Design and synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives via click reactions

Abstract

The synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives at the 4-OH via click reactions is accomplished, and a total of 16 novel sinomenine double N-heterocyclic derivatives are obtained in 74%–95% yields. The C-ring is first transformed into a 1,2-diketone structure under the action of hydrochloric acid, and then reacted with o-phenylenediamine to obtain a C-ring quinoxaline-substituted structure. The 4-OH of sinomenine reacts with chloropropyne to give an alkynyl sinomenine, and then reacts with sodium azide and various benzyl chlorides to give the target compounds. All the synthesized derivatives are characterized by Fourier-transform infrared spectrometry, high resolution mass spectrometry, ¹H NMR, and ¹³C NMR spectroscopy.

Keywords

1,2,3-triazoles click reaction quinoxaline sinomenine synthesis

Sinomenine is mainly extracted from the roots and stems of the Sinomenium acutum^1,2 and exists mostly in the form of sinomenine hydrochloride. It has been found to have unique effects in the treatment of rheumatoid arthritis with 85% rate total effective.^3,4 It also exhibits pharmacological activities including antiarrhythmic, antineoplastic, analgesic and immunoregulatory effects.^5–8 However, some side effects of sinomenine itself, such as slower duration of action and allergies,^1,6,9–13 have limited the application of sinomenine in some diseases. Hence, structural modification research is inevitable as a preferred means to obtain derivatives with higher biological activity and lower side effects.

Structurally, sinomenine is similar to the morphine skeleton and consists of four fused rings. It contains a number of functional groups, such as aryl, methoxyl, phenolic hydroxy, carbonyl, double bond, and N-methyl. So it is very suitable for modification research. Previous structural modification often focused on only one site. Heterocyclic structures often show better biological activities. Therefore, modifying the heterocyclic components of sinomenine is an effective means to improve the biological activity of this natural product. Based on our previous research,^14,15 herein we report a new process for double N-heterocyclic structure modifications on the A-ring and C-rings, respectively, in order to obtain potentially improved pharmacologically active derivatives.

Results and Discussion

Scheme 1 demonstrates the synthetic method toward the double N-heterocyclic sinomenine derivatives in four steps, and 16 target compounds are synthesized in this work. 1,4-Quinoxaline is a six-membered benzo N-heterocyclic ring, and 1,2,3-triazole is a five-membered N-heterocyclic ring. Compounds containing these heterocyclic structures often exhibit good biological activity.^16–18 The 1,2-diketone scaffold sinomenine 2 is an important intermediate for the synthesis of C-ring quinoxaline-substituted sinomenine 3. Commercial sinomenine hydrochloride 1 can be converted into 2 using 10% hydrochloric acid at 90 °C for 5 h,¹⁹ which then reacts with o-phenylenediamine in CHCl₃ to form compound 3. This is the first N-heterocyclic structure installed on the C-ring of sinomenine. Another N-heterocyclic structure, that is 1,2,3-triazole, is then installed on the A-ring at the 4-OH position. The hydrogen atom on 4-OH of compound 3 is substituted with chloropropyne to obtain alkynyl sinomenine 4, which is the key intermediate for synthesizing sinomenine 1,2,3-triazole derivatives. Finally, click reactions of 4 with different benzyl chlorides 5 and NaN₃ yield various C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives substituted at the C-4 position.²⁰

Scheme 1.

Synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives.

Scheme 1 shows the functionalization of the C-ring with a quinoxaline and then A-ring modification with 1,2,3-triazole. We also tried to synthesize the target compounds using another method as shown in Scheme 2, which involves synthesizing the A-ring 1,2,3-triazole first and then the C-ring quinoxaline heterocycle. However, the yield was very low when reducing the C-ring to a 1,2-diketone structure with hydrochloric acid. Hence, the second method was not successful. This may be due to the steric hindrance of the previously synthesized 1,2,3-triazole ring which interferes with the formation of the 1,2-diketone.

Scheme 2.

An inefficient synthesis method of sinomenine 1,2,3-triazole derivatives.

We have synthesized 16 sinomenine derivatives (see Figure 1) using the method shown in Scheme 1 by using benzyl chlorides with different substituents. A wide range of derivatives was obtained with the benzyl moiety possessing ortho, meta, or para substituents, either electron-withdrawing or electron-donating. The derivatives were obtained in 74%–95% yields. The results show that this method is reliable for the synthesis of other sinomenine derivatives.

Figure 1.

The prepared C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives.

