An Unexpected FeCl3-Catalyzed Cascade Reaction of Indoles and o

Letter Cite This: Org. Lett. 2018, 20, 3451−3454

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An Unexpected FeCl3‑Catalyzed Cascade Reaction of Indoles and o‑Hydroxychalcones for the Assembly of Chromane-Bridged Polycyclic Indoles Wenbo Wang, Xuguan Bai, Shaojing Jin, Jiaomei Guo, Yang Zhao, Hongjie Miao, Yanshuo Zhu, Qilin Wang,* and Zhanwei Bu*

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Institute of Functional Organic Molecular Engineering, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, China S Supporting Information *

ABSTRACT: An unexpected FeCl3-catalyzed cascade reaction of simple indoles and o-hydroxychalcone was reported, leading to densely functionalized and strained chromane-bridged polycyclic indoles in moderate to good yields. This reaction not only establishes a new transformation of indoles and o-hydroxychalcones but also provides an efficient method for the synthesis of structurally complex and congested chromane-bridged polycyclic indoles.

P

presence of a Lewis acid,6 while subsequent intramolecular cyclization between the hydroxyl group and the resulting iminium ion could give rise to a chromane-fused indole scaffold 3a (Scheme 1).7 To our surprise, under FeCl3-catalyzed conditions, treating indole 1a with chalcone 2a gave an unknown compound 4a, the structure of which was assigned by

olycyclic indoles are privileged structural units that are frequently found in natural products and pharmaceuticals.1 Accordingly, development of novel synthetic approaches toward these compounds has attracted considerable interest from the synthetic community.2 However, most of the existing methodologies so far either commenced with delicately prefunctionalized indoles or required multistep synthesis to form the polycyclic ring system.3 More efficient routes to synthesize polycyclic indoles from readily accessible starting materials are highly desirable. Herein, we reported a concise construction of bridged polycyclic indoles from simple Nalkylindoles and o-hydroxychalcone. Notably, this methodology forms the rigid bridged polycyclic ring system in a one-pot fashion under mild conditions. Chromanes have also been identified as promising synthetic targets because of their ubiquity in nature as well as their medicinally profound bioactivities.4 Given the intriguing structures and the medicinal relevance of polycyclic indoles and chromanes, we envisioned that the combination of the two in one molecule would generate an array of new compounds endowed with either amplified or new biological activities. Our group has been interested in the chemistry of o-hydroxychalcone by taking advantage of its unique reactivity.5 In our initial design, we envisioned that a N-ethylindole 1a would react with o-hydroxychalcone 2a via a Friedel−Crafts alkylation in the © 2018 American Chemical Society

Scheme 1. Unexpected Reaction between Indole and oHydroxychalcone

Received: April 9, 2018 Published: May 31, 2018 3451

DOI: 10.1021/acs.orglett.8b01107 Org. Lett. 2018, 20, 3451−3454

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Organic Letters Scheme 2. Scope of Substratesa,b

comprehensive NMR study and X-ray analysis. This unexpected formation of this bridged polycyclic indole skeleton is very intriguing in that both chromane and the indole motif are privileged scaffolds in a variety of pharmaceuticals. Thus, we decided to investigate this reaction in detail. To optimize this reaction, reactions between N-ethylindole 1a and o-hydroxychalcone 2a were carried out under different Lewis acid catalysts. When equimolar amounts of 1a and 2a were used, compound 4a was formed in 40% yield under FeCl3 catalysis, accompanied by the side product 5a in 31% yield (Table 1, entry 1). To enhance the synthetic efficiency, we Table 1. Optimization of Reaction Conditionsa

entry

cat.

solvent

time (h)

yield (%)

1 2 3 4 5 6b 7c 8c 9c

FeCl3.6H2O Fe(OTf)3 Cu(OTf)2 CuBr2 TFA FeCl3·6H2O FeCl3·6H2O FeCl3·6H2O FeCl3·6H2O

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN EtOAc CHCl3

12 13 13 11 36 12 12 12 12

40 28 21 29 39 20 78 75 12

a

Unless otherwise noted, the reaction was conducted on a scale of 0.20 mmol of 1a and 0.20 mmol 2a in 1 mL of solvent at 35 °C, and the product was obtained by column chromatography. b2 equiv of 2a was used. c1.5 equiv of 1a was used. a

Unless otherwise noted, the reaction was conducted with 0.30 mmol of 1 and 0.20 mmol of 2 in the presence of 20 mol % of FeCl3·6H2O in 1.0 mL of CH3CN at 35 °C. For all cases, only one diastereoisomer was obtained. bIsolated yields after silica gel column chromatography. c Isolated yields by direct filtration.

