GaCl3-Catalyzed Ring-Opening Carbonyl–Olefin Metathesis - Organic

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Cite This: Org. Lett. 2018, 20, 4954−4958

GaCl3‑Catalyzed Ring-Opening Carbonyl−Olefin Metathesis Haley Albright, Hannah L. Vonesh, Marc R. Becker, Brandon W. Alexander, Jacob R. Ludwig, Ren A. Wiscons, and Corinna S. Schindler* Department of Chemistry, Willard Henry Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States

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ABSTRACT: The development of a Lewis acid-catalyzed ring-opening cross-metathesis reaction which enables selective access to acyclic, unsaturated ketones as the carbonyl−olefin metathesis products is described. While catalytic amounts of FeCl3 were previously identified as optimal to catalyze ringclosing metathesis reactions, the complementary ring-opening metathesis between cyclic alkenes and carbonyl functionalities relies on GaCl3 as the superior Lewis acid catalyst.

T

Table 1. Reaction Optimization for Catalytic Carbonyl− Olefin Ring-Opening Metathesisa

he metathesis reaction between two alkenes is among the most powerful catalytic strategies for carbon−carbon bond formation to enable synthetic access to functionalized olefins.1 One important variation of the olefin metathesis reaction is ringopening cross-metathesis (ROCM) during which a cyclic alkene undergoes ring-opening and subsequent cross-metathesis with another alkene to form more structurally complex olefins, including symmetrically capped (3) and end-differentiated (4) products (Figure 1A).2,3 Carbonyl−olefin metathesis reactions between olefin and carbonyl functionalities similarly enable the construction of carbon−carbon bonds to access functionalized olefins.4,5 However, despite important progress, the currently available procedures for carbonyl−olefin metathesis remain significantly less advanced.6,7 Lewis acid-catalyzed approaches have been recently developed as viable synthetic alternatives to

entry

Lewis acid

cat. loading (mol %)

solvent

conc (M)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

AlCl3 BF3·OEt2 TiCl4 FeBr3 InCl3 FeCl3 FeCl3 FeCl3 FeCl3 GaCl3 GaCl3 GaCl3 GaCl3 GaCl3 Fe(OTf)3 Sc(OTf)3 HCl TfOH

10 10 10 10 10 10 5 20 10 10 5 20 10 10 10 10 10 10

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE

0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.01 0.1 0.1 0.1 0.01 0.5 0.1 0.1 0.1 0.1

0 2 0 0 25 33 11 27 11 47 34 20 8 34 4 13 0 2

a

Conditions: all reactions were performed with 0.4 mmol of benzaldehyde and 0.1 mmol of 1-methylcyclopentene in 1,2dichloroethane (DCE; 0.1 M, 1 mL) at 25 °C for 24 h. Yields were determined by GC analysis.

existing strategies for carbonyl−olefin metathesis.8,9 For example, upon reaction with catalytic amounts of FeCl3, aryl ketone substrates can undergo an intramolecular [2 + 2]cycloaddition to form intermediate oxetanes which subsequently fragment in a retro [2 + 2]-cycloaddition to form the Figure 1. Ring-opening olefin−olefin metathesis and carbonyl−olefin metathesis reactions. © 2018 American Chemical Society

Received: July 3, 2018 Published: July 27, 2018 4954

DOI: 10.1021/acs.orglett.8b02086 Org. Lett. 2018, 20, 4954−4958

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Organic Letters Table 2. Ring Strain of Cyclic Alkenes

a

Ring-strain energy (kcal/mol).11 bConditions: all reactions were performed with 4.0 equiv of 11 and 1.0 equiv of olefin substrates with 10 mol % of GaCl3 in DCE (0.1 M) at 25 °C for 24 h.

