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

Article abstract of DOI:10.1177/1747519820919853

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.

Full text of DOI:10.1177/1747519820919853

919853CHL0010.1177/1747519820919853Journal of Chemical ResearchLu et al.
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Research Paper
Journal of Chemical Research
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Design and synthesis of C-ring quinoxaline-
substituted sinomenine 1,2,3-triazole
derivatives via click reactions
https://doi.org/10.1177/1747519820919853
DOI: 10.1177/1747519820919853
journals.sagepub.com/home/chl
Tong Lu1*, Ling Dong2*, Hongmei Pan1, Xuedan Wu1,
Xia Chen1, Chengwen Gu1, Naili Tao1, Ao Wang1,
Kehua Zhang1 and Jie Jin1
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
Date received: 3 February 2020; accepted: 27 March 2020
H3CO
H3CO
N
O
N
4 steps
N
HO
O
N
CH3
16 compounds
last step yield: 74-95%
N
CH3
HCl
N
modifications at two active sites
R
N
OCH3
Sinomenine is mainly extracted from the roots and stems of inevitable as a preferred means to obtain derivatives with
the Sinomenium acutum1,2 and exists mostly in the form of higher biological activity and lower side effects.
sinomenine hydrochloride. It has been found to have unique
Structurally, sinomenine is similar to the morphine skel-
effects in the treatment of rheumatoid arthritis with 85% eton and consists of four fused rings. It contains a number
rate total effective.3,4 It also exhibits pharmacological activ- of functional groups, such as aryl, methoxyl, phenolic
ities including antiarrhythmic, antineoplastic, analgesic and hydroxy, carbonyl, double bond, and N-methyl. So it is
immunoregulatory effects.5–8 However, some side effects very suitable for modification research. Previous structural
of sinomenine itself, such as slower duration of action and modification often focused on only one site. Heterocyclic
allergies,1,6,9–13 have limited the application of sinomenine structures often show better biological activities. Therefore,
in some diseases. Hence, structural modification research is modifying the heterocyclic components of sinomenine is an
1Key Laboratory of Advanced Functional Materials, Key Laboratory of
and Functional Molecule Design and Interface Process, Anhui Jianzhu
University, Hefei, P.R. China
Corresponding authors:
Kehua Zhang, Key Laboratory of Advanced Functional Materials, Key
Laboratory of and Functional Molecule Design and Interface Process,
Anhui Jianzhu University, Hefei 230601, P.R. China.
Email: zkhzhang@163.com
2Department of Chemistry and Chemical Engineering, Hefei Normal
University, Hefei, P.R. China
* Tong Lu and Ling Dong contributed equally to this paper.
Jie Jin, Key Laboratory of Advanced Functional Materials, Key
Laboratory of and Functional Molecule Design and Interface Process,
Anhui Jianzhu University, Hefei 230601, P.R. China.
Email: jinjie@ahjzu.edu.cn

2
Journal of Chemical Research 00(0)
H3CO
HO
H3CO
HO
H3CO
HO
NH2
A
C
N
CH3
NH2
10% HCl
90 oC
N
N
CH3
N
N
CH3
HCl
CHCl3, r.t.
O
O
75%
84%
O
OCH3
2
3
1
H3CO
H3CO
O
Cl
5a-p
CuI, Et3N, MeCN, t-BuOH/H2O, r.t.
N
O
N
N
R
NaN3
N
N
N
Cl
CH3
CH3
N
N
KOH, DMF, 70 o
C
R
N
86%
74-95%
4
6a-p
Scheme 1. Synthesis of C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives.
