English

• 1.   Introduction

  Phenanthridines and their derivatives are a class of important heterocyclic compounds that occur frequently in natural products as well as synthetic molecules, exhibiting a broad spectrum of biological activities, such as antimalarial, antitumor, cytotoxicity, antimycobacterial, etc.^{[1, 2]} Besides, they have been found wide application in materials science due to their unique optoelectronic properties.^[3] Among the phenanthridine family, 6H-phenanthridines have received special attention due to their unique biological properties and pharmaceutical applications.^[2] Several representative and biologically active compounds containing 6H-phenanthridine scaffold are presented in Figure 1. To date, numerous methods have been established for the construction of 6-substituted phenanthridines^[4~8] involving the classic Pictet-Hubert condensation, ^[5] metal-catalyzed cross-coupling/cyclization, ^[6] radical-mediated cyclization of ortho-substituted biphenyls, ^{[4, 7]} and others.^[8] In contrast, efficient and convenient methods for the preparation of 6H-phenanthridines have been relatively underexplored.^[9] In addition, most of the existing methods for the synthesis of 6H-phenanthridines have one or more limitations with respect to harsh reaction conditions, ^[9a~9e] expensive catalysts, ^{[9b~9d, 9f~9h]} multisteps, ^[9i~9k] narrow scope of substrates, ^{[9i, 9k~9n]} and the starting materials being not readily available.^[9o] Therefore, it is still highly desirable to develop novel and efficient methods for the construction of 6H-phenanthridines from readily available starting materials by using inexpensive catalysts under mild conditions.

  Figure 1

  

  Figure 1.  Several biologically active compounds containing 6-H-phenanthridine scaffold

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  On the other hand, in the past decades, the nucleometallation-triggered difunctionalization of carbon-carbon multiple bonds has received great attention and became one of the most powerful tools for the construction of useful molecules including cyclic compounds.^[10] In this field, we independently disclosed that the combination of the copper powder and Selectfluor [1-(chloromethyl)-4-fluoro-1, 4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), F-TEDA-BF₄] in the presence of water enabled in situ generation of XCuOH species (X＝F or BF₄) which is very active to undergo oxycupration and successive difunctionalization of carbon-carbon multiple bonds (Scheme 1a).^[11a~11e] On the basis of the above-mentioned findings, it was further envisioned that the in situ generated XCuOH might also readily undergo oxycupration towards C＝N bond and thus induce successive difunctionalization of C＝N bond.^[11f] To the best of our knowledge, the nucleometallation-triggered difunctionalizations of C＝N bond have never been reported. Herein the facile synthesis of 6H-phenanthridines involving the copper(0)/Selectfluor system-catalyzed tandem annulation/aromatization of o-aryl benzenesulfonylimides is described by using the oxycupration of C＝N bond as a key step (Scheme 1b).

  Scheme 1

  

  Scheme 1.  Cu(0)/Selectfluor system-catalyzed difunctionalization of carbon-carbon multiple bonds and carbon-nitrogen double bond

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  2.   Results and discussion

  Initially, o-phenyl benzenesulfonamide 1a as the model substrate for the optimization of reaction conditions was selected (Table 1). When 1a was allowed to react with Cu(0) powder (10 mol%) and Selectfluor (2.0 equiv.) in newly purchased acetonitrile at 50 ℃ for 24 h, phenanthridine 2a was indeed formed in 63% yield (Entry 1, Table 1). When anhydrous MeCN was used, the reaction only gave 15% yield of 2a, suggesting that the residual water in solvent may play some role in the reaction (Entry 2, Table).^[12] The yield of 2a could be further improved to 84% by using MeCN/H₂O (V:V＝500:1) solvent system (Entry 3, Table 1). It was found that either increasing or reducing the amount of water in the solvent system had no positive effect on the yield of 2a (Entries 4, 5, Table 1). A series of other solvent systems including toluene, acetone, 1, 4-dioxane, DMF, DMSO, 1, 2-dichloroethane, and methanol were investigated for the reaction, and it was found that MeCN/H₂O (V:V＝500:1) solvent system was the best choice (Entry 6 vs 3, Table 1). The catalytic activity of several copper salts (Cu(I) and Cu(II)) on the reaction was also investigated, and their catalytic performances were proven to be much inferior to that of Cu(0) powder (Entries 7~12 vs 3, Table 1). Control experiments indicated that both Cu(0) and Selectfluor were indispensable for the reaction (Entries 13, 14, Table 1). The screening experiments of oxidants showed that Selectfluor exhibited unique effectiveness on the formation of 2a (Entries 15, 16 vs 3, Table 1). Increasing or lowering the reaction temperature only led to a reduced yield of 2a (Entries 18, 19 vs 3, Table 1). Note that the use of 2 equiv. of Selectfluor is enough for getting satisfactory yield of 2a while a deficient use of Selectfluor (1.0 equiv.) resulted in a lower yield of 2a (Entry 20 vs 3, Table 1).

