O. Grytsai, et al.
BioorganicChemistry104(2020)104271
N-(2-chlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine
(4.4)
mixture of 1-H triazole and 2-H triazole tautomers (1:1). White powder
(180 mg, 68%). 1H NMR (400 MHz, DMSO‑d6): δ 13.90 (s, 0.5H), 12.85
(s, 0.5H), 9.40 (s, 0.5H), 9.17 (d, J = 6.6 Hz, 1.5H), 8.75–8.51 (m, 1H),
8.29 (d, J = 8.5 Hz, 1H), 7.53 (dt, J = 36.4, 6.5 Hz, 1H), 7.19 (d,
J = 35.4 Hz, 2H), 6.50 (d, J = 46.8 Hz, 1H), 2.23 (d, J = 8.0 Hz, 6H).
13C NMR (50 MHz, TFA-d1): δ 154.15, 147.09, 146.28, 145.58, 144.05,
142.12, 135.06, 133.72, 130.97 (2C), 128.33, 124.23 (2C), 21.76 (2C).
LC-MS (m/z): [M+H]+ calc. for C15H16N5+, 266.14; Found: 266.27.
HPLC (λ280): Purity 99.7%; tR: 1.250 min (method 1).
Synthesized following the general procedure
B
using 1-(2-chlor-
ophenyl)-2-methylisothiouronium iodide (0.328 g, 1 mmol) and nico-
tynohydrazide (0.137 g, 1 mmol) to afford the title compound as a
mixture of 1-H triazole and 2-H triazole tautomers (1:1). White powder
(171 mg, 63%). 1H NMR (400 MHz, DMSO‑d6): δ 14.12 (s, 0.5H), 12.61
(s, 0.5H), 9.19 (d, J = 2.1 Hz, 1H), 8.89 (s, 0,5H), 8.62 (d, J = 4.8 Hz,
1H), 8.31 (dt, J = 7.9, 2.0 Hz, 2,5H), 7.61–7.27 (m, 3H), 6.97 (t,
J = 7.6 Hz, 1H). 13C NMR (101 MHz, DMSO‑d6): δ 156.45, 153.32,
149.91, 146.84, 137.16, 133.02, 129.41, 127.94, 127.45, 123.91,
N-(2,5-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine (4.10)
122.25, 120.95, 118.83. LCMS (m/z): [M+H]+ calc. for C13H11ClN5
,
Synthesized following the general procedure B using 1-(2,5-di-
+
272.07; Found: 272.27. HPLC (λ280): Purity 98.9%; tR: 1.275 min
chlorophenyl)-2-methylisothiouronium iodide (0.363 g, 1 mmol) and
nicotynohydrazide (0.137 g, 1 mmol) to afford the title compound as a
mixture of 1-H triazole and 2-H triazole tautomers (1:1). Beige powder
(189 mg, 62%). 1H NMR (200 MHz, DMSO‑d6): δ 14.25 (s, 0.5H), 12.66
(s, 0.5H), 9.16 (dd, J = 2.3, 0.9 Hz, 1H), 8.77–8.17 (m, 4H), 7.50 (dd,
J = 20.2, 7.8 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H). 13C NMR (50 MHz,
DMSO‑d6): δ 150.65, 150.28, 146.84, 138.51 (2C), 133.16, 132.29,
130.69, 124.08, 121.29 (2C), 119.04, 117.51. LC-MS (m/z): [M+H]+
calc. for C13H10Cl2N5+, 306.03; Found: 306.27. HPLC (λ280): Purity
95.6%; tR: 1.358 min (method 1).
(method 1).