desired carbonyl−olefin ring-closing metathesis products. Additionally, examples of intermolecular carbonyl−olefin cross-metathesis and ring-opening metathesis reactions have recently been reported to rely on carbocations as catalysts, albeit resulting in lower overall yields of the isolated products.10 Our studies toward a Lewis acid-catalyzed carbonyl−olefin ringopening metathesis show similar observations of the desired products forming in ∼50% yield, as initially attributed to the formation of regioisomeric oxetane intermediates 7 and 8 and subsequent decomposition of the aldehyde metathesis product 10 (Figure 1B). We herein report insight into the controlling features of this transformation with a specific emphasis on substrate scope and competing reaction pathways. To develop a catalytic carbonyl−olefin ring-opening metathesis reaction, we focused on aryl aldehydes 5 and substituted cyclopentenes 6 as the substrates. We envisioned cyclopentenes 6 as ideal substrates for reaction optimization as the inherent ring strain of the proposed [3.2.0] intermediate oxetane bicycle was expected to facilitate the fragmentation to metathesis products. Additionally, the electronic characteristics of 1substituted cyclopentenes were expected to favor the formation of oxetane 7 and, therefore, ketone 9 as the major metathesis product. Initial efforts centered on the evaluation of distinct Lewis acids varying in strength in the carbonyl−olefin metathesis reaction of benzaldehyde 11 with 1-methylcyclopentene 12 (Table 1). Strong Lewis acids such as AlCl3 or BF3·

Figure 3. NMR fragmentation studies of oxetanes 40 and 41.

OEt2 did not prove efficient in promoting the desired carbonyl− olefin ring-opening metathesis (entries 1 and 2, Table 1). Similarly, TiCl4 and FeBr3 were inefficient catalysts in this transformation (entries 3 and 4, Table 1). However, promising results were obtained with catalytic amounts of InCl3 as the Lewis acid resulting in the formation of ketone 13 as the exclusive metathesis product in 25% yield (entry 5). Increased yields of alkyl ketone 13 in 33% were observed with 10 mol % of FeCl3 (entry 6, Table 1), while alternate FeCl3 loadings as well as running the reaction at lower concentrations did not result in increased yields of 13 (entries 7−9, Table 1). Subsequent efforts identified GaCl3 as the superior Lewis acid catalyst for carbonyl−olefin ring-opening metathesis resulting in the formation of the alkyl ketone 13 in 47% yield (entry 10, Table 1). Varied catalyst loadings of 5% or 20% resulted in diminished

Figure 2. Evaluation of the substrate scope of GaCl3-catalyzed carbonyl−olefin ring-opening metathesis. 4955

DOI: 10.1021/acs.orglett.8b02086 Org. Lett. 2018, 20, 4954−4958

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Organic Letters

Figure 4. Fragmentation studies of oxetane exo-41.

Figure 6. Carbonyl−ene reaction pathway is competing in catalytic carbonyl−olefin ring-opening metathesis reactions.

a variety of substituted, cyclic alkenes with benzaldehyde and GaCl3 as the Lewis acid catalyst (Table 2). Interestingly, yields obtained in the carbonyl−olefin ring-opening metathesis do not correlate to the inherent ring strain of the cyclic alkenes as cycloheptane 17 and cyclooctene 18 with a ring strain of 6.3 and 7.4 kcal/mol, respectively, result in no formation of the desired product, while cyclohexene 16 with a lower ring strain of 1.7 kcal/mol forms the corresponding metathesis product, albeit in a low yield of 18% (Table 2). Next, we evaluated additional aldehydes and cyclic alkenes upon their ability to undergo the desired carbonyl−olefin ring-opening metathesis (Figure 2). A variety of electronically and sterically differentiated aromatic aldehydes proved viable under the reaction conditions and resulted in up to 47% of the metathesis product (19−36, Figure 2). Aliphatic aldehydes were not effective for the promotion of metathesis. Importantly, the corresponding aliphatic ketones were formed as the exclusive products, while no formation of metathesis products 10 resulting upon fragmentation of proposed regioisomeric oxetane 8 were observed. Distinct substitution on the cyclopentene was tolerated (37 and 38, Figure 2), while the corresponding 1-methylcyclohexene formed 39 in 18% yield. Our subsequent efforts aimed at the elucidation of whether the formation of a regiosiomeric mixture of oxetane intermediates (7 and 8) and subsequent selective decomposition of aldehyde 10 was responsible for a maximum of 50% yield of the carbonyl−olefin metathesis product. As part of these studies, we independently prepared a mixture of regioisomeric oxetanes 40 and 41 via a Paterno−Büchi reaction12 (Figure 3A). We were able to enrich this mixture chromatographically to contain predominantly oxetane 40 as the expected major intermediate in carbonyl−olefin metathesis reactions of 11 and 12 (>5:1 ratio 40:41; Figure 3B). The conversion of this enriched mixture of oxetane 40 under the optimal conditions for carbonyl−olefin ring-opening metathesis was subsequently monitored by NMR analysis (Figure 3B). After 10 min, clean conversion to 13 as the single olefinic product was isolated in 61% yield along with 7% yield of benzaldehyde 11. Notably, no significant aldehyde signals were

