English

• 1.   Introduction

  Flavones are popular compounds in the nature, ^[1] and many of their derivatives possess various biological activities with low toxicities^[2] including anti-oxidant, anti-cancer, anti-microbial, anti-inflammatory and anti-allergic activities, ^[3] therefore, many medicinal chemists have been trying to make new flavone derivatives in order to find some highly selective and bioactive compounds.^[4] Selenium is an essential trace element involved in different physiological functions in the human body and it is also an important element in some drug structures.^[5] Organoselenium compounds have been widely used in biochemistry, organic synthesis and material science, ^[5b] which can also be used as catalysts in some reactions.^[5c] One of the efficient ways to introduce selenium element into organic molecules is to construct C—Se bond on their skeletal structures, thus, many simple and convenient methods of constructing C—Se bonds on molecular structures directly via C—H functionalization are highly desired, ^[6] because these methods can omit tedious prefunctionalized steps and will make synthesis more efficient and more environmentally friendly.

  The construction of C—Se bond via C—H functionalization has become a recent research hot spot these days.^[7] Although C—Se is a basic bond in modern organic synthesis, the research on the construction methods of C—Se bond is much less, compared with the construction of C—S bond.^[8] Therefore, convenient methods of introducing selenium element into organic compounds via C—H functionalization are still urgently needed.^[9]

  In Scheme 1, the current synthetic methods to make ArSe-substituted flavone derivatives are all presented, illustrating that ArSeH, ArSeCl and ArSeSeAr have been employed as selenium agents.^[10] Here, we developed a convenient and new method to generate ArSe-substituted flavone derivatives directly using Se powder via C—H functionalization. All ArSe-substitutions were regioselectively added to α-position of flavone ketone functions. Compared with ArSeH, ArSeCl, and ArSeSeAr selenium reagents, using Se powder as a reactant is much easier to handle and more economical.^[11]

  Scheme 1

  

  Scheme 1.  Previously reported synthetic methods to construct ArSe-substituted flavones versus our new method

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  2.   Results and discussion

  Based on the literature and our previous research results, ^[12] Se powder is far less reactive than the other selenium agents. Its solubility in organic solvents is also quite low, so it is necessary to find out a suitable reaction condition for using Se powder to generate selenium-containing compounds. In order to find out a suitable reaction condition for constructing the C—Se bond on flavones, flavone 1a was selected as a representative reactant, and iodobenzene 2a was used as a representative aryl halide. Copper, iron, cobalt or nickel salt catalysts were employed and screened in different solvents at different temperatures. Experimental results are demonstrated in Table 1.

  Table 1

  

  Table 1.  Screening for suitable reaction conditions^a

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  Entry	Cat.	Temp./℃	Solvent	Yieldb/%
  1	CuO	140	DMF	38
  2	FeSO4•7H2O	140	DMF	0
  3	Co(OAc)2•4H2O	140	DMF	12
  4	FeCl3	140	DMF	0
  5	NiBr2	140	DMF	0
  6	CuCN	140	DMF	83
  7	CuCN	120	DMF	55
  8	CuCN	110	DMF	20
  9	CuCN	140	CH3CN	7
  10	CuCN	140	DMSO	0
  11	CuCN	140	Dioxane	0
  12	CuCN	140	DMAC	13
  13	CuCN	140	DCE	0
  14	CuCN	140	THF	17
  15	K4Fe(CN)6•3H2O	140	DMF	0
  16	CuI	140	DMF	11
  17	Cu(OAc)2	140	DMF	56
  18	Fe2(NO2)3•9H2O	140	THF	0
  a Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), iodobenzene (1.5 equiv.), Se (1.5 equiv.), Cat. (20 mol%), solvent (0.5 mL). b Isolated yield of 3a was based on the reactant flavone 1a. Reaction time: 16 h

