At Long Last: Olefin Metathesis Macrocyclization at High

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

At Long Last: Olefin Metathesis Macrocyclization at High Concentration Adrian Sytniczuk,† Michał Dąbrowski,† Łukasz Banach,† Mateusz Urban, Sylwia Czarnocka-Śniadała, Mariusz Milewski, Anna Kajetanowicz, and Karol Grela* Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Ż wirki i Wigury 101, 02-089 Warsaw, Poland

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ABSTRACT: Macrocyclic lactones, ketones, and ethers can be obtained in the High-Concentration Ring-Closing Metathesis (HC-RCM) reaction in high yield and selectivity at concentrations 40 to 380 times higher than those typically used by organic chemists for similar macrocyclizations. The new method consists of using tailored ruthenium catalysts together with applying vacuum to distill off the macrocyclic product as it is formed by the metathetical backbiting of oligomers. Unlike classical RCM, no large quantities of organic solvents are used, but rather inexpensive nonvolatile diluents, such as natural or synthetic paraffin oils. Moreover, use of a protecting atmosphere or a glovebox is not needed, as the new catalysts are perfectly moisture and air stable. In addition, some other cyclic compounds previously reported as unobtainable by RCM in neat conditions, or in high dilutions even, can be formed with the help of the HC-RCM method.

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INTRODUCTION In his Nobel lecture Lavoslav (Leopold) Ružička stated “I was hindered (···) by the general prejudice, shared by myself, against the probability of the existence of a 15- and a 17membered ring”.1 But despite this prejudice, he is today famous for proving that valuable perfume ingredients, muskone and civetone, are in fact macrocyclic compounds, and for his groundbreaking, although low yielding, synthesis of such macrocycles by thermolysis of cerium or thorium dicarboxylic acids salts. Over the years, several methods for preparing of macrocycles, such as use of high dilution conditions (Ziegler, after Ruggali), acyloin condensation (Prelog, Stoll), transestrification−depolymerization (Carothers), McMurry reaction (McMurry), Yamaguchi macrolactonization (Yamaguchi), ring-closing alkene, and alkyne metathesis (Grubbs, Schrock, Fürstner), to list only a few, have been introduced. Despite enormous progress that has been made since the time of Ružička, macrocyclizations are still considered as challenging transformations in organic synthetic chemistry.2 Transition metal catalyzed ring-closing metathesis (RCM) (Scheme 1) has revolutionized retrosynthetic thinking about the construction of macrocyclic compounds and allowed thousands of valuable products to be obtained.3−5 This is a result of the very mild conditions used in metathesis, perfect compatibility of modern ruthenium catalysts with polar or reactive functional groups, and their stability toward air and moisture. Unfortunately, despite the so-called catalyst−substrate templating effect, very elegantly proved experimentally by Fürstner6 (Scheme 2), for medium (8−13 membered) and macrocyclic rings (14+ membered) still the high dilution © XXXX American Chemical Society

Scheme 1. General Entropic Factors that Influence the Concentration-Dependence of RCM Yieldsa

a

Cyclic oligomers not shown. See ref 3.

conditions must be used. This makes, especially from the industrial perspective, large scale access to such compounds problematic, due to the environmental and economic costs of purchasing, storing, transferring, and then at the end separating and disposing large volumes of solvents. A solution to this problem was not known since the first reports7a,b on conformationally unbiased RCM lactone macrocyclization, until the most recent examples,7c preparation of medium and large rings by RCM was always recommended to be conducted under high dilution conditions. For example, in the case of carbocycles and lactones, Fogg recapitulated the following recommended concentrations of a diene in RCM: 5−6membered rings, 100 mM; 7-membered, 5 mM; 8−13Received: May 8, 2018 Published: June 26, 2018 A

DOI: 10.1021/jacs.8b04820 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Article

Journal of the American Chemical Society Scheme 2. Substrate−Catalyst Precoordination as a Key to Macrocycle RCM Formation at High Dilutiona

Chart 1. Olefin Metathesis Catalysts Discussed in This Work

a

See ref 6. Catalyst I = (PCy3)2(Cl)2Ru=CHPh.

