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• It is well documented that quinolines are very important N-heterocyclic compounds which are frequently found in biologically active natural products and pharmaceuticals.^[1] Among the numerous quinoline derivatives, the halogenated quinolines are a class of important one which often act as intermediates in the synthesis of substituted quinolines.^[2] Moreover, many halogenated quinolines such as clioquinol and chloroquine are frequently used as antibiotic and antimalaria agents in clinical application (Figure 1).^[3] Therefore, further development of more simple method for the synthesis of halogenated quinolines remains highly appealing.

  图1 Representative drugs containing the halogenated quinolines Figure1. Representative drugs containing the halogenated quinolines

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  Although many methods have been reported for the synthesis of halogenated quinolines, they are often confined to the functionalization of quinoline scaffolds mainly at the C(2), C(3), C(4), and C(8) positions.^{[4, 5]} Reports involving halogenation of quinolines at the C(5) and C(7) position are quite rare.^[6] Recently, following the developments of transition metal catalyzed C—H activation stratregies, some examples on C(5) functionalized quinolines have been achieved.^[7] However, to the best of our knowledge, only two published examples on the simultaneous C(5) and C(7)-dihalogenation of quinoline are known. In 2015, Xie and coworkers^[6a] have developed an efficient method of Pd-catalyzed synthesis of 5, 7-dichlo-rinated quinolines utilizing quinoline C—H haogenation. More recently, Zhang et al.^[6b] have developed an alternative version of such type to access 5, 7-dibrominated quinolines by means of copper catalysis (Scheme 1). While drawbacks such as narrow substrate scope, noble metal catalyst, employment of stoichiometric oxidant etc. remain with the known synthetic methods, developing complementary catalytic method to run this di-halogenation process is still highly desirable.

  图Scheme 1 Recent methods for the synthesis of C(5) and C(7) di-halogenated quinolones Scheme1. Recent methods for the synthesis of C(5) and C(7) di-halogenated quinolones

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  As a class of important first-row transition metal catalyst, nickel salts were frequently and widely employed in organic synthesis to construct various bioactive compounds due to its particular electronic properties, low cost and low toxicity. Indeed, nickel catalysts have been applied in many types of catalytic transformations such as coupling reactions, ^[8] carbonylation reactions^[9] and heterocycle synthesis.^[10] However, there have been few reports of C—H bond halogenation utilizing a nickel catalyst.^[11] As our continuous interests in the development of nickel catalyzed synthesis and 8-aminoquinoline assisted C—H functionalization for the synthesis biologically relevant small molecules, ^[12] we report herein a C—H halogenation reaction of 8-aminoquinolines that gave the 5, 7-dihalo-generated products with cheap and easily available NiBr₂ catalyst.

  1   Results and discussion

  We began our studies by using amide (1a) and N-bromo-succinimide as the model substrates to optimize the reaction conditions, and the results are summarized in Table 1. When the reaction was carried out in the presence of NiCl₂ (20 mol%) in MeCN at 120 ℃ under O₂ overnight, the di-brominated amide (3a) was successfully isolated in 55% yield (Table 1, Entry 1). The structure of 3a was further confirmed by X-ray diffraction analysis (see the Supporting Information).

  Table 1.  Screening of reaction conditions for dibromination of quinolines^a

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  Entry	Catalyst	Oxidant	Base	Solvent	Yield/% of 3a/2a
  1	NiCl2	O2	—	MeCN	55/30
  2	NiBr2	O2	—	MeCN	87/—
  3	Ni(acac)2	O2	—	MeCN	60/20
  4	Ni(NO3)2	O2	—	MeCN	57/33
  5	—	O2	—	MeCN	—/85
  6	NiBr2	BQ	—	MeCN	55/27
  7	NiBr2	TBHP	—	MeCN	65/25
  8	NiBr2	Ag2O	—	MeCN	60/30
  9	NiBr2	O2	Cs2CO3	MeCN	30/54
  10	NiBr2	O2	Na2CO3	MeCN	28/60
  11	NiBr2	O2	NaHCO3	MeCN	33/59
  12	NiBr2	O2	—	Toluene	55/35
  13	NiBr2	O2	—	PET	—/25
  14	NiBr2	O2	—	DCM	—/82
  15	NiBr2	O2	—	DCE	15/45
  16 b	NiBr2	O2	—	MeCN	84/15
  17 c	NiBr2	O2	—	MeCN	87/12
  18 d	NiBr2	O2	—	MeCN	85/14
  a Reaction conditions: 1a (0.25 mmol), NiBr2 (20 mol%), NBS (2.0 equiv.), MeCN (2.0 mL), stirred at 120 ℃, under O2, overnight, isolated yields. b The reaction temperature is 100 ℃. c The reaction temperature is 110 ℃. d The reaction temperature is 130 ℃.

