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• The xanthone backbone constitutes the central core of a range of naturally occurring products, most as secondary metabolites from fungi, lichens, bacteria and plants [1]. Over thousands of xanthones have been isolated and characterized [2]. Many xanthone-containing plants, have been employed as traditional medicines since ancient time to treat various diseases [3]. This class of compounds has attracted interests due to their special pharmaceutical properties. The xanthone scaffold has been regarded as ‚Äúprivileged structure‚Äù, since members of this structural class can interact with many types of drug targets [4]. Several reactions have been known for the preparation of xanthones, but most of them embark from intramolecular cyclization of the intermediacy of diaryl ethers or benzophenones under harsh reaction conditions (Scheme 1) [5]. In this context, a big challenge to synthesize xanthone derivatives is caused by the free modification of xanthones with different substituents, which is often desired by medicinal and material chemists. Consequently, a general, mild and efficient synthesis of xanthones, especially in the intermolecular mode (which enables a big freedom to tune the subsituents), is in high demand. Larock and his coworkers developed an intermolecular method to prepare xanthones by the coupling of arynes and substituted salicylates [6]. This is an elegant method to prepare substituted xanthones, but an intrinsic drawback is the poor regio-selectivity when monosubstituted arynes are used. Herein, we would like to report a general method to synthesize multi-substituted xanthones 1 by the intermolecular cyclization of salicylates 2 and diaryliodoniums 3 [6, 7] with high tolerance of functional groups. The reactions are catalyzed by Cu (OTf)₂ in regio-selectivity with aryl group of diaryl iodoniums serving as C2 building block (Scheme 2) [8].

  Scheme 1

  

  Scheme 1.  Typical pathways for the synthesis of xanthones

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  Scheme 2

  

  Scheme 2.  The synthesis of multi-substituted xanthones 1 by the intermolecular cyclization of salicylates 2 and diaryl iodoniums 3

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  During our study on the synthesis of heterocycles with diaryliodonium salts [8], we envisioned that the diaryliodonium salts 3 could be attacked by methyl salicylate 2 to give 2-methoxylcarbonyl diaryl ether 4 [9], which was a good precursor for cyclization to give xanthones. The study was stemmed with methyl salicylate (2a), and diphenyliodonium triflat (3a) in the presence of 10% of Cu(OTf)₂ as catalyst in DCE (Table 1).

  Table 1

  

  Table 1.  The optimization of synthesis of xanthone 1aa from salicylate 2a and diphenyl iodonium 3a in presence of catalyst

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  To our delight, the xanthone (1aa) was detected in 19% GC yield at 70 ℃ (Table 1, entry 1). The yield was increased when the temperature was raised. Eventually, the yield was improved to 91% at 130 ℃ (entry 5). The screening of copper-catalysts showed that other copper salts could also catalyze this transformation, but not so efficient as Cu(OTf)₂ (entries 6-9). Interestingly, the use of Ph₂IPF₆ instead of Ph₂IOTf only supplied 35% product, and most isolatable compound was 2-methoxylcarbonyl diphenylether (entry 12). The reaction supplied less product without catalyst, or with other catalysts including FeCl₃ and NiCl₂ (entries 13-15). With further optimization of solvents, DCE was chosen as the best solvent.

  Under the optimal conditions, next, the scope of functionalized diaryliodoniums 3 was examined (Scheme 3). Gratefully, diaryliodoniums with a range of substituents involving halogen atom, electron-withdraw and electron-donating groups all worked well with 2a. The moderate to good yields (up to 89%) of the products were acceptable since these reactions proceeded in two steps in one-pot. Especially, the second step was the Friedel-Crafts acylation of phenyl ring with ester moiety, which was not a strong acylation group. Disappointingly, diaryliodonium salts with electron-withdrawing, 4-CF₃ gave the product 1ai in 26% yield. The diaryliodonium salts with m-substituent gave regio-selective product 1ac and with o-substituent had no influence on the transformation. When the unsymmetrical diaryliodonium salt 3m MesI⁺(4-MeOOCPh)OTf^- was used, only one product of 1am was obtained in 55% yield [10]

  Scheme 3

  

  Scheme 3.  The scope of substituted diaryliodonium salts. ^*Unsymmetric diaryliodonium salt MesI⁺(4-MeOOCPh)OTf^- 3m used

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  Next, a variety of substitutes on salicylates were evaluated with Ph₂I⁺OTf^- 3a and (4-^tBuPh)₂I⁺OTf^- 3k to synthesize xanthones [11] (Scheme 4). In addition to methyl salicylate, the thiophene analogue 2e also reacted well to afford 1ea. To determine the regio-selectivity, more salicylates were examined with (4-^tBuPh)₂I⁺OTf^- 3k. Gratifyingly, all of the reactions proceeded with regio-selectivity maintained at each position.

  Scheme 4

  

  Scheme 4.  The scope of substituted salicylates reacted with Ph₂I⁺OTf^- 3a and (4-^tBuPh)₂I⁺OTf^- 3k to synthesize xanthones

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  When the ester group of salicylates 2 was replaced by acyl group, then xanthenol derivatives [12] were obtained insteadly (Scheme 5). For instance, 2-hydroxyl benzophenone 6 reacted with Ph₂I⁺OTf^- 3a or (4-ClPh)₂I⁺OTf^- 3b to give 9-phenylxanthenol 5a or 5b in useful yields. As mentioned above, when the reaction was carried out at lower temperature (e.g., 80 ℃), the intermediate 2-methoxylcarbonyl diarylether 4 was isolated (Scheme 6). When the isolated intermediate 4a was heated with catalytic amount of HOTf acid, the product 1aa was obtained quantitatively. This demonstrated that the second step of the Friedel-Crafts acylation with ester moiety was catalyzed by HOTf.

  Scheme 5

  

  Scheme 5.  Synthesis of xanthenol 5a and 5b

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  Scheme 6

  

  Scheme 6.  The isolation of intermediate 4a and its transformation into product 1aa

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  In summary, a concise, efficient and regio-selective approach to substituted xanthones 1 with two aromatic components of salicylates 2 and diaryliodonium salts 3 has been realized. The reactions are initiated by the etherification of diaryliodonium salts with salicylates and followed by intramolecular acylation. We believe that this study disclosed a new pathway to oxygencontaining heterocycles from diaryliodonium salts.

  Acknowledgments

  This work was supported by the National Natural Science Foundation of China (Nos. 21372138 and 21672120), The National Key Research and Development Program of China (No. 2016YFB0401400), the Fok Ying Tong Education Foundation of China (No. 151014) and the Postdoctoral Foundation of the PekingTsinghua Joint Center for Life Sciences.

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  Scheme 1  Typical pathways for the synthesis of xanthones

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  Scheme 2  The synthesis of multi-substituted xanthones 1 by the intermolecular cyclization of salicylates 2 and diaryl iodoniums 3

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  Scheme 3  The scope of substituted diaryliodonium salts. ^*Unsymmetric diaryliodonium salt MesI⁺(4-MeOOCPh)OTf^- 3m used

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  Scheme 4  The scope of substituted salicylates reacted with Ph₂I⁺OTf^- 3a and (4-^tBuPh)₂I⁺OTf^- 3k to synthesize xanthones

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  Scheme 5  Synthesis of xanthenol 5a and 5b

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  Scheme 6  The isolation of intermediate 4a and its transformation into product 1aa

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  Table 1.  The optimization of synthesis of xanthone 1aa from salicylate 2a and diphenyl iodonium 3a in presence of catalyst

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