Scheme 2. An inefficient synthesis method of sinomenine 1,2,3-triazole derivatives.
effective means to improve the biological activity of this into 2 using 10% hydrochloric acid at 90°C for 5h,19 which
natural product. Based on our previous research,14,15 herein then reacts with o-phenylenediamine in CHCl3 to form com-
we report a new process for double N-heterocyclic struc- pound 3. This is the first N-heterocyclic structure installed
ture modifications on the A-ring and C-rings, respectively, on the C-ring of sinomenine. Another N-heterocyclic struc-
in order to obtain potentially improved pharmacologically ture, that is 1,2,3-triazole, is then installed on the A-ring at
active derivatives.
the 4-OH position. The hydrogen atom on 4-OH of com-
pound 3 is substituted with chloropropyne to obtain alkynyl
sinomenine 4, which is the key intermediate for synthesiz-
ing 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 shows the functionalization of the C-ring with
a quinoxaline and then A-ring modification with 1,2,3-tria-
zole. We also tried to synthesize the target compounds using
another method as shown in Scheme 2, which involves syn-
thesizing 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
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

Lu et al.
3
6a: R = H
6b: R = 2-Cl
6c: R = 3-Cl
6d: R = 2-Cl,6-Cl 91%
6e: R = 3-Br
6f: R = 2-F,6-F
6g: R = 2-F,3-F
6h: R = 3-F,4-F
86%
85%
89%
85%
95%
95%
89%
80%
74%
90%
90%
6i: R = 3-CH3O
6j: R = 4-CH3O
6k: R = 2-H3C,6-H3C
6l: R = 4-NC
6m:R = 2-H3C
6n: R = 3-H3C
6o: R = 4-H3C
6p: R = 4-CF3O
H3CO
O
N
N
N
N
CH3
90%
92%
95%
85%
N
R
N
Figure 1. The prepared C-ring quinoxaline-substituted sinomenine 1,2,3-triazole derivatives.
hydrochloric acid. Hence, the second method was not suc- recorded on a Rudolph A25829-T polarimeter in CH3OH.
cessful. This may be due to the steric hindrance of the previ- HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy,
ously synthesized 1,2,3-triazole ring which interferes with please see Supplemental Material.
the formation of the 1,2-diketone.
We have synthesized 16 sinomenine derivatives (see
Synthesis of the 1,2-diketone scaffold of
Figure 1) using the method shown in Scheme 1 by using
sinomenine (2)
benzyl chlorides with different substituents. A wide range of
derivatives was obtained with the benzyl moiety possessing Sinomenine hydrochloride (1) (7.31g, 20mmol) was dis-
ortho, meta, or para substituents, either electron-withdraw- solved in 10% HCl solution (100mL), and then refluxed for
ing or electron-donating. The derivatives were obtained in 5h. After the reaction was complete (monitored by TLC),
74%–95% yields. The results show that this method is reli- the reaction solution was cooled to room temperature and
able for the synthesis of other sinomenine derivatives.
the pH was adjusted to 9–10 with NH3·H2O. The solution
was extracted with dichloromethane (3×60mL), 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 purifi-
cation and characterization.
Conclusion
In summary, we have developed a practical approach to syn-
thesize 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-
memberedN-heterocycleandasix-memberedN-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
Synthesis of C-ring quinoxaline-
substituted sinomenine (3)
The 1,2-diketone scaffold sinomenine (2) (6.3g, 20mmol)
and o-phenylenediamine (2.38g, 22mmol) were dissolved in
chloroform (100mL) and the solution was then stirred for 6h
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 (400MHz; CDCl3; TMS):
δ 8.00 (1H, m), 7.86 (1H, m), 7.60 (2H, m), 6.59 (2H, q,
J=8.4Hz), 6.09 (1H, s), 5.02 (1H, d, J=17.2Hz), 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, 2.8Hz), 2.10 (1H, m), 1.97-1.90 (1H, td, J=12.8,
4.8Hz); 13C NMR (100MHz; 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 (υmax, 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.