  Next, different nickel catalysts in the reaction were then screened and NiBr₂ was found to be the best choice which provides the di-brominated product in 87% yield (Table 1, Entries 2~4). Meanwhile, a blank experiment indicated that the nickel catalyst was the key factor, because the desired product 3a was not obtained in the absence of nickel catalyst (Table 1, Entry 5). Furthermore, screening of different oxidants proved the O₂ was the best choice, providing the desired product in 87% yield, and the other oxidants such as 1, 4-benzoquinone (BQ), tert-butyl hydroperoxide (TBHP), Ag₂O gave lower yields (Table 1, Entries 6~8). Different bases such as Cs₂CO₃, K₂CO₃, K₃PO₄ were screened subsequently. The results indicated that they were substantially less effective (Table 1, Entries 9~11). In order to insight into the effect of solvent on the reaction, a variety of solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF) were also examined. The experiment results revealed that attempts to exchange the solvent failed to improve product yield (Table 1, Entries 12~15). Finally, different temperatures on the reaction were investigated. Either higher or lower temperature from 100 ℃ to 130 ℃ can improve the yield (Table 1, Entries 2 and 16~18). Therefore, the optimized condition was to use a combination of NiBr₂ (20 mol%) as catalyst and O₂ as oxidant in MeCN at 120 ℃ (Table 1, Entry 2).

  With this optimum condition in hand, we proceeded to investigate the reaction of NBS with different 8-amido-quinoline derivatives. Generally, the dibromination showed excellent functional group tolerance toward diversely substituted 8-amidoquinolines (Table 2). Both electron-withdrawing and electron-donating aromatic substitutions of carboxamides were turned into the corresponding halogenation products in good yields (3b~3k). From the results, it can be concluded that the reactants with electron-donating substituents afforded the desired products in higher yields compare to those with electron-withdrawing groups (3d 90% yield and 3k 91% yield). In addition, naphthalene substituent was also a suitable substrate for this reaction, affording the product 3l in 82% yield. Moreover, the reaction of NBS with thiophene-fused carboxamides also took place efficiently, providing N-(5, 7-dibromoquinolin-8-yl)-thiophene-2-carboxamide (3m) in 77% yield. The carboxamides with alkyl substitutions were also went smoothly in high yields. For instance, N-(quinolin-8-yl)acetamide and N-(quinolin-8-yl)cyclo-hexanecarboxamide could act as good reaction substrates under the optimized conditions. The desired products 3n and 3o were obtained in yields of 80% and 81%, respectively. In the further study, it is found that chlorination could be occurred as well as bromination at the C(5) and C(7) position of quinolines, and deliver the desire dichlorination products 3p and 3q in good yield. On the other hand, substitution at the quinoline moiety was also explored. The electron-donating methyl-substituents (1r) and electron-withdrawing fluorine-substituents (1s) delivered the desired products 3r and 3s in moderate yields.

  Table 2.  Substrate scope of the dibromination and dichlorination reaction^a

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  Next, we also explored the iodination under the standard condition. To our surprise, we only got the mono-iodi-nation product at the C(5) position of quinoline (Scheme 3).

  图Scheme 3 Iodination reaction under the standard condition Scheme3. Iodination reaction under the standard condition

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  图Scheme 3 Investigation of the mechanism of reaction Scheme5. Investigation of the mechanism of reaction

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  In order to insight into the reaction mechanism more clearly, a series of control experiments were carried out. The reaction was suppressed completely by using the radical scavenger 2, 2, 6, 6-tetramethyl-1-piperidinyl-oxy (TEM-PO) probably suggesting that the reaction may follow a radical pathway. Further experiments about reaction atmosphere replaced with nitrogen gas were also carried out, the yields of products is 40%. This phenomenon indicates that NBS has a dual role in the bromination, not only producing the bromine radical also oxidizing the intermediate instead of O₂ in the process of bromination. Only mono-bromination product at the C(5) position of quinoline was obtained in the absence of nickel catalyst and mono-bromination product at the C(5) position of quinoline could not further turn into the C(5) and C(7) di-bromination quinoline without nickel as the catalyst. These two phenomena show that the nickel is the key in formation the bromination product at the C(7) position of quinoline. Treating 2a with NBS under the standard condition gave 3a in a yield of 85%, indicating that 2a is most likely an intermediate for the formation of 3a from 1a. The reaction was also completely suppressed by treating 2a with NBS and NiBr₂ in the presence of 2 equiv. of TEMPO, indicating that the C(7) halogenation of 2a may mainly proceed via a radical pathway.

  On the basis of the above results and previous reports, ^[13] a plausible mechanism for the formation of 3a is proposed in Scheme 4. First, a radical Br• was generated from NBS under the high temperature, which then reacted with 8-aminoquinoline amides (1a) to generate the intermediate A. Subsequently, intermediate A transferred to a radical intermediate B through electron delocalization. Then, Intermediate B was trapped by Br• in the system to form the intermediate C, which underwent isomerization to give the C(5) halogenation product 2a. Second, 2a coordinates with NiBr₂ to give intermediate D. Then intermediate D was attacked by Br• and the intermediate turned into complex E through a single electron transfer process (SET). Soon afterwards, the intermediate E transformed into F through oxidation. After a proton transfer process, reductive elimination occurs with F to afford terminal product 3a.

