English

• 1.   Introduction

  Indolylsuccinimide, an important motif of aza-hetero- cycles, frequently emerges in natural products^[1] and drug candidates^[2] due to their noteworthy biological activities, ^[3] as well as drug candidates that exhibit high kinase selectivity and anticancer activity.^[4] They are also useful synthetic intermediates for construction of complicate heterocyclic frameworks.^[5] For examples, compound A is a mood stabilizer and able to stimulate steroidogenesis.^[6] Compound B, with remarkable antiangiogenic activity, was discovered from 2, 3-diarylmaleimide derivatives.^[7] Compound C, one clinical candidate, shows great potency in IDO-1 human whole blood assay.^[8] Additionally, compounds D and E exhibit good chemical activities in term of fluorescence (FL), chemiluminescence (CL), and bioluminescence (BL) (Figure 1).^[9]

  Figure 1

  

  Figure 1.  Examples illustrating the importance of indolylsuccinimides

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  Traditionally, indolylsuccinimides were prepared starting from indolylmagnesium bromides and bromomaleimides.^[10] Moreover, they have also been catalyzed by the conjugate addition of indoles to α, β-unsaturated compounds in the presence of Lewis acid.^[11] Recently, transi-tion-metal-catalyzed coupling reactions have been widely applied in indolylsuccinimides synthesis. For example, Zhao group^[12] developed the Michael addition and oxidative dehydrogenation reaction of indoles with maleimides promoted by AlCl₃, obtaining 3-substituted indoles in high yields with excellent regioselectivity. Then, this group^[13] extended the regioselective tandem oxidative coupling reactions from both free and protected (NH) indoles with maleimides catalyzed by palladium. Despite these methods have contributed greatly to this field, there still exist some respective limitations, such as requirement of long reaction times, excess oxidant, pre-functionalized substrates and low efficiency. Therefore, developing high efficiency and convenient method is considerable. Silver salts have concurrently been developed as a newly emerging metal catalyst due to its excellent catalytic activity, high selectivity, long service life, convenient after-treatment, and ease of removal.^[14] With our ongoing efforts to the clean transition-metal-catalyzed C—H bond functionalization, ^[15] herein, we disclose a Ag(I)-catalyzed alkylation of 2-aryl- indoles with maleimides to synthesize 3-(2-aryl-1H-indol- 3-yl)pyrrolidine-2, 5-dione with high yields and excellent regioselectivity, avoiding external oxidants under relatively mild reaction conditions.

  2.   Results and discussion

  Our initial experiment was performed with 2-phenyl- indole (1a) and N-methylmaleimide (2a) as model substrates to optimize the reaction conditions (Table 1). In the presence of 20 mol% AgNTf₂, the reaction of indole 1a with 2a in 1, 2-dichloroethane (DCE) at 80 ℃ under air atmosphere afforded the expected product 3aa in 56% yield (Table 1, Entry 1). The structural and regiochemical assignments of compound 3aa were confirmed by X-ray crystallographic analysis (Figure 2).^[16] To our delight, the yield increased significantly to 86% when 1.0 equiv. of AcOH was added (Table 1, Entry 2). The silver salts, including AgSbF₆, AgOTf, AgBF₄, Ag₂CO₃, AgOAc, AgTFA, were tested. AgNTf₂ was proved to be an optimal catalyst (Table 1, Entries 2~8). Then, an extensive survey of acids (AcOH, HCOOH, TFA, MSA, Ac₂O, PivOH) was performed (Table 1, Entries 9~13). PivOH afforded 3aa in the highest yield of 93% (Table 1, Entry 13). Both raising and lowering the amount of PivOH resulted in lower yield of the target product 3aa (Table 1, Entries 14, 15). Next, several additional parameters were altered in an attempt to further improve yield. It was observed that the solvent played a crucial role. Among the solvents tested, CCl₄ was the optimal choice (Table 1, Entries 15~21). Finally, 80 ℃ was determined to be the optimal reaction temperature. The yield reduced significantly when the reaction temperature decreased or increased (Table 1, Entries 22~24). Subsequently, the loading of 5 mol% AgNTf₂ was most appropriate (Table 1, Entry 24). Moreover, the control experiment indicated that PivOH could not promote the reaction in the absence of the Ag catalyst (Table 1, Entry 25).

