Letter pubs.acs.org/OrgLett
Iodine-Catalyzed Oxidative Coupling To Construct C−O Bonds for the Synthesis of 2,3-Dihydrooxepines Xia Wu, Xiao Geng, Peng Zhao, Yan-dong Wu, and An-xin Wu* Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China S Supporting Information *
ABSTRACT: The iodine-catalyzed catalytic formal [3 + 3 + 1] cycloaddition for the preparation of a seven-membered Oheterocyclic ring is presented, which is an achievement of methyl and carbonyl group reactivity of 3-methyl-5-pyrazolones to forge the Csp3−O bond. This novel protocol provides a straightforward and efficient access to structurally diverse fused O-heterocycles through an iodine-catalyzed iodination/Kornblum oxidation/oxidative coupling/C−O bond formation cascade reaction. This approach demonstrates the unprecedented concurrent realization of the unique reactivity among the methyl, methylene, and carbonyl groups in 3-methyl-5-pyrazolones for the construction of 2,3-dihydrooxepine rings. Moreover, a broad substrate scope displays a graceful diversity-oriented synthetic approach.
M
Scheme 1. Direct Synthesis of Oxepine Derivatives via Oxidative Coupling
edium-sized ring compounds are important in modern organic chemistry due to their ubiquity in Nature and are some of the most important molecules in both academic research and industrial applications.1 Therefore, the efficient synthesis of medium-sized rings is an extremely significant, yet challenging, goal in organic chemistry.2 Extensive research effort has focused on the development of various strategies for preparing mediumsized rings, including macrocyclization3 (such as Corey− Nicolaou, Keck, and Yamaguchi macrolactonizations), ring expansion,4 and annulation.5 However, medium-sized rings are regarded as difficult structures to access because of unfavorable transannular interactions that build up in the product and entropic factors that disfavor cyclization. Few general methods exist for their synthesis. Furthermore, many elegant methods for the construction of these units rely on metal catalysis.6 Therefore, new methods for the efficient construction of medium-sized ring skeletons, especially metal-free-mediated formal addition reactions, are highly desirable. Oxepine and hydrooxepine derivatives are core skeletons in numerous naturally occurring biologically active compounds. These compounds present interesting challenges as potential synthetic targets7 and can also be used as intermediates in heterocycle synthesis.8 Therefore, the synthesis of this class of Oheterocycles has received much attention. C−O bond formation is among the most straightforward and practical methods for forming oxygen-containing rings in organic synthesis.9 In particular, direct oxidative coupling reactions represent green and atom-economic methods for constructing O-heterocycles, including oxepines, via C−O bond formation.10,11 Significantly, in 2011, Esteruelas and Saá presented an osmium-catalyzed 7endo heterocyclization to afford benzoxepines via C−O bond formation from C−H and O−H bonds (Scheme 1a).12 Recently, a rhodium(III)-catalyzed C−H functionalization of o-vinylphenols to benzoxepines via C−C/C−O bond formation was ́ (Scheme 1b).13 Despite described by Mascareñas and Gulias © 2017 American Chemical Society
recent advances in cyclization using C−O bond-forming reactions, the direct coupling of carbonyl and methyl groups to construct Csp3−O bonds to generate the O-heterocyclic rings (such as hydrooxepine rings) remains underdeveloped due to the inherent inertia of Csp3−H in 3-methylpyrazol-5-ones. Herein, we report the direct synthesis of 2,3-dihydrooxepine rings using the three unique reaction sites in 3-methyl-5-pyrazolones (methyl, methylene, and carbonyl, Scheme 1c). As DMSO has recently been identified as a powerful oxidative C−H functionalization reagent,14,15a we envisioned that a halidecontaining reagent in DMSO could be used to catalyze the oxygenation of C−H bonds to build C−C and C−O bonds. Initially, acetophenone (1a) and edaravone (2a) were selected as Received: July 18, 2017 Published: August 23, 2017 4584
DOI: 10.1021/acs.orglett.7b02182 Org. Lett. 2017, 19, 4584−4587
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Organic Letters model substrates for reaction discovery and optimization (Table 1). Gratifyingly, the C−O bond formation product, namely the
Scheme 2. Scope of Aryl Methyl Ketones
Table 1. Optimization of the Reaction Conditionsa
entry
I2 (equiv)
temp (°C)
1 2 3 4 5 6 7 8 9 10 11 12 13 14c 15c
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.5 0.2 0.1 0.1 0.1
100 110 130 130 130 130 130 130 130 130 130 130 140 140 140
additive
yieldb (%) (time (h))
TsOH·H2O FeCl3 ZnCl2 Cu(OTf)2 TfOH HCl TfOH TfOH TfOH TfOH TfOH TfOH
76 (13) 75 (8) 76 (4) 78 (3) 70 (3) 65 (3) 76 (3) 81 (3) 62 (3) 81 (3) 81 (3) 82 (11) 82 (3) 83 (3) 0
effective for heteroaromatic (thiophene, furan, and benzofuranyl rings) methyl ketones which were well tolerated in the reaction system and delivered fused oxepine derivatives 3qa−ta in moderate to good yields. Moreover, α-ionone and aliphatic methyl ketones performed well under the optimized conditions (3ua−wa). For example, 4-methylpentan-2-one 1v reacted with 2a to afford the fused oxepine ring, in which methylene was further oxidized to give product 3va. The scope of the study was then extended to various edaravone derivatives (Scheme 3). Various pyrazolones were
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), I2, and additive (1.0 mmol) heated in DMSO (4 mL). bProducts were obtained in isolated yields. c1.5 mmol of TfOH was used instead of 1.0 mmol of TfOH.