  图Scheme 4 Proposed mechanism for the formation of 3a Scheme4. Proposed mechanism for the formation of 3a

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  2   Conclusion

  In conclusion, we have described an efficient route for the synthesis of C(5) and C(7) di-halogenated quinoline derivatives via a nickel-catalyzed C—H halogenation reaction of 8-aminoquinolines. The reaction proceeds smoothly under mild conditions, leading to the diverse products in good to excellent yields. More transformations incorporating C—H halogenation reaction for the synthesis of biologically interesting moleculars are ongoing in our laboratory.

  3   Experimental section

  3.1   General procedure for the synthesis of product 3

  A 50 mL of schlenk tube was equipped with a magnetic stir bar and charged with the mixture of 1 (0.25 mmol), NXS (2.0 equiv.), NiBr₂ (10.9 mg, 20 mol%), in MeCN (2.0 mL) under O₂. The mixture was stirred at 120 ℃ for overnight. After completion, the mixture was cooled to room temperature and diluted with water (10 mL), extracted with EtOAc (10 mL×3). The combined organic phase was dried over Na₂SO₄. After filtering, the acquired solution was collected and the solvent was removed at reduced pressure. The residue was subjected to silica gel column chromatography to give pure products 3 by using mixed petroleum ether and ethyl acetate [V(petroleum ether):V(ethyl acetate)＝5:1].

  N-(5, 7-Dibromoquinolin-8-yl)benzamide (3a): Yield 87%, white solid. m.p. 156.0~157.0 ℃ (lit.^[6b] 156~157 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 9.15 (s, 1H), 8.84 (dd, J＝4.2, 1.6 Hz, 1H), 8.50 (dd, J＝8.5, 1.4 Hz, 1H), 8.11 (s, 1H), 8.08 (d, J＝4.0 Hz, 2H), 7.64~7.47 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.4, 150.6, 143.8, 136.2, 134.5, 134.1, 134.0, 132.3, 128.7, 128.1, 126.9, 122.8, 120.2, 118.9.

  N-(5, 7-Dibromoquinolin-8-yl)-4-fluorobenzamide (3b): Yield 83%, white solid. m.p. 178.6~179.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.16 (s, 1H), 8.84 (d, J＝4.0 Hz, 1H), 8.51 (d, J＝8.3 Hz, 1H), 8.13~8.05 (m, 3H), 7.57 (dd, J＝8.7, 3.7 Hz, 1H), 7.19 (t, J＝8.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.3 (d, ¹J_CF＝252 Hz), 164.4, 150.6, 143.7, 136.3, 134.5, 133.9, 130.5 (d, ³J_CF＝9 Hz), 130.1, 127.0, 122.9, 120.5, 119.1, 115.8 (d, ²J_CF＝22 Hz); HRMS (ESI⁺) calcd for C₁₆H₁₀Br₂FN₂O [M+H]⁺ 422.9138, found 422.9139.

  N-(5, 7-Dibromoquinolin-8-yl)-4-(trifluoromethyl)benza-mide (3c): Yield 85%, white solid. m.p. 205.4~206.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.23 (s, 1H), 8.85 (dd, J＝4.3, 1.6 Hz, 1H), 8.54 (dd, J＝8.5, 1.6 Hz, 1H), 8.18 (d, J＝8.1 Hz, 2H), 8.13 (s, 1H), 7.77 (d, J＝8.1 Hz, 2H), 7.59 (q, J＝8.5, 4.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 164.2, 150.7, 143.8, 137.1, 136.3, 134.4, 134.0, 133.7, 133.6, 128.5, 127.0, 125.8 (q, J＝4 Hz), 125.0, 123.0, 122.3, 120.8, 119.5; HRMS (ESI⁺) calcd for C₁₇H₁₀Br₂-F₃N₂O [M+H]⁺ 472.9106, found 472.9107.

  N-(5, 7-Dibromoquinolin-8-yl)-4-methylbenzamide (3d): Yield 90%, white solid. m.p. 166.0~167.0 ℃(lit.^[6b] 166~167 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 9.12 (s, 1H), 8.85 (dd, J＝4.3, 1.6 Hz, 1H), 8.52 (dd, J＝8.5, 1.5 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J＝8.0 Hz, 2H), 7.56 (q, J＝4.2 Hz, 1H), 7.32 (d, J＝8.0 Hz, 2H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.3, 150.5, 143.8, 142.9, 136.0, 134.4, 134.3, 131.1, 129.4, 128.1, 126.9, 122.8, 120.1, 118.7, 21.6.

  4-(tert-Butyl)-N-(5, 7-dibromoquinolin-8-yl)benzamide (3e): Yield 94%, white solid. m.p. 219.2~221.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.51 (s, 1H), 8.79 (dd, J＝4.3, 1.6 Hz, 1H), 8.44 (dd, J＝8.6, 1.5 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J＝8.4 Hz, 2H), 7.50~7.44 (m, 3H), 1.35 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.3, 155.8, 150.4, 143.9, 136.1, 134.4, 134.3, 131.0, 127.9, 127.9, 126.9, 125.6, 122.8, 120.6, 118.8, 35.0, 31.2; HRMS (ESI⁺) calcd for C₂₀H₁₉Br₂N₂O [M+H]⁺ 460.9859, found 460.9857.