  The screening started with CuO as catalyst in N, N- dimethylformamide (DMF) at 140 ℃, the reaction afforded 38% yield of expected product 3a (Table 1, Entry 1). Using FeSO₄•7H₂O as catalyst, 3a was not obtained at all (Entry 2). When Co(OAc)₂•4H₂O was used in DMF at 140 ℃, the reaction only gave 12% yield of 3a (Entry 3). Using FeCl₃ or NiBr₂ as catalyst in DMF at 140 ℃ 3a was not obtained (Entries 4, 5). When CuCN was used as catalyst in DMF at 140 ℃, the reaction proceeded well and afforded 83% yield of 3a (Entry 6). Decreasing temperture from 140 to 120 ℃ reduced the reaction yield to 55% (Entry 7). When the reaction temperature was dropped to 110 ℃, the reaction yield was only 20% (Entry 8). When CH₃CN was employed as solvent, 3a was generated in 7% yield at 140 ℃ (Entry 9). In DMSO or dioxane, both reactions did not give expected product 3a (Entries 10, 11). Using dimethylacetamide (DMAC) as solvent at 140 ℃ product 3a was generated in 13% yield (Entry 12). Employing dichloroethane (DCE) as solvent with CuCN as catalyst 3a was not afforded (Entry 13). When tetrahydrofuran (THF) was used as solvent, the reaction gave product 3a in 17% yield (Entry 14). Using K₄Fe(CN)₆•3H₂O as catalyst in DMF 3a was not generated (Entry 15). When CuI catalyst was used in DMF at 140 ℃, the reaction afforded 3a in 11% yield (Entry 16). Using Cu(OAc)₂ in DMF, 3a was gave in 56% yield (Entry 17). Finally using Fe₂(NO₂)₃•9H₂O as catalyst, product 3a was not afforded (Entry 18).

  Based on the above screening, the suitable reaction conditions for the generation of ArSe-substituted flavone derivatives via using selenium powder and an iodoarene (or bromoarene) are: flavone (1.0 equiv.), Se powder (1.5 equiv.), iodobenzene (or bromoarene) (1.5 equiv.), CuCN (20 mol%), and DMF as the solvent at 140 ℃ for 16 h.

  In order to further study the reaction scope, several flavone analogs with electron-donating and electron- withdrawing functions were synthesized based on the method in the literature.^[13] Then these flavones were reacted with Se powder and different aromatic iodo- benzenes (or bromoarenes) which also contained various functional groups. Under the optimized condition found above, most reactions of flavones with iodoarenes proceeded well, giving good yields of the regioselective ArSe-subsituted flavone derivatives via C—H functiona- lization. All experimental results are shown in Table 2. Isolated yields of most reactions ranged from 74% to 85%. Even ortho-iodotoluene with sterically neighboring methyl function also gave 74% or 76% yield of 3g, 3k, respec- tively. Alkyl halides were also tried for this reaction, but all reactions failed to give the expected products.

  Table 2

  

  Table 2.  Synthesis of ArSe-substituted flavone derivatives using different iodoarenes (or bromoarenes) and Se powder^a

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  a Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), iodobenzene (1.5 equiv.), Se (1.5 equiv.), Cat. (20 mol%), solvent (0.5 mL). Isolated yield of 3a was based on the reactant flavone 1a. Reaction time: 16 h.

  Bromoarenes and alkyl bromides were also tried as reactants instead of iodoarenes, but bromoarenes gave low product yields (5%~12%) of 3a, 3e and 3i, and alkyl bromides gave trace amount of products. It's clearly that iodoarenes were more reactive than bromoarenes because the C—Br bond of bromoarenes is stronger than C—I bond. The reason why alkyl bromides failed to give the product is probably that alkyl diselenide intermediate is not as easily formed as aromatic diselenide under the same reaction condition. ¹H NMR spectra confirmed that ArSe- substituents were added to the α-position of flavone ketone functions. This regioselectivity was also proved by comparing ¹H NMR spectra to those reported in literature.^[14]

  Based on experimental results and previous literature, a possible mechanism is proposed in Scheme 2.^[15] The reaction between aromatic halides Ar—X (1) (X＝I and Br) and Se powder could generate ArSeSeAr (A) intermediates via copper catalysis in DMF. Actually, ArSeSeAr (A) can be clearly seen on thin layer chromatography (TLC) analysis during the reaction and this is an important supporting evidence for our mechanism. Then ArSeSeAr could further react with CuCN to insert CuCN producing an arylcopper complex intermediate B. intermediate B further reacts with flavone 1 to give intermediate C, subsequent loss of one proton forms intermediate D followed by reductive elimination producing the final ArSe-substituted flavone derivatives product 3, in the meantime releasing CuCN for the next cycle.

