Letter pubs.acs.org/OrgLett
Synthesis of Functionalized Indenones via Rh-Catalyzed C−H Activation Cascade Reaction Ningning Lv,† Zhengkai Chen,‡ Yue Liu,† Zhanxiang Liu,† and Yuhong Zhang*,†,§ †
Department of Chemistry, Zhejiang University, Hangzhou 310027, China Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China § State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China ‡
S Supporting Information *
ABSTRACT: An efficient and expeditious protocol for the synthesis of diverse difunctionalized indenones through rhodium-catalyzed C−H activation and multistep cascade reaction of benzimidates and alkenes has been developed. The transformation involves the cleavage and formation of multiple bonds in one pot under mild reaction conditions, and Mn(OAc)2 plays an important role in the reaction.
I
powerful directing group and has been applied to numerous C− H functionalization reactions.9 The transformation involves cleavage and formation of multiple bonds in one pot under mild reaction conditions with good functional group tolerance. The pendent ester and/or amino group in the indenone products could be readily transformed into a range of synthetically important compounds.10 We initiated our study by choosing benzimidate 1a and butyl acrylate as model substrates to optimize the reaction conditions (see the Supporting Information). The reaction was conducted with the commonly used catalytic combination of [Cp*RhCl2]2 and Cu(OAc)2 in TFE, and the desired 2-carboxylate-3aminoindenone product was obtained in low yield. Considering the important role of the additive, other additives, such as CsOAc, AgOAc, and Co(OAc)2·4H2O were added to the reaction, and the comparative yields were observed. When Mn(OAc)2 was used as an additive, the yield of the reaction sharply increased to 82%. The effect of the solvent on the reaction was examined, and TFE gave the highest yield. The reaction failed to occur in the absence of [Cp*RhCl2]2 or Mn(OAc)2. It should be noted that an inert atmosphere could totally inhibit the reaction. Among other common metal catalysts, the use of Ru(p-cymene)Cl2 delivered the desired product with moderate efficiency and Cp*Co(CO)I2 did not catalyze the reaction. With the optimal reaction conditions in hand, the scope and limitations of the protocol with respect to benzimidates were investigated (Scheme 1). The effect of diverse alkoxy groups in the benzimidate was first tested. It was found that different alkoxy groups could all smoothly deliver the desired product 3a, with the ethoxy group giving the superior result (82% yield). Significantly, the transformation could be carried out on a 1 mmol scale in reasonable yield. The reaction exhibited broad
ndenones are highly privileged structural motifs that have found extensive applications in synthetic chemistry, pharmaceutical fields, and materials science.1 A great many methods have been developed for the preparation of these valuable compounds over the past few decades. Traditional methods to indenones usually suffer from harsh reaction conditions, multiple steps, and narrow substrate scope.2 In recent years, transitionmetal-catalyzed construction of indenones has been intensively explored through the annulation of alkynes and ortho-functionalized aromatic aldehydes, esters, or nitriles, which has provided a new avenue for the efficient formation of indenones.3 However, prefunctionalization of the aromatic substrates, such as halogenation or metalation, is necessary for these protocols, thus limiting their synthetic utility. Consequently, the development of more facile and straightforward routes to indenones is highly desirable. Transition-metal-catalyzed C−H functionalization reactions have been applied as an appealing and powerful approach for the synthesis of a wide variety of structurally complicated heterocycles without preactivation of the starting materials.4 For indenone syntheses, the direct cleavage of C−H bonds for the construction of indenones could overcome the disadvantages of the use of ortho-functionalized aromatic substrates, and a series of C−H functionalization reactions enabling synthetic strategies were successfully developed through transition-metal-catalyzed5 or metal-free-mediated6 annulation of aromatic ring derivatives and internal alkynes over the past few years. In these methods, 2,3-diaryl-substituted indenones are the major products since internal diarylalkynes show good reactivity. Encouraged by the above seminal works and our continued endeavors on heterocyclic syntheses via C−H functionalization reactions,7 we herein disclose an unprecedented mild and powerful approach for the assembly of valuable 2-ester-3-aminoindenones from readily available benzimidates and electron-deficient alkenes, which constitutes the first example of rhodium-catalyzed C−H alkenylation8 of benzimidates and sequential cascade reaction. It should be noted that the imidate group is known as a © 2017 American Chemical Society
Received: March 27, 2017 Published: May 9, 2017 2588
DOI: 10.1021/acs.orglett.7b00906 Org. Lett. 2017, 19, 2588−2591
Letter
Organic Letters Scheme 1. Scope of Benzimidatesa,b
Scheme 2. Scope of Alkenesa,b
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (5 mol %), Mn(OAc)2 (1 equiv), 4 Å MS (50 mg), solvent (1 mL), under air, 70 °C, 24 h. bIsolated yields determined by flash column chromatography are shown.