  N-(5, 7-Dibromoquinolin-8-yl)-2-fluorobenzamide (3f): Yield 79%, white solid. m.p. 148.1~149.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.27 (d, J＝13.1 Hz, 1H), 8.91 (dd, J＝4.2, 1.6 Hz, 1H), 8.51 (dd, J＝8.5, 1.6 Hz, 1H), 8.23 (td, J＝7.8, 1.9 Hz, 1H), 8.12 (s, 1 H), 7.59~7.54 (m, 2H), 7.32 (td, J＝7.6, 1.1 Hz, 1H), 7.26~7.21 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.3, 161.1(d, ¹J_CF＝248 Hz), 159.9, 151.1, 144.3, 136.0, 134.2, 134.0 (d, ³J_CF＝9 Hz), , 133.8, 132.6, 127.1, 124.9, 122.8, 121.3, 119.8, 116.4 (d, ²J_CF＝24 Hz); HRMS (ESI⁺) calcd for C₁₆H₁₀Br₂FN₂O [M+H]⁺ 422.9138429, found 422.9139.

  2-Chloro-N-(5, 7-dibromoquinolin-8-yl)benzamide (3g): Yield 75%, white solid. m.p. 178.4~179.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.88 (s, 2H), 8.48 (d, J＝8.3 Hz, 1H), 8.09 (s, 1H), 7.91 (d, J＝7.2 Hz, 1H), 7.55 (q, J＝4.0 Hz, 1H), 7.48 (d, J＝7.6 Hz, 1H), 7.44~7.36 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 164.2, 150.9, 144.1, 136.0, 134.6, 134.4, 134.3, 133.5, 131.8, 131.7, 130.7, 127.0, 127.0, 122.9, 120.8, 119.6; HRMS (ESI⁺) calcd for C₁₆H₁₀Br₂ClN₂O [M+H]⁺ 438.8843, found 438.8845.

  N-(5, 7-Dibromoquinolin-8-yl)-3-fluorobenzamide (3h): Yield 79%, white solid. m.p. 152.1~152.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.43 (s, 1H), 8.81 (dd, J＝4.3, 1.6 Hz, 1H), 8.46 (dd, J＝8.5, 1.6 Hz, 1H), 8.07 (s, 1H), 7.84 (d, J＝8.4 Hz, 1H), 7.72 (dt, J＝9.3, 2.0 Hz, 1H), 7.53 (q, J＝8.5, 4.2 Hz, 1H), 7.44 (td, J＝8.0, 5.4 Hz, 1H), 7.27~7.22 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 164.2, 162.8 (d, ¹J_CF＝246 Hz), 150.6, 143.9, 136.2, 134.4, 133.8, 130.4 (d, ³J_CF＝8 Hz), 127.0, 123.5 (d, ²J_CF＝29 Hz), 122.9, 120.7, 119.4, 119.1, 115.3, 115.2; HRMS (ESI⁺) calcd for C₁₆H₁₀Br₂FN₂O [M+H]⁺ 422.9138, found 422.9138.

  3-Bromo-N-(5, 7-dibromoquinolin-8-yl)benzamide (3i): Yield 81%, white solid. m.p. 175.2~177.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.48 (s, 1H), 8.81 (dd, J＝4.2, 1.6 Hz, 1H), 8.45 (dd, J＝8.6, 1.6 Hz, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.97 (d, J＝8.0 Hz, 1H), 7.65 (d, J＝8.0 Hz, 1H), 7.53 (q, J＝4.2 Hz, 1H), 7.31 (t, J＝7.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 164.1, 150.7, 143.9, 136.2, 135.8, 135.2, 134.4, 133.7, 131.2, 130.2, 127.0, 126.5, 122.9, 122.9, 120.8, 119.5; HRMS (ESI⁺) calcd for C₁₆H₁₀Br₃N₂O [M+H]⁺ 482.8338, found 482.8338.

  N-(5, 7-Dibromoquinolin-8-yl)-3-methylbenzamide (3j): Yield 79%, white solid. m.p. 146.7~148.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.15 (s, 1H), 8.85 (d, J＝3.2 Hz, 1H), 8.50 (d, J＝8.4 Hz, 1H), 8.11 (s, 1H), 7.88~7.86 (m, 2H), 7.56 (q, J＝4.0 Hz, 1H), 7.40 (d, J＝4.5 Hz, 2H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.6, 150.5, 143.7, 138.6, 136.2, 134.5, 134.1, 133.9, 133.1, 128.7, 128.6, 126.9, 125.1, 122.8, 120.2, 118.8, 21.4; HRMS (ESI⁺) calcd for C₁₇H₁₃Br₂N₂O [M+H]⁺ 418.9389, found 418.9388.

