J. Han, et al.
BioorganicChemistry101(2020)103962
1H), 7.55–7.52 (d, J = 9.0 Hz, 2H), 7.39–7.34 (t, J = 6.0 Hz, 2H),
7.21–7.14 (m, 2H), 7.10–7.07 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H) ppm;
HRMS (ESI): m/z [M+H]+. Calcd for C14H14ClN2OS: 293.0510, found:
293.0514. HPLC: tR = 20.687 min, 99.4% purity.
4-Benzoyl-N-(4-nitrophenyl)piperazine-1-carbothioamide 5h.
The synthesis and purification method are similar to 4a except that
phenyl(piperazin-1-yl)methanone is substituted for 2-methoxyaniline.
1H NMR (300 MHz, DMSO‑d6): δ = 9.93 (s, 1H), 8.20–8.17 (d,
J = 9.0 Hz, 2H), 7.64–7.61 (d, J = 9.0 Hz, 2H), 7.48 (s, 5H), 3.33 (s,
4-(Methylsulfonyl)-N-(4-nitrophenyl)piperazine-1-carbothioa-
mide 5a. The synthesis and purification method are similar to 4a ex-
cept that 1-(methylsulfonyl)piperazine is substituted for 2-methox-
yaniline. 1H NMR (300 MHz, DMSO‑d6):δ = 9.99 (s, 1H), 8.20–8.17 (t,
J = 1.9 Hz, 2H), 7.64–7.61 (d, J = 9.0 Hz, 2H), 4.05 (s, 4H), 3.24 (s,
8H) ppm; HRMS (ESI): m/z [M+H]+
. Calcd for C18H19N4O3S:
371.1172, found: 371.1169. HPLC: tR = 17.081 min, 99.2% purity.
2-(4-((4-Nitrophenyl)carbamothioyl)piperazin-1-yl)benzoic
acid 5i. The synthesis and purification method are similar to 4a except
that sodium 2-(piperazin-1-yl)benzoate is substituted for 2-methox-
yaniline. 1H NMR (300 MHz, DMSO‑d6): δ = 15.48 (s, 1H), 10.03 (s,
1H), 8.24–8.21 (d, J = 9.0 Hz, 2H), 7.98–7.95 (d, J = 9.0 Hz, 1H),
7.69–7.58 (m, 4H), 7.38–7.33 (t, J = 9.0 Hz, 1H), 4.17 (t, 4H), 3.21 (t,
4H) ppm; HRMS (ESI): m/z [M+H]-. Calcd for C18H19N4O4S: 387.1122,
found: 387.1147. HPLC: tR = 15.576 min, 93.0% purity. The dis-
sociation of carboxylic acid sodium for 5i disturbed the results of HPLC.
NMR spectra also validated the purity of 5i.
4H), 2.95 (s, 3H) ppm; HRMS (ESI): m/z [M+H]+
. Calcd for
C
12H17N4O4S2: 345.0686, found: 345.0669. HPLC: tR = 13.266 min,
98.6% purity.
4-Benzoyl-N-(4-chloropyridin-2-yl)piperazine-1-carbothioa-
mide 5b. The synthesis method is similar to 4a except that phenyl
(piperazin-1-yl)methanone is substituted for 2-methoxyaniline and 3 is
substituted for 2. The reaction mixture was evaporated under reduced
pressure and purified by silica gel column chromatography (PE/
EA = 1/1). 1H NMR (400 MHz, DMSO‑d6):δ = 10.18 (s, 1H), 8.28–8.27
(d, J = 4.0 Hz, 1H), 7.74 (s, 1H), 8.03 (s, 2H), 7.47 (s, 5H), 7.19–7.18
(d, J = 4 Hz, 1H), 4.01–3.99 (d, J = 8.0 Hz, 4H), 3.92 (s, 2H), 3.72 (s,
4-(2-Cyanophenyl)-N-(4-nitrophenyl)piperazine-1-carbothioa-
mide 5j. The synthesis and purification method are similar to 4a except
that 2-(piperazin-1-yl)benzonitrile is substituted for 2-methoxyaniline.