Figure 5. NMR experiments of the GaCl3-catalyzed carbonyl−olefin ring-opening metathesis reaction.

yields of 34% and 20%, respectively (entries 11 and 12, Table 1). Similarly, other concentrations resulted in lower yields of the desired metathesis product 13 (entries 13 and 14, Table 1). Metal triflates such as Fe(OTf)3 or Sc(OTf)3 and Brønsted acids were not effective in promoting the desired ring-opening metathesis reaction, which is consistent with our previous observations in Lewis acid-catalyzed carbonyl−olefin metathesis (entries 15−18, Table 1). Importantly, alkyl ketone 13 was the only metathesis product isolated for all of the catalysts evaluated, while the corresponding aldehyde 10 was not observed. We next investigated the effect of ring strain11 in the carbonyl−olefin ring-opening metathesis reaction by converting 4956

DOI: 10.1021/acs.orglett.8b02086 Org. Lett. 2018, 20, 4954−4958

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Organic Letters observed in the NMR spectra from the aldehyde metathesis product. In the ensuing experiments, we were able to obtain exo41 as a single regio- and stereoisomer and subject it to 10 mol % of GaCl3 (Figure 4A) in NMR studies. Importantly, exo-41 corresponds to the minor oxetane regioisomer that could be formed under carbonyl−olefin metathesis conditions of 11 and 12. However, no formation of aldehyde 42 was observed, and the reaction resulted in complete decomposition of substrate. To determine the stability of the anticipated carbonyl−olefin metathesis products 13 and 42, we prepared both compounds independently and subjected them to the optimized reaction conditions (Figure 4B). While methyl ketone 13 proved stable under the reaction conditions, aldehyde 42 underwent rapid decomposition. Based on these results, we turned our attention to in situ NMR experiments of GaCl3-catalyzed carbonyl−olefin metathesis between 11 and 12 (Figure 5). Within 20 min, the exclusive formation of one set of alkene signals is observed which corresponds to methyl ketone 13 (blue, Figure 5B). However, a new set of signals at 3.4 ppm also appeared which did not correspond to ketone 13 (orange, Figure 5B). After 24 h, signals corresponding to a second, unknown compound formed (gray, Figure 5B). Importantly, no signals corresponding to oxetanes 40 or 41 were observed in the course of these NMR studies. Our subsequent efforts were aimed at the isolation and identification of both byproducts. Upon conducting the reaction on larger scale, pure samples of both compounds were isolated. Byproduct A formed immediately within 20 min as a competing compound to the desired metathesis product 13 and was identified as bicyclopentane 44, formed in 20% yield (Figure 6). The second byproduct B, formed in 10% yield, was characterized as pyran 45. Importantly, both compounds are not formed in a carbonyl− olefin metathesis reaction path and do not represent products resulting from fragmentation of intermediate oxetanes 40 and 41 or decomposition of aldehyde 42. These results are consistent with the regioselective formation of oxetane 40 as the exclusive intermediate in catalytic carbonyl−olefin ring-opening metathesis reactions. Furthermore, the formation of both bicyclopentane 44 and pyran 45 is consistent with a competing carbonyl−ene reaction path to result in diene 43 as a reactive intermediate which subsequently undergoes addition with a second equivalent of 1-methylcyclopentene 12 to form bicyclopentane 44 or a second equivalent of benzaldehyde 11 to form pyran 45 (Figure 6). Our studies of Lewis acid catalyzed carbonyl−olefin ringopening metathesis reactions revealed important insight into the controlling features of this reaction pathway. Specifically, the carbonyl−olefin ring-opening metathesis reactions proceed via selective formation of one oxetane regioisomer which subsequently fragments to result in aliphatic ketones as the exclusive metathesis product. The low yields observed in the current Lewis acid-catalyzed carbonyl−olefin ring-opening metathesis protocols are a direct result of competing carbonyl−ene reaction pathways. Thus, the design of catalyst systems with the ability to favor one pathway over the other holds great promise to develop high yielding carbonyl−olefin ring-opening metathesis reactions of general synthetic utility.