attempted some other iron(III) and copper(II) salts, but no increase in the yield was noticed (Table 1, entries 2−4). Trifluoroacetic acid (TFA) also catalyzed the reaction, but a longer reaction time was needed (Table 1, entry 5). Structurally, product 4a has one additional acetophenone moiety compared with the starting material. This implied that 2 equiv of 2a was needed to accomplish this transformation. Therefore, we next investigated the effect of substrate ratio. When the molar ratio of 1a to 2a was 1:2, the yield of 4a decreased to 20%, and 5a was obtained in 42% yield. On the contrary, an increase in the yield of 4a was observed when an excess of indole 1a was used (Table 1, entries 6 vs 7). A survey of reaction solvent revealed that solvents had a significant effect on the yields. When ethyl acetate was used, 4a was obtained in 75% yield (Table 1, entry 8). However, when the reaction was conducted in CHCl3, the yield of 4a dropped dramatically to 12% (Table 1, entry 9). The optimized reaction conditions were found to be 0.30 mmol of 1a and 0.20 mmol of 2a with 20 mol % of FeCl3·6H2O in CH3CN at 35 °C for the formation of 4a. With the optimal reaction conditions in hand, the substrate scope was explored (Scheme 2). First, we evaluated the generality of indoles bearing different N-alkyl substituents, and the results are listed in Scheme 2. Generally, the reactions proceeded well, delivering the desired chromane-bridged polycyclic indoles 4a−g in moderate to good yields. Indoles bearing a chloride or bromine atom at the C5 position also proved to be compatible, allowing the synthesis of 4h and 4i in 41% and 56% yields, respectively. Afterward, a broad range of o-

hydroxychalcones with different electronic and substitution patterns were investigated. Gratifyingly, all of them were tolerable, and the reaction proceeded smoothly to give the desired products 4j−o in 63−85% yields. It seemed that when R3 was an electron-donating group, such as methyl, a much better yield was obtained than for the reactions with electronwithdrawing groups (4j vs 4k,l). Substrates 2e−f bearing a methyl group at different positions were also suitable reaction partners, leading to 4m and 4n in 70% and 74% yields, respectively. Likewise, 2g with a much bulkier isopropyl group could participate in this reaction successfully to afford 4o in 82% yield. Notably, products 4k and 4l were precipitated from the homogeneous reaction system. Thus, only a simple filtration was needed to purify them, avoiding the use of column chromatography. More importantly, this reaction proceeded in a highly diastereoselective manner. Only one diastereoisomer was obtained for the examples, although the products contain three contiguous stereocenters, one of which was a quaternary center. The structure and relative configuration of 4a were unambiguously determined by X-ray diffraction, and the relative configurations of other products 4 were assigned by analogy. On the basis of the experimental results and previous reports on 3-alkenylindole chemistry,8 a plausible reaction mechanism 3452

DOI: 10.1021/acs.orglett.8b01107 Org. Lett. 2018, 20, 3451−3454

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Organic Letters was proposed to explain the reaction pathway and stereochemistry (Scheme 3). Initially, in the presence of FeCl3, a

Scheme 5. Crossover Experiment

Scheme 3. Plausible Reaction Mechanism

Scheme 6. Chemical Transformations of 4a and 4l

retro-aldol reaction of o-hydroxychalcone 2a occurred to give salicylaldehyde and acetophenone, which could be captured by N-benzylindole 1g to generate bisindole 5g and intermediate A, respectively. Then a [4 + 2] cycloaddition between intermediate A and 2a took place to deliver intermediate B. The generation of intermediates A and B was verified by HRMS analysis (for details, see the Supporting Information). Subsequently, intermediate B was converted into α,βunsaturated imine C after oxidation by air followed by an intramolecular 1,4-addition by the attack of the hydroxyl group to yield the desired product 4g. To verify the possible pathway, some control experiments were conducted. First, we attempted a three-component, onepot domino reaction among 1i, acetophenone, and ohydroxychalcone 2d according to Yan’s procedure,8b and chromane-bridged polycyclic indole 4p was obtained in 20% yield (Scheme 4), whose structure was determined by X-ray

boronic acid 9 was conducted, and the corresponding product 10 with an additional indole core was obtained in 70% yield. In summary, we have developed an efficient and practical strategy to assembly highly complex and strained chromanebridged polycyclic indoles by an unexpected FeCl3-catalyzed cascade reaction of indoles with o-hydroxychalcones. The salient features of this reaction include easily available starting materials, mild reaction conditions, simple procedure, broad substrate scope, and in particular, the newly formed interesting indole bridged polycyclic skeletons. This work not only provides an expedient and facile method for the construction of complex chromane bridged polycyclic indoles but also establishes a new transformation of indoles and o-hydroxychalcones.