membered, 0.5 mM; and 14+ macrocycles, 5 mM.7d At concentrations higher than recommended, a large amount of polymeric products is isolated after the reaction. These polymers are coming directly from a diene in a process called acyclic diene metathesis polymerization (ADMET) but can be also produced at the expense of the already formed macrocyclic product, in the ring-opening metathesis polymerization (ROMP) process (Scheme 1). Increasing dilutions favor the macrocycle; however, conducting RCM in very high dilution is not only unreasonable from the economic point of view but also simply low yielding because RCM below concentrations of about 0.5 mM is then too slow to compete with catalyst deactivation.3 In a fundamental work, Fogg showed that ADMET was kinetically favored even at high dilution, but importantly, oligomers, once formed, can be later converted into expected macrocycle in a process called backbiting (BB-RCM, Scheme 1), as the equilibrium between a macrocycle and higher molecular mass products is controlled by the concentration.8

Scheme 3. ADMET−then−BB-RCM Approach and the GC Trace of the Obtained Producta

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RESULTS AND DISCUSSION Our goal was to utilize the inherent reversibility of olefin metathesis to produce macrocylic products relevant to the flavor and fragrance (F+F) industry9 at concentrations much higher than normally used for RCM macrocyclizations (5 mM). We anticipated that under carefully selected conditions ADMET oligomers can be effectively backbited to yield the expected RCM macrocyclic product. Once the macrocycle is formed, we planned to “remove” it from the above-discussed equilibrium (and from the reaction mixture) under vacuum.10 We assumed that the key to success lies in the right choice of a catalyst (Chart 1). Metathesis of internal, mostly (E)configured C−C double bonds in the ADMET product is considerably slower than the terminal ones. Such unhurried backbiting is a problem because it increases the opportunity for competing catalyst decomposition, which reduces the yield and can contribute to side reactions like C−C double bond shifts (“alkene isomerization”). Therefore, in the first set of experiments we used fast initiating but at the same time reasonably stable catalyst II developed in our laboratories.9 To reconcile our expectations with reality, diene 1 was reacted without solvent with II (1 mol %) at conditions shown in Scheme 3 to form the ADMET polymer. The reaction was conducted according to the literature protocol,12 leading to a viscous material. The polymer was then subjected to the

a

RVP = rotary vane oil pump.

second stage of the process: BB-RCM depolymerization. To do so, after addition of a neutral diluent (silicone oil) and a fresh portion of catalyst, the reaction flask was mounted into a glass B


Article

Journal of the American Chemical Society Chart 2. High-Concentration RCM (HC-RCM)a

a

(a) Selectivity = (Int. of E + Z)/(Int. of all products), determined by GC. ODP = oil diffusion pump. (b) GC traces of products from entries 3 and 10. (c) TLC analyses of reaction mixture from experiment ceased after 20 min. Starting from the left are S = standard of the substrate 6, R = sample of reaction mixture, P = standard of the product 7, CS = cospot (all three together). (d) Example of a reaction/distillation Hickman glass apparatus used in our study.

alkene isomerization during the process. The failure of the above experiments explains why, despite knowledge of all the needed conceptual elements in the literature (i.e., analogy to Carothers’ acid-catalyzed depolymerization, general metathesis mechanism, Fogg’s BB-RCM concept), there is no single example of successful metathesis-based synthesis of macrocycles at very high concentrations combined with distillation (unsuccessf ul examples were also scarce16). The missing element is apparently the catalyst. With the belief that we would be able to find a catalyst with sufficient activity and stability to make the ring−chain equilibrium convert oligomers selectively into the expected product, and that it is possible to remove this product in vacuo as soon as it is formed, our efforts were continued. Profiting from our collection of catalysts (Chart 1) we conducted a number of optimizations using this time a bis-internal diene 6 leading to industrially valuable 16-membered macrocycle 7 (unsaturated analogue of Exaltolide). To make this research phase smooth and to save time, we used an oil diffusion pump (ODP). This allowed each high-concentration RCM experiment (HCRCM) to be conducted only for 8 h, and at lower temperature (110 °C), but at the same time we could expect that any molecule of the macrocyle produced by BB-RCM can be distilled off under such high vacuum (the pump nominal pressure is 10−6 mBar at the pump inlet; unfortunately, due to sensor mounting limitations, we do not know the actual pressure in the reaction/distillation flask). The diluent was a paraffin oil, and diene concentration was 9 wt % (0.25 mol/kg, ca. 200 mM). Under such conditions eleven Ru metathesis catalysts were screened (Chart 2a). In the case of popular general-purpose catalysts, such as II, III, and V−VII, mixtures of heavily isomerized products were formed making the product GC trace appear like the Gaussian distribution again (Chart 2b). Undeterred, we decided to continue experimentation with the in-house designed catalysts. The reward was not far away, as for complexes XI,17 XII,18 and recently published heterogeneous XIII@MOF,19 we observed almost ideal selectivity and surprisingly very high yields (Chart 2a). For

