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4.3.2. Synthesis of 2,6-bis(4-aminophenyl)-4-[4-(methylthio)phenyl]pyridine (2) (Figure S2A)
p-Aminoacetophenone (5 g, 37 mMol) was added to a suspension of crushed NaOH (1.5 g,
37 mmol) in PEG300 (20 mL) at room temperature. The suspension was stirred and heated to 80 ◦C to
form a clear solution. Then, p-methylthiobenzaldehyde (2.8 g, 18.5 mmol) was added to the reaction
mixture and heated at 110 ◦C for 4 h, after which NH4OAc (42.7 g, 555 mmol) was added and the
heating was reduced to 100 ◦C and stirred for 4 h. After cooling to room temperature, 400 mL cold water
was added to the mixture to get a precipitate which was filtered and further purified through silica
gel chromatography using DCM:MeOH (0–5%) as eluent affording compound
2
as a brown-yellow
powder (52%); 1H-NMR
δ
(300 MHz, CDCl3) 8.37 (d, 4H, J = 8.70 Hz, 2H-20 and 2H-60), 7.95 (s, 2H,
H-3 and H-5), 7.92 (d, 4H, J = 8.70 Hz, 2H-30 and 2H-50), 7.73 (d, 2H, J = 8.70 Hz, H-200 and H-600),
7.44 (d, 2H, J = 8.70 Hz, H-300 and H-500), 5.89 (br, 4H, 2NH2), 2.59 (s, 3H, CH3S). MALDI-TOF MS m/z
[M + H]+ Calcd C24H21N3S: 384.1529, Found: 384.1523.
4.3.3. Synthesis of 2,6-bis(4-azidophenyl)-4-[4-(methylthio)phenyl]pyridine (3) (Figure S2A)
Compound 2 (200 mg, 0.5 mmol) was added to 15 mL 6N HCl and the reaction mixture was cooled
to 0 ◦C and NaNO2 (138 mg, 2 mmol) was added and was stirred for 30 min under cold condition.
Sodium azide (195 mg, 3 mmol) was added to the reaction mixture portion-wise under cold condition;
and the reaction mixture was allowed to stir at room temperature for 2 h. The mixture was neutralized
with sodium bicarbonate and extracted with ethyl acetate (3
×
30 mL). The organic part was evaporated
under vacuum at 30 ◦C to afford compound
3 as yellow crystals (98%); as a yellow solid which was
used for next reaction. IR (KBr) 2105 cm-1 (N3). MALDI-TOF MS m/z [M+H]+ Calcd for C24H18N7S;
436.1339, Found: 436.1326.
4.3.4. General Procedure For The Synthesis of 2,6-bis{4-[4-(substituted-aminoalkyl)-1H-1,2,3-triazol-1-
yl]phenyl}-4-[4-(methylthio)phenyl]pyridines 1a–c
Compound
3 (50 mg, 0.1 mmol) was added to a mixture of 4 mL H2O and THF (1:1), then
CuSO4 5H2O (0.002 mmol) and sodium ascorbate (0.1 mmol) were added to the mixture and stirred.
·
After 5 min, the appropriate substituted alkyne (0.3 mmol) was added and stirred for 12 h at room
temperature. The solvent was evaporated under reduced pressure, and the residue was washed with
water followed by diethyl ether to afford the desired bis-triazolylarylpyridine compound 1a–c.
4-[4-(Methylthio)phenyl]-2,6-bis{4-[4-(3-pyrrolidin-1-ylpropyl)-1H-1,2,3-triazol-1 yl]phenyl}pyridine (1a).
Yellow crystals (84%); 1H-NMR (300 MHz, CDCl3) 8.39 (d, 4H, J = 8.80 Hz, 2H-20 and 2H-60),
δ
7.96 (s, 2H, H-3 and H-5), 7.92 (d, 4H, J = 8.80 Hz, 2H-30 and 2H-50), 7.86 (s, 2H, 2H triazol.), 7.74 (d, 2H,
J = 8.40 Hz, H-200 and H-600), 7.43 (s, 2H, J = 8.40 Hz, H-300 and H-500), 2.91 (t, 4H, J = 7.50 Hz, 2NCH2),
2.63-2.53 (m, 12H, 6 NCH2), 2.59 (s, 3H, CH3S), 2.06-1.96 (m, 4H, 2CH2 pyrrol.), 1.84-1.77 (m, 4H,
2CH2 pyrrol.). 13C-NMR (75 MHz, CDCl3)
δ 157.5 (C-2 and C-6), 151.4 (C-4), 150.2 (C-4 triazol.), 142.1
(C-400), 140.6 (C-10), 138.9 (C-40), 135.9 (C-100), 129.8 (C-30 and C-50), 128.7 (C-200 and C-600), 127.9 (C-300
and C-500), 121.8 (C-20 and C-60), 120.2 (C-5 triazol.), 118.5 (C-3 and C-5), 58.3 (NCH2), 56.8 (NCH2),
28.4 (CH2), 27.4 (CH2), 24.9 (CH2), 16.8 (CH3S). MALDI-TOF MS m/z [M+H]+ Calcd for C42H48N9S;
710.3748, Found: 710.3740.
2,6-Bis{4-[4-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,3-triazol-1-yl]phenyl}-4-[4-(methylthio)phenyl]-
pyridine (1b)
Orange crystals (68 %); 1H-NMR (300 MHz, CDCl3) 8.38 (d, 4H, J = 8.70 Hz, 2H-20 and 2H-60),
δ
7.96 (s, 2H, H-3 and H-5), 7.92 (d, 4H, J = 8.70 Hz, 2H-30 and 2H-50), 7.86 (s, 2H, 2H triazol.), 7.73 (d, 2H,
J = 8.50 Hz, H-200 and H-600), 7.43 (d, 2H, J = 8.50 Hz, H-300 and H-500), 2.89 (t, 4H, J = 7.50 Hz, 2NCH2),
2.66-2.42 (m, 20 H, 2NCH2 and 8NCH2 piperaz.), 2.59 (s, 3H, CH3S), 2.32 (s, 6H, 2NCH3), 2.02-1.92 (m,
4H, 2CH2). 13C-NMR (75 MHz, CDCl3)
δ
157.5 (C-2 and C-6), 151.3 (C-4), 150.1 (C-4 triazol.), 142.1
(C-400), 140.6 (C-10), 139.0 (C-40), 136.1 (C-100), 129.7 (C-30 and C-50), 128.8 (C-200 and C-600), 128.0 (C-300