Conclusion

In summary, we have developed a practical approach to synthesize novel C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives in good to excellent yields via click reactions. The sinomenine derivatives possess both a five-membered N-heterocycle and a six-membered N-heterocycle, thus enriching the library of sinomenine derivatives. At the same time, we also studied different synthetic methods toward such derivatives. All the products were characterized by ¹H NMR, ¹³C NMR, high resolution mass spectrometry (HRMS), and Fourier-transform infrared spectrometry (FTIR). These new sinomenine derivatives may be beneficial for future drug research and development.

Experimental

Sinomenine and all the reagents are commercially available (Macklin and China National Pharmaceutical Group Corporation) and used directly without further purification. Reactions were monitored by the thin-layer chromatography (TLC) with GF₂₅₄ silica gel plates, and products were purified by the column chromatography over brand 300–400 mesh silica gel with CH₂Cl₂/CH₃OH/NH₃·H₂O (200:10:1–400:10:1 v/v) as eluents. Melting points were measured with a Jinke SGWX-4B melting point apparatus and are uncorrected. All NMR spectra were recorded on a Bruker AV-III 400 MHz NMR spectrometer using CDCl₃ as the solvent and tetramethylsilane (TMS) as an internal standard. FTIR spectra were recorded on a Nicolet 6700 FTIR spectrometer. HRMS measurements were conducted with an Agilent model G6220 mass spectrometer. The optical rotations of six representative target products were recorded on a Rudolph A25829-T polarimeter in CH₃OH. HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy, please see Supplemental Material.

Synthesis of the 1,2-diketone scaffold of sinomenine (2)

Sinomenine hydrochloride (1) (7.31 g, 20 mmol) was dissolved in 10% HCl solution (100 mL), and then refluxed for 5 h. After the reaction was complete (monitored by TLC), the reaction solution was cooled to room temperature and the pH was adjusted to 9–10 with NH₃·H₂O. The solution was extracted with dichloromethane (3 × 60 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated to give compound 2 in 84% yield. The intermediate product was used directly without purification and characterization.

Synthesis of C-ring quinoxaline-substituted sinomenine (3)

The 1,2-diketone scaffold sinomenine (2) (6.3 g, 20 mmol) and o-phenylenediamine (2.38 g, 22 mmol) were dissolved in chloroform (100 mL) and the solution was then stirred for 6 h at room temperature under a nitrogen atmosphere. After the reaction was complete (monitored by TLC), the solvent was evaporated to give a brown powder. The product was further purified by the column chromatography using CH₂Cl₂/CH₃OH/NH₃·H₂O (200:10:1 v/v) as eluent to give C-ring quinoxaline-substituted sinomenine (3). White powder; yield 75%; m.p.: 240–242 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.00 (1H, m), 7.86 (1H, m), 7.60 (2H, m), 6.59 (2H, q, J = 8.4 Hz), 6.09 (1H, s), 5.02 (1H, d, J = 17.2 Hz), 3.71 (3H, s), 3.25-2.89 (6H, m), 2.58 (2H, m), 2.48 (3H, s), 2.22 (1H, td, J = 12.4, 2.8 Hz), 2.10 (1H, m), 1.97-1.90 (1H, td, J = 12.8, 4.8 Hz); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.8, 153.4, 144.7, 144.5, 141.3, 141.2, 130.9, 128.6, 128.6, 128.5, 128.1, 123.1, 118.6, 108.9, 56.6, 55.8, 46.9, 44.5, 42.9, 42.6, 38.0, 36.2, 33.5, 23.3; IR (υ_max, cm⁻¹): 2929, 1602, 1578, 1481, 1438, 1274, 1228, 1150, 1052, 758; HRMS: m/z calcd for C₂₄H₂₆N₃O₂ [M+H]⁺: 388.2025; found: 388.2018.

Synthesis of alkynyl sinomenine (4)