the reaction, causing the trifluoroethyl group to be attached in the product 4e, the structure of which was also determined by single-crystal X-ray diffraction analysis.11 Other electrondeficient alkenes, such as acrylamide, could successfully participate in the reaction and deliver the target product in moderate yield (4f, 4g). When acrylonitrile was used in the reaction, only the product of alkenylation and subsequent cyclization (4h) was isolated. The transformation was further extended to vinyl phosphonate and vinyl sulfonate coupling partners, leading to the corresponding indenone products in acceptable yields (4i−k, 45−60%). Styrene was inactive under the reaction conditions, and no desired indenone product was detected. To gain insight into the reaction mechanism, preliminary investigations were conducted as outlined in Scheme 3. First, when the reaction was terminated at 3 h, 1H-isoindole intermediate 5 was successfully isolated in 95% yield, illustrating that the reaction first underwent alkenylation and intramolecular cyclization (Scheme 3, eq 1). Then we carefully performed the reaction starting from compound 5 under different conditions. The reaction did not proceed in the absence of Mn(OAc)2. Furthermore, the desired indenone product was readily formed only in the presence of Mn(OAc)2, even when [Cp*RhCl2]2 was absent (Scheme 3, eq 2). These observations showed that 5 possibly acts as the key intermediate of the reaction and that Mn(OAc)2 is indispensable for the subsequent transformation. Notably, when the reaction was carried out in degassed TFE under a nitrogen atmosphere, only traces of indenone product were observed, further underscoring the utmost importance of
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (5 mol %), Mn(OAc)2 (1 equiv), 4 Å MS (50 mg), solvent (1 mL), under air, 70 °C, 24 h. bIsolated yields determined by flash column chromatography are shown. c1 mmol scale.
substrate scope, and a variety of electron-donating or electronwithdrawing groups were well-tolerated under the standard conditions, leading to the corresponding indenone products in moderate to good yields (3b−o), which revealed that the electronic factor of the benzimidate had a negligible impact on the reaction. Aryl substrates bearing a halogen atom (F, Cl, or Br) at different positions of phenyl ring were smoothly tolerated under the optimized conditions to deliver indenone products (3e−g, 3i−k). It is worth mentioning that a mixture of indenone products was isolated with regard to several meta-substituted substrates (3k, 3l). Some heterocyclic or naphthyl moieties were also compatible with the reaction system, giving rise to fused indenones, albeit in relatively lower yields (3p−r). Interestingly, when the furylimidate was subjected to the optimal conditions, only alkenylated product 3s was observed. The generality and compatibility of the present protocol were further explored by the use of various alkenes (Scheme 2). The reaction proceeded well with diverse acrylates, and the relevant indenone products were delivered in good yields (4a, 4b, 4d, 4e). In the case of tert-butyl acrylate, only a 20% yield was obtained (4c), presumably because of steric hindrance by the bulky tertbutyl group. The exact structure of product 4c was verified by single-crystal X-ray diffraction analysis.11 With respect to phenyl acrylate, it was noteworthy that transesterification occurred in 2589