  Figure 2

  

  Figure 2.  X-ray molecular structure of the product 3aa

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  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Catalyst	Additive	Solvent	Yieldb/%
  1	AgNTf2	—	DCE	56
  2	AgNTf2	AcOH	DCE	86
  3	AgSbF6	AcOH	DCE	70
  4	AgOTf	AcOH	DCE	78
  5	AgBF4	AcOH	DCE	82
  6	Ag2CO3	AcOH	DCE	NR
  7	AgOAc	AcOH	DCE	NR
  8	AgTFA	AcOH	DCE	Trace
  9	AgNTf2	HCOOH	DCE	89
  10	AgNTf2	TFAc	DCE	73
  11	AgNTf2	MSAd	DCE	92
  12	AgNTf2	Ac2O	DCE	80
  13	AgNTf2	PivOH	DCE	93
  14e	AgNTf2	PivOH	DCE	54
  15f	AgNTf2	PivOH	DCE	61
  16	AgNTf2	PivOH	DMF	NR
  17	AgNTf2	PivOH	CH3OH	32
  18	AgNTf2	PivOH	CH3CN	NR
  19	AgNTf2	PivOH	Toluene	86
  20	AgNTf2	PivOH	CHCl3	89
  21	AgNTf2	PivOH	CCl4	96
  22g	AgNTf2	PivOH	CCl4	97
  23h	AgNTf2	PivOH	CCl4	78
  24i	AgNTf2	PivOH	CCl4	82
  25	—	PivOH	CCl4	NR
  a Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (20 mol%), and additive (1.0 equiv) at 80 ℃ for 12 h in solvent (2.0 mL) under air. b Isolated yield. c TFA: trifluoroacetic acid. d MFA: methanesulfonic acid. e PivOH (0.5 equiv). f PivOH (2.0 equiv.). g 1a (0.1 mmol), 2a (0.12 mmol), AgNTf2 (5 mol%). h At 60 ℃. i At 100 ℃.

  With the optimized reaction conditions in hand, we turned our attention to the scope of the substrates for this transformation (Table 2). The reaction was compatible with a variety of 2-phenylindoles affording the desired products in moderate to good yields. A wide range of ma-leimides were firstly evaluated in the reaction with 2-phenylindole (1a) (Table 2, 3aa~3ah). The maleimides with N-alkyl substituted (such as Me, Et, and cyclohexyl) maleimides gave the desired products (3aa, 97%; 3ab, 70%; 3ac, 80%) in good to excellent yields. N-Phenyl maleimide (3ad, 46%) obtained a medium yield, perhaps due to its good conjugate structure with maleimide ring. N- Benzyl functionalities readily furnished the desired product 3ae in 95% yield. Additionally, evaluation of electronic effects on the aryl ring of N-aryl maleimides turned out great yields (3af, and 3ag, 96%, and 86%). And the dimethyl maleate (3ah, 73%) also had a good transformation in the reaction.

  Table 2

  

  Table 2.  Scope of substrates^a, ^b

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  Then, substituted 2-phenylindoles with N-methyl maleimide were subjected to the optimized reaction conditions. It was found that the identity of the 2-phenylindoles substituents has no obviously influence the reaction yields. Generally, 4'-methyl, 3'-methyl, 2'-methyl 2-phenylindoles afforded excellent yields (3ba, 73%; 3ca, 86%; 3da, 90%). And 3'-methoxy, 2'-methoxy 2-phenylindoles could obtain good yields (3ea, 88%; 3fa, 90%). Then, 2-phenylindoles with halogen and trifluoromethyl generally have slightly lower yields (3ga, 70%; 3ha, 76%; 3ia, 85%; 3ja, 64%). These results suggest that electron-withdrawing substituents could slightly decrease the reactivity of the 2-phenyl- indoles by reducing the nucleophilicity of the 3-position. Additionally, halogens on the indole ring (3la, 3ma, 3na, 3oa, and 3pa) were tolerated and given excellent yields, providing useful synthetic handles for further functionalization. In addition, N-methyl-2-phenylindole could give the product 3qa in 94% yield, and 2-methylindole was also applied to this catalytic system, giving the product 3ra in 52% yield.

  Some control experiments were conducted to gain insight into the reaction mechanism (Scheme 1). When the radical scavenger 2, 2, 6, 6-tetramethylpiperidinooxy (TEM- PO) was affiliated to the reaction system, the desired product 3ae was not detected. Considering the selective oxidation of TEMPO may hinder the reaction, we switched to 2, 6-di-tert-butyl-4-methylphenol (BHT), which had little influence on the yield of the product 3ae. In addition, when the reaction was performed under N₂ atmosphere, the desired product 3ae was obtained in 65% yield. These results indicated that the radical process was ruled out, and molecular oxygen does not play a crucial role in this reaction.