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Catalyst	Oxidant	Solvent	Temp./℃	Yieldb/%
  1	Cu(0)	Selectfluor	MeCNc	50	63
  2	Cu(0)	Selectfluor	Anhydrous MeCN	50	15
  3	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	50	84 (80)d
  4	Cu(0)	Selectfluor	MeCN/H2O (V:V＝800:1)	50	82
  5	Cu(0)	Selectfluor	MeCN/H2O (V:V＝250:1)	50	72
  6	Cu(0)	Selectfluor	Solvente/H2O (V:V＝500:1)	50	0
  7	CuI	Selectfluor	MeCN/H2O (V:V＝500:1)	50	55
  8	CuCl	Selectfluor	MeCN/H2O (V:V＝500:1)	50	63
  9	CuBr	Selectfluor	MeCN/H2O (V:V＝500:1)	50	77
  10	Cu2O	Selectfluor	MeCN/H2O (V:V＝500:1)	50	72
  11	CuCl2	Selectfluor	MeCN/H2O (V:V＝500:1)	50	47
  12	Cu(OAc)2	Selectfluor	MeCN/H2O (V:V＝500:1)	50	48
  13	—	Selectfluor	MeCN/H2O (V:V＝500:1)	50	0
  14	Cu(0)	—	MeCN/H2O (V:V＝500:1)	50	0
  15	Cu(0)	NFSIf	MeCN/H2O (V:V＝500:1)	50	0
  16	Cu(0)	Other oxidantg	MeCN/H2O (V:V＝500:1)	50	0
  17	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	25	69
  18	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	80	80
  19	Cu(0)h	Selectfluor	MeCN/H2O (V:V＝500:1)	50	76
  20	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	50	46i, 82j
  a Reaction conditions: 1a (0.3 mmol), Cu(0) powder (10 mol% based on 1a), oxidant (2.0 equiv.), solvent (3.5 mL), 50 ℃ under N2 atmosphere for 24 h unless otherwise noted. b GC yield by using dodecane as an internal standard. c Newly purchased CH3CN was used without dehydration. d Isolated yield. e Tested solvents include toluene, acetone, 1, 4-dioxane, DMF, DMSO, 1, 2-dichloroethane and methanol. f NFSI: N-fluorobenzenesulfonimide. g Other tested oxidants include PhI(OAc)2, DDQ and K2S2O8. h The amount of Cu(0) is 5 mol% based on 1a. i The amount of Selectfluor is 1.0 equiv. j The amount of Selectfluor is 3.0 equiv.

  With the optimized reaction conditions, we then set out to investigate the reaction scope (Table 2). Firstly, the effect of functional groups in the aryl ring A (R¹) on the reaction was studied. As shown in Table 2, both electron-donating and electron-withdrawing substituents in the aryl ring A of 1 were compatible with the reaction conditions, among which alkyl, halo (F, Cl, Br), and trifluoromethoxy groups were included. It seemed that the electronic nature of R¹ had no obvious effect on the reaction outcome in terms of the yield. In most cases, the reaction could give moderate to good yields of desired products (60%~80%, 2a~2j, Table 2). Substrate 1j bearing a meta-chloro group in ring A provided a single product (2j, 66%) with exclusive regio-selectivity at the more steric hindrance position which was in accordance with previous report.^[8h] Next, the effect of substituents (R²) in aryl ring B of 1 on the reaction was further investigated. A range of substrates bearing electron-rich or electron-deficient substituents in ring B were workable for the reaction (1k~1u, Table 2). Similarly, the electronic properties of R² had no obvious effect on the reaction performance and the yield of products (2k~2u, Table 2). Unfortunately, 2-phenylnico- tinaldehyde derived sulfonylimide 1w failed to give the desired product while the starting material was almost recovered (2w, Table 2).