Scheme 3. Scope of 3-Methyl-5-pyrazolones
oxepine ring, was obtained when I2, NIS, and HI were used as catalyst (for details, see the Supporting Information). The best result was obtained by using iodine as catalyst, and 2.0 equiv of 2a was used. The structure of this compound was unambiguously confirmed by X-ray crystallographic analysis (see the SI). Different reaction temperatures were tested and found to have an important influence on the reaction yield and reaction rate (Table 1, entries 2 and 3). Subsequently, a series of Brønsted and Lewis acids (TsOH·H2O, FeCl3, ZnCl2, Cu(OTf)2, TfOH, and HCl) were screened as additives in the reaction, and the TfOH was found to be superior in promoting the reaction (Table 1, entries 4−9). To our surprise, the reaction proceeded smoothly, even when the amount of I2 was decreased to 10 mol % (Table 1, entries 10−12). The temperature and TfOH were further increased to accelerate the reaction rate and increase the yield of the reaction. The best results were obtained in 140 °C and 1.5 equiv of TfOH (Table 1, entries 13 and 14). However, the reaction did not proceed in the absence of I2 (Table 1, entry 15), which indicated that iodine was a critically important mediator in this transformation. Having optimized the reaction conditions, we next examined the scope of the iodine-catalyzed C−O bond formation reaction by testing a series of aryl methyl ketone substrates containing differrent substitution patterns and various functional groups. A variety of functional groups, including methyl, methoxy, ethoxy, 3,4-methylenedioxyl, nitro, cyano, carbomethoxy, chloro, and bromo substituents, were tolerated and underwent the desired transformation to deliver corresponding products 3aa−na in moderate to good yields (Scheme 2). The electronic and steric properties of the aromatic ketone substrate had little effect on reaction efficiency. Furthermore, the phenyl ring was successfully replaced by naphthalene moieties to yield the desired products 3oa and 3pa. Encouragingly, our optimized conditions were also
found to participate smoothly in the reaction. Electron-neutral (4-CH3) and halogen (2-Cl, 3-Cl, and 4-Cl) groups on the phenyl rings in 3-methyl-1-phenyl-1H-pyrazol-5(4H)-ones were tolerated, affording the corresponding products in moderate to good yields (3ab−ae). A sulfonamide and nitro group attached to the phenyl ring in the pyrazolone was well tolerated, with expected product 3af and 3ah obtained in 79% and 83% yields, respectively. Moreover, 1,3-dimethyl-1H-pyrazol-5(4H)-one reacted smoothly under the optimized conditions to provide the desired product 3ag in 81% yield. In addition, 3-ethyl-5pyrazolones performed well with 1a to give 3ai and 3ai′ in 82% 4585
DOI: 10.1021/acs.orglett.7b02182 Org. Lett. 2017, 19, 4584−4587
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Organic Letters yield. A cross-reaction between 2a, 2f, and 1a could give expected four products in a total 83% yield. To test the substrate generality of this I2-catalyzed C−O bond formation reaction (Scheme 4), a variety of substrates, including
Scheme 5. Control Experiments
Scheme 4. Substrate Diversity and Application
2-bromo-1-phenylethanone, phenylacetylene, 2-hydroxy-1-phenylethanone, styrene, and 1-phenylethanol, were tested and found to be compatible and reacted with 2a to afford desired product 3aa in moderate to good yields. Moreover, as an interesting application of the present reaction, the γ-dicarbonyl functional group in the products easily underwent further transformation. Novel fused heterocycle 10a was readily prepared in 87% yield by treating 3aa with hydrazine hydrate in DMF (Scheme 4). Notably, the novel fused heterocyclic scaffold in 10a has not been reported previously. To