  Scheme 1

  

  Scheme 1.  Control experiments

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  On the basis of the results obtained and previous literatures, ^[17] a plausible mechanism for the reaction is proposed and depicted in Figure 3. Initially, N-methylmale- imide (2a) was activated by Ag(I) to form intermediate A. Then electrophilic attack of 2-phenylindole to the intermediate A gave intermediate B, which delivered the desired product 3aa and catalytically active Ag(I) through protodemetalation. In the catalytic cycle, Ag(I) as a catalyst promotes the procedure by increasing the electrophilic ability of α, β-unsaturated compounds.^{[17a, 18]}

  Figure 3

  

  Figure 3.  Plausible reaction mechanism

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  3.   Conclusions

  In summary, the alkylation of 2-arylindole with maleimides has been developed using silver(I) as catalyst. Under the optimized reaction conditions, a broad range of 3- (2-pheny-1H-indol-3-yl)pyrrolidine-2, 5-diones were con- veniently obtained in moderate to excellent yields under relatively mild reaction conditions.

  4.   Experimental section

  4.1   General experimental information

  All reactions were carried out under an air atmosphere (≈15 mL volume) equipped with a magnetic stirring element. Unless otherwise stated, all commercial reagents were used without additional purification. Column chromatography was undertaken on silica gel (200~300 mesh) using a proper eluent system. ¹H NMR, ¹⁹F NMR, and ¹³C NMR spectra were recorded on a spectrometer at 400, 376 and 100 MHz, respectively, with deuteraterated chloroform as solvent. The chemical shifts δ are reported relative to tetramethylsilane (δ＝0) or residual CHCl₃ (δ＝77.00). High-resolution mass spectrometry (HRMS) was performed on a Q-TOF spectrometer using electrospray ionization (ESI). X-ray analysis was performed with a single-crystal X-ray diffractometer. The 2-arylindoles^[19] and maleimides^[20] were prepared according to references. The solvents and reagents were obtained from the commercial suppliers and used without further purification.

  4.2   General synthesis procedure

  A mixture of 2-phenylindole (0.1 mmol), N-methylmale- imide (0.12 mmol), AgNTf₂ (5 mol%) and PivOH (0.1 mmol) in carbon tetrachloride (2 mL) in a sealed tube was stirred at 80 ℃ for 12 h. After cooling to room temperature, the mixture was purified by column chromatography on silica gel (EtOAc/petroleum ether, V:V＝1:3) to afford the desired product 3aa.

  Methyl-3-(2-phenyl-1H-indol-3-yl)pyrrolidine-2, 5-dione (3aa): Pale yellow solid. 29.5 mg, 97% yield. m.p. 184~186 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (s, 1H), 7.60~7.57 (m, 2H), 7.48~7.39 (m, 3H), 7.35 (d, J＝8.2 Hz), 7.25~7.15 (m, 2H), 7.10~7.07 (m, 1H), 4.39 (t, J＝7.1 Hz, 1H), 3.12 (s, 3H), 3.09 (t, J＝7.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.8, 137.6, 136.0, 131.9, 129.1, 128.8, 128.7, 126.1, 122.8, 120.5, 118.2, 111.6, 107.7, 37.9, 36.2, 25.2; HRMS (ESI) calcd for C₁₉H₁₇N₂O₂ [M+H]⁺ 305.1285, found 305.1287.

  Ethyl-3-(2-phenyl-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ab): White solid. 22.2 mg, 70% yield. m.p. 193~195 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.49 (s, 1H), 7.61~7.59 (m, 2H), 7.49~7.41 (m, 3H), 7.33 (t, J＝8.0 Hz), 7.23~7.19 (m, 2H), 7.13~7.09 (m, 1H), 4.39 (t, J＝7.2 Hz, 1H), 3.73 (dd, J＝7.1, 14.5 Hz, 2H), 3.09 (d, J＝7.8 Hz, 2H), 1.21 (t, J＝6.7 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.8, 176.7, 137.6, 136.1, 131.9, 129.0, 128.8, 128.6, 126.1, 122.7, 120.4, 118.2, 111.7, 107.7, 37.8, 36.2, 34.2, 13.1; HRMS (ESI) calcd for C₂₀H₁₉N₂O₂ [M+H]⁺ 319.1441, found 319.1444.

  Cyclohexyl-3-(2-phenyl-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ac): White solid. 29.6 mg, 80% yield. m.p. 224~226 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 7.61~7.59 (m, 2H), 7.47~7.40 (m, 3H), 7.32 (t, J＝8.2 Hz, 1H), 7.20~7.16 (m, 2H), 7.10~7.06 (m, 1H), 4.30 (t, J＝7.1 Hz, 1H), 4.18~4.09 (m, 1H), 3.03 (s, 1H), 3.01 (s, 1H), 2.33~2.17 (m, 2H), 1.83 (d, J＝13.1 Hz, 2H), 1.65 (d, J＝10.4 Hz, 3H), 1.36~1.19 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 137.6, 136.1, 131.9, 129.1, 128.8, 128.6, 126.1, 122.7, 120.4, 118.3, 111.6, 108.1, 52.2, 37.5, 35.9, 28.9, 25. 9, 25.1; HRMS (ESI) calcd for C₂₄H₂₅N₂O₂ [M+H]⁺ 373.1911, found 373.1913.