1
by H NMR, 13C NMR, high resolution mass spectrometry
(HRMS), and Fourier-transform infrared spectrometry
(FTIR). These new sinomenine derivatives may be benefi-
cial 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 chromatogra-
phy (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 400MHz 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 opti-
cal rotations of six representative target products were
Synthesis of alkynyl sinomenine (4)
The C-ring quinoxaline-substituted sinomenine (3) (3.87g,
10mmol), chloropropyne (1.49g, 20mmol), and KOH
(1.12g, 20mmol) were dissolved in DMF (50mL), and the

4
Journal of Chemical Research 00(0)
solution was refluxed for 8h at 70°C. After the reaction 7.35-7.28 (3H, m), 6.84 (1H, d, J=8.4Hz), 6.67 (1H, d,
was complete (monitored by TLC), the DMF was evapo- J=8.4Hz), 5.78 (2H, s), 5.20 (2H, dd, J=15.6, 11.6Hz),
rated and the crude alkynyl sinomenine (4) was dissolved 4.87 (1H, d, J=17.2Hz), 3.69 (3H, s), 3.22-2.90 (6H, m),
indichloromethane(20mL),washedwithbrine(3×20mL), 2.52 (2H, m), 2.46 (3H, s), 2.17-2.10 (1H, m), 2.01-1.89
dried over anhydrous sodium sulfate, and then evaporated (2H, m); 13C NMR (100MHz; CDCl3; TMS): δ 153.6,
to give compound 4 as a brown powder. Yield: 86%; m.p.: 153.1, 151.1, 146.6, 145.6, 141.3, 141.2, 133.5, 132.8,
56–58°C; 1H NMR (400MHz; CDCl3; TMS): δ 7.99 (1H, 130.7, 130.6, 130.4, 130.1, 129.9, 128.8, 128.6, 128.5,
m), 7.85 (1H, m), 7.60 (2H, m), 6.82 (1H, d, J=8.4Hz), 128.1, 127.6, 124.0, 123.7, 111.0, 65.6, 56.3, 55.5, 51.5,
6.65 (1H, d, J=8.4Hz), 4.93 (1H, d, J=17.2Hz), 4.88-4.65 46.6, 44.9, 42.9, 42.8, 39.5, 36.5, 33.5, 23.6; IR (υmax
,
(2H, m), 3.71 (3H, s), 3.23-2.90 (6H, m), 2.55 (2H, m), 2.47 cm−1): 2906, 1595, 1573, 1474, 1433, 1333, 1271, 1208,
(3H, s), 2.40 (1H, t, J=2.4Hz), 2.21-2.13 (2H, m), 1.99- 1152, 1048, 755; HRMS: m/z calcd for C34H34N6O2Cl
1.92 (1H, m); 13C NMR (100MHz; CDCl3; TMS): δ 153.7, [M+H]+: 593.2432; found: 593.2433.
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, C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
46.8, 45.1, 43.0, 42.9, 39.5, 36.6, 33.6, 23.5; IR (υmax
,
derivatives (6c). Brown powder; yield: 90%; m.p.: 98–
cm−1): 3283, 2907, 2114, 1600, 1570, 1478, 1435, 1275, 100°C; 1H NMR (400MHz; CDCl3; TMS): δ 8.27 (1H, s),
1215, 1152, 1036, 761; HRMS: m/z calcd for C27H28N3O2 7.85 (1H, m), 7.76 (1H, m), 7.59 (2H, m), 7.38-7.32 (3H,
[M+H]+: 426.2176; found: 426.2172.
m), 7.26 (1H, s), 6.85 (1H, d, J=8.4Hz), 6.68 (1H, d,
J=8.4Hz), 5.63 (2H, q, J=15.2Hz), 5.19 (2H, dd, J=21.2,
11.6Hz), 4.86 (1H, d, J=17.6Hz), 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 (100MHz; CDCl3; TMS): δ
153.6, 153.1, 151.1, 146.6, 145.6, 141.3, 141.2, 133.5,
Synthesis of C-ring quinoxaline-
substituted sinomenine 1,2,3-triazole
derivatives (6a–p); general procedure
Benzyl chloride (5) (2mmol) and NaN3 (143g, 2.2mmol) 132.8, 130.7, 130.6, 130.4, 130.1, 129.9, 128.8, 128.6,
were dissolved in DMF (10mL) and reacted for 24h at 128.5, 128.1, 127.6, 124.0, 123.7, 111.0, 65.6, 56.3, 55.5,
room temperature. After the reaction was complete, a solu- 51.5, 46.6, 44.9, 42.9, 42.8, 39.5, 36.5, 33.5, 23.6; IR (υmax
,
tion of compound 4 (425.5mg, 1mmol), CuI (38mg, cm−1): 2907, 1602, 1575, 1480, 1435, 1334, 1275, 1209,
0.2mmol), and Et3N (202.4mg, 2mmol) in a co-solvent of 1150, 1049, 763; HRMS: m/z calcd for C34H34N6O2Cl
MeCN/t-BuOH/H2O (10mL, 1:3:6 v/v) was poured into the [M+H]+: 593.2432; found: 593.2429.