  N-(5, 7-Dibromoquinolin-8-yl)-3, 5-dimethylbenzamide (3k): Yield 91%, white solid. m.p. 158.5~160.2 ℃; 1H NMR (400 MHz, CDCl₃) δ: 9.11 (s, 1H), 8.84 (d, J＝4.0 Hz, 1H), 8.48 (d, J＝8.4 Hz, 1H), 8.09 (s, 1H), 7.68 (s, 2H), 7.54 (q, J＝4.0 Hz, 1H), 7.21 (s, 1H), 2.40 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 150.6, 143.8, 138.5, 136.1, 134.5, 134.2, 133.9, 133.8, 126.9, 125.8, 122.8, 120.3, 118.8, 21.3; HRMS (ESI⁺) calcd for C₁₈H₁₅Br₂-N₂O[M+H]⁺ 432.9547, found 432.9547.

  N-(5, 7-Dibromoquinolin-8-yl)-2-naphthamide (3l): Yield 82%, white solid. m.p. 174.7~176.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.39 (s, 1H), 8.83 (d, J＝4.2 Hz, 1H), 8.58 (s, 1H), 8.48 (d, J＝8.5 Hz, 1H), 8.11~8.06 (m, 2H), 7.93~7.85 (m, 3H), 7.59~7.51 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.6, 150.6, 143.9, 136.1, 135.2, 134.4, 134.2, 132.6, 131.2, 129.2, 128.9, 128.6, 128.0, 127.8, 126.9, 126.8, 124.3, 122.8, 120.3, 119.0; HRMS (ESI⁺) calcd for C₂₀H₁₃Br₂N₂O [M+H]⁺ 454.9389, found 454.9389.

  N-(5, 7-Dibromoquinolin-8-yl)thiophene-2-carboxamide (3m): Yield 77%, yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ: 9.59 (s, 1H), 8.84 (d, J＝4.0 Hz, 1H), 8.48 (d, J＝8.4 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J＝3.7 Hz, 1H), 7.56~7.54 (m, 2H), 7.12 (t, J＝4.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.9, 150.5, 143.9, 138.5, 136.3, 134.5, 133.6, 131.4, 130.1, 127.9, 127.0, 122.9, 120.8, 119.2; HRMS (ESI⁺) calcd for C₁₄H₉Br₂N₂OS [M+H]⁺ 410.8797, found 410.8797.

  N-(5, 7-dibromoquinolin-8-yl)acetamide (3n): Yield 80%, white solid. m.p. 87~88 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.86 (dd, J＝4.4, 1.6 Hz, 1H), 8.46 (dd, J＝8.8, 1.6 Hz, 2H), 8.05 (s, 1H), 7.53 (q, J＝4.4 Hz, 1H), 2.32 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 168.7, 150.8, 144.2, 136.1, 134.2, 133.9, 130.9, 128.8, 127.0, 122.7, 23.7; HRMS (ESI⁺) calcd for C₁₁H₉Br₂N₂O [M+H]⁺ 342.9076, found 342.9078.

  N-(5, 7-Dibromoquinolin-8-yl)cyclohexanecarboxamide (3o): Yield 81%, white solid. m.p. 97~98 ℃ (lit.^[6b] 202~203 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 8.86 (dd, J＝4.2, 1.6 Hz, 1H), 8.46 (dd, J＝8.5, 1.6 Hz, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.54 (dd, J＝8.5, 4.2 Hz, 1H), 2.52 (tt, J＝11.6, 3.5 Hz, 1H), 2.16~2.10 (m, 2H), 1.91~1.85 (m, 2H), 1.75~1.62 (m, 3H), 1.41~1.28 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 174.1, 150.6, 144.0, 135.9, 134.3, 133.9, 126.9, 122.7, 120.5, 118.8, 45.9, 29.7, 25.8, 25.7.

  N-(5, 7-Dichloroquinolin-8-yl)benzamide (3p): Yield 64%, yellow solid. m.p. 111.3~113.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.23 (s, 1H), 8.86 (dd, J＝4.3, 1.6 Hz, 1H), 8.52 (dd, J＝8.5, 1.6 Hz, 1H), 8.11~8.04 (m, 2H), 7.74 (s, 1H), 7.59~7.46 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.4, 150.6, 143.5, 133.9, 133.5, 132.3, 131.5, 129.9, 128.7, 128.6, 128.6, 128.1, 125.2, 122.4; HRMS (ESI⁺) calcd for C₁₆H₁₁Cl₂N₂O [M+H]⁺ 317.0243, found 317.0242.

  N-(5, 7-Dichloroquinolin-8-yl)acetamide (3q): Yield 62%, yellow solid. m.p. 180.3~180.5 ℃ (lit.^[6a] 179~180 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 8.87 (dd, J＝4.0, 1.6 Hz, 1H), 8.67 (brs, 1H), 8.49 (dd, J＝4.0, 1.6 Hz, 1H), 7.68 (s, 1H), 7.51~7.55 (m, 1H), 2.33 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 168.8, 150.7, 143.8, 136.1, 133.5, 131.8, 128.4, 125.3, 122.6, 122.3, 23.6.