distillation apparatus and the reaction was continued under vacuum, using a rotary vane oil pump (RVP). The GC-MS analysis of the same sample showed that products between groups differ from the expected macrocyclic lactone 2 by ± (n × 14) mass units. Peaks inside each group have a similar molecular mass that suggests, in addition to the usual (E) and (Z) isomerism, also C−C double bond migrations occur inside a macrocycle ring (for a hydrogenation experiment supporting this, see SI). Apparently, these products are the result of a series of isomerizations that occurred during the process, which leads to a very complex chromatogram. Unluckily, among the wide range of nonmetathesis pathways promoted by the Ru metathesis catalysts, olefin isomerization is particularly common.13 Unfortunately, varying temperature (120 to 150 °C), and diluent (silicon oil, liquid and solid paraffin, etc.) was not helpful, as in all cases mixtures of fully isomerized (E/Z)macrocycles of 11 to 21 members were obtained, with a maximal yield of 24% (Scheme 3). Obviously, such a complicated mixture of products is not attractive for the F&F industry. However, with this proof of principle we decided to combine the separate steps of ADMET and BBRCM into one operation. This should make use of a catalyst more efficient and reduce the possibility for side reactions leading to isomerized products. Moreover, as a substrate we chose compound 5 instead of terminal diene 1. We hypothesized that the internal character of the C−C double bonds in 5 will slow down the ADMET process and thus make BB-RCM more competitive allowing avoidance of quick catalyst decomposition and unwanted side reactions. In addition, we decided to increase the amount of the paraffin diluent and use 2,3,5,6-tetrafluorobenzoquinone, an additive known to cease the C−C double bond isomerization (Scheme 3, bottom).14 Regrettably, all these attempts were unsuccessful. We next replaced II with the newly introduced catalyst IV,15 which is known to be stable up to 150 °C, but to no avail. We were able to distill off a bigger amount of material, up to 61%, but the GC chromatogram trace was again showing a Gaussian distribution of peaks, as in the previous cases, witnessing severe C


Article

Journal of the American Chemical Society Scheme 4. Further Optimization and Assessing the Scope of HC-RCMa

a

(a) Investigation of different diluents. PE = polyethylene. Ionic liquid = 1-butyl-2,3-dimethylimidazolium hexafluorophosphate. PAO = poly-αolefin synthetic oil. (b) Various macrocycles produced using this method. All experiments conduced at molality b = 0.25 mol/kg.

experiment was ceased before the first drops of distillate were collected (Chart 2c). TLC analysis of the reaction mixture shows the presence of ADMET products and only traces of substrate 6 (for almost identical TLC picture, see Figure 3.88 in ref 3). This suggests that in the very first minutes of the reaction the substrate is converted mainly into oligomeric and polymeric species (note a large spot at Rf = 0 in TLC; for NMR analysis of the polymer, see SI). Notably, the same TLC proves that macrocycle 7 already started to form. Having achieved for the first time a successful RCM macrocyclization in a concentration of 0.25 mol/kg (ca. 200 mM; so 40 times higher than recommended) we were curious if the method developed by us can work with other substrates. However, before attempting this, a short optimization was undertaken, using XII as the model catalyst (for more details, see the SI). From various diluents, such as liquid and white (wax) paraffin, low-MW PE, and 1-butyl-2,3-dimethylimidazolium hexafluorophosphate ionic liquid, clearly paraffins behave the best (Scheme 4). We expected good results from low MW PE, as it is completely not volatile and should be liquid at the reaction temperature (mp. 90 °C). Unfortunately, the high viscosity of the liquid PE renders stirring almost impossible, and this probably was reflected in the rather low yield of the product (although formed in high selectivity). In