reaction mixture and stirred for another 10h at room tem-
perature. After the reaction was complete (monitored by C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
TLC), the solvent was evaporated and the solid residue was derivatives (6d). Brown powder; yield: 91%; m.p.: 103–
dissolved in dichloromethane (20mL). The solution was 104°C; 1H NMR (400MHz; CDCl3; TMS): δ 8.19 (1H, s),
washed with brine (3×20mL), dried over anhydrous 7.83 (2H, m), 7.58 (2H, m), 7.43 (2H, m), 7.32-7.28 (1H,
sodium sulfate, and then evaporated to give the crude target m), 6.82 (1H, d, J=8.4Hz), 6.66 (1H, d, J=8.4Hz), 5.96
compound 6. The product was then purified by the column (2H, dd, J=17.6, 14.4Hz), 5.17 (2H, dd, J=15.2, 11.6Hz),
chromatography using CH2Cl2/CH3OH/NH3·H2O (400:10:1 4.87 (1H, d, J=17.2Hz), 3.67 (3H, s), 3.21-2.89 (6H, m),
v/v) on silica gel to give the C-ring quinoxaline-substituted 2.52 (2H, m), 2.45 (3H, s), 2.14-2.07 (1H, m), 1.99-1.83
sinomenine 1,2,3-triazole derivatives 6a–p.
(2H, m); 13C NMR (100MHz; CDCl3; TMS): δ 153.7,
153.1, 151.0, 146.7, 145.1, 141.2, 136.9, 131.0, 130.8,
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole 130.7, 130.4, 128.9, 128.8, 128.6, 128.5, 128.0, 123.6,
derivatives (6a). Brown powder; yield: 74%; m.p.: 87– 123.5, 111.0, 65.6, 56.2, 55.5, 49.1, 46.6, 44.8, 43.0, 42.9,
1
89°C; H NMR (400MHz; CDCl3; TMS): δ 8.22 (1H, s), 39.5, 36.5, 33.6, 23.5; IR (υmax, cm−1): 2906, 1581, 1566,
7.84 (1H, m), 7.73 (1H, m), 7.58 (2H, m), 7.45-7.38 (5H, m), 1477, 1435, 1335, 1277, 1209, 1151, 1049, 760; HRMS:
6.90 (1H, d, J=8.4Hz), 6.68 (1H, d, J=8.4Hz), 5.65 (2H, dd, m/z calcd for C34H33N6O2Cl2 [M+H]+: 627.2042; found:
J=31.6, 14.8Hz), 5.18 (2H, dd, J=17.6, 11.2Hz), 4.86 (1H, 627.2038. [α]2D0 =+30.14 (c 0.16, CH3OH).
d, J=17.2Hz), 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 C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
(100MHz; CDCl3; TMS): δ 153.5, 153.0, 151.2, 146.6, derivatives (6e). Brown powder; yield: 90%; m.p.: 108–
145.7, 141.3, 141.2, 134.9, 130.7, 130.4, 129.1, 128.8, 128.7, 110°C; 1H NMR (400MHz; CDCl3; TMS): δ 8.29 (1H, s),
128.6, 128.5, 128.2, 128.1, 123.7, 123.6, 111.1, 65.6, 56.4, 7.86 (1H, m), 7.76 (1H, m), 7.62-7.50 (4H, m), 7.33-7.28
55.6, 54.3, 46.7, 44.9, 42.9, 42.8, 39.5, 36.5, 33.5, 23.6; IR (2H, m), 6.85 (1H, d, J=8.4Hz), 6.68 (1H, d, J=8.4Hz),
(υmax, cm−1): 2909, 1602, 1575, 1480, 1435, 1334, 1278, 5.63 (2H, q, J=15.2Hz), 5.21 (2H, dd, J=21.6, 11.6Hz),
1213, 1150, 1053, 763; HRMS: m/z calcd for C34H35N6O2 4.85 (1H, d, J=17.6Hz), 3.68 (3H, s), 3.23-2.90 (6H, m),
[M+H]+: 559.2821; found: 559.2817.