  N-(5, 7-Dibromo-6-methylquinolin-8-yl)benzamide (3r): Yield 65%, white solid. m.p. 188.2~188.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.19 (s, 1H), 8.76 (dd, J＝4.4, 1.6 Hz, 1H), 8.58 (dd, J＝8.8, 1.2 Hz, 1H), 8.07 (d, J＝7.2 Hz, 2H), 7.57 (t, J＝7.6 Hz 1H), 7.47~7.52 (m, 3H), 2.91 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 149.8, 142.4, 137.4, 136.6, 134.1, 134.0, 132.2, 128.7, 128.1, 127.2, 125.1, 122.9, 120.8, 25.8; HRMS (ESI⁺) calcd for C₁₇H₁₂Br₂N₂NaO [M+Na]⁺ 440.9209, found 440.9214.

  N-(5, 7-Dibromo-6-fluoroquinolin-8-yl)benzamide (3s): Yield 59%, white solid. m.p. 203.3~204.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.34 (s, 1H), 8.79 (d, J＝3.6 Hz, 1H), 8.51 (d, J＝8.0 Hz, 1H), 8.08 (d, J＝7.2 Hz, 2H), , 7.56~7.62 (m, 3H), 7.52 (t, J＝7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.2, 154.3 (d, ¹J_CF＝245 Hz), 149.6 (d, ⁴J_CF＝3 Hz), 140.3, 136.1 (d, ⁴J_CF＝3 Hz), 135.4, (d, ³J_CF＝7 Hz), 133.8, 132.5, 128.8, 128.1 (d, ²J_CF＝29 Hz), 126.9 (d, ⁴J_CF＝3 Hz), 110.8 (d, ²J_CF＝27 Hz), 102.9, (d, ²J_CF＝24 Hz), 100.0; HRMS (ESI⁺) calcd for C₁₆H₉Br₂FN₂NaO [M+Na]⁺ 444.8958, found 44.8948.

  N-(5-Iodoquinolin-8-yl)benzamide (3t): Yield 66%, white solid. m.p. 154~157 ℃ (lit.^[6c] 154~157 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.75 (s, 1H), 8.82 (dd, J＝4.2, 1.6 Hz, 1H), 8.71 (d, J＝8.3 Hz, 1H), 8.39 (dd, J＝8.5, 1.6 Hz, 1H), 8.13 (d, J＝8.3 Hz, 1H), 8.07 (dd, J＝6.5, 1.7 Hz, 2H), 7.59~7.54 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.4, 148.9, 140.8, 139.4, 138.3, 135.5, 134.9, 132.1, 129.7, 128.9, 127.3, 123.2, 117.9, 89.5.

  4-(tert-Butyl)-N-(5-iodoquinolin-8-yl)benzamide (3u): Yield 75%. yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ: 10.52 (s, 1H), 8.59 (dd, J＝4.2, 1.5 Hz, 1H), 8.52 (d, J＝8.3 Hz, 1H), 8.14 (dd, J＝8.5, 1.5 Hz, 1H), 7.92~7.86 (m, 3H), 7.43 (d, J＝8.4 Hz, 2H), 7.32 (dd, J＝8.5, 4.2 Hz, 1H), 1.25 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ: 165.3, 155.6, 148.8, 140.7, 139.3, 138.3, 135.6, 132.0, 129.6, 127.2, 125.8, 123.2, 117.8, 89.4, 35.1, 31.2; HRMS (ESI⁺) calcd for C₂₀H₂₀IN₂O[M+H]⁺ 431.0615, found 431.0614.

  Supporting Information The ¹H NMR and ¹³C NMR spectra for compound 3 and the single crystal data of compound 3a. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

• 1. [1]

     (a) Kouznetsov, V. V. ; Mendez, L. Y. ; Gomez, C. M. Curr. Org. Chem. 2005, 9, 141.
     (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
     (c) Tokoro, Y. ; Nagai, A. ; Kokado, K. ; Chujo, Y. Macromolecules 2009, 42, 2988.
     (d) Solomon, V. R. ; Lee, H. Curr. Med. Chem. 2011, 18, 1488.
     (e) Liu, G. ; Yi, M. ; Liu, L. ; Wang, J. ; Wang, J. Chem. Commun. 2015, 51, 2911.