DOI: 10.1021/acs.orglett.7b00906 Org. Lett. 2017, 19, 2588−2591
Letter
Organic Letters Scheme 3. Mechanistic Investigations
Scheme 4. Proposed Reaction Mechanism
intermediate E.15 At this stage, intermediate F is produced upon Mn(OAc)2-promoted C−N bond cleavage and 1,3-H transfer, and F is proposed to undergo intramolecular nucleophilic addition to furnish the final product 3a with the release of EtOH. The intermediates of D and E have been successfully detected by LC−HRMS during the reaction, partially supporting the proposed reaction pathway (Scheme 3, eq 2, condition C). The 2-ester-3-aminoindenone product could undergo a series of late-stage derivatizations to afford useful scaffolds (Scheme 5),
air or oxygen (Scheme 3, eq 3). To confirm the source of the additional oxygen atom in the indenone product, the reaction was carried out under an atmosphere of 18O2, and the oxygen isotope was successfully detected in the desired product, revealing that the additional oxygen atom in the indenone product is derived from ambient O2 (Scheme 3, eq 4). When the radical-scavenging reagent 2,6-di-tert-butyl-4-methylphenol (BHT) was added to the standard reaction, the product of coupling between 5 and BHT was detected by GC−MS, revealing that a single-electron-transfer process might be involved in the reaction on the basis of the methine position in 5 (Scheme 3, eq 5). On the basis of the preliminary mechanistic investigation and previous reports,12 a plausible reaction mechanism is proposed, as depicted in Scheme 4. Initially, the active catalyst [Cp*Rh(OAc) 2 ] is generated from ligand exchange between [Cp*RhCl2]2 and Mn(OAc)2 and undergoes coordination with 1a and C−H metalation to yield rhodacycle complex A with the loss of acetic acid. Then migratory insertion of the alkene into A affords intermediate B, and subsequent β-H elimination leads to the formation of alkenylated product C with release of the Rh(I) catalyst, which can be oxidized to the Rh(III) catalyst by Mn(III) to complete the catalytic cycle. Subsequently, the intramolecular aza-Michael addition occurs to deliver 1H-isoindole intermediate 5, which can be obtained by the analogous transformation using a Ru(II) catalyst.13 Compound 5 is converted into intermediate D in the presence of Mn(OAc)2 and air/O2 via a Mn(III)-mediated single-electron-oxidation process.14 D probably could be reduced by Mn(II) or react with intermediate 5 to access
Scheme 5. Synthetic Applications
such as the optoelectronic compound 616 and the synthetically important and biologically active indane-1,3-dione 7.17 In addition, the amino group in the indenone was readily transformed into an amide group to give compound 8. In summary, we have developed an unprecedented mild and facile approach for the assembly of structurally diverse indenone scaffolds through Rh(III)-catalyzed C−H activation and multistep cascade reaction of benzimidates and alkenes. The reaction presumably proceeds through a cascade C−H alkenylation, 2590
DOI: 10.1021/acs.orglett.7b00906 Org. Lett. 2017, 19, 2588−2591
Letter
Organic Letters
Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766. (4) For selected recent reviews, see: (a) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (c) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (e) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212. (f) Gulías, M.; Mascarenas, J. L. Angew. Chem., Int. Ed. 2016, 55, 11000. (5) (a) Li, B.-J.; Wang, H.-Y; Zhu, Q.-L; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51, 3948. (b) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. J. Am. Chem. Soc. 2014, 136, 5424. (c) Qi, Z.; Wang, M.; Li, X. Org. Lett. 2013, 15, 5440. (d) Yu, W.; Zhang, W.; Liu, Z.; Zhang, Y. Chem. Commun. 2016, 52, 6837. (e) Kong, L.; Yang, X.; Zhou, X.; Yu, S.; Li, X. Org. Chem. Front. 2016, 3, 813. (6) (a) Zhao, P.; Liu, Y.; Xi, C. Org. Lett. 2015, 17, 4388. (b) Yan, X.; Zou, S.; Zhao, P.; Xi, C. Chem. Commun. 2014, 50, 2775. (7) (a) Zhang, J.; Chen, H.; Lin, C.; Liu, Z.; Wang, C.; Zhang, Y. J. Am. Chem. Soc. 2015, 137, 12990. (b) Yan, Q.; Chen, Z.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2016, 3, 678. (c) Liu, Y.; Wang, C.; Lv, N.; Liu, Z.; Zhang, Y. Adv. Synth. Catal. 2017, 359, 1351. (8) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (b) Liu, b.; Fan, y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 468. (9) (a) Wang, J.; Zha, S.; Chen, K.; Zhang, F.; Song, C.; Zhu, J. Org. Lett. 2016, 18, 2062. (b) Wang, X.; Jiao, N. Org. Lett. 2016, 18, 2150. (c) Wang, H.; Li, L.; Yu, S.; Li, Y.; Li, X. Org. Lett. 2016, 18, 2914. (d) Wang, Q.; Li, X. Org. Lett. 2016, 18, 2102. (e) Li, L.; Wang, H.; Yu, S.; Yang, X.; Li, X. Org. Lett. 2016, 18, 3662. (10) (a) Qiu, L.; Wang, X.; Zhao, N.; Xu, S.; An, Z.; Zhuang, X.; Lan, Z.; Wen, L.; Wan, X. J. Org. Chem. 2014, 79, 11339. (b) Qiu, L.; Yu, C.; Zhao, N.; Chen, W.; Guo, Y.; Wan, X.; Yang, R.; Liu, Y. Chem. Commun. 2012, 48, 12225. (c) Wydysh, E. A.; Medghalchi, S. M.; Vadlamudi, A.; Townsend, C. A. J. Med. Chem. 2009, 52, 3317. (d) Heald, R. A.; Stevens, M. F. G. Org. Biomol. Chem. 2003, 1, 3377. (e) Gao, P.; Liu, J.; Wei, Y. Org. Lett. 2013, 15, 2872. (f) Reddy, R. S.; Prasad, P. K.; Ahuja, B. B.; Sudalai, A. J. Org. Chem. 2013, 78, 5045. (11) The structures of compounds 4c and 4e were determined by Xray crystallography (see the Supporting Information for full details). CCDC 1523633 (4c) and 1537745 (4e) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif. (12) (a) Han, S.; Shin, Y.; Sharma, S.; Mishra, N. K.; Park, J.; Kim, M.; Kim, M.; Jang, J.; Kim, I. S. Org. Lett. 2014, 16, 2494. (b) Yao, J.; Feng, R.; Lin, C.; Liu, Z.; Zhang, Y. Org. Biomol. Chem. 2014, 12, 5469. (c) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430. (d) Mishra, N. K.; Park, J.; Sharma, S.; Han, S.; Kim, M.; Shin, Y.; Jang, J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Chem. Commun. 2014, 50, 2350. (13) Li, X. G.; Sun, M.; Liu, K.; Liu, P. N. Adv. Synth. Catal. 2015, 357, 395. (14) (a) Li, P.; Zhao, J.; Xia, C.; Li, F. Org. Lett. 2014, 16, 5992. (b) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.; Jiao, N. J. Am. Chem. Soc. 2015, 137, 6059. (c) Shi, L.; Zhong, X.; She, H.; Lei, Z.; Li, F. Chem. Commun. 2015, 51, 7136. (15) (a) Bender, C. O.; Bonnett, R.; Smith, R. G. J. Chem. Soc. C 1970, 1251. (16) (a) Burckstummer, H.; Tulyakova, E. V.; Deppisch, M.; Lenze, M. R.; Kronenberg, N. M.; Gsanger, M.; Stolte, M.; Meerholz, K.; Wurthner, F. Angew. Chem., Int. Ed. 2011, 50, 11628. (b) Wilbuer, J.; Schnakenburg, G.; Esser, B. Eur. J. Org. Chem. 2016, 2016, 2404. (17) (a) Partridge, B. M.; Gonzalez, J. S.; Lam, H. W. Angew. Chem., Int. Ed. 2014, 53, 6523. (b) Schroder, S. P.; Taylor, N. J.; Jackson, P.; Franckevicius, V. Org. Lett. 2013, 15, 3778.