  Phenyl-3-(2-phenyl-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ad): White solid. 16.7 mg, 46% yield. m.p. 117~ 119 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (s, 1H), 7.69~7.67 (dd, J＝1.7, 8.3 Hz, 2H), 7.55~7.52 (m, 2H), 7.51~7.49 (m, 2H), 7.48~7.45 (m, 2H), 7.42~7.39 (m, 4H), 7.27~7.25 (m, 1H), 7.20~7.16 (m, 1H), 4.60 (dd, J＝6.6, 8.5 Hz, 1H), 3.30 (dd, J＝3.3, 8.7 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 177.8, 175.7, 137.7, 136.1, 132.1, 131.9, 129.3, 129.2, 128.9, 128.8, 128.7, 126.5, 126.2, 122.9, 120.7, 118.2, 111.7, 107.9, 38.0, 36.3; HRMS (ESI) calcd for C₂₄H₁₉N₂O₂ [M+H]⁺ 367.1441, found 367.1447.

  1-Benzyl-3-(2-phenyl-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ae): White solid. 36.1 mg, 96% yield. m.p. 105~ 107 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.62 (s, 1H), 7.54~ 7.51 (dd, J＝2.4, 6.1 Hz, 4H), 7.40~7.38 (m, 6H), 7.22 (d, J＝8.0 Hz, 1H), 7.17~7.13 (m, 1H), 6.97~6.91 (m, 2H), 4.84 (dd, J＝13.9, 26.5 Hz, 2H), 4.40 (dd, J＝5.9, 8.9 Hz, 1H), 3.12~2.99 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.9, 176.5, 137.6, 136.1, 135.7, 131.9, 129.30, 129.0, 128.8, 128.7, 128.6, 128.2, 126.0, 122.6, 120.2, 118.3, 111.7, 107.6, 42.9, 37.9, 36.2; HRMS (ESI) calcd for C₂₅H₂₁N₂O₂ [M+H]⁺ 381.1598, found 381.1600.

  3-(2-Phenyl-1H-indol-3-yl)-1-(p-tolyl)pyrrolidine-2, 5-dione (3af): White solid. 37.8 mg, 95% yield. m.p. 125~ 127 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.45 (s, 1H), 7.43~7.37 (m, 1H), 7.36~7.34 (m, 1H), 7.31~7.27 (m, 2H), 7.20~7.16 (m, 1H), 7.15~7.06 (m, 3H), 4.37 (dd, J＝5.2, 6.6 Hz, 1H), 3.13 (s, 3H), 3.10 (t, J＝4.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.1, 176.0, 138.9, 137.7, 136.1, 131.9, 123.0, 129.5, 129.08, 129.1, 128.9, 128.7, 126.3, 126.2, 122.7, 120.6, 118.1, 111.8, 107.8, 38.0, 36.3, 21.3; HRMS (ESI) calcd for C₂₅H₂₁N₂O₂ [M+H]⁺ 381.1598, found 381.1601.

  1-(4-Fluorophenyl)-3-(2-phenyl-1H-indol-3-yl)pyrro-lidine-2, 5-dione (3ag): Pale red solid. 33.0 mg, 86% yield. m.p. 115~117 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.31 (s, 1H), 7.62 (dd, J＝1.7, 8.2 Hz, 2H), 7.50~7.43 (m, 3H), 7.38~7.32 (m, 4H), 7.24~7.20 (m, 1H), 7.18~7.12 (m, 3H), 4.55 (dd, J＝6.4, 8.3 Hz, 1H), 3.25 (dd, J＝3.2, 8.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 177.8, 175.6, 164.2, 160.8, 137.8, 136.1, 131.8, 129.2, 128.9, 128.8, 128.4, 128.3, 122.9, 120.7, 118.0, 116.4, 116.2, 111.8, 38.0, 36.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.14 (s); HRMS (ESI) calcd for C₂₄H₁₈N₂O₂ [M+H]⁺ 385.1347, found 385.1350.