  2. [2]

     (a) Madrid, P. B. ; Sherrill, J. ; Liou, A. P. ; Weisman, J. L. ; Derisi, J. L. ; Guy, R. K. Bioorg. Med. Chem. Lett. 2005, 15, 1015.
     (b) Tardito, S. ; Barilli, A. ; Bassanetti, I. ; Tegoni, M. ; Bussolati, O. ; Franchi-Gazzola, R. ; Mucchino, C. ; Marchio, L. J. Med. Chem. 2012, 55, 10448.
     (c) Abouelhassan, Y. ; Garrison, V. G. ; Burch, M. ; Wong, W. ; Norwood, V. M. ; Huigens, R. W. Bioorg. Med. Chem. Lett. 2014, 24, 5076.
     (d) Vippagunta, S. R. ; Dorn, A. ; Matile, H. ; Bhattacharjee, A. K. ; Karle, J. M. ; Ellis, W. Y. ; Ridley, R. G. ; Vennerstrom, J. L. J. Med. Chem. 1999, 42, 4630.
     (e) Bhat, S. ; Shim, J. S. ; Zhang, F. ; Chong, C. R. ; Liu, J. O. Org. Biomol. Chem. 2012, 10, 2979.
     (f) Borchardt, R. T. J. Med. Chem. 1973, 16, 382.
     (g) Liu, Y. -C. ; Wei, J. -H. ; Chen, Z. -F. ; Liu, M. ; Gu, Y. -Q. ; Huang, K. -B. ; Li, Z. -Q. ; Liang, H. Eur. J. Med. Chem. 2013, 69, 554.

  3. [3]

     (a) Jiang, H. ; Taggart, H. ; Zhang, X. ; Benbrook, D. M. ; Lind, S. E. ; Ding, W. -Q. Cancer Lett. 2011, 312, 11.
     (b) Heidary, D. K. ; Howerton, B. S. ; Glazer, E. C. J. Med. Chem. 2014, 57, 8936.

  4. [4]

     (a) Sun, K. ; Lv, Y. ; Wang, J. ; Sun, J. ; Liu, L. ; Jia, M. ; Liu, X. ; Z. Li, Z. ; Wang, X. ; Org. Lett. 2015, 17, 4408.
     (b) Wasa, M. ; Worrell, B. T. ; Yu, J. Q. Angew. Chem. , Int. Ed. 2010, 49, 1275.
     (c) Tobisu, M. ; Hyodo, I. ; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070.
     (d) Berman, A. M. ; Lewis, J. C. ; Bergman, R. G. ; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926.
     (e) Zhao, D. ; Wang, W. ; Yang, F. ; Lan, J. ; Yang, L. ; Gao, G. ; You, J. Angew. Chem. , Int. Ed. 2009, 48, 3296.

  5. [5]

     (a) Boudet, N. ; Lachs, J. R. ; Knochel, P. Org. Lett. 2007, 9, 5525.
     (b) Kwak, J. ; Kim, M. ; Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
     (c) Chen, Q. ; du Jourdin, X. M. ; Knochel, P. J. Am. Chem. Soc. 2013, 135, 4958.
     (d) Tsai, C. -C. ; Shih, W. -C. ; Fang, C. -H. ; Li, C. -Y. ; Ong, T. -G. ; Yap, G. P. J. Am. Chem. Soc. 2010, 132, 11887.

  6. [6]

     (a) Guo, H. ; Chen, M. ; Jiang, P. ; Chen, J. ; Pan, L. ; Wang, M. ; Xie, C. ; Zhang, Y. Tetrahedron 2015, 71, 70.
     (b) Xu, J. ; Zhu, X. ; Zhou, G. ; Ying, B. ; Ye, P. ; Su, L. ; Shen, C. ; Zhang, P. Org. Biomol. Chem. 2016, 14, 3016.
     (c) Liu, X. X. ; Wu, Z, Y. ; Luo, X. L. ; He, Y, Q. ; Zhou, X, Q. ; Fan, Y. X. ; Huang. G. S. RSCAdv. 2016, 6, 71485.

  7. [7]

     (a) Gu, L.; Lu, T.; Zhang, M.; Tou, L.; Zhang, Y. Adv. Synth. Catal. 2013, 355, 1077.
     (b) Nishina, Y.; Takami, K. Green Chem. 2012, 14, 2380.
     (c) Nishina, Y.; Hashimoto, H.; Kimura, N.; Miyata, N.; Fujii, T.; Ohtanid, B.; Takada, J. RSC Adv. 2012, 2, 6420.
     (d) Janin, Y. L. Chem. Rev. 2012, 112, 3924.
     (e) Podgorsek, A.; Zupan, M.; Iskra, J. Angew. Chem., Int. Ed. 2009, 48, 8424.
     (f) Zhang, J.; Hao, X.; Wang, Z.; Ren, C.; Niu, J.; Song, M. Chin. J. Org. Chem. 2017, 37, 1237(in Chinese).
     (张家恒, 郝新奇, 王正龙, 任常久, 牛俊龙, 宋毛平, 有机化学, 2017, 37, 1237.)
     (g) Luo, F.; Long, Y.; Li, Z.; Zhou, X. Acta Chim. Sinica 2016, 74, 805(in Chinese).
     (罗飞华, 龙洋, 李正凯, 周向葛, 化学学报, 2016, 74, 805.)