intramolecular cyclization, single-electron oxidation, C−N bond cleavage/1,3-H transfer, and intramolecular nucleophilic addition sequence. Notable features of the protocol include mild operating conditions, broad substrate scope, and good functional group tolerance. The reaction could be readily scaled up to gram scale, and the obtained difunctionalized indenones could be transformed into diverse valuable compounds through suitable late-stage derivatization and modification. This method may offer an efficient tool for the synthesis of biologically or pharmaceutically useful molecules.
■
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00906. Typical experimental procedure and characterization data for all products (PDF) Crystallographic data for compound 4c (CIF) Crystallographic data for compound 4e (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Yuhong Zhang: 0000-0002-1033-3429 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Funding from the National Natural Science Foundation of China (21472165, 21672186, 21602202) and the Program for the Natural Science Foundation of Zhejiang Province (LY16B020005) is acknowledged. We also thank the group of Prof. Hongjun Ren at Zhejiang Sci-Tech University for their kind help with the LC−HRMS measurements.
■
REFERENCES
(1) (a) Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A. J. Med. Chem. 1989, 32, 2163. (b) Jeffrey, J. L.; Sarpong, R. Org. Lett. 2009, 11, 5450. (c) McDevitt, R. E.; Malamas, M. S.; Manas, E. S.; Unwalla, R. J.; Xu, Z. B.; Miller, C. P.; Harris, H. A. Bioorg. Med. Chem. Lett. 2005, 15, 3137. (d) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550. (e) Banide, E. V.; O’Connor, C.; Fortune, N.; Ortin, Y.; Milosevic, S.; Muller-Bunz, H.; McGlinchey, M. J. Org. Biomol. Chem. 2010, 8, 3997. (f) Yum, E. K.; Park, W. S.; Kim, S. H.; Kang, S. K.; Kim, S. S.; Ahn, J. H. Chem. Lett. 2008, 37, 1068. (g) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Jung, W. H.; Yang, S. D.; Kim, S. J.; Woo, J. R.; Lee, J. H.; Cheon, H. G.; Kim, S. S. J. Med. Chem. 2006, 49, 4781. (h) Kayaleh, N. E.; Gupta, R. C.; Johnson, F. J. Org. Chem. 2000, 65, 4515. (2) (a) Marvel, C. S.; Hinman, C. W. J. Am. Chem. Soc. 1954, 76, 5435. (b) Martens, H.; Hoornaert, G. Tetrahedron 1974, 30, 3641. (c) Floyd, M. B.; Allen, G. R. J. Org. Chem. 1970, 35, 2647. (d) Galatsis, P.; Manwell, J. J.; Blackwell, J. M. Can. J. Chem. 1994, 72, 1656. (3) (a) Larock, R. C.; Doty, M.; Cacchi, S. J. Org. Chem. 1993, 58, 4579. (b) Larock, R. C.; Tian, Q.; Pletnev, A. J. Am. Chem. Soc. 1999, 121, 3238. (c) Liu, C.; Korivi, R. P.; Cheng, C.-H. Chem. - Eur. J. 2008, 14, 9503. (d) Pletnev, A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. (e) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227. (f) Miura, T.; Murakami, M. Org. Lett. 2005, 7, 3339. (g) Rao, M.; Dhanorkar, R. Tetrahedron 2014, 70, 8067. (h) Feng, J.; Lu, G.; Lv, M.; Cai, C. J. Org. Chem. 2014, 79, 10561. (i) Harada, Y.; Nakanishi, J.; Fujihara, H.; 2591
DOI: 10.1021/acs.orglett.7b00906 Org. Lett. 2017, 19, 2588−2591