  Scheme 2

  

  Scheme 2.  Proposed reaction mechanism

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  3.   Conclusions

  In summary, a new method of constructing C—Se bond on the α-position of flavone ketone function using Se powder via C—H functionalization was developed, generating ArSe-substituted flavone derivatives regioselectively in good yields. Compared with previously reported methods of using ArSeH, ArSeCl and ArSeSeAr as selenium sources, this method is more convenient. This method is probably more suitable for a large scale production. Further study to expand the scope of this methodology are still underway.

  4.   Experimental section

  4.1   Instruments and agents

  ¹H NMR and ¹³C NMR spectra were recorded on a Bruker DRX-400 spectrometer operating at 400 MHz and 100 MHz respectively. HRMS spectrometry (LC-HRMS) was recorded on a LXQ Spectrometer (Thermo Scientific) operating in the ESI-TOF mode (MeOH as a solvent). All reactions were carried out in sealed tubes, stirring was achieved with an oven-dried magnetic stirring bar. Solvents were purified by standard methods unless otherwise noted. Commercially available reagents were purchased from Aladdin Company in China and used without further purification, expect those described in detail. Flash column chromatography was performed on silica gel (200~300 mesh). All reactions were monitored by TLC analysis. Deuterated solvents were purchased from Cambridge Isotope laboratories.

  4.2   General procedure for the syntheses of compounds 3a~3l

  Flavone 1a (0.5 mmol, 1.0 equiv.), Se powder (1.5 equiv.) and iodobenzene (1.5 equiv.) were added to a dried flask with DMF (0.5 mL), followed by the addition of CuCN (0.2 equiv.). The mixture was stirred at 140 ℃. After 16 h, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash chromatography (petroleum ether/EtOAc, V:V＝100:1) on silica gel to give 3a as a colorless oil in 85% yield. The same procedure was applied to the production of other compounds 3b~3l.

  3-(Phenylselanyl)-4H-chromen-4-one (3a): 85% isolated yield (128.3 mg) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ: 8.26 (ddd, J＝7.7, 1.7, 0.7 Hz, 1H), 7.91 (s, 1H), 7.69 (ddd, J＝8.7, 7.1, 1.7 Hz, 1H), 7.65~7.59 (m, 2H), 7.44 (td, J＝8.0, 7.5, 1.0 Hz, 2H), 7.37~7.29 (m, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.16, 156.35, 155.74, 133.85, 133.81, 129.54, 128.17, 128.12, 126.36, 125.55, 123.17, 118.06, 117.87; IR (KBr) ν: 3062, 2928, 1637, 1463, 1112, 762 cm^－1; HRMS (ESI-TOF) calcd for C₁₅H₁₀- NaO₂Se (M+Na)⁺ 324.9738, found 324.9752.

  3-((4-Chlorophenyl)selanyl)-4H-chromen-4-one (3b): 83% isolated yield (139.4 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.25 (dd, J＝8.0, 1.7 Hz, 1H), 8.03 (s, 1H), 7.70 (ddd, J＝8.7, 7.1, 1.7 Hz, 1H), 7.59~7.51 (m, 2H), 7.49~7.41 (m, 2H), 7.30~7.24 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.02, 156.46, 156.36, 134.84, 134.35, 133.96, 129.64, 126.70, 126.40, 125.71, 123.28, 118.10, 117.24; IR (KBr) ν: 3039, 2926, 2360, 1635, 1461, 1077, 754 cm^－1; HRMS (ESI-TOF) calcd for C₁₅H₉ClNaO₂Se (M+Na)⁺ 358.9349, found 358.9352.

  3-((4-Methoxyphenyl)selanyl)-4H-chromen-4-one (3c): 80% isolated yield (132.8 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.24 (dd, J＝8.2, 1.7 Hz, 1H), 7.70~7.59 (m, 4H), 7.41 (dtd, J＝8.1, 3.4, 1.1 Hz, 2H), 6.92~6.85 (m, 2H), 3.82 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.28, 160.23, 156.30, 153.86, 137.11, 133.67, 126.19, 125.38, 122.90, 119.38, 118.01, 117.08, 115.37, 55.33; IR ν: 3072, 2932, 1642, 1490, 1245, 756 cm^－1; HRMS (ESI-TOF) calcd for C₁₆H₁₂NaO₃Se (M+Na)⁺ 354.9844, found 354.9868.