N-(2-bromophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine
(4.5)
Synthesized following the general procedure B using 1-(2-bromo-
phenyl)-2-methylisothiouronium iodide (0.372 g, 1 mmol) and nicoty-
nohydrazide (0.137 g, 1 mmol) to afford the title compound as a mix-
ture of 1-H triazole and 2-H triazole tautomers (1:1). White powder
(211 mg, 67%). 1H NMR (400 MHz, DMSO‑d6): δ 14.11 (s, 0.5H), 12.69
(s, 0.5H), 9.18 (d, J = 2.2 Hz, 1H), 8.88–8.47 (m, 2H), 8.36–8.14 (m,
2H), 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.57–7.45 (m, 1H), 7.44–7.33 (m,
1H), 6.92 (t, J = 7.7 Hz, 1H). 13C NMR (101 MHz, DMSO‑d6): δ 156.53,
153.52, 149.90, 146.82, 138.32, 133.02, 132.69, 128.55, 127.27,
123.91, 123.18, 119.36, 111.84. LC-MS (m/z): [M+H]+ calc. for
N-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine (4.11)
Synthesized following the general procedure
B using 1-(3,4-di-
chlorophenyl)-2-methylisothiouronium iodide (0.363 g, 1 mmol) and
nicotynohydrazide (0.137 g, 1 mmol) to afford the title compound as a
mixture of 1-H triazole and 2-H triazole tautomers (7:3). White powder
(180 mg, 59%). 1H NMR (400 MHz, DMSO‑d6): δ 14.10 (s, 0.7H), 13.13
(s, 0.3H), 9.87 (d, J = 60.4 Hz, 1H), 9.15 (s, 1H), 8.77–8.55 (m, 1H),
8.29 (d, J = 7.9 Hz, 1H), 7.94 (s, 1H), 7.67–7.39 (m, 3H). 13C NMR
(101 MHz, DMSO‑d6): δ 160.21, 150.89, 150.40, 146.87, 142.08,
133.28, 131.03, 130.54, 124.09, 123.28, 120.14, 116.67, 116.12. LC-
MS (m/z): [M+H]+ calc. for C13H10Cl2N5+, 306.03; Found: 306.27.
HPLC (λ280): Purity 98.5%; tR: 1.325 min (method 1).
C
13H11BrN5+, 316.02; Found: 316.13. HPLC (λ280): Purity 98.0%; tR:
1.275 min (method 1).
N-(3-bromophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine
(4.6)
Synthesized following the general procedure B using 1-(3-bromo-
phenyl)-2-methylisothiouronium iodide (0.372 g, 1 mmol) and nicoty-
nohydrazide (0.137 g, 1 mmol) to afford the title compound as a mix-
ture of 1-H triazole and 2-H triazole tautomers (1:1). Beige powder
(227 mg, 72%). 1H NMR (400 MHz, DMSO‑d6): δ 14.04 (s, 0.5H), 13.06
(s, 0.5H), 9.65 (s, 1H), 9.15 (dd, J = 5.6, 2.2 Hz, 1H), 8.66 (d,
J = 8.4 Hz, 1H), 8.29 (dt, J = 8.0, 2.0 Hz, 1H), 7.91 (t, J = 2.0 Hz,
1H), 7.67–7.41 (m, 2H), 7.21 (t, J = 8.2 Hz, 1H), 7.00 (s, 1H). 13C NMR
(101 MHz, DMSO‑d6): δ 160.46, 150.79, 150.27, 146.85, 143.46,
133.22, 130.69, 124.05, 123.35, 121.89, 121.63, 117.97, 114.81. LC-
MS (m/z): [M+H]+ calc. for C13H11BrN5+, 316.02; Found: 316.33.
HPLC (λ280): Purity 96.2%; tR: 1.233 min (method 1).
N-(3,5-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine (4.12)
