of active pharmaceutical ingredients and specialty chemicals.2 However, the efficiency of NHC-based complexes (e.g., 1−5, Figure 1) is not sufficient for the synthesis of some industrially important classes of compounds. Among these compounds, special attention should be paid to nitriles and macrocyclic musks. Cross metathesis (CM) with acrylonitrile offers a straightforward path to linear nitriles which are easily transformable into aldehydes, acids, and amines.3 For example, CM between renewable methyl 9-decenoate 11 and acrylonitrile delivers a precursor for polyamide 11 (12, Scheme 1). Moreover, dozens of drugs and drug candidates (e.g., Rilpiviryne4) contain nitrile functionality,5 and these could benefit from efficient CM with molecules bearing nitrile groups. As proven by Fogg et al., the active species generated from 1 decompose readily in the presence of acetonitrile.6 Acrylonitrile is known to poison not only 1 and its highly active analogues 4a,b but also more robust Hoveyda-type catalysts 2 and 3.7 Accordingly, CM with acrylonitrile has gained great attention, and significant efforts have been made to optimize this reaction. In most cases, however, the turnover numbers (TONs) below 100 were obtained.8 As a result of intensive optimization, Bruneau, Couturier, and colleagues reached TON of 12 160 for 2a and 13 280 for 3a in CM with acrylonitrile.9 These results demonstrate the limited possibilities for improvement by © 2017 American Chemical Society
Received: February 23, 2017 Revised: May 25, 2017 Published: July 5, 2017 5443
DOI: 10.1021/acscatal.7b00597 ACS Catal. 2017, 7, 5443−5449
Research Article
ACS Catalysis
NHC-based catalysts.18 Recently, however, we reported on complex 9 which proved to be efficient in the formation of internal CC, achieving TONs up to 315 000. For this project, we focused on performing a structure−activity relationship (SAR) study, which would not be possible with bis(CAAC) complexes, because the majority of these catalysts show low to moderate activity (measured as turnover frequency − TOF). In turn, we wanted to take advantage of the possibility of electronic activation of Hoveyda-type catalysts with nitro group19 in order to reduce the reaction temperature and/or shorten the reaction time. The known method for synthesis of CAAC-ruthenium benzylidene complexes utilizes 6a as the precursor.18 Thus, modification of benzylidene ligand would require tedious preparation of appropriate first generation complex (e.g., 6b).20 Therefore, we started our study by developing a more straightforward method for the synthesis of CAAC-ligated catalysts (Scheme 2). In our three-step-one-pot method, CAAC generated from appropriate salt (e.g., 13a)21 is reacted with readily available indenylidene catalyst 14. The resulting bis(CAAC) complex is contacted with 15 in the presence of CuCl providing the expected Hoveyda-type (pre)catalysts. With this approach, seven new complexes were obtained with low to moderate yields. The most sterically demanding CAAC could not be introduced with our method, so the catalyst 19b was synthesized from 6b (for completeness of SAR study). On the other hand, we were able to introduce very small CAAC bearing N-Mes substituent and two methyl groups on quaternary carbon atom (see 16a). Installation of this carbene on 6a was reported previously to be impossible to achieve.18a,c It is hypothesized that complexation of carbene with lithium cations, liberated from lithium hexamethyldisilazane (LiHMDS) upon deprotonation of 13a, slows down decomposition of otherwise highly unstable sterically unhindered CAAC.22 Catalytic performance of complexes 16−19 was tested in CM of ethyl 10-undecenoate 20 with acrylonitrile (Table 1). Productive TON is a crucial factor for industrial implementation of acrylonitrile metathesis to the manufacturing of relatively inexpensive polyamide 11. This fact together with easy separation of 21 from unreacted 20 and dimeric byproduct 22, prompted us to focus on catalyst efficiency only. Accordingly, the initial reaction conditions were adjusted to avoid full conversions and thus better differentiate the complexes under study. Thus, the reaction was run at 0.1 M and 70 °C, by using 2 equivalents of acrylonitrile added at the beginning of the reaction and with only 300 ppm of catalysts. A dramatic influence of CAAC ligand structure was noticed not only on TON but also on selectivity to CM product. Most striking was the very low activity of complexes 19a,b, which contain isopropyl substituents in ortho positions of N-aryl ring. Likewise, complexes 18a,b bearing one isopropyl group in Naryl substituent exhibited reduced activity and selectivity. Interestingly, nonactivated analogues of 18a,b and 19b were reported by Grubbs to be among the best catalysts for ethenolysis of methyl oleate.18a Apparently, a small molecule of ethylene is needed to activate these sterically demanding complexes. 18a,c Furthermore, catalysts with two methyl substituents at quaternary carbon adjacent to the carbene center proved to be much less efficient and selective than analogues bearing one phenyl substituent at this position. No such effect was observed by Grubbs in ethenolysis.18a Thus,
Figure 1. Ru-based complexes for OM (Mes −2,4,6-trimethylphenyl; Dipp −2,6-diisopropylphenyl; Dmp −2,6-dimethylphenyl; Ph = phenyl; Cy = cyclohexyl; Py = pyridine).