  3-(2-Phenyl-1H-indol-3-yl)hexane-2, 5-dione (3ah): White solid. 22.2 mg, 73% yield. m.p. 180~182 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (s, 1H), 7.74 (d, J＝8.0 Hz, 1H), 7.67 (t, J＝1.4 Hz, 2H), 7.53~7.49 (m, 2H), 7.46~7.41 (m, 1H), 7.38 (d, J＝8.0 Hz, 2H), 7.24~7.20 (m, 1H), 7.16~7.12 (m, 1H), 4.57 (dd, J＝4.7, 10.6 Hz, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.58~3.46 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 173.9, 172.4, 136.2, 135.8, 132.3, 129.1, 128.8, 128.5, 127.1, 122.5, 120.3, 120.1, 111.0, 108.7, 52.4, 51.8, 38.5, 36.2; HRMS (ESI) calcd for C₂₀H₂₀N₂O₂ [M+H]⁺ 306.1489, found 306.1492.

  Methyl-3-(2-(p-tolyl)-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ba): White solid. 23.2 mg, 73% yield. m.p. 198~ 200 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.53 (d, J＝7.9 Hz, 2H), 7.41 (d, J＝8.2 Hz, 1H), 7.32 (d, J＝7.9 Hz, 2H), 7.25~7.17 (m, 2H), 7.14~7.09 (m, 1H), 4.42 (t, J＝6.9 Hz, 1H), 3.17 (s, 3H), 3.13 (t, J＝6.4 Hz, 2H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 138.8, 137.7, 135.9, 128, 128.9, 128.7, 126.2, 122.7, 120.5, 118.1, 111.5, 107.4, 37.9, 36.2, 25.2, 21.4; HRMS (ESI) calcd for C₂₀H₁₉N₂O₂ [M+H]⁺ 319.1441, found 319.1447.

  1-Methyl-3-(2-(m-tolyl)-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ca): Pale red solid. 27.4 mg, 86% yield. m.p. 201~ 203 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.28 (s, 1H), 7.43 (d, J＝6.2 Hz, 2H), 7.40 (d, J＝7.5 Hz, 2H), 7.28 (s, 1H), 7.26~7.21 (m, 1H), 7.19 (d, J＝7.7 Hz, 1H), 7.14~7.10 (m, 1H), 4.44 (dd, J＝6.2, 8.4 Hz, 1H), 3.17 (s, 3H), 3.12 (dd, J＝4.2, 9.1 Hz, 2H), 2.45 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ: 179.0, 176.9, 138.9, 137.7, 135.9, 131.8, 129.5, 129.4, 129.0, 126.2, 125.9, 122.7, 120.5, 118.2, 111.6, 107.6, 37.9, 36.2, 25.2, 21.6; HRMS (ESI) calcd for C₂₀H₁₉N₂O₂ [M+H]⁺ 319.1441, found 319.1447.

  Methyl-3-(2-(o-tolyl)-1H-indol-3-yl)pyrrolidine-2, 5-dione (3da): White solid. 28.7 mg, 90% yield. m.p. 112~ 114 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.33~7.29 (m, 3H), 7.26 (d, J＝7.2 Hz, 1H), 7.21~7.16 (m, 3H), 7.11~7.07 (m, 1H), 3.99 (dd, J＝5.6, 9.3 Hz, 1H), 2.95 (s, 3H), 3.01~2.86 (m, 2H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.7, 176.9, 138.2, 136.7, 135.8, 131.3, 131.2, 130.5, 129.3, 125.8, 122.5, 120.3, 117.9, 111.5, 108.9, 37.7, 36.3, 25.0, 20.1; HRMS (ESI) calcd for C₂₀H₁₉N₂O₂ [M+H]⁺ 319.1441, found 319.1442.

  3-(2-(3-Methoxyphenyl)-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3ea): Pale red solid. 29.4 mg, 88% yield. m.p. 98~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.39~7.34 (m, 2H), 7.21~7.18 (m, 1H), 7.17~7.16 (m, 2H), 7.15 (t, J＝0.9 Hz, 1H), 7.10~7.06 (m, 1H), 6.67~6.94 (m, 1H), 4.42 (t, J＝7.3 Hz, 1H), 3.83 (s, 3H), 3.12 (s, 3H), 3.09 (d, J＝7.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 160.0, 137.50, 136.0, 133.2, 130.2, 126.1, 122.8, 121.0, 120.5, 118.2, 114.4, 114.3, 111.6, 107.7, 55.4, 37.9, 36.1, 25.2; HRMS (ESI) calcd for C₂₅H₂₁N₂O₂ [M+H]⁺ 335.1390, found 335.1396.