  8. [8]

     For selected example, (a) Zhang, J. ; Chen, T. ; Yang, J. ; Han, L. Chem. Commun. 2015, 51, 7540.
     (b) Li, X. ; Feng, Z. ; Jiang, Z. ; Zhang, X. Org. Lett. 2015, 17, 5570.
     (c) Li, K. ; Wu, Q. ; Lan, J. ; You, J. Nat. Commun. 2015, 6, 8404.
     (d) Jin, L. ; Wan, L. ; Feng, J. ; Cai, C. Org. Lett. 2015, 17, 4726.

  9. [9]

     (a) Cho, C. S. ; Lee, J. W. ; Lee, D. Y. ; Shim, S. C. ; Kim, T. J. Chem. Commun. 1996, 2115.
     (b) Nogi, K. ; Fujihara, T. ; Terao, J. ; Tsuji, Y. J. Org. Chem. 2015, 80, 11618.
     (c) Tjutrins, J. ; Shao, J. ; Yempally, V. ; Bengali, A. A. ; Arndtsen, B. A. Organometallics 2015, 34, 1802.
     (d) Lo, W. ; Hu, C. ; Berenson, T. ; Tracer, N. ; Shlian, D. ; Khaloo, M. ; Benhaim, A. ; Jiang, J. Chem. Commun. 2015, 51, 9432.
     (e) Hoshimoto, Y. ; Ohata, T. ; Sasaoka, Y. ; Ohashi, M. ; Ogoshi, S. J. Am. Chem. Soc. 2014, 136, 15877.

  10. [10]

      (a) Ohashi, M. ; Kishizaki, O. ; Ikeda, H. ; Ogoshi, S. J. Am. Chem. Soc. 2009, 131, 9160.
      (b) Sato, Y. ; Saito, N. ; Mori, M. J. Am. Chem. Soc. 2000, 122, 2371.
      (c) Yeh, C. H. ; Korivi, R. P. ; Cheng, C. H. Angew. Chem. , Int. Ed. 2008, 47, 4892.
      (d) Stolley, R. M. ; Duong, H. A. ; Thomas, D. R. ; Louie, J. J. Am. Chem. Soc. 2012, 134, 15154.
      (e) Thakur, A. ; Facer, M. E. ; Louie, J. Angew. Chem. , Int. Ed. 2013, 52, 12161.

  11. [11]

      Zhan, B.-B.; Liu, Y.-H.; Hu, F.; Shi, B.-F. Chem. Commun. 2016, 52, 4934. doi: 10.1039/C6CC00822D

  12. [12]

      (a) Hao, W. Y. ; Tian, J. ; Li, W. ; Shi, R. ; Huang, Z. ; Lei. A. W. Chem. Asian J. 2016, 11, 1664.
      (b) Wan, J. -P. ; Li, Y. ; Liu, Y. Org. Chem. Front. 2016, 3, 768.
      (c) Liu, Y. ; Huang, M. ; Wei, L. Asian J. Org. Chem. 2017, 6, 41.

  13. [13]

      He, Y.; Zhao, N.; Qiu, L.; Zhang, X.; Fan, X. Org. Lett. 2016, 18, 6054. doi: 10.1021/acs.orglett.6b02998

• 

  Figure 1  Representative drugs containing the halogenated quinolines

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  Scheme 1  Recent methods for the synthesis of C(5) and C(7) di-halogenated quinolones

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  Scheme 3  Iodination reaction under the standard condition

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  Scheme 3  Investigation of the mechanism of reaction

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  Scheme 4  Proposed mechanism for the formation of 3a

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  Table 1.  Screening of reaction conditions for dibromination of quinolines^a

  Entry	Catalyst	Oxidant	Base	Solvent	Yield/% of 3a/2a
  1	NiCl2	O2	—	MeCN	55/30
  2	NiBr2	O2	—	MeCN	87/—
  3	Ni(acac)2	O2	—	MeCN	60/20
  4	Ni(NO3)2	O2	—	MeCN	57/33
  5	—	O2	—	MeCN	—/85
  6	NiBr2	BQ	—	MeCN	55/27
  7	NiBr2	TBHP	—	MeCN	65/25
  8	NiBr2	Ag2O	—	MeCN	60/30
  9	NiBr2	O2	Cs2CO3	MeCN	30/54
  10	NiBr2	O2	Na2CO3	MeCN	28/60
  11	NiBr2	O2	NaHCO3	MeCN	33/59
  12	NiBr2	O2	—	Toluene	55/35
  13	NiBr2	O2	—	PET	—/25
  14	NiBr2	O2	—	DCM	—/82
  15	NiBr2	O2	—	DCE	15/45
  16 b	NiBr2	O2	—	MeCN	84/15
  17 c	NiBr2	O2	—	MeCN	87/12
  18 d	NiBr2	O2	—	MeCN	85/14
  a Reaction conditions: 1a (0.25 mmol), NiBr2 (20 mol%), NBS (2.0 equiv.), MeCN (2.0 mL), stirred at 120 ℃, under O2, overnight, isolated yields. b The reaction temperature is 100 ℃. c The reaction temperature is 110 ℃. d The reaction temperature is 130 ℃.

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  Table 2.  Substrate scope of the dibromination and dichlorination reaction^a

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•