2.54 (2H, m), 2.47 (3H, s), 2.19-2.12 (1H, m), 2.00-1.89 (2H,
m); 13C NMR (100MHz; CDCl3; TMS): δ 153.6, 153.1,
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole 151.1, 146.5, 146.0, 141.3, 141.1, 137.2, 131.8, 131.0, 130.8,
derivatives (6b). Brown powder; yield: 90%; m.p.: 85– 130.7, 130.6, 128.8, 128.7, 128.4, 128.1, 126.7, 123.8, 123.7,
1
86°C; H NMR (400MHz; CDCl3; TMS): δ 8.27 (1H, s), 123.1, 111.0, 65.6, 56.2, 55.6, 53.5, 46.6, 44.9, 43.0, 42.9,
7.85 (1H, m), 7.80 (1H, m), 7.58 (2H, m), 7.47 (1H, m), 39.7, 36.5, 33.5, 23.6; IR (υmax, cm−1): 2904, 1597, 1572,

Lu et al.
5
1477, 1432, 1334, 1275, 1210, 1151, 1048, 760; HRMS: m/z C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
calcd for C34H34N6O2Br [M+H]+: 637.1927; found: derivatives (6i). Brown powder; yield: 86%; m.p.: 90–
637.1930. [α]2D0 =+28.67 (c 0.15, CH3OH).
91°C; H NMR (400MHz; CDCl3; TMS): δ 8.24 (1H, s),
1
7.85 (1H, m), 7.75 (1H, m), 7.61-7.54 (2H, m), 7.35-7.31
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole (1H, m), 6.97 (1H, m), 6.92 (2H, m), 6.84 (1H, d, J=8.4Hz),
derivatives (6f). Brown powder; yield: 92%; m.p.: 102– 6.67 (1H, d, J=8.4Hz), 5.61 (2H, dd, J=32, 14.8Hz), 5.18
104°C; 1H NMR (400MHz; CDCl3; TMS): δ 8.27 (1H, s), (2H, dd, J=16.4, 12Hz), 4.86 (1H, d, J=17.6Hz), 3.80
7.90-7.85 (2H, m), 7.60 (2H, m), 7.42-7.35 (1H, m), 7.01 (3H, s), 3.68 (3H, s), 3.22-2.91 (6H, m), 2.55 (2H, m), 2.47
(2H, m), 6.83 (1H, d, J=8.4Hz), 6.67 (1H, d, J=8.4Hz), (3H, s), 2.19-2.12 (1H, m), 2.00-1.90 (2H, m); 13C NMR
5.74 (2H, dd, J=17.6, 14.4Hz), 5.17 (2H, dd, J=18.4, (100MHz; CDCl3; TMS): δ 160.1, 153.6, 153.1, 151.1,
11.6Hz), 4.87 (1H, d, J=17.6Hz), 3.68 (3H, s), 3.22-2.90 146.6, 145.7, 141.3, 141.2, 136.4, 130.8, 130.6, 130.2,
(6H, m), 2.52 (2H, m), 2.46 (3H, s), 2.16-2.09 (1H, m), 128.8, 128.6, 128.5, 128.1, 123.7, 120.3, 114.2, 113.7,
1.99-1.86 (2H, m); 13C NMR (100MHz; CDCl3; TMS): δ 111.1, 65.6, 56.3, 55.5, 55.3, 54.2, 46.6, 44.9, 42.9, 42.8,
162.8, 162.7, 160.3, 160.2, 153.7, 153.1, 151.1, 146.7, 39.6, 36.5, 33.5, 23.6; IR (υmax, cm−1): 2903, 1613, 1571,
145.6, 141.3, 131.5, 131.4, 131.2, 130.8, 130.7, 128.8, 1477, 1518, 1477, 1437, 1335, 1274, 1210, 1152, 758;
128.6, 128.1, 123.7, 123.6, 112.0, 111.9, 111.8, 111.7, HRMS: m/z calcd for C35H37N6O3 [M+H]+: 589.2927;
111.3, 111.1, 111.0, 110.9, 65.6, 56.3, 55.5, 46.6, 44.9, 43.0, found: 589.2924.