  3-(2-(2-Methoxyphenyl)-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3fa): White solid. 29.4 mg, 88% yield. m.p. 98~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.37 (s, 1H), 7.38~7.33 (m, 2H), 7.21~7.14 (m, 4H), 6.69~6.94 (m, 1H), 4.41 (t, J＝7.6 Hz, 1H), 3.83 (s, 3H), 3.12 (s, 3H), 3.08 (d, J＝7.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 159.9, 137.5, 136.0, 133.2, 130.2, 126.1, 122.8, 121.0, 120.5, 118.2, 114.4, 114.2, 111.7, 107.7, 55.4, 37.9, 36.1, 25.2; HRMS(ESI) calcd for C₂₅H₂₁N₂O₂ [M+H]⁺ 335.1390, found 335.1394.

  3-(2-(4-Fluorophenyl)-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3ga): White solid. 29.4 mg, 88% yield. m.p. 106~108 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.21 (s, 1H), 7.63~7.59 (m, 2H), 7.38 (d, J＝8.0 Hz, 1H), 7.24~7.16 (m, 3H), 7.15 (t, J＝1.2 Hz, 1H), 7.12~7.09 (m, 1H), 4.32 (t, J＝7.6 Hz, 1H), 3.15 (s, 3H), 3.12 (d, J＝7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.9, 176.7, 163.1 (d, J＝249.6 Hz), 136.6, 136.0, 130.7 (d, J＝8.6 Hz), 127.9, 126.0, 122.9, 120.7, 118.2, 116.2 (d, J＝22.1 Hz), 111.6, 107.9, 37.8, 36.0, 25.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.14 (s); HRMS (ESI) calcd for C₁₉H₁₆F- N₂O₂ [M+H]⁺ 323.1190, found 323.1194.

  3-(2-(4-Chlorophenyl)-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3ha): Pale red solid. 25.6 mg, 76% yield. m.p. 217~219 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.21 (s, 1H), 7.59~7.56 (m, 2H), 7.48~7.45 (m, 2H), 7.39 (d, J＝7.8 Hz, 1H), 7.26~7.21 (m, 1H), 7.16 (t, J＝7.7 Hz, 1H), 7.13~7.09 (m, 1H), 4.33 (t, J＝7.4 Hz, 1H), 3.15 (s, 3H), 3.12 (d, J＝7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.8, 176.7, 136.4, 136.1, 134.9, 130.3, 130.1, 129.4, 126.0, 123.1, 120.7, 118.3, 111.7, 108.2, 37.8, 36.0, 25.3; HRMS (ESI) calcd for C₁₉H₁₆ClN₂O₂ [M+H]⁺ 339.0895, found 339.0899.

  3-(2-(4-Bromophenyl)-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3ia): Pale red solid. 32.3 mg, 85% yield. m.p. 237~239 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.22 (s, 1H), 7.62~7.60 (m, 2H), 7.52~7.49 (m, 2H), 7.39 (d, J＝8.2 Hz, 1H), 7.25~7.21 (m, 1H), 7.16 (t, J＝7.7 Hz, 1H), 7.13~7.09 (m, 1H), 4.33 (t, J＝7.4 Hz, 1H), 3.15 (s, 3H), 3.11 (d, J＝7.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.8, 176.7, 136.4, 136.1, 132.3, 130.7, 130.3, 126.0, 123.1, 123.1, 120.7, 118.3, 111.7, 108.2, 37.8, 36.0, 25.3; HRMS (ESI) calcd for C₁₉H₁₆BrN₂O₂ [M+H]⁺ 383.0390, found 383.0392.

  1-Methyl-3-(2-(4-(trifluoromethyl) phenyl)-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ja): White solid. 23.7 mg, 64% yield. m.p. 210~212 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (s, 1H), 7.70 (s, 4H), 7.36 (d, J＝8.2 Hz, 1H), 7.25~7.21 (m, 1H), 7.16 (t, J＝7.6 Hz, 1H), 7.13~7.09 (m, 1H), 4.35 (t, J＝7.6 Hz, 1H), 3.16 (s, 3H), 3.13 (d, J＝7.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.8, 176.6, 136.3, 136.0, 135.3, 129.0, 126.1, 126.1, 126.0, 126.0, 125.9, 123.4, 120.9, 118.5, 111.8, 108.9, 37.8, 36.0, 25.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.61 (s); HRMS (ESI) calcd for C₂₀H₁₆F₃N₂O₂ [M+H]⁺ 373.1158, found 373.1159.