  3-((2-Fluorophenyl)selanyl)-4H-chromen-4-one (3d): 76% isolated yield (121.6 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.24 (dd, J＝8.0, 1.7 Hz, 1H), 8.05 (s, 1H), 7.70 (ddd, J＝8.7, 7.0, 1.7 Hz, 1H), 7.58~7.39 (m, 3H), 7.38~7.23 (m, 1H), 7.08 (dtd, J＝11.0, 8.0, 7.5, 1.3 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.08, 161.67(d, J＝243 Hz), 156.78, 156.38, 134.99 (d, J_C-F＝2.6 Hz), 133.95, 130.16 (d, J_C-F＝7.7 Hz), 126.35, 125.70, 125.09 (d, J_C-F＝3.6 Hz), 123.22, 118.12, 115.90, 115.67, 115.48 (d, J_C-F＝6.9 Hz); IR (KBr) ν: 3056, 2917, 1645, 1486 cm^－1; HRMS (ESI-TOF) calcd for C₁₅H₉FNaO₂Se (M+Na)⁺ 342.9644, found 354.9637.

  6-Methyl-3-(p-tolylselanyl)-4H-chromen-4-one (3e): 80% isolated yield (132.0 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.00 (d, J＝2.2 Hz, 1H), 7.77 (s, 1H), 7.55~7.42 (m, 3H), 7.30 (d, J＝8.6 Hz, 1H), 7.11 (d, J＝7.8 Hz, 2H), 2.44 (s, 3H), 2.33 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.32, 154.96, 154.62, 138.37, 135.50, 135.01, 134.46, 130.38, 125.52, 124.12, 122.74, 118.18, 117.78, 21.19, 20.97; IR (KBr) ν: 3059, 2918, 2362, 1645, 1483, 1312, 757 cm^－1; HRMS (ESI-TOF) calcd for C₁₇H₁₄NaO₂Se (M+Na)⁺ 353.0051, found 353.0058.

  3-((3-Chlorophenyl)selanyl)-6-methyl-4H-chromen-4-one (3f): 79% isolated yield (138.2 mg) as a colorless oil; ¹H-NMR (CDCl₃, 400 MHz) δ: 8.11 (s, 1H), 8.07~8.01 (m, 1H), 7.55~7.49 (m, 2H), 7.45 (dt, J＝7.3, 1.5 Hz, 1H), 7.38 (d, J＝8.6 Hz, 1H), 7.29~7.18 (m, 2H), 2.47 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.02, 157.27, 154.68, 135.89, 135.26, 134.95, 132.28, 130.78, 130.72, 130.35, 127.91, 125.74, 123.07, 117.88, 116.27, 20.97; IR (KBr) ν: 3042, 2936, 2359, 1633, 1479, 1314 cm^－1; HRMS (ESI-TOF) calcd for C₁₆H₁₁NaO₂Se (M+Na)⁺ 372.9505, found 372.9496.

  6-Chloro-7-methyl-3-(o-tolylselanyl)-4H-chromen-4-one (3g): 74% isolated yield (134.7 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.20 (s, 1H), 7.63 (s, 1H), 7.49 (dd, J＝7.7, 1.2 Hz, 1H), 7.35~7.23 (m, 3H), 7.12 (td, J＝7.3, 2.1 Hz, 1H), 2.51 (d, J＝1.9 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 174.17, 154.66, 154.41, 143.17, 140.72, 134.63, 132.19, 130.54, 128.69, 128.26, 127.07, 125.82, 121.95, 119.82, 117.33, 22.37, 20.82; IR (KBr) ν: 3062, 2928, 1627, 1452, 1076, 754 cm^－1; HRMS (ESI-TOF) calcd for C₁₇H₁₃ClNaO₂Se (M+Na)⁺ 386.9662, found 386.9677.