gain insight into the mechanism of this reaction, we conducted a series of experiments. Acetophenone 1a (1.0 mmol) was heated with I2 (0.1 mmol) and TfOH (1.5 mmol) in DMSO at 140 °C to afford phenylglyoxal 1ab and the corresponding hydrated species 1ac in quantitative yield (Scheme 5a). To verify whether this reaction was initiated by iodination, we conducted the experiment using α-iodoketone 1aa under the optimized conditions. The desired product, 3aa, was obtained in 85% yield (Scheme 5b). Moreover, the reaction of phenylglyoxal 1ac with edaravone 2a performed smoothly under the same conditions (Scheme 5c). These results confirmed that phenacyl iodine 1aa and phenylglyoxal 1ab were intermediates in this transformation. Subsequently, the reaction of hydrated species 1ac with 2a without additional I2 afforded product 4a in 42% yield (Scheme 5d). However, the reaction did not proceed in substrates with R = C(CH3)3, possibly due to steric hindrance under the reaction conditions (Scheme 5d). Furthermore, product 4a reacted under the optimized conditions to give hydrooxepine ring 3aa in 85% yield (Scheme 5e). These results indicated that 4a was a key intermediate in this transformation. Next, a 13C-labeling experiment was conducted under the optimized conditions using acetophenone-β-13C as the substrate, which gave the expected product (3aa′) in 80% yield (Scheme 5f). This result confirmed that methyl ketones provided one carbon to form the oxepine ring. Based on the results described above and those of previous reports,15 a catalytic pathway was proposed (Scheme 6). Assisted by enolization, acetophenone was iodinated using iodine to give α-iodoketone 1aa. Kornblum oxidation occurred to form 2-oxo-
Scheme 6. Proposed Mechanism
2-phenylacetaldehyde 1ab with the release of HI and DMS. In the presence of TfOH, activated aldehyde intermediate 1ab′ was formed and then attacked by the enol form of edaravone 2a to give intermediate A, which underwent dehydration to yield intermediate B. Next, another equivalent of 2a could react with intermediate B to give intermediate 4a via Michael addition. Product 4a could then be iodinated to obtain intermediates C or C′ in the presence of molecular iodine. Finally, the desired product 3aa was afforded via an in situ iodination-based oxidative coupling between Csp3−H and carbonyl groups and oxidative 4586
DOI: 10.1021/acs.orglett.7b02182 Org. Lett. 2017, 19, 4584−4587
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Organic Letters
(4) For selected examples, see: (a) Zhao, W.; Li, Z. J.; Sun. J. Am. Chem. Soc. 2013, 135, 4680. (b) Mukai, C.; Ohta, Y.; Oura, Y.; Kawaguchi, Y.; Inagaki, F. J. Am. Chem. Soc. 2012, 134, 19580. (c) Mei, L. Y.; Wei, Y.; Tang, X. Y.; Shi, M. J. Am. Chem. Soc. 2015, 137, 8131. (5) For selected examples, see: (a) Sun, H.; Nikolovska-Coleska, Z.; Lu, J.; Meagher, J. L.; Yang, C. Y.; Qiu, S.; Tomita, Y.; Ueda, Y.; Jiang, S.; Krajewski, K.; Roller, P. P.; Stuckey, J. A.; Wang, S. J. Am. Chem. Soc. 2007, 129, 15279. (b) Kaul, R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70, 3838. (c) Creighton, C. J.; Leo, G. C.; Du, Y.; Reitz, A. B. Bioorg. Med. Chem. 2004, 12, 4375. (6) (a) Hesse, M., Ed. Ring Enlargement in Organic Chemistry; WileyVCH: Weinheim, 1991. (b) Xu, Q. L.; Dai, L. X.; You, S. L. Chem. Sci. 2013, 4, 97. (c) Vo, C. V. T.; Luescher, M. U.; Bode, J. W. Nat. Chem. 2014, 6, 310. (7) (a) Vaquero, J. J.; Cuadro, A. M.; Herradón, B. Modern Heterocyclic Chemistry; Wiley-VCH: Weinheim, 2011; pp 1865−1988. (b) Riley, D. L.; van Otterlo, W. A. L. In Heterocycles in Natural Product Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp 537−549. (c) Faulkner, D. J. Nat. Prod. Rep. 1987, 4, 539. (d) Yet, L. Chem. Rev. 2000, 100, 2963. (e) Xu, X. F.; Hu, W. H.