  Table 2

  

  Table 2.  Synthesis of 2 via Cu(0)/Selecfluor system-catalyzed annulation/aromatization of o-aryl benzenesulfonylimides 1^{a, b}

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  To gain insight into the mechanism of the Cu(0)/Select- fluor system-catalyzed annulation/aromatization of o-aryl benzenesulfonylimides, several mechanistic experiments were made (Scheme 2). Firstly, the measurement of the intermolecular KIE between 1a and 1a-d₅ on the basis of the competitive dehydrogenative cross-coupling was carried out. The intermolecular k_H/k_D of 1a to 1a-d₅ was determined to be 1.85, indicating that the cleavage of the C—H bond might be involved in the rate-determining step (Scheme 2). When 1a was allowed to react under the standard reaction conditions except using the preparative HOCuX (X＝F or BF₄)^{[11a, 11f]} as a catalyst, the reaction could also proceed smoothly and afford 2a in 80% yield (Scheme 2). This result suggests that HOCuX (X＝F or BF₄) might play a key role in the catalytic cycle.

  Scheme 2

  

  Scheme 2.  Preliminary mechanistic studies

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  Based on the above experiments and previous literature, ^{[11, 13, 14]} a possible mechanism for the Cu(0)/Selectfluor system-catalyzed annulation/aromatization of 1a is proposed in Scheme 3. First, the redox reaction between Cu(0) and Selectfluor may produce a copper species FCuBF₄ (5) and release base 6.^[11a] With the aid of 6, 5 may be transferred into copper species XCuOH (X＝F or BF₄, 7) in the presence of water.^[11] Then, an oxycupration of 7 to the C—N double bond in 1a followed by dehydrogenative cross-coupling^{[11e, 13]} would deliver intermediate 10. Finally, 10 might undergo Julia-type olefination^[14] to give the aromatization product 2a.

  Scheme 3

  

  Scheme 3.  Proposed mechanism for the annulation/aromatize- tion of 1a

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  3.   Conclusions

  In summary, a facile and efficient method for the preparation of 6H-phenanthridines involving Cu(0)/Select-fluor system-catalyzed tandem oxycupration/C—H amination/ aromatization of o-aryl benzenesul-fonylimides was described. The present protocol for the synthesis of 6H-phe- nanthridines has several advantages including mild reaction conditions (50 ℃), the use of inexpensive copper catalyst, and easy availability of the starting materials.

  4.   Experimental section

  4.1   General experimental information

  Unless otherwise stated, all reagents were purchased from commercial suppliers and used without purifications. Melting points are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker ADVANCE III at 25 ℃ in CDCl₃ at 500 (or 600) MHz and 125 (or 150) MHz, respectively. GC-MS experiments were performed with an Agilent 6890N GC system equipped with a 5973N mass-selective detector. High resolution mass spectra (HRMS) were obtained on a water GCT premier TOF MS with EI or ESI source. CH₃CN is dehydrated by CaH₂ before preparation of the combined solvent CH₃CN/H₂O (V:V＝500:1).

  4.2   General procedure for the synthesis of starting material 1

  All o-aryl benzenesulfonylimides (1) were synthesized from the corresponding o-aryl benzaldehydes and benzenesulfonamide according to the literature procedure.^[15] The o-aryl benzaldehydes were synthesized by the standard Suzuki-Miyaura cross-coupling reaction between an ortho-bromobenzaldehyde derivative and an arylboronic acid.^[16]

  4.3   General procedure for the synthesis of 2

  1 (0.3 mmol), Cu(0) powder (1.92 mg, 10 mol%), Selectfluor (212.6 mg, 0.6 mmol, 2 equiv.), and CH₃CN/H₂O (V:V＝500:1) (3.5 mL) were added to a 15 mL flask. Then the reaction mixture was stirred at 50 ℃ for 24 h under N₂ atmosphere. Upon completion, the resulting mixture was diluted with CH₂Cl₂ (10 mL) and filtered through Celite. After evaporation of the solvent under vacuum, the residue was purified by column chromatography on silica gel (100~200 mesh) using petroleum ether-EtOAc (V:V＝10:1) as eluent to give pure 2.

  Phenanthridine (2a): White solid (43.0 mg, 80%), m.p. 109~111 ℃ (lit.^[17] 107~108 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.27 (s, 1H), 8.53 (t, J＝8.5 Hz, 2H), 8.21 (d, J＝8.5 Hz, 1H), 8.00 (d, J＝7.5 Hz, 1H), 7.82~7.79 (m, 1H), 7.75~7.72 (m, 1H), 7.67~7.64 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 153.4, 144.4, 132.4, 130.9, 130.0, 128.61, 128.57, 127.4, 127.0, 126.3, 124.0, 122.1, 121.7.