1H NMR (300 MHz, DMSO‑d6): δ = 9.96–9.95 (d, J = 3.0 Hz, 1H),
8.20–8.17 (d, J = 9.0 Hz, 2H), 7.77–7.74 (m, 1H), 7.66–7.61 (m, 3H),
7.24–7.21 (d, J = 9.0 Hz, 1H), 7.17–7.14 (d, J = 9.0 Hz, 2H),
4.13–4.12 (m, 4H), 3.33–3.30 (t, J = 6.0 Hz, 4H) ppm; HRMS (ESI): m/
z [M+H]+. Calcd for C18H18N5O2S: 368.1176, found: 368.1179. HPLC:
tR = 21.459 min, 96.3% purity.
2H) ppm; HRMS (ESI): m/z [M+H]+
. Calcd for C17H18ClN4OS:
361.0884, found: 361.0877. HPLC: tR = 16.754 min, 95.2% purity.
N-(5-Chloro-2-methoxyphenyl)-4-(pyrimidin-2-yl)piperazine-1-
carbothioamide 5c. The synthesis and purification method are similar
to 4a except that 2-(piperazin-1-yl)pyrimidine is substituted for 2-
methoxyaniline and 1 is substituted for 2. 1H NMR (400 MHz,
DMSO‑d6):δ = 8.96 (s, 1H), 8.42–8.41 (d, J = 4.0 Hz, 2H), 7.34 (s, 1H),
7.27–7.24 (m, 1H), 7.08–7.05 (d, J = 12.0 Hz, 1H), 6.71–6.68 (t,
J = 8.0 Hz, 1H), 4.02–4.01 (m, 4H), 3.86–3.78 (m, 4H), 3.36 (s, 3H)
ppm; HRMS (ESI): m/z [M+H]+. Calcd for C16H19ClN5OS: 364.0993,
found: 364.0970. HPLC: tR = 19.765 min, 99.6% purity.
4-(2-Amino-4-methoxyphenyl)-N-(4-nitrophenyl)piperazine-1-
carbothioamide 5k. 5-methoxy-2-(piperazin-1-yl)aniline (0.2 g,
0.97 mmol) was dissolved in acetone (5 mL). The acetone solution
(2 mL) of 2 (0.17 g, 0.97 mmol) was slowly dropped, after the reaction
was cooled to −5 °C in nitrogen atmosphere. The reaction mixture was
stirred at −5 °C for 40 min. The solvent was evaporated under reduced
pressure, and the compound 5k was purified by silica gel column
chromatography. 1H NMR (300 MHz, DMSO‑d6): δ = 9.92 (s, 1H),
8.19–8.16 (d, J = 9.0 Hz, 2H), 7.63–7.60 (d, J = 9.0 Hz, 2H),
6.85–6.82 (d, J = 9.0 Hz, 1H), 6.28 (s, 1H), 6.12–6.09 (d, J = 9.0 Hz,
1H), 6.28 (s, 2H), 4.09 (s, 4H), 3.63 (s, 3H), 2.81 (s, 4H) ppm; HRMS
N-(5-Chloro-2-methoxyphenyl)-4-(4-fluorophenyl)piperazine-
1-carbothioamide 5d. The synthesis and purification method are si-
milar to 4a except that 1-(4-fluorophenyl)piperazine is substituted for
2-methoxyaniline and 1 is substituted for 2. 1H NMR (400 MHz,
DMSO‑d6):δ = 8.99 (s, 1H), 7.32–7.31 (d, J = 4.0 Hz, 1H), 7.26–7.24
(m, 1H), 7.11–7.05 (m, 3H), 7.03–6.99 (m, 2H), 4.06–4.04 (t, J = 4 Hz,
4H), 3.77 (s, 3H), 3.19–3.17 (t, J = 4.0 Hz, 4H) ppm; HRMS (ESI): m/z
(ESI): m/z [M+H]+
. Calcd for C18H22N5O3S: 388.1438, found:
[M+H]+
.