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Experimental procedures, crystal structure data and NMR studies (PDF) Accession Codes

CCDC 1849848 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Corinna S. Schindler: 0000-0003-4968-8013 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NIH/National Institute of General Medical Sciences (R01-GM118644), the Alfred P. Sloan Foundation, and the David and Lucile Packard Foundation for financial support. H.A. and J.R.L. thank the National Science Foundation for predoctoral fellowships. M.R.B. thanks the Rackham Graduate School for an international student fellowship.

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REFERENCES

(1) Handbook of Metathesis, 2nd ed.; Grubbs, R. H., Wenzel, A. G., O’Leary, D. J., Khosravi, E., Eds.; Wiley-VCH: Weinheim, 2015; Vols. 1−3. (2) For selected examples, see: (a) Snapper, M. L.; Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478−1479. (b) Tallarico, J. A.; Randall, M. L.; Snapper, M. L. Tetrahedron 1997, 53, 16511−16520. (c) Michaut, M.; Parrain, J.-L.; Santelli, M. Chem. Commun. 1998, 0, 2567−2568. (d) Arjona, O.; Csáky, A. G.; Murcia, C.; Plumet, J.; Mula, M. B. J. Organomet. Chem. 2001, 627, 105−108. (e) Arjona, O.; Csáky, A. G.; Plumet, J. Synthesis 2000, 2000, 857−861. (f) Katayama, H.; Urushima, H.; Nishioka, T.; Wada, C.; Nagao, M.; Ozawa, F. Angew. Chem., Int. Ed. 2000, 39, 4513−4515. (g) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168−8170. (h) Cuny, G. D.; Cao, J.; Hauske, J. R. Tetrahedron Lett. 1997, 38, 5237−5240. (i) Morgan, J. P.; Morrill, C.; Grubbs, R. H. Org. Lett. 2002, 4, 67−70. (j) Weeresakare, G. M.; Liu, Z.; Rainier, J. D. Org. Lett. 2004, 6, 1625−1627. (3) Selectivity for the end-differentiated product (4) can be achieved in ROCM reactions and is found to be dependent on both substrate and metal−alkylidene catalyst. After the initial ring-opening metathesis reaction, a subsequent cross-metathesis with another equivalent of cyclic olefin can occur which results in oligomeric products (4) For carbonyl−olefin metathesis reactions proceeding via oxetane photoadducts, see: (a) Jones, G., II; Schwartz, S. B.; Marton, M. T. J. Chem. Soc., Chem. Commun. 1973, 11, 374−375. (b) Jones, G., II; Acquadro, M. A.; Carmody, M. A. J. Chem. Soc., Chem. Commun. 1975, 6, 206−207. (c) Carless, H. A. J.; Trivedi, H. S. J. Chem. Soc., Chem. Commun. 1979, 8, 382−383. (d) D’Auria, M.; Racioppi, R.; Viggiani, L. Photochem. Photobiol. Sci. 2010, 9, 1134−1138. (e) Pérez-Ruiz, R.; Gil, S.; Miranda, M. A. J. Org. Chem. 2005, 70, 1376−1381. (f) Pérez-Ruiz, R.; Miranda, M. A.; Alle, R.; Meerholz, K.; Griesbeck, A. G. Photochem. Photobiol. Sci. 2006, 5, 51−55. (g) Valiulin, R. A.; Kutateladze, A. G. Org. Lett. 2009, 11, 3886−3889. (h) Valiulin, R. A.; Arisco, T. M.; Kutateladze, A. G. J. Org. Chem. 2011, 76, 1319−1332. (i) Valiulin, R. A.; Arisco, T. M.; Kutateladze, A. G. J. Org. Chem. 2013, 78, 2012− 2025.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02086. 4957