  3-Methylphenanthridine (2b): Yellow solid (34.8 mg, 60%), m.p. 80~81 ℃ (lit.^[18] 78~79 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.27 (s, 1H), 8.56 (d, J＝8.0 Hz, 1H), 8.46 (d, J＝8.5 Hz, 1H), 8.03 (d, J＝8.0 Hz, 1H), 8.00 (s, 1H), 7.86~7.82 (m, 1H), 7.69~7.66 (m, 1H), 7.52 (dd, J＝8.5, 1.5 Hz, 1H), 2.61 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 153.5, 144.5, 138.9, 132.6, 131.0, 130.7, 129.6, 128.8, 128.7, 127.0, 126.1, 122.0, 121.7, 21.5.

  3-Isopropylphenanthridine (2c): Yellow liquid (42.5 mg, 64%); ¹H NMR (CDCl₃, 500 MHz) δ: 9.27 (s, 1H), 8.55 (d, J＝8.5Hz, 1H), 8.48 (d, J＝8.5 Hz, 1H), 8.07 (d, J＝1.5Hz, 1H), 8.01 (d, J＝8.0 Hz, 1H), 7.83~7.80 (m, 1H), 7.66 (t, J＝7.5 Hz, 1H), 7.58 (dd, J＝8.0, 1.5 Hz, 1H), 3.22~3.14 (m, 1H), 1.41 (d, J＝6.5 Hz, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ: 153.4, 149.7, 144.7, 132.6, 130.9, 128.7, 127.0, 126.9, 126.5, 126.1, 122.1, 121.7, 34.1, 23.9; HRMS (EI) calcd for C₁₆H₁₅N 221.1204, found 221.1199.

  3-(tert-Butyl)phenanthridine (2d): Yellow liquid (45.2 mg, 64%); ¹H NMR (CDCl₃, 500 MHz) δ: 9.27 (s, 1H), 8.55 (d, J＝8.5 Hz, 1H), 8.48 (d, J＝8.5 Hz, 1H), 8.22 (d, J＝2.0 Hz, 1H), 8.00 (d, J＝8.0 Hz, 1H), 7.83~7.80 (m, 1H), 7.76 (d, J＝8.5, 2.0 Hz, 1H), 7.67~7.64 (m, 1H), 1.49 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ: 153.3, 152.0, 144.4, 132.4, 130.8, 128.6, 127.7, 126.9, 126.1, 126.0, 125.3, 121.8, 121.6, 34.9, 31.3; HRMS (EI) calcd for C₁₇H₁₇N 235.1361, found 235.1367.

  3-Phenylphenanthridine (2e): White solid (57.4 mg, 75%); m.p. 151~153 ℃; ¹H NMR(CDCl₃, 500 MHz) δ: 9.33 (s, 1H), 8.63 (dd, J＝8.5, 4.5 Hz, 2H), 8.46 (d, J＝1.5 Hz, 1H), 8.07 (d, J＝7.5 Hz, 1H), 7.96 (dd, J＝8.5, 1.5 Hz, 1H), 7.90~9.87 (m, 1H), 7.82 (d, J＝7.5 Hz, 2H), 7.73 (t, J＝7.5Hz, 1H), 7.54 (t, J＝7.5 Hz, 2H), 7.44 (t, J＝7.0 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 154.0, 144.9, 141.4, 140.2, 132.4, 131.1, 129.0, 128.8, 128.0, 127.8, 127.5, 127.4, 126.4, 126.2, 123.1, 122.8, 121.9; HRMS (EI) calcd or C₁₉H₁₃N 255.1048, found 255.1043.

  3-Fluorophenanthridine (2f): White solid (37.3 mg, 63%); m.p. 109~111 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.28 (s, 1H), 8.54~8.50 (m, 2H), 8.04 (d, J＝8.0 Hz, 1H), 7.87~7.83 (m, 2H), 7.72~7.68 (m, 1H), 7.45~7.41 (m, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 162.6 (d, J＝247.5 Hz), 154.7, 145, 7 (d, J＝11.3 Hz), 132.3, 131.4, 128.9, 127.3, 125.9, 124.1 (d, J＝8.8 Hz), 121.6, 120.8, 116.1, (d, J＝23.8 Hz), 114.6 (d, J＝21.3 Hz); HRMS (EI) calcd for C₁₃H₈FN 197.0641, found 197.0645.