Scheme 1. Metathesis Reactions for Which Industrialization Is Hindered by Low Efficiency of NHC-Based Catalysts
wide application of OM in the production of macrocyclic musks. From the practical point of view, full conversion of substrate with high TON is particularly important due to the tedious separation of starting material from the cyclic product and high price of metathesis catalyst. Possibilities for new modifications of NHC-alkylidenes which could provide improvements of catalyst efficiency (measured as TON) are very limited. Therefore, we turned our attention to catalysts bearing CAAC ligands.17 These complexes (e.g., 7, 8) are known for their excellent efficiency in CM with ethylene leading to terminal CC, while their performance in the formation of internal olefins was tested only in benchmark ring closing metathesis of diethyl malonate derivatives and was reported to be, at best, only comparable to those observed for 5444
DOI: 10.1021/acscatal.7b00597 ACS Catal. 2017, 7, 5443−5449
Research Article
ACS Catalysis Scheme 2. New CAAC-Ru Benzylidenes Synthesis; (* Obtained from 6b)
this case, the reaction rate were not notably affected as final conversions for all catalysts were observed after 5 min. These results suggest that the poisoning effect of acrylonitrile is related not only to its coordinative properties but also to the possibility of formation of the (Carbene)Cl2RuCHCN complex. To check the reactivity of cyanomethylidenes formed by complexes 17a,b, and 3b, we ran RCM of 25 (Scheme 3), which most probably starts from the initiation on the terminal, more electron-rich double bond. Thus, RCM of 25 will lead, after each catalytic cycle, to the formation of cyanomethylidenes with the general formula 26, activity of which will determine the catalyst performance. In this transformation, 17b was observed to be four times more efficient than 17a and 3b. Importantly, TONs in RCM of 25 were significantly lower than those observed for RCM of 23, ran in the presence of 2 eq of acrylonitrile, proving the critical role of 26. On the basis of these results, it is clear that slow addition of acrylonitrile leads to higher TONs obtained for CM with this reagent, in first instance, by limiting the formation of 26. The most important intermediates for CM of 20 with acrylonitrile which were considered in our DFT calculations are presented in Scheme 4. It shall be noted that although the differences between calculated energetic barriers are rather low, they are fully consistent with experimental results. The discussed reaction may follow two paths, either commencing with the acrylonitrile (path 1) or ethyl 10-undecenoate 20 (path 2) attack. In the case of 3b and 17a, the difference in the Gibbs free energy favors path 2 over path 1 by 3.03 and 3.34 kcal mol−1, respectively, suggesting that path 1 does not have a practical meaning. This difference is only 1.66 kcal mol−1 for 17b, which given the expected accuracy of the calculation of around 1 kcal mol−1 suggests that both paths are viable.26 Following path 2, the next crucial intermediate is ruthenium alkylidene (int2) which can react either with acrylonitrile (int7) to produce 21 or with a second molecule of 20 (int3) to produce 22. For 17a the reaction with 20 is kinetically favored by 2.50 kcal mol−1, which would translate to the final ratio of 22: 21 being 36:1. In contrast, for int2 formed from 3b and 17b the acrylonitrile attack and second molecule of 20 attack is equally probable (a
small or medium N-aryl substituents and large substituent at quaternary carbon atom are necessary for good catalyst performance in CM with acrylonitrile. These precise steric requirements highlight the importance of SAR studies. After a short optimization (see Supporting Information for details), we have found that the best results can be obtained at a concentration of 0.25 M. The slow addition of catalyst and one equivalent of acrylonitrile (2 eq of acrylonitrile in total) together with active removal of ethylene allowed us to achieve TON of 24 800 with 17b.23 At these conditions 3b was less selective and provided twice lower TON (Table 1). Catalyst 16b showed better selectivity than 17b but lower TON. A further increase of TON to 28 500 was observed for 17b, when the reaction was run at 85 °C. In these conditions, CM between 11 and acrylonitrile with 20 ppm of 17b provided 12, the precursor of polyamide 11 with TON of 30 000 and selectivity of 82%. Grubbs et al. suggested that better selectivity of CAACligated complexes in ethenolysis reaction, when compared to NHC-systems, originates from higher stability of active species rather than from better kinetic selectivity (with longer catalyst lifetimes, the probability of a reaction with dimer is increased).18a Importantly, dimerization of 20 was accomplished with 17a and 17b, with similar TONs exceeding 40 000. The difference in performance of these complexes in CM with acrylonitrile must therefore be related to this reagent. Further experiments and density functional theory (DFT) calculations have been performed to reveal the origins of differences between 17a, 17b, and 3b. First, we performed a modified version of the simple, but very informative experiment proposed by Fogg et al. (Table 2).24 The ring closing metathesis (RCM) of diethyl diallylmalonate 23, was run in the presence of acrylonitrile or acetonitrile to test the stability of active species in the presence of these reagents. In accordance with our expectations, excellent productivity of 17b in the presence of acrylonitrile was observed, whereas the activity of 17a and 3b was significantly inhibited.25 Importantly, each catalyst required more time to show the maximum possible conversion. Acetonitrile showed a lower negative effect on the catalyst productivity (as evidenced by higher TONs achieved by 17a and 3b) than acrylonitrile. In 5445
DOI: 10.1021/acscatal.7b00597 ACS Catal. 2017, 7, 5443−5449
Research Article
ACS Catalysis Table 1. CM of Ethyl 10-Undecenoate with Acrylonitrile
Table 2. RCM of Diethyl Diallylmalonate 23 in the Presence of Nitriles
entry
[Ru]
RCN
time [min]a
GC yield [%]
TON
1 2 3 4 5 6 4 5 6
17a 17a 17b 17b 3b 3b 17a 17b 3b
acrylonitrile acrylonitrile acrylonitrile acrylonitrile acrylonitrile acrylonitrile CH3CN CH3CN CH3CN
5 120 5 120 5 120 5 5 5
19 28 71 >99 23 28 60 >99 95
950 1400 3550 5000 1150 1400 3000 5000 4750
a
Conversions without RCN were quantitative within 5 min for each catalyst.