The C-ring quinoxaline-substituted sinomenine (3) (3.87 g, 10 mmol), chloropropyne (1.49 g, 20 mmol), and KOH (1.12 g, 20 mmol) were dissolved in DMF (50 mL), and the solution was refluxed for 8 h at 70 °C. After the reaction was complete (monitored by TLC), the DMF was evaporated and the crude alkynyl sinomenine (4) was dissolved in dichloromethane (20 mL), washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and then evaporated to give compound 4 as a brown powder. Yield: 86%; m.p.: 56–58 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 7.99 (1H, m), 7.85 (1H, m), 7.60 (2H, m), 6.82 (1H, d, J = 8.4 Hz), 6.65 (1H, d, J = 8.4 Hz), 4.93 (1H, d, J = 17.2 Hz), 4.88-4.65 (2H, m), 3.71 (3H, s), 3.23-2.90 (6H, m), 2.55 (2H, m), 2.47 (3H, s), 2.40 (1H, t, J = 2.4 Hz), 2.21-2.13 (2H, m), 1.99-1.92 (1H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.7, 153.2, 150.9, 146.2, 141.4, 141.3, 131.0, 130.7, 128.8, 128.6, 128.0, 123.6, 111.0, 79.7, 75.2, 59.7, 56.3, 55.6, 46.8, 45.1, 43.0, 42.9, 39.5, 36.6, 33.6, 23.5; IR (υ_max, cm⁻¹): 3283, 2907, 2114, 1600, 1570, 1478, 1435, 1275, 1215, 1152, 1036, 761; HRMS: m/z calcd for C₂₇H₂₈N₃O₂ [M+H]⁺: 426.2176; found: 426.2172.

Synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6a–p); general procedure

Benzyl chloride (5) (2 mmol) and NaN₃ (143 g, 2.2 mmol) were dissolved in DMF (10 mL) and reacted for 24 h at room temperature. After the reaction was complete, a solution of compound 4 (425.5 mg, 1 mmol), CuI (38 mg, 0.2 mmol), and Et₃N (202.4 mg, 2 mmol) in a co-solvent of MeCN/t-BuOH/H₂O (10 mL, 1:3:6 v/v) was poured into the reaction mixture and stirred for another 10 h at room temperature. After the reaction was complete (monitored by TLC), the solvent was evaporated and the solid residue was dissolved in dichloromethane (20 mL). The solution was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and then evaporated to give the crude target compound 6. The product was then purified by the column chromatography using CH₂Cl₂/CH₃OH/NH₃·H₂O (400:10:1 v/v) on silica gel to give the C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives 6a–p.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6a)

Brown powder; yield: 74%; m.p.: 87–89 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.22 (1H, s), 7.84 (1H, m), 7.73 (1H, m), 7.58 (2H, m), 7.45-7.38 (5H, m), 6.90 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.65 (2H, dd, J = 31.6, 14.8 Hz), 5.18 (2H, dd, J = 17.6, 11.2 Hz), 4.86 (1H, d, J = 17.2 Hz), 3.67 (3H, s), 3.23-2.93 (6H, m), 2.58 (2H, m), 2.48 (3H, s), 2.21-2.14 (1H, m), 2.00-1.91 (2H, m); ¹³C NMR (100 MHz; CDCl3; TMS): δ 153.5, 153.0, 151.2, 146.6, 145.7, 141.3, 141.2, 134.9, 130.7, 130.4, 129.1, 128.8, 128.7, 128.6, 128.5, 128.2, 128.1, 123.7, 123.6, 111.1, 65.6, 56.4, 55.6, 54.3, 46.7, 44.9, 42.9, 42.8, 39.5, 36.5, 33.5, 23.6; IR (υ_max, cm⁻¹): 2909, 1602, 1575, 1480, 1435, 1334, 1278, 1213, 1150, 1053, 763; HRMS: m/z calcd for C₃₄H₃₅N₆O₂ [M+H]⁺: 559.2821; found: 559.2817.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6b)

Brown powder; yield: 90%; m.p.: 85–86 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.27 (1H, s), 7.85 (1H, m), 7.80 (1H, m), 7.58 (2H, m), 7.47 (1H, m), 7.35-7.28 (3H, m), 6.84 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 5.78 (2H, s), 5.20 (2H, dd, J = 15.6, 11.6 Hz), 4.87 (1H, d, J = 17.2 Hz), 3.69 (3H, s), 3.22-2.90 (6H, m), 2.52 (2H, m), 2.46 (3H, s), 2.17-2.10 (1H, m), 2.01-1.89 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.1, 146.6, 145.6, 141.3, 141.2, 133.5, 132.8, 130.7, 130.6, 130.4, 130.1, 129.9, 128.8, 128.6, 128.5, 128.1, 127.6, 124.0, 123.7, 111.0, 65.6, 56.3, 55.5, 51.5, 46.6, 44.9, 42.9, 42.8, 39.5, 36.5, 33.5, 23.6; IR (υ_max, cm⁻¹): 2906, 1595, 1573, 1474, 1433, 1333, 1271, 1208, 1152, 1048, 755; HRMS: m/z calcd for C₃₄H₃₄N₆O₂Cl [M+H]⁺: 593.2432; found: 593.2433.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6c)