  3-Chlorophenanthridine (2g): White solid (39.7 mg, 62%); m.p. 106.8~108.2 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.21 (s, 1H), 8.43 (d, J＝8.5 Hz, 1H), 8.37 (d, J＝9.0 Hz, 1H), 8.12 (d, J＝1.5 Hz, 1H), 7.98 (d, J＝7.5 Hz, 1H), 7.82 (t, J＝7.0 Hz, 1H), 7.68 (t, J＝7.5 Hz, 1H), 7.56 (dd, J＝9.0, 2.0 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 154.5, 144.9, 134.2, 131.9, 131.3, 129.2, 128.8, 127.7, 127.5, 126.1, 123.4, 122.4, 121.6; HRMS (EI) calcd for C₁₃H₈ClN 213.0345, found 213.0340.

  3-Bromophenanthridine (2h): White solid (49.6 mg, 64%); m.p. 129~131 ℃ (lit.^[19] 110~112 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.27 (s, 1H), 8.54 (d, J＝8.0 Hz, 1H), 8.40 (d, J＝8.5 Hz, 1H), 8.34 (d, J＝2.0 Hz, 1H), 8.05 (d, J＝8.0 Hz, 1H), 7.89~7.86 (m, 1H), 7.77~7.72 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 154.6, 145.4, 132.6, 132.1, 131.4, 130.3, 128.9, 127.9, 126.3, 123.7, 122.9, 122.4, 121.7.

  3-(Trifluoromethoxy)phenanthridine (2i): White solid (50.5 mg, 64%); m.p. 87~89 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.25 (s, 1H), 8.60 (dd, J＝12.0, 9.0 Hz, 2H), 8.10 (d, J＝8.0 Hz, 1H), 8.06 (s, 1H), 7.94~7.90 (m, 1H), 7.79~7.75 (m, 1H), 7.57 (m, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 155.0, 149.2, 145.3, 132.1, 131.6, 129.0 128.0, 126.4, 124.1, 122.7, 121.9, 120.9, 120.7 (q, J＝256.7 Hz), 120.4; HRMS (EI) calcd for C₁₄H₈F₃NO 263.0558, found 263.0554.

  4-Chlorophenanthridine (2j): White solid (42.3 mg, 66%); m.p. 100~102 ℃ (lit.^[20] 98~102 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.25 (s, 1H), 8.50 (dd, J＝5.5, 3.0 Hz, 2H), 8.11 (d, J＝8.5 Hz, 1H), 8.05 (d, J＝8.0 Hz, 1H), 7.89~7.86 (m, 1H), 7.75 (t, J＝7.5 Hz, 1H), 7.68 (dd, J＝9.0, 2.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 153.8, 142.9, 133.1, 131.62, 131.56, 131.3, 129.2, 128.9, 128.2, 126.5, 125.2, 121.93, 121.90.

  9-Methylphenanthridine (2k): Yellow solid (38.3 mg, 66%); m.p. 85~86 ℃ (lit.^[21] 82~84 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.21 (s, 1H), 8.53 (d, J＝8.5 Hz, 1H), 8.34 (s, 1H), 8.18 (dd, J＝8.0, 0.5 Hz, 1H), 7.90 (d, J＝8.0 Hz, 1H), 7.74~7.71 (m, 1H), 7.67~7.63 (m, 1H), 7.49 (dd, J＝8.0, 0.5 Hz, 1H), 2.63 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 153.2, 144.5, 141.4, 132.6, 133.0, 129.2, 128.52, 128.46, 126.8, 124.5, 124.0, 122.1, 121.4, 22.4.

  9-Chlorophenanthridine (2l): White solid (45.5 mg, 71%); m.p. 113~115 ℃ (lit.^[22] 118.5 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.16 (s, 1H), 8.43 (s, 1H), 8.36 (d, J＝8.0 Hz, 1H), 8.15 (d, J＝8.0 Hz, 1H), 7.88 (d, J＝8.5 Hz, 1H), 7.74 (t, J＝7.5 Hz, 1H), 7.64 (t, J＝7.5 Hz, 1H), 7.57 (dd, J＝8.5, 1.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.5, 144.5, 137.3, 133.5, 130.1, 130.0, 129.3, 128.0, 127.3, 124.4, 122.8, 122.1, 121.5.

