Silver-Catalyzed C—H Alkylation of 2-Arylindoles with Maleimides

Chao Pi Yaping Qu Xiuling Cui Yangjie Wu

Citation:  Pi Chao, Qu Yaping, Cui Xiuling, Wu Yangjie. Silver-Catalyzed C—H Alkylation of 2-Arylindoles with Maleimides[J]. Chinese Journal of Organic Chemistry, 2020, 40(3): 740-747. doi: 10.6023/cjoc201907040 shu

银催化2-芳基吲哚与马来酰亚胺C—H键烷基化反应

    通讯作者: 崔秀灵, cuixl@zzu.edu.cn
    吴养洁, wyj@zzu.edu.cn
  • 基金项目:

    科技部国际合作重点专项 2016YFE0132600

    科技部国际合作重点专项(No.2016YFE0132600)资助项目

摘要: 发展了一种银催化高效高区域选择性的2-芳基吲哚C-3位烷基化反应.在温和条件下,能以高达97%的收率得到目标化合物,且该方法操作简单,不需要外加氧化剂.

English

  • 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

    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.

    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

    Table 1

    Table 1.  Optimization of the reaction conditionsa
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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 substratesa, 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

    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

    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.

    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.

    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, J1.7, 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, J0.9 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, J7.6 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

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

    Scheme 1  Control experiments

    Figure 3  Plausible reaction mechanism

    Table 1.  Optimization of the reaction conditionsa

    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 substratesa, b

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  • 发布日期:  2020-03-01
  • 收稿日期:  2019-07-26
  • 修回日期:  2019-10-23
  • 网络出版日期:  2019-11-01
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