42.9, 41.5, 41.4, 41.3, 39.6, 36.5, 33.6, 23.6; IR (υmax, cm−1):
2906, 1625, 1595, 1473, 1434, 1334, 1274, 1231, 1153, C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
1047, 763; HRMS: m/z calcd for C34H33N6O2F2 [M+H]+: derivatives (6j). Brown powder; yield: 85%; m.p.: 92–93°C;
595.2633; found: 595.2630. (13C data assignment for this 1H NMR (400MHz; CDCl3; TMS): δ 8.19 (1H, s), 7.84 (1H,
compound, please see Supplemental Material.)
m), 7.72 (1H, m), 7.61-7.53 (2H, m), 7.35-7.33 (2H, m), 6.94
(2H, d, J=8Hz), 6.83 (1H, d, J=8.4Hz), 6.67 (1H, d,
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole J=8.4Hz), 5.57 (2H, dd, J=35.2, 14.8Hz), 5.17 (2H, dd,
derivatives (6g). Brown powder; yield: 95%; m.p.: 89– J=17.2, 11.6Hz), 4.86 (1H, d, J=17.2Hz), 3.81 (3H, s), 3.67
1
91°C; H NMR (400MHz; CDCl3; TMS): δ 8.29 (1H, s), (3H, s), 3.21-2.88 (6H, m), 2.52 (2H, m), 2.45 (3H, s), 2.17-
7.86 (2H, m), 7.60 (2H, m), 7.24-7.11 (3H, m), 6.84 (1H, d, 2.10 (1H, m), 1.99-1.85 (2H, m); 13C NMR (100MHz;
J=8.4Hz), 6.68 (1H, d, J=8.4Hz), 5.73 (2H, d, J=1.2Hz), CDCl3; TMS): δ 159.9, 153.6, 153.1, 151.1, 146.6, 145.5,
5.19 (2H, dd, J=26.4, 11.6Hz), 4.86 (1H, d, J=17.2Hz), 141.2, 141.1, 130.8, 130.6, 129.7, 128.8, 128.6, 128.5, 128.0,
3.68 (3H, s), 3.23-2.90 (6H, m), 2.53 (2H, m), 2.46 (3H, s), 126.9, 123.7, 123.5, 114.4, 111.1, 65.6, 56.2, 55.5, 55.3,
2.17-2.10 (1H, m), 2.00-1.87 (2H, m); 13C NMR (100MHz; 53.7, 46.6, 44.9, 42.9, 42.8, 39.6, 36.5, 33.5, 23.5ppm; IR
CDCl3; TMS): δ 153.6, 153.1, 151.8, 151.7, 151.0, 149.9, (υmax, cm−1): 2904, 1616, 1587, 1477, 1513, 1477, 1437,
149.8, 149.3, 149.2, 147.5, 147.3, 146.5, 145.9, 141.3, 141.2, 1335, 1277, 1248, 1175, 1156, 1052, 1034, 764; HRMS: m/z
130.8, 130.7, 128.8, 128.7, 128.5, 128.1, 125.2, 125.2, 125.2, calcd for C35H37N6O3 [M+H]+: 589.2927; found: 589.2929.
125.2, 124.9, 124.9, 124.8, 124.8, 124.6, 124.5, 123.8, 123.7, [α]2D0 =+26.97 (c 0.09, CH3OH).
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 (υmax, cm−1): 2904, C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
1629, 1600, 1476, 1438, 1335, 1278, 1215, 1150, 1052, 763; derivatives (6k). Brown powder; yield: 89%; m.p.: 99–
HRMS: m/z calcd for C34H33N6O2F2 [M+H]+: 595.2633; 100°C; 1H NMR (400MHz; CDCl3; TMS): δ 7.96 (1H, s),
found: 595.2628. [α]2D0 =+26.65 (c 0.33, CH3OH).