  9-Fluoro-3-isopropylphenanthridine (2m): White solid (46.7 mg, 65%); m.p. 57~59 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.20 (s, 1H), 8.33 (d, J＝8.0 Hz, 1H), 8.11 (dd, J＝10.0, 2.0 Hz, 1H), 8.04 (d, J＝2.0 Hz, 1H), 8.00 (dd, J＝9.0, 5.5 Hz, 1H), 7.57 (dd, J＝8.5, 2.0 Hz, 1H), 7.39~7.35 (m, 1H), 3.21~3.13 (m, 1H), 1.40 (d, J＝7.0 Hz, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ: 164.1 (d, J＝250.0 Hz), 152.5, 150.6, 144.7, 134.8 (d, J＝10.0 Hz), 131.4 (d, J＝10.0 Hz), 127.0, 126.6, 123.1, 122.3, 121.6, 116.3 (d, J＝25.0 Hz), 106.9 (d, J＝21.3 Hz), 34.1, 23.9; HRMS (EI) calcd for C₁₆H₁₄FN 239.1110, found 239.1115.

  9-Chloro-3-isopropylphenanthridine (2n): White solid (46.8 mg, 61%); m.p. 169~171 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.16 (s, 1H), 8.43 (s, 1H), 8.36 (d, J＝8.0 Hz, 1H), 8.15 (d, J＝8.0 Hz, 1H), 7.88 (d, J＝8.5 Hz, 1H), 7.74 (t, J＝7.5 Hz, 1H), 7.64 (t, J＝7.5 Hz, 1H), 7.57 (dd, J＝8.5, 1.5 Hz, 1H), 3.23~3.14 (m, 1H), 1.40 (d, J＝7.0 Hz, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.5, 144.5, 137.3, 133.5, 130.1, 130.0, 129.3, 128.0, 127.3, 124.4, 122.8, 122.1, 121.5, 34.1, 23.9; HRMS (EI) calcd for C₁₆H₁₄ClN 255.0815, found 255.0811.

  8-Chlorophenanthridine (2o): White solid (40.4 mg, 63%); m.p. 99~101 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.11 (s, 1H), 8.38 (dd, J＝7.5, 5.0 Hz, 2H), 8.15 (d, J＝8.0 Hz, 1H), 7.90 (d, J＝2.0 Hz, 1H), 7.74~7.71 (m, 1H), 7.68 (dd, J＝9.0, 2.5 Hz, 1H), 7.65~7.61 (m, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.1, 144.2, 133.2, 131.3, 130.6, 130.2, 128.9, 127.5, 127.4, 127.0, 123.5, 123.4, 121.9; HRMS (EI) calcd for C₁₃H₈ClN 213.0345, found 213.0342.

  8-Chloro-3-isopropylphenanthridine (2p): White solid (46.0 mg, 60%); m.p. 49~51 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.21 (s, 1H), 8.50 (d, J＝1.5 Hz, 1H), 8.38 (d, J＝8.5 Hz, 1H), 8.04 (d, J＝1.5 Hz, 1H), 7.94 (d, J＝8.5 Hz, 1H), 7.61~7.58 (m, 2H), 3.23~3.14 (m, 1H), 1.40 (d, J＝7.0 Hz, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.6, 150.6, 144.9, 132.8, 131.5, 131.0, 127.7, 127.1, 127.03, 126.94, 123.6, 122.0, 121.6, 34.1, 23.9; HRMS (EI) calcd for C₁₆H₁₄ClN 255.0815, found 255.0812.

  N-8-Chloro-3-fluorophenanthridine (2q): White solid (47.3 mg, 68%); m.p. 144~146 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.14 (s, 1H), 8.41 (dd, J＝9.0, 6.0 Hz, 1H), 8.36 (d, J＝8.5 Hz, 1H), 7.94 (d, J＝2.0 Hz, 1H), 7.80 (dd, J＝9.5, 2.5 Hz, 1H), 7.74 (dd, J＝8.5, 2.0 Hz, 2H), 7.43~7.40 (m, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 162.7 (d, J＝247.5 Hz), 153.3, 145.6 (d, J＝12.5 Hz), 133.1, 131.9, 130.5, 127.7, 126.6, 123.9 (d, J＝10.0 Hz), 123.4, 120.2, 116.6 (d, J＝23.8 Hz), 114.8 (d, J＝21.3 Hz); HRMS (EI) calcd for C₁₃H₇ClFN 231.0251, found 231.0255.