Brown powder; yield: 90%; m.p.: 98–100 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.27 (1H, s), 7.85 (1H, m), 7.76 (1H, m), 7.59 (2H, m), 7.38-7.32 (3H, m), 7.26 (1H, s), 6.85 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.63 (2H, q, J = 15.2 Hz), 5.19 (2H, dd, J = 21.2, 11.6 Hz), 4.86 (1H, d, J = 17.6 Hz), 3.68 (3H, s), 3.23-2.91 (6H, m), 2.56 (2H, m), 2.47 (3H, s), 2.20-2.13 (1H, m), 2.00-1.88 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.1, 146.6, 145.6, 141.3, 141.2, 133.5, 132.8, 130.7, 130.6, 130.4, 130.1, 129.9, 128.8, 128.6, 128.5, 128.1, 127.6, 124.0, 123.7, 111.0, 65.6, 56.3, 55.5, 51.5, 46.6, 44.9, 42.9, 42.8, 39.5, 36.5, 33.5, 23.6; IR (υ_max, cm⁻¹): 2907, 1602, 1575, 1480, 1435, 1334, 1275, 1209, 1150, 1049, 763; HRMS: m/z calcd for C₃₄H₃₄N₆O₂Cl [M+H]⁺: 593.2432; found: 593.2429.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6d)

Brown powder; yield: 91%; m.p.: 103–104 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.19 (1H, s), 7.83 (2H, m), 7.58 (2H, m), 7.43 (2H, m), 7.32-7.28 (1H, m), 6.82 (1H, d, J = 8.4 Hz), 6.66 (1H, d, J = 8.4 Hz), 5.96 (2H, dd, J = 17.6, 14.4 Hz), 5.17 (2H, dd, J = 15.2, 11.6 Hz), 4.87 (1H, d, J = 17.2 Hz), 3.67 (3H, s), 3.21-2.89 (6H, m), 2.52 (2H, m), 2.45 (3H, s), 2.14-2.07 (1H, m), 1.99-1.83 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.7, 153.1, 151.0, 146.7, 145.1, 141.2, 136.9, 131.0, 130.8, 130.7, 130.4, 128.9, 128.8, 128.6, 128.5, 128.0, 123.6, 123.5, 111.0, 65.6, 56.2, 55.5, 49.1, 46.6, 44.8, 43.0, 42.9, 39.5, 36.5, 33.6, 23.5; IR (υ_max, cm⁻¹): 2906, 1581, 1566, 1477, 1435, 1335, 1277, 1209, 1151, 1049, 760; HRMS: m/z calcd for C₃₄H₃₃N₆O₂Cl₂ [M+H]⁺: 627.2042; found: 627.2038. ${[α]}_{D}^{20}$ = +30.14 (c 0.16, CH₃OH).

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6e)

Brown powder; yield: 90%; m.p.: 108–110 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.29 (1H, s), 7.86 (1H, m), 7.76 (1H, m), 7.62-7.50 (4H, m), 7.33-7.28 (2H, m), 6.85 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.63 (2H, q, J = 15.2 Hz), 5.21 (2H, dd, J = 21.6, 11.6 Hz), 4.85 (1H, d, J = 17.6 Hz), 3.68 (3H, s), 3.23-2.90 (6H, m), 2.54 (2H, m), 2.47 (3H, s), 2.19-2.12 (1H, m), 2.00-1.89 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.1, 146.5, 146.0, 141.3, 141.1, 137.2, 131.8, 131.0, 130.8, 130.7, 130.6, 128.8, 128.7, 128.4, 128.1, 126.7, 123.8, 123.7, 123.1, 111.0, 65.6, 56.2, 55.6, 53.5, 46.6, 44.9, 43.0, 42.9, 39.7, 36.5, 33.5, 23.6; IR (υ_max, cm⁻¹): 2904, 1597, 1572, 1477, 1432, 1334, 1275, 1210, 1151, 1048, 760; HRMS: m/z calcd for C₃₄H₃₄N₆O₂Br [M+H]⁺: 637.1927; found: 637.1930. ${[α]}_{D}^{20}$ = +28.67 (c 0.15, CH₃OH).