  3-((4-(tert-Butyl)phenyl)selanyl)-6-chloro-7-methyl-4H-chromen-4-one (3h): 78% isolated yield (158.3 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.19 (s, 1H), 7.77 (s, 1H), 7.57 (d, J＝8.4 Hz, 2H), 7.38~7.31 (m, 3H), 2.50 (s, 3H), 1.32 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 174.14, 154.80, 154.60, 151.76, 143.1, 134.33, 132.14, 126.76, 125.84, 123.86, 122.03, 119.79, 118.36, 34.67, 31.23, 20.83; IR (KBr) ν: 3066, 2924, 1625, 1448, 758 cm^－1; HRMS (ESI-TOF) calcd for C₂₀H₁₉ClNaO₂Se (M+Na)⁺ 429.0131, found 429.0126.

  6-Chloro-3-(p-tolylselanyl)-4H-chromen-4-one (3i): 82% isolated yield (143.5 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.20 (d, J＝2.6 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J＝2.6 Hz, 1H), 7.55 (d, J＝8.1 Hz, 2H), 7.40 (d, J＝8.9 Hz, 1H), 7.16 (d, J＝7.8 Hz, 2H), 2.37 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 174.13, 154.64, 154.52, 138.78, 134.89, 133.96, 131.36, 130.51, 125.60, 123.81, 123.42, 119.78, 118.95, 21.20; IR (KBr) ν: 3057, 1650, 1467, 1303, 1079, 825, 810 cm^－1; HRMS (ESI-TOF) calcd for C₁₆H₁₁ClNaO₂Se (M+Na)⁺ 372.9505, found 372.9496.

  3-((4-Methoxyphenyl)selanyl)-6-methyl-4H-chromen-4-one (3j): 72% isolated yield (124.6 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.07~7.96 (m, 1H), 7.71~7.55 (m, 3H), 7.46 (dd, J＝8.6, 2.2 Hz, 1H), 7.30 (d, J＝8.6 Hz, 1H), 6.96~6.82 (m, 2H), 3.81 (s, 3H), 2.45 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.34, 160.16, 154.60, 153.98, 136.98, 135.41, 134.96, 125.41, 122.60, 118.98, 117.76, 117.31, 115.32, 55.32, 20.95; IR (KBr) ν: 3057, 2920, 1644, 1485, 1025, 819 cm^－1; HRMS (ESI-TOF) calcd for C₁₇H₁₄NaO₃Se (M+Na)⁺ 369.0000, found 368.9995.

  3-(o-Tolylselanyl)-4H-benzo[h]chromen-4-one (3k): 76% isolated yield (139.1 mg) as a colorless oil; ¹H NMR (CDCl₃, 400 MHz) δ: 8.41 (dd, J＝8.2, 1.3 Hz, 1H), 8.19 (d, J＝8.8 Hz, 1H), 7.94 (dd, J＝7.8, 1.3 Hz, 1H), 7.85~7.58 (m, 5H), 7.38~7.26 (m, 2H), 7.18 (dd, J＝7.2, 2.1 Hz, 1H), 2.56 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 175.17, 153.90, 152.70, 141.23, 135.78, 135.40, 130.60, 129.43, 128.94, 128.14, 127.90, 127.24, 127.16, 125.65, 123.88, 122.19, 121.07, 119.73, 119.02, 22.50; IR (KBr) ν: 2918, 2362, 1645, 1484, 1311 cm^－1; HRMS (ESI-TOF) calcd for C₂₀H₁₄NaO₂Se (M+H)⁺ 389.0051, found 389.0041.

  3-(p-Tolylselanyl)-4H-benzo[h]chromen-4-one (3l): 79% isolated yield (144.6 mg) as a colorless oil; ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (dd, J＝8.2, 1.3 Hz, 1H), 8.18 (d, J＝8.8 Hz, 1H), 7.93 (dd, J＝7.7, 1.3 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J＝8.8 Hz, 1H), 7.75~7.57 (m, 4H), 7.19 (d, J＝7.8 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 175.05, 153.82, 152.92, 138.78, 135.76, 135.19, 130.56, 129.38, 128.13, 127.20, 125.58, 123.88, 123.33, 122.18, 121.10, 120.98, 119.07, 21.24; IR (KBr) ν: 2927, 2284, 1626, 1384, 1098, 759 cm^－1; HRMS (ESI-TOF) calcd for C₂₀H₁₄NaO₂Se (M+H)⁺ 389.0051, found 389.0041.