the first time we were able to enjoy really clean GC traces, composed practically of only two peaks: the (Z)- and (E)geometrical isomers of the expected macrocycle 7 (Chart 2b). The reason why these complexes do not give the Gaussianlike distribution of products, although not completely clear for us, can be associated with the relative catalyst stability. The unsymmetrical N-heterocyclic ligands (uNHC) bearing XI and XII are extremely stable and have been designed to reach high selectivity in the industrially important self-metathesis of αolefins13 and in ethenolysis of natural products.17,18 Therefore, we think that their high immunity to form Ru−H species (and probably also other isomerization-active species, such as dimetallic complexes or even nanoparticles)20 was the key to success. Of note, other uNHC complexes (VIII-X) also provided selectivities higher than 60%, while catalysts II, III, and V−VII with standard SIMes and SIPr NHC ligands21 with no exception gave selectivities below 50%. It is not a coincidence that also catalyst XIII19 is known for its superior selectivity in the self-metathesis of α-olefins, but only if protected inside a metal−organic framework (MOF).22 Therefore, we were not surprised that this system gave good results in the present study as well (Chart 2a, entry 11). In order to prove that the studied HC-RCM process proceeds via backbiting of the ADMET polymer, one D


Article

Journal of the American Chemical Society the case of an ionic liquid, erosion of both yield and selectivity was observed. Very interesting analogues of natural paraffin are PAOsbranched hydrocarbon oligomers made by polymerization of α-olefinsused widely as synthetic motor oils. In our HC-RCM, both PAO4 (from Exxon Mobil) and PAO6 (from Chevron Phillips) worked very well. Using the oil diffusion pump still, as it was more efficient in this exploratory stage of investigation, eight dienes were tested in HC-RCM with practical catalysts XI and XII and at a molality of 0.25 mol/kg (to report such high concentrations we prefer to use molality [mol/kg] instead of molarity [mol/dm3]; however, the latter is also provided for convenience). To our delight all of the tested dienes, both internal and terminal ones, yielded expected macrocyclic products with good to excellent selectivity (all but one >90%) in high yield (Scheme 4). From 13-membered (E/Z)-yuzu lactone (9) to 17-membered valuable Isoambrettolide (17) products were formed with the same ease; only the 19-memebered ring (19) was obtained in lower yield (55%). Diene 12, an ester of biosourced oleic acid and citronellol, led to a lower yield as well (56%), but it should be noted that in this case metathesis proceeds between one disubstituted and one trisubstituted C− C double bond, a challenging situation even at high dilution. Not only lactones but also a macrocyclic ether (10) can be produced by this method. Encouraged by the above-mentioned results, we attempted to examine our HC-RCM protocol with a nonmacrocyclic substrate as well. Seven-membered ketones can be relatively easily formed by RCM; however, if this cyclization is not facilitated by the Thorpe−Ingold effect, high dilution (5 mM) is recommended.3 For example, it was reported that ketone 21 cannot be formed by RCM in neat conditions.23 We were therefore pleased to see that diene 20 was effectively cyclized at 200 mM, leading selectively to the expected product 21 in 79% isolated yield (Scheme 5).

However, our prospective goal is to offer this methodology to industrial users, after further development. To bring us closer to this future goal we decided to test HC-RCM in more practical conditions, namely using the standard rotary-vane pump present in practically all organic chemistry laboratories worldwide. The piece of hardware available in our laboratories, the Vacuumbrandt RZ 2.5 introductory-level pump, was certified to give a maximum vacuum of 10−3 mBar. As we checked using a separate McLeod vacuum gauge installed at the end of the glass reaction/distillation apparatus, the HCRCM of a model diene (6) was operational at pressure 10−2 mBar. Therefore, using a standard laboratory pump we were able to prove that valuable musks, an unsaturated analogue of Exaltolide (7) and (E/Z)-civetone (27), can be successfully obtained in 92% and 69% yield (Scheme 6), at a concentration

Scheme 5. Probing the Limits of HC-RCM

a Green color denotes biosourced fragments. bAt 0.5 g scale. cAt 3 g scale. Reaction was performed for 2 × 6 h.