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6f)

Brown powder; yield: 92%; m.p.: 102–104 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.27 (1H, s), 7.90-7.85 (2H, m), 7.60 (2H, m), 7.42-7.35 (1H, m), 7.01 (2H, m), 6.83 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 5.74 (2H, dd, J = 17.6, 14.4 Hz), 5.17 (2H, dd, J = 18.4, 11.6 Hz), 4.87 (1H, d, J = 17.6 Hz), 3.68 (3H, s), 3.22-2.90 (6H, m), 2.52 (2H, m), 2.46 (3H, s), 2.16-2.09 (1H, m), 1.99-1.86 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 162.8, 162.7, 160.3, 160.2, 153.7, 153.1, 151.1, 146.7, 145.6, 141.3, 131.5, 131.4, 131.2, 130.8, 130.7, 128.8, 128.6, 128.1, 123.7, 123.6, 112.0, 111.9, 111.8, 111.7, 111.3, 111.1, 111.0, 110.9, 65.6, 56.3, 55.5, 46.6, 44.9, 43.0, 42.9, 41.5, 41.4, 41.3, 39.6, 36.5, 33.6, 23.6; IR (υ_max, cm⁻¹): 2906, 1625, 1595, 1473, 1434, 1334, 1274, 1231, 1153, 1047, 763; HRMS: m/z calcd for C₃₄H₃₃N₆O₂F₂ [M+H]⁺: 595.2633; found: 595.2630. (13C data assignment for this compound, please see Supplemental Material.)

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6g)

Brown powder; yield: 95%; m.p.: 89–91 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.29 (1H, s), 7.86 (2H, m), 7.60 (2H, m), 7.24-7.11 (3H, m), 6.84 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.73 (2H, d, J = 1.2 Hz), 5.19 (2H, dd, J = 26.4, 11.6 Hz), 4.86 (1H, d, J = 17.2 Hz), 3.68 (3H, s), 3.23-2.90 (6H, m), 2.53 (2H, m), 2.46 (3H, s), 2.17-2.10 (1H, m), 2.00-1.87 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.8, 151.7, 151.0, 149.9, 149.8, 149.3, 149.2, 147.5, 147.3, 146.5, 145.9, 141.3, 141.2, 130.8, 130.7, 128.8, 128.7, 128.5, 128.1, 125.2, 125.2, 125.2, 125.2, 124.9, 124.9, 124.8, 124.8, 124.6, 124.5, 123.8, 123.7, 118.0, 117.8, 111.0, 65.5, 56.2, 55.5, 47.2, 47.2, 47.2, 46.6, 45.0, 43.0, 42.9, 39.7, 36.5, 33.5, 23.5; IR (υ_max, cm⁻¹): 2904, 1629, 1600, 1476, 1438, 1335, 1278, 1215, 1150, 1052, 763; HRMS: m/z calcd for C₃₄H₃₃N₆O₂F₂ [M+H]⁺: 595.2633; found: 595.2628. ${[α]}_{D}^{20}$ = +26.65 (c 0.33, CH₃OH).

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6h)

Brown powder; yield: 85%; m.p.: 87–88 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.26 (1H, s), 7.86 (1H, m), 7.75 (1H, m), 7.59 (2H, m), 7.24-7.18 (2H, m), 7.13 (1H, m), 6.85 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.61 (2H, dd, J = 29.2, 15.2 Hz), 5.20 (2H, dd, J = 27.6, 11.6 Hz), 4.85 (1H, d, J = 17.6 Hz), 3.68 (3H, s), 3.23-2.89 (6H, m), 2.54 (2H, m), 2.46 (3H, s), 2.18-2.11 (1H, m), 2.00-1.88 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.2, 151.8, 151.8, 151.7, 151.6, 151.0, 149.3, 149.3, 149.2, 149.1, 146.5, 146.0, 141.3, 141.1, 132.0, 132.0, 132.0, 131.9, 130.8, 130.7, 128.9, 128.7, 128.3, 128.1, 124.3, 124.3, 124.3, 124.2, 123.8, 123.6, 118.0, 117.9, 117.3, 117.2, 111.0, 65.6, 56.2, 55.5, 53.0, 46.5, 44.9, 42.9, 42.8, 39.8, 36.5, 33.5, 23.5; IR (υ_max, cm⁻¹): 2907, 1600, 1587, 1480, 1435, 1334, 1264, 1213, 1153, 1048, 763; HRMS: m/z calcd for C₃₄H₃₃N₆O₂F₂ [M+H]⁺: 595.2633; found: 595.2631. ${[α]}_{D}^{20}$ = +27.25 (c 0.21, CH₃OH).