  Supporting Information    ¹H NMR and ¹³C NMR spectra of products. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

• 1. [1]

     (a) Espargaro, A.; Ginex, T.; Vadell, M. D.; Busquets, M. A.; Estelrich, J.; Munoz-Torrero, D.; Luque, F. J.; Sabate, R. J. Nat. Prod. 2017, 80, 278.
     (b) Tsou, L. K.; Lara-Tejero, M.; RoseFigura, J.; Zhang, Z. J.; Wang, Y. C.; Yount, J. S.; Lefebre, M.; Dossa, P. D.; Kato, J.; Guan, F.; Lam, W.; Cheng, Y. C.; Galan, J. E.; Hang, H. C. J. Am. Chem. Soc. 2016, 138, 2209.
     (c) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109, 3012.

  2. [2]

     (a) Chen, H.; Olatunji, O. J.; Zhou, Y. J. Nat. Med. 2016, 70, 610.
     (b) Zhou, Z.; Tang, M.; Liu, Y.; Zhang, Z.; Lu, R.; Lu, J. Anti-Cancer Drugs 2017, 28, 446.
     (c) Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F. Chem. Rev. 2014, 114, 4960.

  3. [3]

     (a) Kim, Y.-W.; Hackett, J. C.; Brueggemeier, R. W. J. Med. Chem. 2004, 47, 4032.
     (b) Francisco, V.; Figueirinha, A.; Costa, G.; Liberal, J.; Ferreira, I.; Lopes, M. C.; García-Rodríguez, C.; Cruz, M. T.; Batista, M. T. J. Nat. Prod. 2016, 79, 1423.
     (c) Wang, Q.; Du, X.; Zhou, B.; Li, J.; Lu, W.; Chen, Q.; Gao, J. Biomed. Pharmacother. 2017, 96, 396.
     (d) Van Acker A. A. F.; Hageman, A. J.; Haenen R. M. M. G.; Van der Vijgh J. F. W.; Bast, A.; Menge, M. P. B. W. J. Med. Chem. 2000, 43, 3752.
     (e) Lin, S.; Koh, J.-J.; Aung, T. T.; Ling, W.; Sin, W.; Lim, F.; Wang, L.; Lakshminarayanan, R.; Zhou, L.; Tan, D.; Cao, D.; Beuerman, R. W.; Ren, L.; Liu S. J. Med. Chem. 2017, 60, 6152.
     (f) Ribeiro, A.; Piló-Veloso, D.; Romanha, A. J.; Carlos, L.; Zani, C. J. Nat. Prod. 1997, 60, 836.

  4. [4]

     (a) Qiu, L.; Chen, K. Fitoterapia 2013, 84, 140.
     (b) Lu, Y.; Zhang, R.; Liu, S.; Zhao, Y.; Gao, J.; Zhu, L. Eur. J. Pharmacol. 2016, 771, 130.
     (c) Zheng, W.; Huang, Y. J. Med. Chem. Commun. 2014, 5, 297.
     (d) Xie, M.; Xu, Y.; Shen, H.; Shen, S.; Ge, Y.; Xie, J. Int. J. Pharm. 2014, 474, 223.
     (e) Zhang, X. P.; Miao, J. H.; Sun, Y. B. Chin. J. Org. Chem. 2009, 29, 1555 (in Chinese).
     (张晓鹏, 苗江欢, 孙玉标, 有机化学, 2009, 29, 1555.)
     (f) Qiu, L. P.; Chen, K. P. Fitoterapia 2013, 84, 140.
     (g) Lu, Y. P.; Zhang, R.; Liu, S. Y.; Zhao, Y.; Gao, J.; Zhu, L. Eur. J. Pharmacol. 2016, 771, 130.