Scheme 6. Preparation of Macrocycles with Musk Smell by HC-RCM Using Standard Laboratory Vacuum Pumpa

of 0.25 mol/kg (ca. 200 mM, 9−11 wt %) under practical vacuum, which conditions can be considered practical. As the HC-RCM process seems to work well with internal olefins, we simply utilized a renewable biobased material, oleic acid, as the substrate in the synthesis of 7 and 27, without a need to convert it first by ethenolysis into 9-decenoic acid.24 Fortunately, the other products of this RCM reaction, olefins derived from the C−C double bond end groups (C2H5, C8H17, for details see SI), were easy to separate from the musk. To push the limits of our HC-RCM method, we repeated the cyclization of 6 under an even higher concentration (33 wt %, 1.23 mol/kg, so ca. 700 mM) and still enjoyed a very good 78% isolated yield of 16-membered macrocycle 7 in 0.5 g scale and a 68% yield in 3 g scale (Scheme 6). Bearing in mind that the recommended concentration for macrocyclic lactones formation in classical RCM in solution is ca. 140 times lower (5 mM), our method, although still at the beginning of development, seems to have some practical perspective (Scheme 6). For example, to produce 3 g of 7 using classical RCM at 5 mM, assuming the quantitative yield of this process, one should use 2.5 L of the organic solvent. In our case, we need only 15 g (18 mL) of PAO6, a diluent that had its origin in a nearby gas station.

Finally, 16-membered macrocycle 4, described by Fürstner as impossible to be observed in RCM, even at high dilution, due to lack of a templating effect,6 in our method was formed at 200 mM concentration, although in limited yield (22%, Scheme 5). However, taking in account that in this case there are no conformational constraints that can reduce the entropic penalty of the cyclization and that this is the very first reported example of a purely hydrocarbon unbiased macrocycle ever observed in RCM, this result is of theoretical importance. In the introductory research stage and for assessing the scope, the expensive diffusion vacuum pump was used. E


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Journal of the American Chemical Society ORCID

Finally, we attempted macrocylization in highly concentrated mixtures. The same HC-RCM process conducted at 67 wt % diene 6 in PAO6 (concentration 4.9 mol/kg, ca. 1400 mM) gave only a 26% isolated yield of 7, however, with sill satisfactory selectivity of 89%. When we attempted using almost neat conditions (90 wt %, 25 mol/kg, ca. 1900 mM, 0.95 mol % of XI), still 34% of musk macrocycle 7 was produced with 83% selectivity. By continuing the distillation for a longer time and with 1.7 mol % of XI it was possible to increase the yield to 65%, although at the cost of eroded selectivity (72%; for details, see SI). Despite the fact that this time the concentration was 280−380 times higher than those used typically for a solution-based RCM, and no special hardware other than standard laboratory vacuum pump is needed, we are not fully satisfied with these results. However, to improve HC-RCM in close-to-neat conditions, process engineers should be involved, as we think that further optimization is more related to chemical engineering (e.g., choosing appropriate distillation/reactor equipment, optimization of pumping protocol, stirring, time, etc.) than to olefin metathesis chemistry. Yet, we see our main achievement is proving that production of macrocycles by RCM is possible at concentrations never reported before, if the correct conditions and the catalyst are provided. In summary, we showed for the first time that macrocyclic lactones, ethers, and ketones (including 7-membered one) can be obtained in high yield and selectivity at concentrations 40 to 380 times higher than those typically used by organic chemists for similar macrocyclizations. Unlike in classical RCM, in our method no regular organic solvents such as anhydrous toluene or CH2Cl2 are used, but rather inexpensive nonvolatile diluents, such as paraffin oil or PAO. Also, the use of a protecting atmosphere, Schlenk techniques, or a glovebox is not needed, as the HC-RCM reactions can be set up in air as the newly designed catalysts are moisture and air stable. It is astonishing that, despite its logical simplicity, there is no documented application of such a BB-RCM/distillation protocol in the selective production of macrocycles at high concentrations. Likley, the missing element was a proper catalyst, and more specifically, a catalyst possessing longevity combined with activity sufficient to react with a sterically hindered ADMET polymer. The low stability of classical Ru catalysts propagating species under such demanding conditions translates into severe isomerization of double bonds by catalyst decomposition products, thus to formation of complicated mixtures of products. The quest for better catalysts for RCM continues,25 and we were pleased to find that a few of our catalysts, originally designed to offer high fidelity in the selfmetathesis of α-olefins, also made the selective highconcentration RCM of macrocycles possible for the first time.