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6i)

Brown powder; yield: 86%; m.p.: 90–91 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.24 (1H, s), 7.85 (1H, m), 7.75 (1H, m), 7.61-7.54 (2H, m), 7.35-7.31 (1H, m), 6.97 (1H, m), 6.92 (2H, m), 6.84 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 5.61 (2H, dd, J = 32, 14.8 Hz), 5.18 (2H, dd, J = 16.4, 12 Hz), 4.86 (1H, d, J = 17.6 Hz), 3.80 (3H, s), 3.68 (3H, s), 3.22-2.91 (6H, m), 2.55 (2H, m), 2.47 (3H, s), 2.19-2.12 (1H, m), 2.00-1.90 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 160.1, 153.6, 153.1, 151.1, 146.6, 145.7, 141.3, 141.2, 136.4, 130.8, 130.6, 130.2, 128.8, 128.6, 128.5, 128.1, 123.7, 120.3, 114.2, 113.7, 111.1, 65.6, 56.3, 55.5, 55.3, 54.2, 46.6, 44.9, 42.9, 42.8, 39.6, 36.5, 33.5, 23.6; IR (υ_max, cm⁻¹): 2903, 1613, 1571, 1477, 1518, 1477, 1437, 1335, 1274, 1210, 1152, 758; HRMS: m/z calcd for C₃₅H₃₇N₆O₃ [M+H]⁺: 589.2927; found: 589.2924.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6j)

Brown powder; yield: 85%; m.p.: 92–93 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.19 (1H, s), 7.84 (1H, m), 7.72 (1H, m), 7.61-7.53 (2H, m), 7.35-7.33 (2H, m), 6.94 (2H, d, J = 8 Hz), 6.83 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 5.57 (2H, dd, J = 35.2, 14.8 Hz), 5.17 (2H, dd, J = 17.2, 11.6 Hz), 4.86 (1H, d, J = 17.2 Hz), 3.81 (3H, s), 3.67 (3H, s), 3.21-2.88 (6H, m), 2.52 (2H, m), 2.45 (3H, s), 2.17-2.10 (1H, m), 1.99-1.85 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 159.9, 153.6, 153.1, 151.1, 146.6, 145.5, 141.2, 141.1, 130.8, 130.6, 129.7, 128.8, 128.6, 128.5, 128.0, 126.9, 123.7, 123.5, 114.4, 111.1, 65.6, 56.2, 55.5, 55.3, 53.7, 46.6, 44.9, 42.9, 42.8, 39.6, 36.5, 33.5, 23.5 ppm; IR (υ_max, cm⁻¹): 2904, 1616, 1587, 1477, 1513, 1477, 1437, 1335, 1277, 1248, 1175, 1156, 1052, 1034, 764; HRMS: m/z calcd for C₃₅H₃₇N₆O₃ [M+H]⁺: 589.2927; found: 589.2929. ${[α]}_{D}^{20}$ = +26.97 (c 0.09, CH₃OH).

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6k)

Brown powder; yield: 89%; m.p.: 99–100 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 7.96 (1H, s), 7.84 (1H, m), 7.63-7.52 (3H, m), 7.24 (1H, m), 7.15 (2H, d, J = 7.6 Hz), 6.82 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 8.4 Hz), 5.70 (2H, q, J = 14.8 Hz), 5.12 (2H, dd, J = 28, 11.6 Hz), 4.84 (1H, d, J = 17.2 Hz), 3.64 (3H, s), 3.20-2.89 (6H, m), 2.52 (2H, m), 2.45 (3H, s), 2.43 (6H, s), 2.15-2.08 (1H, m), 1.99-1.82 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.1, 146.7, 145.0, 141.2, 138.2, 130.8, 130.7, 130.7, 129.1, 129.0, 128.7, 128.6, 128.5, 128.0, 123.6, 123.1, 111.0, 65.6, 56.2, 55.5, 48.5, 46.6, 44.7, 43.0, 42.9, 39.6, 36.5, 33.6, 23.6, 19.9; IR (υ_max, cm⁻¹): 2904, 1595, 1573, 1477, 1435, 1334, 1278, 1212, 1153, 1048, 764; HRMS: m/z calcd for C₃₆H₃₉N₆O₂ [M+H]⁺: 587.3134; found: 587.3133.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6l)