Scheme 3. RCM with Formation of Ruthenium Cyanomethylidenes
probable than in the case of 17a and 3b, yet still less likely than path 4. Importantly, a viable regeneration of (pre)catalyst in the reaction of int4 with 2-isopropoxy-4-nitro styrene can strongly influence the kinetic selectivity.27 Therefore, the kinetic selectivity to heterocoupled product depends on the relative likelihood of formation of int1 vs int5, int3 vs int7, and int8 vs int9 as well as regeneration of (pre)catalyst. It must be also noted that olefin metathesis is a reversible process, and our calculations show that 21 is thermodynamically favored (by 1.64 kcal mol−1) over 22. The selectivity observed experimentally is therefore a result of kinetics and thermodynamics, influenced additionally by the excess of acrylonitrile. Nevertheless, experiments and DFT calculations led us to conclusion that (i) superior performance of 17b in comparison to both 17a and 3b is related to its resistance toward decomposition induced by acrylonitrile (ii) advantage of 17b over 17a originates mostly from better kinetic selectivity, (iii) 3b shows good kinetic selectivity, but final TON (and achievement of thermodynamic equilibrium) is compromised by too low stability of active species. Next, the most promising complex 17b was tested in challenging RCM of 10 leading to 16-membered lactone 27 (the precursor of Exaltolide, Table 3). Close analogues of 17b, namely, 8, 17a, as well as bis(CAAC) complex 9 and state-of-the-art NHC-based complexes were also tested for comparison. Only 30 ppm of 17b was required to achieve a yield of 90%, which corresponds to an excellent TON of 30 000 (Table 3, entry 9). It is worth noting that the reaction took only 20 min. At this loading, neither the classical NHC-based complexes 1, 2b, 3b, 5 nor CAAC-ligated complexes 8, 9, or 17a could provide significant amounts of product. Importantly, 45 ppm of 17b assured nearly
a 1 ppm = 0.0001 mol % calculated based on 20. bdetermined by GC, for details regarding calculation of selectivity, yield, and TON, see the Supporting Information. c1 equiv of acrylonitrile and catalyst added dropwise over 1 h. d85 °C.
difference of 0.39 kcal mol−1 in favor of int7 for 3b, and 0.04 kcal mol−1 in favor of int3 for 17b). As a result, 3b and 17b show better selectivity than 17a. For 17b, the selectivity to 21 might be additionally improved by viability of path 1 which leads exclusively to CM product. Upon formation of methylidene intermediate (int4) the catalytic cycle can follow either path 3 (similar to path 1) started with the association of acrylonitrile or path 4 (similar to path 2) commenced with the association of 20. For all computationally studied systems (3b, 17a, and 17b), path 4 is the most probable option. In the case of 3b, the Gibbs free energy difference of 6.55 kcal mol−1 in favor of path 4 implies that path 3 has absolutely no practical meaning. The Gibbs free energy difference for 17a is lower (4.25 kcal mol−1) but still large enough to almost completely favor path 4. On the other hand the 2.62 kcal mol−1 Gibbs free energy difference found for 17b indicates that path 3 is more 5446
DOI: 10.1021/acscatal.7b00597 ACS Catal. 2017, 7, 5443−5449
Research Article
ACS Catalysis
Scheme 4. Schematic Representation of Essential Intermediates in the CM of Ethyl 10-Undecenoate (20) with Acrylonitrilea
a The numbers represent differences in the Gibbs free energy between selected intermediates for 3b, 17a,b (for clarity reasons the scheme is not consistent with the Gibbs free energy scale).
Table 3. Comparison of Different Ru-Complexes in Macrocyclization
entry
[Ru], ppm
C [mM]
conv. [%]
GC yield [%]a
E/Z
TON
1 2 3 4 5 6 7 8 9 10 11 12
1, 30 1, 300 2b, 30 3b, 30 5, 30 8, 30 10, 30 17a, 30 17b, 30 17b, 45 17b, 15 17b, 10
5 5 5 5 5 5 5 5 5 5 10 20
17 ± 1 99 ± 1 10 ± 1 5±2
