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Palladium-catalyzed diarylative dearomatization of indoles with aryl thioesters
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Wei Huanga, Ming-Liang Hand, e, Yu-Wen Liub, c, Hui Xu**, b, Hui-Xiong Dai*, b, c
Chinese Chemical Letters | 2021, 32(9) : 2765 - 2768
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Chinese Chemical Letters | 2021, 32(9): 2765-2768
• Communication •
Palladium-catalyzed diarylative dearomatization of indoles with aryl thioesters
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Wei Huanga, Ming-Liang Hand, e, Yu-Wen Liub, c, Hui Xu**, b, Hui-Xiong Dai*, b, c
Affiliations
  • a School of Pharmacy, Nanchang University, Nanchang 330006, China
  • b Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
  • c University of Chinese Academy of Sciences, Beijing 100049, China
  • d Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China
  • e Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
Published: 2021-09-15 doi: 10.1016/j.cclet.2021.02.048
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We report herein a palladium-catalyzed diarylative dearomatization of indole by employing thioester and arylboronic acid as the aryl electrophiles. The reaction involved a decarbonylation/migratory insertion/terminal Suzuki coupling procedure. Substrates bearing various functional groups are well tolerated in the reaction, affording the diarylated indoline skeletons in moderate to good yields.

Thioester  /  Decarbonylation  /  Dearomatization  /  Indolines skeleton  /  Diarylation
Wei Huang, Ming-Liang Han, Yu-Wen Liu, Hui Xu, Hui-Xiong Dai. Palladium-catalyzed diarylative dearomatization of indoles with aryl thioesters[J]. Chinese Chemical Letters, 2021 , 32 (9) : 2765 -2768 . DOI: 10.1016/j.cclet.2021.02.048
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Indoline derivatives represent an important class of nitrogen-containing heterocyclic scaffolds, which are commonly found in biologically active natural products and pharmaceuticals [1-3]. Dearomatization of indole is a very attractive tool to construct indoline-based skeletons with fused polycyclic scaffolds [4]. In recent years, transition-metal-catalyzed intramolecular migratory insertion strategies for highly region-and stereoselective dearomatization of indoles have been widely explored (Scheme 1a) [5]. In 2001, Grigg and coworkers reported a seminal work on the palladium-catalyzed dearomatization of indoles via a domino Heck-type mechanism [6]. Since then, Lautens, Jia, Liang et al. developed Pd- and Ni-catalyzed dearomative difunctionalization of indoles (including arylalkynylation, arylcyanation, aryliodination, arylborylation, arylarylation, arylborylation, arylphosphoylation and hydroarylation) (Scheme 1a) [7, 8]. In 2015, Jia and coworkers reported the first Pd-catalyzed enantioselective dearomatization of indoles via intramolecular hydroarylation reactions [8a]. Despite of significant advantages, aryl halides are often employed as the aryl electrophile. To further explore the substrate scope, conversion of readily available carboxylic acids derivatives as new aryl electrophiles in dearomatization of indoles would be highly appealing.
Aryl thioesters could be conveniently prepared from aryl carboxylic acids and corresponding thiols. Thioesters are reactive but bench stable, and often act as electrophilic acylating reagent in the macrolactones synthesis and peptides ligation [9]. C(O)-S bonds of thioesters are known to undergo the oxidative addition to low-valent metals including Pd, Ni and Rh, enabling the thioester to be versatile and practical building block in organic synthesis [10]. For example, palladium-catalyzed cross coupling of thioester with organometallic reagents have been widely applied in the ketone synthesis [11]. The Fukuyama reduction with Et3SiH could facilely and selectively reduce thioesters to the aldehydes [12]. Catellani-type difunctionalization of aryl halide with thioesters has been demonstrated by Gu [13]. Decarbonylative thiolation and borylation of thioesters were successfully achieved by Yamamoto, Wenkert, Kambe, Sanford and Hosoya [14, 15]. Very recently, our group reported palladium-catalyzed decarbonylation of aryl thioester to dearomatize indoles via an intramolecular reductive Heck reaction (Scheme 1b) [16]. Based on previous work and our continued interest in the construction indoline scaffolds, we report herein the diastereoselective dearomative diarylation of indoles using aryl thioesters and arylboronic acids as the arylation reagents (Scheme 1c). The reaction proceeded via a decarbonylation-Heck-Suzuki sequence. Our protocol shows excellent functional group tolerance in both coupling partners, thus allowing for the rapid construction of polycyclic indoline skeletons.