Brown powder; yield: 85%; m.p.: 110–112 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.30 (1H, s), 7.86 (1H, m), 7.71 (3H, m), 7.63-7.55 (2H, m), 7.46 (2H, m), 6.86 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.73 (2H, dd, J = 26.8, 15.6 Hz), 5.20 (2H, dd, J = 35.6, 11.6 Hz), 4.84 (1H, d, J = 17.2 Hz), 3.69 (3H, s), 3.23-2.89 (6H, m), 2.54 (2H, m), 2.46 (3H, s), 2.19-2.12 (1H, m), 2.01-1.88 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.2, 151.1, 146.5, 146.2, 141.3, 141.1, 140.2, 132.8, 130.9, 130.8, 128.8, 128.6, 128.5, 128.2, 128.2, 123.8, 118.2, 112.6, 111.1, 65.6, 56.2, 55.5, 53.4, 46.6, 45.0, 43.0, 42.9, 39.8, 36.6, 33.6, 23.6; IR (υ_max, cm⁻¹): 2904, 2231, 1610, 1572, 1480, 1434, 1334, 1277, 1207, 1153, 1049, 763; HRMS: m/z calcd for C₃₅H₃₄N₇O₂ [M+H]⁺: 584.2774; found: 584.2772.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6m)

Brown powder; yield: 95%; m.p.: 86–88 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.10 (1H, s), 7.84 (1H, m), 7.68 (1H, m), 7.60-7.52 (2H, m), 7.34-7.28 (4H, m), 6.83 (1H, d, J = 8.4 Hz), 6.66 (1H, d, J = 8.4 Hz), 5.65 (2H, dd, J = 35.2, 14.8 Hz), 5.16 (2H, dd, J = 13.6, 11.6 Hz), 4.86 (1H, d, J = 17.6 Hz), 3.66 (3H, s), 3.21-2.88 (6H, m), 2.51 (2H, m), 2.45 (3H, s), 2.36 (3H, s), 2.16-2.09 (1H, m), 2.01-1.84 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.0, 146.6, 145.3, 141.2, 141.1, 137.0, 132.8, 131.0, 130.8, 130.7, 129.5, 129.0, 128.8, 128.6, 128.5, 128.0, 126.6, 123.7, 123.6, 111.1, 65.6, 56.2, 55.5, 52.4, 46.6, 44.8, 42.9, 42.8, 39.6, 36.5, 33.5, 23.5, 19.1; IR (υ_max, cm⁻¹): 2907, 1601, 1572, 1477, 1435, 1334, 1277, 1215, 1153, 1048, 760; HRMS: m/z calcd for C₃₅H₃₇N₆O₂ [M+H]⁺: 573.2978; found: 573.2984. ${[α]}_{D}^{20}$ = +28.57 (c 0.09, CH₃OH).

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6n)

Brown powder; yield: 95%; m.p.: 82–84 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.24 (1H, s), 7.85 (1H, m), 7.73 (1H, m), 7.61-7.53 (2H, m), 7.32-7.29 (1H, m), 7.19 (3H, m), 6.84 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 5.61 (2H, dd, J = 33.6, 14.8 Hz), 5.18 (2H, dd, J = 16, 11.2 Hz), 4.87 (1H, d, J = 17.2 Hz), 3.67 (3H, s), 3.22-2.91 (6H, m), 2.54 (2H, m), 2.47 (3H, s), 2.36 (3H, s), 2.19-2.12 (1H, m), 2.00-1.90 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.2, 146.7, 145.7, 141.3, 141.2, 138.9, 134.9, 130.8, 130.7, 129.4, 129.0, 128.9, 128.8, 128.6, 128.5, 128.1, 125.3, 123.7, 123.6, 111.2, 65.7, 56.3, 55.6, 54.3, 46.6, 44.9, 43.0, 42.8, 39.6, 36.6, 33.6, 23.6, 21.4; IR (υ_max, cm⁻¹): 2904, 1611, 1572, 1476, 1437, 1334, 1277, 1210, 1151, 1050, 762; HRMS: m/z calcd for C₃₅H₃₇N₆O₂ [M+H]⁺: 573.2978; found: 573.2971.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6o)

Brown powder; yield: 89%; m.p.: 87–88 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.20 (1H, s), 7.85 (1H, m), 7.73 (1H, m), 7.61-7.53 (2H, m), 7.29 (2H, m), 7.22 (2H, m), 6.83 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 5.60 (2H, dd, J = 32.8, 14.8 Hz), 5.17 (2H, dd, J = 16.8, 11.6 Hz), 4.86 (1H, d, J = 16.8 Hz), 3.67 (3H, s), 3.21-2.89 (6H, m), 2.52 (2H, m), 2.46 (3H, s), 2.37 (3H, s), 2.17-2.10 (1H, m), 1.99-1.89 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.1, 151.1, 146.7, 145.6, 141.3, 141.2, 138.6, 131.9, 130.8, 130.6, 129.8, 128.8, 128.6, 128.5, 128.2, 128.1, 123.7, 123.5, 111.1, 65.6, 56.3, 55.5, 54.1, 46.6, 44.9, 42.9, 42.8, 39.7, 36.5, 33.6, 23.6, 21.2; IR (υ_max, cm⁻¹): 2906, 1601, 1572, 1480, 1435, 1335, 1277, 1210, 1151, 1050, 763; HRMS: m/z calcd for C₃₅H₃₇N₆O₂ [M+H]⁺: 573.2978; found: 573.2983.