  5. [5]

     (a) Shirizi, A. N.; Tiwari, R.; Oh, D.; Sullivan, S.; Kumar, A.; Beni, Y.; Parang, K. Mol. Pharmaceutics 2014, 11, 3631.
     (b) Cao, S.; Durrani, F. A.; Rustum, Y. M. Clin. Cancer Res. 2004, 10, 2561.
     (c) Madhunapantula, S. V.; Desai, D.; Sharma, A.; Huh, S. J.; Amin, S.; Robertson, G. P. Mol. Cancer. Ther. 2008, 7, 1297.
     (d) Liu, M.; Li, Y.; Yu, L.; Xu, Q.; Jiang, X. Sci. China, Chem. 2018, 61, 294.
     (e) Yu, L.; Wu, Y.; Chen, T.; Pan, Y.; Xu, Q. Org. Lett. 2013, 15, 144.
     (f) Jing, X.; Yuan, D.; Yu, L. Adv. Synth. Catal. 2017, 359, 1194.
     (g) Wang, Y.; Yu, L.; Zhu, B.; Yu, L. J. Mater. Chem. A 2016, 4, 10828.
     (h) Yu, L.; Chen, F.; Ding, Y. ChemCatChem 2016, 8, 1033.
     (i) Yu, L.; Li, H.; Zhang, X.; Ye, J.; Liu, J.; Xu, Q.; Lautens, M. Org. Lett. 2014, 16, 1346.

  6. [6]

     (a) Zhao, W. N.; Xie, P.; Bian, Z. G.; Zhou, A. H.; Ge, H.; Zhang, M.; Ding, Y.; Zheng, L. J. Org. Chem. 2015, 80, 9167.
     (b) Niu, B.; Zhao, W. N.; Ding, Y. C.; Bian, Z.; Pittman, C. U. Jr.; Zhou, A. H.; Ge, H. J. Org. Chem. 2015, 80, 7251.
     (c) Yatabe, T.; Jin, X.; Mizuno, N.; Yamaguchi, K. ACS Catal. 2018, 8, 4969.
     (d) Zhao, X.; Zhou, J.; Lin, S.; Jin, X.; Liu, R. Org. Lett. 2017, 19, 976.
     (e) Yang, Y. Q. Nat. Prod. Res. 2016, 30, 1628.

  7. [7]

     (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
     (b) Thanna, S.; Goins, C. M.; Knudson, S. E.; Slayden, R. A.; Ronning, D. R.; Sucheck, S. J. J. Org. Chem. 2017, 82, 3844.
     (c) Arisawa, M.; Fujimoto, K.; Morinaka, S.; Yamaguchi, M. J. Am. Chem. Soc. 2005, 127, 12226.
     (d) Joussot, J.; Schoenfelder, A.; Larquetoux, L.; Nicolas, M.; Suffert, J.; Blond, J. Synthesis 2016, 48, 3364.
     (e) Chen, J.; Zhou, X. J. Chin. J. Org. Chem. 1987, 7, 331 (in Chinese).
     (陈坚, 周洵钧, 有机化学, 1987, 7, 331.)
     (f) Zheng, W. P. Mini-Rev. Med. Chem. 2013, 13, 132.

  8. [8]

     (a) Zhao, W. N.; Xie, P.; Bian, Z. G.; Zhou, A. H.; Ge, H.; Niu, B.; Ding, Y. C. RSC Adv. 2015, 5, 59861.
     (b) Shi, L.-F.; Zhang, X.-G.; Zhang, X.-H. Tetrahedron 2016, 72, 8617.

  9. [9]

     (a) Alla, S. K.; Sadhu, P.; Punniyamurthy, T. J. Org. Chem. 2014, 79, 7502.
     (b) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433.
     (c) Yuan, R.; Wang, Y. J.; Huang, S. Y.; Dou, P. F.; Zhang, L. Y.; Chen, W.; Ren, X. X.; Zhou, S. L.; Wan, Y.; Wu, H. Chin. J. Org. Chem. 2018, 38, 3338 (in Chinese).
     (苑睿, 王园江, 黄树颖, 窦鹏飞, 张珑严, 陈雯, 任璇璇, 周生亮, 宛瑜, 吴翚, 有机化学, 2018, 38, 3338.)

  10. [10]

      (a) Rafique, J.; Saba, S.; Schneider, A. R.; Franco, M. S.; Silva, S. M.; Braga, A. L. ACS Omega 2017, 2, 2280.
      (b) Zhong, S.; Liu, Y.; Cao, X.; Wan, J.-P. ChemCatChem 2017, 9, 465.
      (c) Benhur, G.; Adriane, S.; Bruning, C. A.; Back, D. F.; Henrique, M., P.; Nogueira, C. W.; Zeni, G. Adv. Synth. Catal. 2011, 353, 2042.