We began our studies by employing S-ethyl 2-(2-methylindole-1-carbonyl)benzothioate 1a and phenylboronic acid 2a as the model substrates. After carefully screening of various ligands, bases, solvents, copper and palladium salts, ultimately, the desired dearomatization product 3b was obtained in 61% yield (Table 1, entry 1, see Supporting information for detailed optimization). Phosphine ligands are found to be essential in the reaction (entries 2-7). Among various phosphine ligands, bidentate dppf (1, 1'-bis(diphenylphosphino)ferrocene) ligand proved to be most effective. Other mono- and bidentate phophine ligands were also effective, albeit with somewhat lower yields. Copper salts are proposed to scavenge the ethanethiol released over the course of the reaction by forming the strong Cu-S bond, thus facilitating the decarbonylation and migratory insertion process [11]. After screening of copper salts, CuTC was the optimal. When Na2CO3 was replaced by KHCO3 and CsF, 45% and 28% yields of product 3a were obtained (entries 8 and 9). Regarding the solvent employed, DCE afforded 32% yield of product, while toluene gave no dearomatization product (entries 10 and 11). Among various palladium catalysts examined, Pd(TFA)2 proved to be most effective, and other palladium salts afforded lower yields (entries 12-14).
With the optimal reaction conditions in hand, we commenced to explore the substrate scope of dearomatizative diarylation of indole 1a with various aryl boronic acids 2. As shown in Scheme 2, under the optimized conditions (10 mol% of Pd(TFA)2, 12 mol% of dppf, 2.0 equiv. of Na2CO3, 1.5 equiv. of CuTC, 90 ℃, 12h), aryl boronic acid bearing electron-donating and -withdrawing groups (-Me, -OMe, -F, -Cl, and -CF3) were well tolerated, affording the desired products (3a-3e, 3g, 3i, 3k) in moderate to good yields. The structure of product 3k was determined by X-ray analysis. Very sensitive bromide and alkene groups were well tolerated, leaving functional handles for further transformations via transition metal-catalyzed cross coupling reaction. 2-Naphthylboronic acid was also suitable substrate, furnishing the dearomatization product 3l in 56% yield. Next, we investigated the substrate scopes of the S-ethyl 2-(2-methylindole-1-carbonyl)arylthioate 1 under the standard conditions. When C2-phenyl-substituted indole 1m was employed as the substrate, the corresponding product 3m was obtained in 49% yield. Other electron-rich and -poor aryl groups at C2 position of indole were well tolerated, giving the dearomatization product 3n-3t in 43%-57% yields. To our delight, the protocol could be extended to thiophene-containing substrate, albeit in lower yield (3u). The reaction performed well when C2-alkyl- and ester-substituted indole substrates were employed (3v-3x). Methyl, methoxyl, t-butyl, fluoro, and bromo substituents at other positions of indole were also investigated, giving the desired products 3y-3ac in 38%-57% yields. It is worth noting that dr values of > 20:1 are observed for products 3a-3ac based on the NMR analysis of the crude reaction mixture.
Based on experimental results and previous reports [7-10], a plausible mechanism for the Pd(0)-catalyzed ligand-promoted diarylative dearomatization of indoles is illustrated in Scheme 3. The reaction is initiated by the oxidative addition of Pd(0) catalyst into the thioester 1a, generating the Pd(II) complex A. Cu salts coordinate to the sulfur atom to polarize the Pd-S bond. Then the phosphine ligand promote the decarbonylation of thioester to afford arylpalladium B. Subsequent intramolecular migratory insertion of arylpalladium into indole ring give the dearomatization intermediate C. Transmetallation of intermediate C with phenylboronic acid 2a results in intermediate D, which then undergo the reductive elimination to give the final product 3a with the regeneration of the active Pd(0) species.
In summary, we have developed a palladium-catalyzed diarylative dearomatization of indole thioester, affording the fused polycyclic indoline skeletons in moderate to good yields. Aryl thioesters were employed as the aryl electrophiles via decarbonylation of thioesters. Our protocol shown broad substrate scope, and sensitive -Cl, -Br and alkene groups could be tolerated, leaving a functional handle for further structure diversification.
Declaration of competing interest
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The authors report no declarations of interest.
Acknowledgments
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We gratefully acknowledge the Shanghai Institute of Materia Medica, the Chinese Academy of Sciences, the National Natural Science Foundation of China (Nos. 21772211 and 21920102003), the Youth Innovation Promotion Association CAS (Nos. 2014229 and 2018293), the Science and Technology Commission of Shanghai Municipality (Nos. 17JC1405000 and 18431907100), the Program of Shanghai Academic Research Leader (No. 19XD1424600), the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (No. 2018ZX09711002-006) for financial support.
Appendix A. Supplementary data
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Supplementarymaterial related to this article can befound, in the online version, at doi:https://doi.org/10.1016/j.cclet.2021.02.048.
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Year 2021 volume 32 Issue 9
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doi: 10.1016/j.cclet.2021.02.048
  • Receive Date：2021-01-18
  • Online Date：2026-01-04
  • Published：2021-09-15
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  • Received：2021-01-18
  • Revised：2021-02-20
  • Accepted：2021-02-22
Affiliations
    a School of Pharmacy, Nanchang University, Nanchang 330006, China
    b Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
    c University of Chinese Academy of Sciences, Beijing 100049, China
    d Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China
    e Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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