  3-(2-(3-Fluorophenyl(-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3ka): Pale red solid. 30.9 mg, 96% yield. m.p. 106~108 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (s, 1H), 7.46~7.31 (m, 4H), 7.23~7.19 (m, 1H), 7.17~7.12 (m, 2H), 7.08 (dd, J＝0.9, 7.9 Hz, 1H), 4.38 (dd, J＝6.6, 8.2 Hz, 1H), 3.14 (s, 3H), 3.12 (t, J＝6.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.9, 176.7, 136.2 (d, J＝1.8 Hz), 136.1, 133.9 (d, J＝7.9 Hz), 130.8, 130.7, 125.9, 124.5 (d, J＝3.1 Hz), 123.1, 120.6, 118.3, 115.7 (d, J＝3.2 Hz), 115.5 (d, J＝1.5 Hz), 111.8, 108.2, 37.8, 36.1, 25.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: －111.37 (s); HRMS (ESI) calcd for C₁₉H₁₆FN₂O₂ [M+H]⁺ 323.1190, found 323.1192.

  Methyl-3-(6-methyl-2-phenyl-1H-indol-3-yl)pyrro-lidine-2, 5-dione (3la): White solid. 28.5 mg, 90% yield. m.p. 216~218 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.23 (s, 1H), 7.56~7.53 (m, 2H), 7.45~7.41 (m, 2H), 7.40~7.36 (m, 1H), 7.11 (s, 1H), 7.04~7.01 (d, J＝8.1 Hz, 1H), 6.09 (dd, J＝1.0, 8.1 Hz, 1H), 4.35 (t, J＝7.1 Hz, 1H), 3.11 (s, 3H), 3.06 (d, J＝7.6 Hz, 2H), 2.42(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.1, 176.9, 136.9, 136.5, 132.7, 132.0, 129.0, 128.7, 128.5, 123.9, 122.2, 117.8, 111.6, 107.5, 37.9, 36.2, 25.2, 21.7; HRMS (ESI) calcd for C₂₀H₁₉N₂O₂ [M+H]⁺ 319.1441, found 319.1444.

  Methyl-3-(5-methyl-2-phenyl-1H-indol-3-yl)pyrro-lidine-2, 5-dione (3ma): White solid. 26.0 mg, 82% yield. m.p. 216~218 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H), 7.60~7.58 (m, 2H), 7.49~7.42 (m, 3H), 7.26 (t, J＝8.4 Hz, 1H), 7.04~7.02 (dd, J＝1.5, 8.4 Hz, 1H), 6.90 (d, J＝0.8 Hz, 1H), 4.38 (t, J＝7.6 Hz, 1H), 3.14 (s, 3H), 3.09 (d, J＝7.6 Hz, 2H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 137.7, 134.4, 132.0, 129.8, 129.1, 128.6, 126.4, 124.4, 117.8, 111.3, 107.1, 37.9, 36.1, 25.3, 21.7; HRMS (ESI) calcd for C₂₀H₁₉N₂O₂ [M+H]⁺ 319.1441, found 319.1443.

  3-(5-Fluoro-2-phenyl-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3na): White solid. 30.1 mg, 89% yield. m.p. 108~110 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.59~7.56 (m, 2H), 7.51~7.44 (m, 3H), 7.30 (dd, J＝4.5, 8.9 Hz, 1H), 6.98~6.93 (m, 1H), 6.80 (dd, J＝2.3, 9.3 Hz, 1H), 4.36 (dd, J＝5.5, 9.6 Hz, 1H), 3.14 (s, 3H), 3.11~2.99 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.8, 176.5, 158.0 (d, J＝236.1 Hz), 139.4, 132.5, 131.5, 129.1, 128.9, 128.7, 126.4 (d, J＝9.8 Hz), 112.4 (d, J＝9.8 Hz), 111.1 (d, J＝25.8 Hz), 107.7 (d, J＝4.9 Hz), 103.5 (d, J＝24.6 Hz), 37.7, 36.0, 25.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: －122.66 (s); HRMS (ESI) calcd for C₁₉H₁₆F- N₂O₂ [M+H]⁺ 323.1190, found 323.1193.

  3-(5-Chloro-2-phenyl-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3oa): White solid. 27.7 mg, 82% yield. m.p. 122~124 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.59~7.56 (m, 2H), 7.51~7.44 (m, 3H), 7.30 (dd, J＝4.5, 8.9 Hz, 1H), 6.98~6.93 (m, 1H), 6.80 (dd, J＝2.3, 9.3 Hz, 1H), 4.36 (dd, J＝5.5, 9.6 Hz, 1H), 3.14 (s, 3H), 3.11~2.99 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.6, 176.4, 139.1, 134.3, 131.4, 129.2, 129.1, 128.8, 127.2, 126.1, 123.2, 117.6, 112.6, 107.4, 37.7, 36.1, 25.4; HRMS (ESI) calcd for C₁₉H₁₆ClN₂O₂ [M+H]⁺ 339.0895, found 339.0897.