  11. [11]

      (a) Min, L.; Wu, G.; Liu, M.; Gao, W.; Ding, J.; Chen, J.; Huang, X.; Wu, H. J. Org. Chem. 2016, 81, 7584.
      (b) Gao, C.; Wu, G.; Min, L.; Liu, M.; Gao, W.; Ding, J.; Chen, J.; Huang, X.; Wu, H. J. Org. Chem. 2017, 82, 250.

  12. [12]

      Tang, Q.; Bian, Z.; Wu, W.; Wang, J.; Xie, P.; Pittman, C. U., Jr.; Zhou, A. J. Org. Chem. 2017, 82, 10617. doi: 10.1021/acs.joc.7b01320

  13. [13]

      (a) Stubbing, L.; Li, F.; Furkert, D.; Caprio, V.; Brimble, M. Tetrahedron 2012, 68, 6948.
      (b) Yang, Y.; Qi, X.; Liu, R.; He, Q.; Yang, C. RSC Adv. 2016, 6, 103895.
      (c) Jaen, J.; Wise, L.; Heffner, T.; Pugsley, T.; Meltzer, L. J. Med. Chem. 1991, 34, 248.
      (d) He, Q.; So, C.; Bian, Z.; Hayashi, T.; Wang, J. Chem.-Asian J. 2015, 10, 540.

  14. [14]

      Ding, Y. C.; Wu, W.; Zhao, W. N.; Li, Y.; Xie, P.; Huang, Y.; Liu, Y.; Zhou, A. H. Org. Biomol. Chem. 2016, 14, 1428. doi: 10.1039/C5OB02073E

  15. [15]

      (a) Mohan, B.; Hwang, S.; Woo, H.; Park, K. H. Tetrahedron 2014, 70, 2699.
      (b) Soleiman-Beiji, M.; Yavari, I.; Sadeghizadeh, F. RSC Adv. 2015, 5, 87564.
      (c) Li, Z.; Ke, F.; Deng, H.; Xu, H.; Xiang, H.; Zhou, X. Org. Biomol. Chem. 2013, 11, 2943.
      (d) Singh, D.; Deobald, A. M.; Camargo, L. S.; Tabarelli, G.; Rodrigues, O. D.; Braga, A. Org. Lett. 2010, 12, 3288.
      (e) Guo, T. Synth. Commun. 2017, 47, 2053.

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  Scheme 1  Previously reported synthetic methods to construct ArSe-substituted flavones versus our new method

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  Scheme 2  Proposed reaction mechanism

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  Table 1.  Screening for suitable reaction conditions^a

  Entry	Cat.	Temp./℃	Solvent	Yieldb/%
  1	CuO	140	DMF	38
  2	FeSO4•7H2O	140	DMF	0
  3	Co(OAc)2•4H2O	140	DMF	12
  4	FeCl3	140	DMF	0
  5	NiBr2	140	DMF	0
  6	CuCN	140	DMF	83
  7	CuCN	120	DMF	55
  8	CuCN	110	DMF	20
  9	CuCN	140	CH3CN	7
  10	CuCN	140	DMSO	0
  11	CuCN	140	Dioxane	0
  12	CuCN	140	DMAC	13
  13	CuCN	140	DCE	0
  14	CuCN	140	THF	17
  15	K4Fe(CN)6•3H2O	140	DMF	0
  16	CuI	140	DMF	11
  17	Cu(OAc)2	140	DMF	56
  18	Fe2(NO2)3•9H2O	140	THF	0
  a Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), iodobenzene (1.5 equiv.), Se (1.5 equiv.), Cat. (20 mol%), solvent (0.5 mL). b Isolated yield of 3a was based on the reactant flavone 1a. Reaction time: 16 h

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  Table 2.  Synthesis of ArSe-substituted flavone derivatives using different iodoarenes (or bromoarenes) and Se powder^a

  a Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), iodobenzene (1.5 equiv.), Se (1.5 equiv.), Cat. (20 mol%), solvent (0.5 mL). Isolated yield of 3a was based on the reactant flavone 1a. Reaction time: 16 h.

  下载: 导出CSV
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