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Organic Letters (5) For Brønsted and Lewis acid-mediated carbonyl−olefin metathesis reactions, see: (a) Schopov, I.; Jossifov, C. Makromol. Chem., Rapid Commun. 1983, 4, 659−662. (b) Soicke, A.; Slavov, N.; Neudörfl, J.-M.; Schmalz, H.-G. Synlett 2011, 2011, 2487−2490. (c) van Schaik, H.-P.; Vijn, R.-J.; Bickelhaupt, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1611−1612. (d) Jossifov, C.; Kalinova, R.; Demonceau, A. Chim. Oggi 2008, 26, 85−87. (6) For a stoichiometric approach relying on molybdenum alkylidenes, see: Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 3800−3801. (7) For organocatalytic approaches, see: (a) Griffith, A. K.; Vanos, C. M.; Lambert, T. H. J. Am. Chem. Soc. 2012, 134, 18581−18584. (b) Hong, X.; Liang, Y.; Griffith, A. K.; Lambert, T. H.; Houk, K. N. Chem. Sci. 2014, 5, 471−475. (c) Naidu, V. R.; Bah, J.; Franzén, J. Eur. J. Org. Chem. 2015, 2015, 1834−1839. (8) Ludwig, J. R.; Schindler, C. S. Synlett 2017, 28, 1501−1509. (9) (a) Ludwig, J. R.; Zimmerman, P. M.; Gianino, J. B.; Schindler, C. S. Nature 2016, 533, 374−379. (b) McAtee, C. M.; Riehl, P. S.; Schindler, C. S. J. Am. Chem. Soc. 2017, 139, 2960−2963. (c) Ludwig, J. R.; Phan, S.; McAtee, C. M.; Zimmerman, P. M.; Devery, J. J., III; Schindler, C. S. J. Am. Chem. Soc. 2017, 139, 10832−10842. (d) Groso, E. J.; Golonka, A. N.; Harding, R. A.; Alexander, B. W.; Sodano, T. M.; Schindler, C. S. ACS Catal. 2018, 8, 2006−2011. (e) Ma, L.; Li, W.; Xi, H.; Bai, X.; Ma, E.; Yan, X.; Li, Z. Angew. Chem., Int. Ed. 2016, 55, 10410−10413. (f) Catti, L.; Tiefenbacher, K. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/anie.201712141. (10) Tran, U. P. N.; Oss, G.; Pace, D. P.; Ho, J.; Nguyen, T. V. Chem. Sci. 2018, 9, 5145−5151. (11) Schleyer, P. V. R.; Williams, J. E.; Blanchard, K. R. J. Am. Chem. Soc. 1970, 92, 2377. (12) Griesback, A. G.; Stadtmueller, S. J. Am. Chem. Soc. 1991, 113, 6923−6928.

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DOI: 10.1021/acs.orglett.8b02086 Org. Lett. 2018, 20, 4954−4958