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2011, 50, 11152. (f) Nicolaou, K. C.; Yu, R. C.; Shi, L.; Cai, Q.; Lu, M.; Heretsch, P. Org. Lett. 2013, 15, 1994. (8) Nasveschuk, C. G.; Rovis, T. Angew. Chem., Int. Ed. 2005, 44, 3264. (9) (a) Dyker, G. Handbook of C−H Transformations Applications in Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (c) Le Bras, J.; Muzart, J. Chem. Soc. Rev. 2014, 43, 3003. (d) Race, N. J.; Schwalm, C. S.; Nakamuro, T.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 15881. (e) Yang, Q. L.; Li, Y. Q.; Ma, C.; Fang, P.; Zhang, X. J.; Mei, T. S. J. Am. Chem. Soc. 2017, 139, 3293. (10) (a) Cheng, X. F.; Li, Y.; Su, Y. M.; Yin, F.; Wang, J. Y.; Sheng, J.; Vora, H. U.; Wang, X. S.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 1236. (b) Wu, X.; Geng, X.; Zhao, P.; Zhang, J. J.; Wu, Y. D.; Wu, A. X. Chem. Commun. 2017, 53, 3438. (c) Modak, A.; Dutta, U.; Kancherla, R.; Maity, S.; Bhadra, M.; Mobin, S. M.; Maiti, D. Org. Lett. 2014, 16, 2602. (d) Yang, M. Y.; Jiang, X. Y.; Shi, W. J.; Zhu, Q. L.; Shi, Z. J. Org. Lett. 2013, 15, 690. (11) (a) Alvarado, J.; Fournier, J.; Zakarian, A. Angew. Chem., Int. Ed. 2016, 55, 11625. (b) Chan, L.; McNally, A.; Toh, Q. Y.; Mendoza, A.; Gaunt, M. J. Chem. Sci. 2015, 6, 1277. (c) Lindstedt, E.; Ghosh, R.; Olofsson, B. Org. Lett. 2013, 15, 6070. (12) Varela-Fernández, A.; García-Yebra, C.; Varela, J. A.; Esteruelas, M. A.; Saá, C. Angew. Chem., Int. Ed. 2010, 49, 4278. (13) Seoane, A.; Casanova, N.; Quiñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 834. (14) (a) Wu, X.; Zhao, P.; Geng, X.; Zhang, J. J.; Gong, X. X.; Wu, Y. D.; Wu, A. X. Org. Lett. 2017, 19, 3319. (b) Wu, X.; Zhang, J. J.; Liu, S.; Gao, Q. H.; Wu, A. X. Adv. Synth. Catal. 2016, 358, 218. (15) (a) Liang, Y. F.; Li, X. Y.; Wang, X. Y.; Zou, M. C.; Tang, C. H.; Liang, Y. J.; Song, S.; Jiao, N. J. Am. Chem. Soc. 2016, 138, 12271. (b) Wu, X.; Gao, Q. H.; Liu, S.; Wu, A. X. Org. Lett. 2014, 16, 2888. (c) Wu, X.; Geng, X.; Zhao, P.; Zhang, J. J.; Gong, X. X.; Wu, Y. D.; Wu, A. X. Org. Lett. 2017, 19, 1550.
dehydrogenation pathway. Notably, in this process, iodine completed the catalytic cycle via a redox reaction. In summary, we have developed I2-catalyzed formal [3 + 3 + 1] cycloaddition involving C−O bond formation via oxidative coupling Csp3−H and carbonyl groups in edaravone derivatives. This process offers a highly efficient and practical route to building fused oxepine derivatives and displayed a broad substrate scope suitable for diversity oriented synthetic approaches. Inexpensive and nontoxic DMSO was used as both the solvent and oxidant, which also plays a key role in promoting iodine recycling. Moreover, this approach, using the methyl group in 3-methyl-5-pyrazolones to construct a Csp3−O bond, is unprecedented. Further studies aimed at elucidating the detailed mechanism and exploiting this C−O bond formation type reaction in appropriate synthetic applications are currently underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02182. Experimental procedures, product characterizations, crystallographic data, and 1H and 13C NMR spectra (PDF) Crystallographic data for 3aa (CIF) Crystallographic data for 4a′ (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
An-xin Wu: 0000-0001-7673-210X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant Nos. 21472056 and 21602070). We also thank Dr. Chuanqi Zhou, Hebei University, for analytical support. This work was supported by “The Fundamental Research Funds for the Central Universities” (CCNU15ZX002 and CCNU16A05002). This work was also supported by the 111 Project B17019.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02182 Org. Lett. 2017, 19, 4584−4587