7.84 (1H, m), 7.63-7.52 (3H, m), 7.24 (1H, m), 7.15 (2H, d,
J=7.6Hz), 6.82 (1H, d, J=8.4Hz), 6.64 (1H, d, J=8.4Hz),
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole 5.70 (2H, q, J=14.8Hz), 5.12 (2H, dd, J=28, 11.6Hz),
derivatives (6h). Brown powder; yield: 85%; m.p.: 87– 4.84 (1H, d, J=17.2Hz), 3.64 (3H, s), 3.20-2.89 (6H, m),
1
88°C; H NMR (400MHz; CDCl3; TMS): δ 8.26 (1H, s), 2.52 (2H, m), 2.45 (3H, s), 2.43 (6H, s), 2.15-2.08 (1H, m),
7.86 (1H, m), 7.75 (1H, m), 7.59 (2H, m), 7.24-7.18 (2H, m), 1.99-1.82 (2H, m); 13C NMR (100MHz; CDCl3; TMS): δ
7.13 (1H, m), 6.85 (1H, d, J=8.4Hz), 6.68 (1H, d, J=8.4Hz), 153.6, 153.1, 151.1, 146.7, 145.0, 141.2, 138.2, 130.8,
5.61 (2H, dd, J=29.2, 15.2Hz), 5.20 (2H, dd, J=27.6, 130.7, 130.7, 129.1, 129.0, 128.7, 128.6, 128.5, 128.0,
11.6Hz), 4.85 (1H, d, J=17.6Hz), 3.68 (3H, s), 3.23-2.89 123.6, 123.1, 111.0, 65.6, 56.2, 55.5, 48.5, 46.6, 44.7, 43.0,
(6H, m), 2.54 (2H, m), 2.46 (3H, s), 2.18-2.11 (1H, m), 2.00- 42.9, 39.6, 36.5, 33.6, 23.6, 19.9; IR (υmax, cm−1): 2904,
1.88 (2H, m); 13C NMR (100MHz; CDCl3; TMS): δ 153.6, 1595, 1573, 1477, 1435, 1334, 1278, 1212, 1153, 1048,
153.2, 151.8, 151.8, 151.7, 151.6, 151.0, 149.3, 149.3, 149.2, 764; HRMS: m/z calcd for C36H39N6O2 [M+H]+: 587.3134;
149.1, 146.5, 146.0, 141.3, 141.1, 132.0, 132.0, 132.0, 131.9, found: 587.3133.
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, C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
56.2, 55.5, 53.0, 46.5, 44.9, 42.9, 42.8, 39.8, 36.5, 33.5, 23.5; derivatives (6l). Brown powder; yield: 85%; m.p.: 110–
IR (υmax, cm−1): 2907, 1600, 1587, 1480, 1435, 1334, 1264, 112°C; 1H NMR (400MHz; CDCl3; TMS): δ 8.30 (1H, s),
1213, 1153, 1048, 763; HRMS: m/z calcd for C34H33N6O2F2 7.86 (1H, m), 7.71 (3H, m), 7.63-7.55 (2H, m), 7.46 (2H,
[M+H]+: 595.2633; found: 595.2631. [α]2D0 =+27.25 (c m), 6.86 (1H, d, J=8.4Hz), 6.68 (1H, d, J=8.4Hz), 5.73
0.21, CH3OH).
(2H, dd, J=26.8, 15.6Hz), 5.20 (2H, dd, J=35.6, 11.6Hz),

6
Journal of Chemical Research 00(0)
4.84 (1H, d, J=17.2Hz), 3.69 (3H, s), 3.23-2.89 (6H, m), (υmax, cm−1): 2906, 1601, 1572, 1480, 1435, 1335, 1277,
2.54 (2H, m), 2.46 (3H, s), 2.19-2.12 (1H, m), 2.01-1.88 1210, 1151, 1050, 763; HRMS: m/z calcd for C35H37N6O2
(2H, m); 13C NMR (100MHz; CDCl3; TMS): δ 153.6, [M+H]+: 573.2978; found: 573.2983.