C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives (6p)

Brown powder; yield: 80%; m.p.: 97–99 °C; ¹H NMR (400 MHz; CDCl₃; TMS): δ 8.29 (1H, s), 7.85 (1H, m), 7.69 (3H, m), 7.61-7.50 (2H, m), 7.49 (2H, m), 6.85 (1H, d, J = 8.4 Hz), 6.68 (1H, d, J = 8.4 Hz), 5.72 (2H, dd, J = 33.2, 15.2 Hz), 5.20 (2H, dd, J = 22.8, 11.6 Hz), 4.85 (1H, d, J = 17.2 Hz), 3.68 (3H, s), 3.22-2.90 (6H, m), 2.54 (2H, m), 2.46 (3H, s), 2.19-2.12 (1H, m), 2.01-1.91 (2H, m); ¹³C NMR (100 MHz; CDCl₃; TMS): δ 153.6, 153.2, 151.1, 146.5, 146.2, 141.3, 141.2, 139.0, 130.8, 130.8, 128.9, 128.6, 128.3, 128.2, 126.2, 126.1, 126.1, 126.1, 123.8, 123.7, 111.0, 65.6, 56.2, 55.5, 53.6, 46.6, 45.0, 43.1, 42.9, 39.8, 36.6, 33.6, 23.6; IR (υ_max, cm⁻¹): 2904, 1622, 1573, 1479, 1439, 1421, 1323, 1277, 1210, 1123, 1066, 763; HRMS: m/z calcd for C₃₅H₃₄N₆O₃F₃ [M+H]⁺: 643.2644; found: 643.2647.

Supplemental Material

3.Supplementary_information-2 – Supplemental material for Design and synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives via click reactions

Supplemental material, 3.Supplementary_information-2 for Design and synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives via click reactions by Tong Lu, Ling Dong, Hongmei Pan, Xuedan Wu, Xia Chen, Chengwen Gu, Naili Tao, Ao Wang, Kehua Zhang and Jie Jin in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Anhui University Natural Science Research Project (KJ2019A0770 and KJ2019JD19) and the Science and Technology Innovation Foundation for College Students (C19063, C19263, C19546, and C19559).

ORCID iD

Jie Jin

Supplemental material

Supplemental material for this article is available online.

References

Yamasaki

Acta Med Okayama 1976; 30: 1.

Tai

Hopkins

SJ.

Drug Future 1998; 23: 45.

Liu

Zhou

Chin Tradit Herb Drugs 1997; 28: 247.

Liu

Teng

, et al. Acta Pharmacol Sin 2005; 40: 127.

Zheng

Luo

Gao

, et al. J Chem Res 2012; 36: 315.

Mark

Schneeberger

Seiler

, et al. Transplantation 2003; 75: 940.

Candinas

Mark

Kaever

, et al. Transplantation 1996; 62: 1855.

Liu

Chan

Zhou

, et al. Life Sci 2005; 77: 3197.

Wang

Zhang

Jiang

, et al. Chem Nat Compd 2018; 54: 131.

10.

Song

Shen

Tang

, et al. Int Immunopharmacol 2010; 10: 679.

11.

Teng

Liu

Zhang

, et al. Eur J Med Chem 2012; 50: 63.

12.

Zheng

Zhu

Han

, et al. J Chem Res 2014; 38: 734.

13.

Liu

Riese

Resch

, et al. Arzneimittelforsch 1994; 44: 1223.

14.

Pan

, et al. J Chem Res 2019; 43: 469.

15.

Jin

Teng

Liu

, et al. Eur J Med Chem 2013; 62: 280.

16.

Wang

Lou

, et al. Sci China Chem 2012; 55: 2537.

17.

Mackman

Sangi

Sperandio

, et al. J Med Chem 2015; 58: 1630.

18.

Galloux

Tarus

Blazevic

, et al. J Virol 2012; 86: 8375.

19.

Yan

, et al. Acta Pharm Sin 2004; 39: 180.

20.

Chai

Guan

, et al. Bioorg Med Chem Lett 2012; 22: 5849.

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