Calcd for C18H20ClFN3OS: 380.0994, found: 380.0970.
388.1439. HPLC: tR = 15.519 min, 97.7% purity.
HPLC: tR = 19.835 min, 99.4% purity.
N-(4-Nitrophenyl)-4-(pyrimidin-2-yl)piperazine-1-carbothioa-
mide 5e. The synthesis and purification method are similar to 4a ex-
cept that 2-(piperazin-1-yl)pyrimidine is substituted for 2-methox-
yaniline. 1H NMR (300 MHz, DMSO‑d6):δ = 9.92 (s, 1H), 8.42–8.41 (d,
J = 3.0 Hz, 2H), 8.20–8.17 (d, J = 9.0 Hz, 2H), 7.66–7.63 (d,
J = 9.0 Hz, 2H), 6.71–6.70 (d, J = 3.0 Hz, 1H), 4.05–3.87 (d, 8H) ppm;
HRMS (ESI): m/z [M+H]+. Calcd for C15H17N6O2S: 345.1128, found:
345.1123. HPLC: tR = 11.547 min, 97.1% purity.
Acknowledgements
This study was supported by the Ministry of Science and Technology
of China (National Key R&D Program of China, 2017YFB0202600), the
“Personalized Medicines Molecular Signature-based Drug Discovery
and Development” (Strategic Priority Research Program of the Chinese
Academy of Sciences, XDA12020368) to Hong Ding; the Chang Jiang
Scholars Program, the National Program for Support of Top-Notch
Young Professionals, the National Science Fund for Distinguished
Young Scholars (81725011) to Yao Zhao; the National Natural Science
Foundation of China (81802495), the Shanghai Sailing Program
(18YF1403400) to Qilin Zhang.
N-(4-Nitrophenyl)-4-phenylpiperazine-1-carbothioamide
5f.
The synthesis and purification method are similar to 4a except that 1-
phenylpiperazine is substituted for 2-methoxyaniline. 1H NMR
(300 MHz, DMSO‑d6):δ = 9.95 (s, 1H), 8.20–8.17 (d, J = 9.0 Hz, 2H),
7.65–7.62 (d, J = 9.0 Hz, 2H), 7.28–7.25 (d, J = 9.0 Hz, 2H),
7.00–6.97 (d, J = 9.0 Hz, 2H), 6.85–6.80 (m, 1H), 4.08 (s, 4H), 3.28 (s,
Appendix A. Supplementary material
4H) ppm; HRMS (ESI): m/z [M+H]+
. Calcd for C17H19N4O2S:
343.1223, found: 343.1219. HPLC: tR = 21.284 min, 97.0% purity.
N-(4-Nitrophenyl)-4-(pyridin-2-yl)piperazine-1-carbothioa-
mide 5g. The synthesis and purification method are similar to 4a ex-
cept that 1-(pyridin-2-yl)piperazine is substituted for 2-methoxyaniline.
1H NMR (300 MHz, DMSO‑d6): δ = 9.91 (s, 1H), 8.20–8.14 (m, 1H),
7.96 (s, 1H), 7.66 (s, 1H), 7.63–7.60 (t, J = 6.0 Hz, 1H), 7.58–7.55 (d,
J = 9.0 Hz, 1H), 6.88–6.85 (d, J = 9.0 Hz, 1H), 6.71–6.68 (t,
J = 9.0 Hz, 1H), 4.07–4.04 (t, J = 3.0 Hz, 4H), 3.68–3.64 (d,
J = 6.0 Hz, 4H), 2.90 (s, 2H), 2.74 (s, 2H) ppm; HRMS (ESI): m/z [M
+H]+. Calcd for C16H18N5O2S: 344.1176, found: 344.1173. HPLC:
tR = 19.758 min, 97.0% purity.
Supplementary data to this article can be found online at https://
References
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