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, C-ring quinoxaline-substituted sinomenine 1,2,3-tri-
118.2, 112.6, 111.1, 65.6, 56.2, 55.5, 53.4, 46.6, 45.0, 43.0, azole derivatives (6p). Brown powder; yield: 80%; m.p.:
1
42.9, 39.8, 36.6, 33.6, 23.6; IR (υmax, cm−1): 2904, 2231, 97–99 °C; H NMR (400 MHz; CDCl3; TMS): δ 8.29
1610, 1572, 1480, 1434, 1334, 1277, 1207, 1153, 1049, (1H, s), 7.85 (1H, m), 7.69 (3H, m), 7.61-7.50 (2H, m),
763; HRMS: m/z calcd for C35H34N7O2 [M+H]+: 584.2774; 7.49 (2H, m), 6.85 (1H, d, J = 8.4 Hz), 6.68 (1H, d,
found: 584.2772.
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
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole (3H, s), 3.22-2.90 (6H, m), 2.54 (2H, m), 2.46 (3H, s),
derivatives (6m). Brown powder; yield: 95%; m.p.: 86– 2.19-2.12 (1H, m), 2.01-1.91 (2H, m); 13C NMR
1
88°C; H NMR (400MHz; CDCl3; TMS): δ 8.10 (1H, s), (100 MHz; CDCl3; TMS): δ 153.6, 153.2, 151.1, 146.5,
7.84 (1H, m), 7.68 (1H, m), 7.60-7.52 (2H, m), 7.34-7.28 146.2, 141.3, 141.2, 139.0, 130.8, 130.8, 128.9, 128.6,
(4H, m), 6.83 (1H, d, J=8.4Hz), 6.66 (1H, d, J=8.4Hz), 128.3, 128.2, 126.2, 126.1, 126.1, 126.1, 123.8, 123.7,
5.65 (2H, dd, J=35.2, 14.8Hz), 5.16 (2H, dd, J=13.6, 111.0, 65.6, 56.2, 55.5, 53.6, 46.6, 45.0, 43.1, 42.9, 39.8,
11.6Hz), 4.86 (1H, d, J=17.6Hz), 3.66 (3H, s), 3.21-2.88 36.6, 33.6, 23.6; IR (υmax, cm−1): 2904, 1622, 1573,
(6H, m), 2.51 (2H, m), 2.45 (3H, s), 2.36 (3H, s), 2.16-2.09 1479, 1439, 1421, 1323, 1277, 1210, 1123, 1066, 763;
(1H, m), 2.01-1.84 (2H, m); 13C NMR (100MHz; CDCl3; HRMS: m/z calcd for C35H34N6O3F3 [M+H]+: 643.2644;
TMS): δ 153.6, 153.1, 151.0, 146.6, 145.3, 141.2, 141.1, found: 643.2647.
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, Declaration of conflicting interests
55.5, 52.4, 46.6, 44.8, 42.9, 42.8, 39.6, 36.5, 33.5, 23.5,
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
19.1; IR (υmax, 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]2D0 =+28.57 (c 0.09, CH3OH).
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
C-ring quinoxaline-substituted sinomenine 1,2,3-triazole
derivatives (6n). Brown powder; yield: 95%; m.p.: 82–
1
84°C; H NMR (400MHz; 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 Science and Technology Innovation Foundation for College
Students (C19063, C19263, C19546, and C19559).
(1H, m), 7.19 (3H, m), 6.84 (1H, d, J=8.4Hz), 6.67 (1H, d,
J=8.4Hz), 5.61 (2H, dd, J=33.6, 14.8Hz), 5.18 (2H, dd,
J=16, 11.2Hz), 4.87 (1H, d, J=17.2Hz), 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 (100MHz;
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 (υmax, 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.
ORCID iD
Jie Jin
https://orcid.org/0000-0001-7842-3116
Supplemental material
Supplemental material for this article is available online.
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derivatives (6o). Brown powder; yield: 89%; m.p.: 87–
1
88°C; H NMR (400MHz; CDCl3; TMS): δ 8.20 (1H, s),
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