  3-Chloro-8-fluorophenanthridine (2r): White solid (44.5 mg, 64%); m.p. 165~167 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.15 (s, 1H), 8.44 (dd, J＝9.0, 5.0 Hz, 1H), 8.31 (d, J＝9.0 Hz, 1H), 8.10 (d, J＝2.5 Hz, 1H), 7.61 (dd, J＝8.0, 2.5 Hz, 1H), 7.58~7.55 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 161.5 (d, J＝248.8 Hz), 153.4 (d, J＝1.3 Hz), 144.6, 134.1, 129.4, 128.6 (d, J＝1.3 Hz), 127.9, 127.3 (d, J＝8.8 Hz), 124.4 (d, J＝8.8 Hz), 123.2, 122.1, 120.6 112.8 (d, J＝21.3 Hz); HRMS (EI) calcd for C₁₃H₇ClFN 231.0251, found 231.0254.

  8-Bromophenanthridine (2s): White solid (41.0 mg, 53%); m.p. 96~98 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.19 (s, 1H), 8.51 (dd, J＝8.0, 1.0 Hz, 1H), 8.44 (d, J＝8.5 Hz, 1H), 8.19 (dd, J＝8.0, 1.0 Hz, 1H), 8.17 (d, J＝2.0 Hz, 1H), 7.91 (dd, J＝8.5, 2.0 Hz, 1H), 7.80~7.76 (m, 1H), 7.71~7.68 (m, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.1, 144.3, 134.1, 131.1, 130.9, 130.3, 129.1, 127.52, 127.48, 123.8, 123.5, 122.0, 121.3; HRMS (EI) calcd for C₁₃H₈BrN 256.9840, found 256.9847.

  8-Methylphenanthridine (2t): Yellow solid (35.9 mg, 62%), m.p. 80~82 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 9.23 (s, 1H), 8.55 (d, J＝8.4Hz, 1H), 8.51 (d, J＝8.4Hz, 1H), 8.19~8.17 (m, 1H), 7.83 (s, 1H), 7.73~7.65 (m, 3H), 2.61 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 153.3, 144.3, 137.5, 132.8, 130.5, 130.1, 128.19, 128.15, 127.0, 126.6, 124.2, 122.0, 121.8, 21.5; HRMS (EI) calcd for C₁₄H₁₁N 193.0891, found 193.0896.

  7-Fluorophenanthridine (2u): White solid (33.1 mg, 56%); m.p. 114~116 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 9.49 (s, 1H), 8.37 (d, J＝8.5 Hz, 1H), 8.19~8.14 (m, 2H), 7.72~7.59 (m, 3H), 7.23 (t, J＝8.0 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 159.9 (d, J＝247.5 Hz), 146.0 (d, J＝6.3 Hz), 144.3, 134.0 (d, J＝2.5 Hz), 131.2 (d, J＝8.8 Hz), 130.2, 128.1, 127.3, 122.9, 122.3, 117.5 (d, J＝3.8 Hz), 115.8 (d, J＝13.8 Hz), 111.9 (d, J＝18.8 Hz); HRMS (EI) calcd for C₁₃H₈FN 197.0641, found 197.0644.

  Benzo[c]phenanthridine (2v)^[23]: White solid (33.0 mg, 48%); m.p. 141~143 ℃ (lit.^[23] 136 ℃); ¹H NMR (CDCl₃, 500 MHz) δ: 9.50 (s, 1H), 9.43 (d, J＝8.5 Hz, 1H), 8.68 (d, J＝8.5 Hz, 1H), 8.56 (d, J＝9.0 Hz, 1H), 8.16 (d, J＝8.0 Hz, 1H), 8.05 (d, J＝9.0 Hz, 1H), 8.01 (d, J＝8.0 Hz, 1H), 7.92~7.88 (m, 1H), 7.82~7.78 (m, 1H), 7.76~7.70 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.0, 141.5, 133.3, 132.9, 132.1, 130.8, 128.7, 127.9, 127.7, 127.4, 127.1, 127.0, 126.9, 124.8, 122.2, 121.1, 119.9; HRMS (EI) calcd for C₁₇H₁₁N 229.0891, found 229.0896.

  4.4   Intermolecular kinetic isotope effects (KIE) based on substrate 1a and 1a-d₅

  1a (64.3 mg, 0.2 mmol), 1a-d₅ (65.3 mg, 0.2 mmol), Cu(0) powder (2.56 mg, 10 mol%), Selectfluor (283.5 mg, 0.8 mmol, 2 equiv.), and CH₃CN/H₂O (V:V＝500:1, 4.5 mL) were added to a 15 mL flask. Then the reaction mixture was stirred at 50 ℃ for 12 h. Upon completion, the resulting mixture was diluted with CH₂Cl₂ (10 mL) and filtered through Celite. After evaporation of the solvent under vacuum, the residue was purified by column chromatography on silica gel (100~200 mesh) using petroleum ether-EtOAc (V:V＝10:1) as eluent to give pure products. On the basis of ¹H NMR spectra analysis, the intermolecular competitive KIE was calculated as k_H/k_D≈1.85.