Scheme 4. Control Experiment

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ASSOCIATED CONTENT

S Supporting Information *

diffraction. This implied that 3-alkenylindole was one of the intermediates to initiate subsequent conversion. Then a crossover experiment of 1g, 2a, and 2e was performed (Scheme 5). After the reaction was completed, we could obtain four inseparable products (4g, 4m, 4m′, and 4m″) with similar polarity, and two of them were crossover products (4m′ and 4m″), which could also be evidenced by HRMS analysis. This further verified that this reaction proceeded via a retro-aldol/ Friedel−Crafts alkylation/[4 + 2] cycloaddition sequence. To highlight the synthetic utility of this methodology, some chemical transformations were conducted (Scheme 6). By treatment of 4a with NaBH4, the reduction reaction proceeded completely within 10 min to give product 8 in 95% yield with 1.8:1 dr. In addition, the presence of bromine atom in 4l offers an opportunity for further access to new functionalized molecules. Thus, Suzuki coupling between 4l and 2-indolyl

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01107. Experimental procedures, mechanistic studies, characterization data, crystallographic data, and NMR spectra for 4a−p, 8, and 10 (PDF) Accession Codes

CCDC 1557517 and 1833978 contain 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 3453

DOI: 10.1021/acs.orglett.8b01107 Org. Lett. 2018, 20, 3451−3454

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Organic Letters

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(5) (a) Zhu, Y.-S.; Zhou, J.; Jin, S.-J.; Dong, H.-H.; Guo, J.-M.; Bai, X.-G.; Wang, Q.-L.; Bu, Z.-W. Chem. Commun. 2017, 53, 11201. (b) Zhu, Y.-S.; Guo, J.; Jin, S.-J.; Guo, J.-M.; Bai, X.-G.; Wang, Q.-L.; Bu, Z.-W. Org. Biomol. Chem. 2018, 16, 1751. (6) For selected examples, see: (a) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418. (b) Xiong, H.; Xu, H.; Liao, S.H.; Xie, Z.-W.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851. (c) Liao, L.-H.; Shu, C.; Zhang, M.-M.; Liao, Y.-J.; Hu, X.-Y.; Zhang, Y.-H.; Wu, Z.-J.; Yuan, W.-C.; Zhang, X.-M. Angew. Chem., Int. Ed. 2014, 53, 10471. (d) Han, L.; Liu, C.; Zhang, W.; Shi, X.-X.; You, S.-L. Chem. Commun. 2014, 50, 1231. (e) Ruchti, J.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 16756. (f) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288. (g) Feng, L.-W.; Ren, H.; Xiong, H.; Wang, P.; Wang, L.-J.; Tang, Y. Angew. Chem., Int. Ed. 2017, 56, 3055. (7) Yin, She, and co-workers reported an iodine-catalyzed domino Michael addition−intramolecular cyclization sequence of indoles and o-hydroxychalcones, leading to 2-aryl-4-(indol-3-aryl)-4H-chromenes; see: Yin, G.-D.; Fan, L.; Ren, T.-B.; Zheng, C.-Y.; Tao, Q.; Wu, A.-X.; She, N.-F. Org. Biomol. Chem. 2012, 10, 8877. (8) (a) Chen, S. P.; Li, Y. X.; Ni, P. H.; Yang, B. C.; Huang, H. W.; Deng, G. J. J. Org. Chem. 2017, 82, 2935. (b) Yang, R. Y.; Sun, J.; Tao, Y.; Sun, Q.; Yan, C. G. J. Org. Chem. 2017, 82, 13277.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qilin Wang: 0000-0003-4637-0392 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (U1504206), the Foundation of He’nan Educational Committee (18A150002), and Henan University (yqpy20170008) was appreciated. We also thank Prof. Zhi-Jun Wu, Chengdu Institute of Biology, Chinese Academy of Sciences, for HRMS analysis and Prof. Xiao-Nian Li, Kuming Institute of Botany, Chinese Academy of Sciences, for X-ray crystallographic analysis.

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DOI: 10.1021/acs.orglett.8b01107 Org. Lett. 2018, 20, 3451−3454