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Michał Dąbrowski: 0000-0002-2128-1812 Karol Grela: 0000-0001-9193-3305 Author Contributions †

A.S., M.D., and Ł.B. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Science Centre (Poland) for the NCN MAESTRO Grant No. DEC-2012/04/A/ST5/ 00594 for funding this work.

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(1) https://www.nobelprize.org/nobel_prizes/chemistry/laureates/ 1939/ruzicka-lecture.pdf. (2) Martí-Centelles, V.; Pandey, M. D.; Burguete, M. I.; Luis, S. V. Chem. Rev. 2015, 115, 8736−8834. (3) van Lierop, B. J.; Lummiss, J. A. M.; Fogg, D. E. In Olefin Metathesis: Theory and Practice; Grela, K., Ed.; Wiley and Sons: 2014; pp 85−152. (4) Hanson, R.; Maitra, S.; Chegondi, R.; Markley, J. L. In Handbook of Metathesis, Vol. 2; Grubbs, R. H., O’Leary, D. J., Eds.; Wiley-VCH: 2015; pp 1−170. (5) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783−3816. (6) Fürstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics 2002, 21, 331−335. (7) (a) Fürstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942− 3943. (b) Wiegers, W. J.; Van Loveren, A. G.; Hanna, M. R.; Luccarelli, D.; Bowen, D. R.; Vock, M. H. Macrocyclic carbonates, processes for preparing same, organoleptic uses thereof and intermediates used in said process. US4490544, 1984. (c) For a recent report showing that when RCM is conduced at 35 mM concentration, the macrocyclic musk yield is reduced almost by half (from 70% to 40%), see: Olszewski, T. K.; Tracz, A.; Gawin, A.; Bieniek, M.; Skowerski, K. New J. Chem. 2018, 42, 8609−8614. (d) See Table 3.2 in ref 3. (8) (a) Conrad, J. C.; Edelman, M. D.; Duarte Silva, J. A.; Monfette, S.; Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007, 129, 1024−1025. (b) For a discussion of the Jacobson−Stockmayer theory in the context of RCM, see: Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2006, 10, 185−202. (9) For selected reviews, see: (a) Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Fráter, G. Angew. Chem., Int. Ed. 2000, 39, 2980−3010. (b) Williams, A. S. Synthesis 1999, 1999, 1707−1723. (c) Fráter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633−7703. (d) Gradillas, A.; Pérez-Castells, J. In Metathesis in Natural Product Synthesis; Cossy, J., Ed.; Wiley-VCH: 2010; pp 149−182. (e) For one of early industrial disclosures on macrocyclic musk production by RCM, see ref 7b. (10) Up-to-date static vacuum was used in olefin metathesis (including RCM) to remove ethylene, which has a beneficial effect on the reaction outcome. For a representative reference, see: Ahmed, T. S.; Grubbs, R. H. Angew. Chem. 2017, 129, 11365−11368. (11) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318−9325. (12) Li, H.; da Silva, L. C.; Schulz, M. D.; Rojas, G.; Wagener, K. B. Polym. Int. 2017, 66, 7−12. (13) For isomerization as an unintended side reaction encountered during self-metathesis of α-olefins, see: Rouen, M.; Queval, P.; Borré, E.; Falivene, L.; Poater, A.; Berthod, M.; Hugues, F.; Cavallo, L.; Baslé, O.; Olivier-Bourbigou, H.; Mauduit, M. ACS Catal. 2016, 6, 7970−7976. (14) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160−17161. (15) Czarnocki, S. J.; Czelusniak, I.; Olszewski, T. K.; Malinska, M.; Wozniak, K.; Grela, K. ACS Catal. 2017, 7, 4115−4121.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b04820. Materials and methods, synthesis of substrates, detailed experimental procedures, and copies of NMR spectra of products (PDF)

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REFERENCES

AUTHOR INFORMATION

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At Long Last: Olefin Metathesis Macrocyclization at High

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