  4.5   Reaction of 1a in the standard reaction conditions except using the preparative HOCuX as the catalysis

  1a (0.3 mmol), HOCuX (X＝F or BF₄, 10 mol%, prepared according to our previous work^[11a]), Selectfluor (212.6 mg, 0.6 mmol, 2 equiv.), and CH₃CN/H₂O (V:V＝500:1) solvent (3.5 mL) were added to a 15 mL flask. Then the reaction mixture was stirred at 50 ℃ for 24 h. Upon completion, the resulting mixture was diluted with CH₂Cl₂ (10 mL) and filtered through Celite. After evaporation of the solvent under vacuum, the residue was purified by column chromatography on silica gel (100~200 mesh) using petroleum ether-EtOAc (V:V＝10:1) as eluent to give pure 2a (43.0 mg, 80%).

  Supporting Information ¹H NMR, ¹³C NMR and HRMS of the products 2a~2w. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

  
  
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• 

  Figure 1  Several biologically active compounds containing 6-H-phenanthridine scaffold

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  Scheme 1  Cu(0)/Selectfluor system-catalyzed difunctionalization of carbon-carbon multiple bonds and carbon-nitrogen double bond

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  Scheme 2  Preliminary mechanistic studies

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  Scheme 3  Proposed mechanism for the annulation/aromatize- tion of 1a

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  Table 1.  Optimization of the reaction conditions^a

  Entry	Catalyst	Oxidant	Solvent	Temp./℃	Yieldb/%
  1	Cu(0)	Selectfluor	MeCNc	50	63
  2	Cu(0)	Selectfluor	Anhydrous MeCN	50	15
  3	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	50	84 (80)d
  4	Cu(0)	Selectfluor	MeCN/H2O (V:V＝800:1)	50	82
  5	Cu(0)	Selectfluor	MeCN/H2O (V:V＝250:1)	50	72
  6	Cu(0)	Selectfluor	Solvente/H2O (V:V＝500:1)	50	0
  7	CuI	Selectfluor	MeCN/H2O (V:V＝500:1)	50	55
  8	CuCl	Selectfluor	MeCN/H2O (V:V＝500:1)	50	63
  9	CuBr	Selectfluor	MeCN/H2O (V:V＝500:1)	50	77
  10	Cu2O	Selectfluor	MeCN/H2O (V:V＝500:1)	50	72
  11	CuCl2	Selectfluor	MeCN/H2O (V:V＝500:1)	50	47
  12	Cu(OAc)2	Selectfluor	MeCN/H2O (V:V＝500:1)	50	48
  13	—	Selectfluor	MeCN/H2O (V:V＝500:1)	50	0
  14	Cu(0)	—	MeCN/H2O (V:V＝500:1)	50	0
  15	Cu(0)	NFSIf	MeCN/H2O (V:V＝500:1)	50	0
  16	Cu(0)	Other oxidantg	MeCN/H2O (V:V＝500:1)	50	0
  17	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	25	69
  18	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	80	80
  19	Cu(0)h	Selectfluor	MeCN/H2O (V:V＝500:1)	50	76
  20	Cu(0)	Selectfluor	MeCN/H2O (V:V＝500:1)	50	46i, 82j
  a Reaction conditions: 1a (0.3 mmol), Cu(0) powder (10 mol% based on 1a), oxidant (2.0 equiv.), solvent (3.5 mL), 50 ℃ under N2 atmosphere for 24 h unless otherwise noted. b GC yield by using dodecane as an internal standard. c Newly purchased CH3CN was used without dehydration. d Isolated yield. e Tested solvents include toluene, acetone, 1, 4-dioxane, DMF, DMSO, 1, 2-dichloroethane and methanol. f NFSI: N-fluorobenzenesulfonimide. g Other tested oxidants include PhI(OAc)2, DDQ and K2S2O8. h The amount of Cu(0) is 5 mol% based on 1a. i The amount of Selectfluor is 1.0 equiv. j The amount of Selectfluor is 3.0 equiv.

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  Table 2.  Synthesis of 2 via Cu(0)/Selecfluor system-catalyzed annulation/aromatization of o-aryl benzenesulfonylimides 1^{a, b}

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•