  3-(5-Bromo-2-phenyl-1H-indol-3-yl)-1-methylpyrro-lidine-2, 5-dione (3pa): Pale red solid. 29.9 mg, 78% yield. m.p. 112~114 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.59~7.56 (m, 2H), 7.51~7.44 (m, 3H), 7.30 (dd, J＝4.5, 8.9 Hz, 1H), 6.98~6.93 (m, 1H), 6.80 (dd, J＝2.3, 9.3 Hz, 1H), 4.36 (dd, J＝5.5, 9.6 Hz, 1H), 3.14 (s, 3H), 3.11~2.99 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 178.6, 176.3, 138.9, 134.6, 131.3, 129.2, 129.1, 128.8, 127.9, 125.7, 120.7, 113.7, 113.0, 107.3, 37.7, 36.1, 25.4; HRMS (ESI) calcd for C₁₉H₁₆BrN₂O₂ [M+H]⁺ 383.0390, found 383.0390.

  1-Methyl-3-(1-methyl-2-phenyl-1H-indol-3-yl)pyrro-lidine-2, 5-dione (3qa): White solid. 29.5 mg, 94% yield. m.p. 165~168 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.52~7.48 (m, 5H), 7.36 (d, J＝8.2 Hz, 1H), 7.28~7.21 (m, 2H), 7.11 (t, J＝7.6 Hz, 1H), 4.16 (dd, J＝5.5, 9.6 Hz, 1H), 3.14 (s, 3H), 3.11~2.99 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 135.5, 133.2, 126.0, 121.6, 119.9, 117.1 (2C), 110.9 (2C), 106.8, 37.7, 36.2, 25.2, 11.6.

  1-Methyl-3-(2-methyl-1H-indol-3-yl)pyrrolidine-2, 5-dione (3ra): White solid. 7.3 mg, 52% yield. m.p. 108~110 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (s, 1H), 7.23 (d, J＝8.0 Hz, 2H), 7.12~7.08 (m, 1H), 7.07~7.00 (m, 2H), 4.18 (dd, J＝5.2, 9.6 Hz, 1H), 3.20~3.13 (m, 4H), 2.99~2.90 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 179.0, 176.9, 135.5, 133.2, 126.0, 121.6, 119.9, 117.1, 110.9, 106.8, 37.7, 36.2, 25.2, 11.6.

  Supporting Information ¹H NMR, ¹⁹F NMR and ¹³C NMR spectra of the 3aa~3ah and 3ba~3ra, and X-ray crystallographic data of 3aa. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Figure 1  Examples illustrating the importance of indolylsuccinimides

  下载: 全尺寸图片 幻灯片
  

  Figure 2  X-ray molecular structure of the product 3aa

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Control experiments

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  Figure 3  Plausible reaction mechanism

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction conditions^a

  Entry	Catalyst	Additive	Solvent	Yieldb/%
  1	AgNTf2	—	DCE	56
  2	AgNTf2	AcOH	DCE	86
  3	AgSbF6	AcOH	DCE	70
  4	AgOTf	AcOH	DCE	78
  5	AgBF4	AcOH	DCE	82
  6	Ag2CO3	AcOH	DCE	NR
  7	AgOAc	AcOH	DCE	NR
  8	AgTFA	AcOH	DCE	Trace
  9	AgNTf2	HCOOH	DCE	89
  10	AgNTf2	TFAc	DCE	73
  11	AgNTf2	MSAd	DCE	92
  12	AgNTf2	Ac2O	DCE	80
  13	AgNTf2	PivOH	DCE	93
  14e	AgNTf2	PivOH	DCE	54
  15f	AgNTf2	PivOH	DCE	61
  16	AgNTf2	PivOH	DMF	NR
  17	AgNTf2	PivOH	CH3OH	32
  18	AgNTf2	PivOH	CH3CN	NR
  19	AgNTf2	PivOH	Toluene	86
  20	AgNTf2	PivOH	CHCl3	89
  21	AgNTf2	PivOH	CCl4	96
  22g	AgNTf2	PivOH	CCl4	97
  23h	AgNTf2	PivOH	CCl4	78
  24i	AgNTf2	PivOH	CCl4	82
  25	—	PivOH	CCl4	NR
  a Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (20 mol%), and additive (1.0 equiv) at 80 ℃ for 12 h in solvent (2.0 mL) under air. b Isolated yield. c TFA: trifluoroacetic acid. d MFA: methanesulfonic acid. e PivOH (0.5 equiv). f PivOH (2.0 equiv.). g 1a (0.1 mmol), 2a (0.12 mmol), AgNTf2 (5 mol%). h At 60 ℃. i At 100 ℃.

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  Table 2.  Scope of substrates^a, ^b

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