Synthesized following the general procedure
B using 1-(3,5-di-
chlorophenyl)-2-methylisothiouronium iodide (0.363 g, 1 mmol) and
nicotynohydrazide (0.137 g, 1 mmol) to afford the title compound as a
mixture of 1-H triazole and 2-H triazole tautomers (6:4). White powder
(198 mg, 65%). 1H NMR (400 MHz, DMSO‑d6): δ 14.15 (s, 0.4H), 12.70
(s, 0.6H), 9.18 (m, J = 2.1 Hz, 1.6H), 8.63 (s, 1H), 8.52–8.02 (m, 2.4H),
7.74–7.24 (m, 3H). 13C NMR (101 MHz, DMSO‑d6): δ 153.81, 147.08,
146.89, 145.48, 142.13, 139.72, 134.50, 133.39, 131.38, 131.16,
130.85, 130.42, 128.19. LC-MS (m/z): [M+H]+ calc. for
5-(pyridin-3-yl)-N-(p-tolyl)-1,2,4-triazol-3-amine (4.7) Synthesized
following the general procedure
B using 2-methyl-1-(p-tolyl)iso-
thiouronium iodide (0.308 g, 1 mmol) and nicotynohydrazide (0.137 g,
1 mmol) to afford the title compound as a mixture of 1-H triazole and 2-
H triazole tautomers (6:4). White powder (110 mg, 44%). 1H NMR
(400 MHz, DMSO‑d6): δ 14.15 (s, 0.4H), 12.70 (s, 0.6H), 9.18 (m,
J = 2.1 Hz, 1.6H), 8.63 (s, 1H), 8.52–8.02 (m, 2.4H), 7.74–7.24 (m,
3H). 13C NMR (101 MHz, DMSO‑d6): δ 153.81, 147.08, 146.89, 145.48,
142.13, 139.72, 134.50, 133.39, 131.38, 131.16, 130.85, 130.42,
128.19. LC-MS (m/z): [M+H]+ calc. for C13H10Cl2N5+, 306.03; Found:
306.27. HPLC (λ280): Purity 98.2%; tR: 1.383 min (method 1).
C
13H10Cl2N5+, 306.03; Found: 306.27. HPLC (λ280): Purity 98.2%; tR:
1.383 min (method 1).
N-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-2-amine [42] (5) A solution
of 2-nicotinoyl-N-phenylhydrazinecarboxamide (1.19 g, 5 mmol) in
POCl3 (5 mL) was refluxed for 2 h. After cooling to room temperature,
the reaction mixture was poured into a cold water (200 mL). After
stirring for 10 min the precipitated product was collected by filtration,
washed with water and Et2O, and dried under reduced pressure yielding
to a pure product as a white powder (0.74 g, 62%). 1H NMR (400 MHz,
DMSO‑d6): δ 10.79 (s, 1H), 9.07 (dd, J = 2.3, 0.9 Hz, 1H), 8.74 (dd,
J = 4.8, 1.6 Hz, 1H), 8.26 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.65–7.58
(m, 3H), 7.41–7.34 (m, 2H), 7.03 (tt, J = 7.4, 1.1 Hz, 1H). 13C NMR
(101 MHz, DMSO‑d6): δ 160.30, 155.96, 151.59, 146.33, 138.52,
133.18, 129.21 (2C), 124.40, 122.15, 120.46, 117.23 (2C). LC-MS (m/
z): [M+H]+ calc. for C13H11N4O+, 239,09; Found: 239,13. HPLC
(λ280): Purity 98.4%; tR: 3.617 min (method 1).
N-(4-chlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine
(4.8)
Synthesized following the general procedure using 1-(4-chlor-
B
ophenyl)-2-methylisothiouronium iodide (0.329 g, 1 mmol) and nico-
tynohydrazide (0.137 g, 1 mmol) to afford the title compound as a
mixture of 1-H triazole and 2-H triazole tautomers (1:1). Beige powder
(192 mg, 71%). 1H NMR (400 MHz, DMSO‑d6): δ 13.99 (s, 0.5H), 12.95
(s, 0.5H), 9.62 (d, J = 67.9 Hz, 1H), 9.15 (dd, J = 8.0, 2.3 Hz, 1H),
8.65 (s, 1H), 8.29 (dt, J = 7.9, 2.0 Hz, 1H), 7.70–7.43 (m, 3H), 7.32 (d,
J = 13.3 Hz, 2H). 13C NMR (101 MHz, TFA-d1): δ 153.91, 147.05,
146.54, 145.50, 142.11, 138.59, 133.71, 133.14 (2C), 130.85, 128.16
(2C). LC-MS (m/z): [M+H]+ calc. for C13H11ClN5+, 272.07; Found:
272.33. HPLC (λ280): Purity 99.4%; tR: 1.233 min (method 1).
N-phenyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine [43] (6) To a dry
2-nicotinoyl-N-phenylhydrazinecarbothioamide (0.408 g, 1.5 mmol)
H2SO4 (15 mL, 30 mmol) was added slowly with syringe at 0 °C and the
stirring solution was left overnight at room temperature under argon
atmosphere. After the reaction was completed as monitored by TLC the
reaction mixture was poured into a cold water (200 mL) and the pH was
adjusted to 7 with NaOH solution. White precipitate was separated by
N-(3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,2,4-triazol-3-amine
(4.9)
Synthesized following the general procedure B using 1-(3,5-dimethyl-
phenyl)-2-methylisothiouronium iodide (0.322 g, 1 mmol) and nicoty-
nohydrazide (0.137 g, 1 mmol) to afford the title compound as a
8