D. Osmaniye, B.N. Sag˘lık, S. Levent et al.
Journal of Molecular Structure 1246 (2021) 131198
When looking at the data obtained, the fact that the com-
pounds show anticancer activity in relation to breast cancer is ob-
servable. Compound 5e is very important for both its anticancer
activity and aromatase inhibitory property. In summary, structural
modifications can be further made on the basis of the new tria-
zoles to look for compounds with higher inhibitory activity against
the human aromatase enzyme.
4.1.5. Synthesis of target compounds (5a-5h)
5-((2,4-Dichlorophenoxy)methyl)-4-ethyl-4H-1,2,4-triazole-
3-thiol (4) (0.485 gr, 1.6 mmol) and the appropriate 2-
bromoacetophenone (1.6 mmol) were reacted in the presence
of potassium carbonate in acetone (≥99.5%) at room temperature.
After completion of the reaction, the solvent was removed under
reduced pressure. The residue was washed with water to remove
potassium carbonate, then dried and recrystallized from EtOH.
4. Experimental
4.1.5.1. 2-((5-((2,4-Dichlorophenoxy)methyl)-4-ethyl-4H-1,2,4-triazol-
3-yl)thio)-1-phenylethan-1-one (5a). Yield: 85 %, M.P.: 167.8-169.2
°C. 1H-NMR (300 MHz, DMSO-d6): δ = 1.33 (3H, t, J=7.2 Hz,
-CH2CH3), 4.09 (2H, q, J=7.2 Hz, -CH2CH3), 5.00 (2H, s, -CH2-),
5.41 (2H, s, -CH2-), 7.42-7.43 (2H, m, 1,2,4-Trisubstituebenzene),
7.56 (2H, t, J=7.5 Hz, Monosubstituebenzene), 7.61 (1H, dd, J1=0.8
Hz, J2=1.9 Hz, 1,2,4-Trisubstituebenzene), 7.69 (1H, t, J=7.4 Hz,
Monosubstituebenzene), 8.03 (2H, d, J=7.2 Hz, Monosubstitueben-
zene). 13C-NMR (75 MHz, DMSO-d6): δ = 15.51, 33.03, 40.99,
61.19, 116.14, 122.83, 125.87, 128.59, 129.30, 129.31, 129.93, 134.25,
135.72, 151.17, 152.36, 193.14. HRMS (m/z): [M+H]+ calcd for
C19 H17 N3O2SCl2: 422.0491; found: 422.0489.
4.1. Chemistry
All reagents purchased from commercial suppliers were used
without additional purification. (M.p.), and the melting points de-
termined on the Mettler Toledo-MP90 Melting Point System are
uncorrected. For 1H-NMR (nuclear magnetic resonance), a Bruker
DPX 300 FT-NMR spectrometer was used and for 13C-NMR, a
Bruker DPX 75 MHz spectrometer (Bruker Bioscience, Billerica, MA,
USA). The coupling constants (J) were expressed in Hertz (Hz).
Mass spectra were recorded on an LCMS-IT-TOF (Shimadzu, Kyoto,
Japan) using the ESI method.
4.1.5.2. 1-(4-Chlorophenyl)-2-((5-((2,4-dichlorophenoxy)methyl)-
4-ethyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one (5b). Yield: 79 %,
M.P.: 199.4-201.3 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 1.33
(3H, t, J=7.2 Hz, -CH2CH3), 4.09 (2H, q, J=7.2 Hz, -CH2CH3),
4.98 (2H, s, -CH2-), 5.41 (2H, s, -CH2-), 7.42-7.43 (2H, m, 1,2,4-
Trisubstituebenzene), 7.61 (1H, br.s., 1,2,4-Trisubstituebenzene),
7.63 (2H, d, J=8.7 Hz, 1,4-Disubstituebenzene), 8.04 (2H, d,
J=8.6 Hz, 1,4-Disubstituebenzene). 13C-NMR (75 MHz, DMSO-d6):
δ = 15.50, 30.45, 40.85, 61.18, 116.14, 122.83, 125.88, 128.59,
129.42, 129.93, 130.81, 134.45, 139.15, 150.73, 151.21, 152.36,
192.71. HRMS (m/z): [M+H]+ calcd for C19 H16 N3O2SCl3: 456.0102;
found: 456.0096.
4.1.1. Synthesis of ethyl 2-(2,4-dichlorophenoxy)acetate (1)
2,4-Dichlorophenol (4.859 gr, 0.030 mol) was dissolved in ace-
tone (ACS reagent) (≥99.5%). Sodium hydride (0.864 gr, 0.036 mol)
was added in reaction mixture as 4 portions. Ethyl 2-chloroacetate
(3.69 mL, 0.036 mol) was added to the reaction medium; then,
the reaction was continued in the microwave reactor for 20 m. At
the end of the reaction, the solvent was removed. The filtrate was
washed with water, dried, and recrystallized from EtOH. The prod-
uct was obtained in 80% yield.
4.1.2. Synthesis of 2-(2,4-dichlorophenoxy)acetohydrazide (2)
Ethyl 2-(2,4-dichlorophenoxy)acetate (1) (5.952 gr, 0.024 mol)
was dissolved in ethanol (absolute) (50 mL). A solution of hy-
drazine hydrate in ethanol was added dropwise to the reaction
medium. After the dropping was completed, the reaction was
stirred for 5 h at room temperature. The precipitated product was
filtered. The hydrazide (2) was washed 3 times with cold ethanol
(95%) to remove the excess of hydrazine hydrate. The product was
obtained in 75% yield.
4.1.5.3. 2-((5-((2,4-Dichlorophenoxy)methyl)-4-ethyl-4H-1,2,4-triazol-
3-yl)thio)-1-(4-fluorophenyl)ethan-1-one (5c). Yield: 82 %, M.P.:
191.7-192.9 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 1.33 (3H,
t, J=7.2 Hz, -CH2CH3), 4.09 (2H, q, J=7.2 Hz, -CH2CH3), 4.99
(2H, s, -CH2-), 5.41 (2H, s, -CH2-), 7.38 (2H, d, J=8.8 Hz, 1,4-
Disubstituebenzene), 7.42-7.43 (2H, m, 1,2,4-Trisubstituebenzene),
7.61 (1H, dd, J1=0.8 Hz, J2=1.9 Hz, 1,2,4-Trisubstituebenzene), 8.11
(2H, dd, J1=4.8 Hz, J2=8.8 Hz, 1,4-Disubstituebenzene). 13C-NMR
(75 MHz, DMSO-d6): δ = 15.51, 29.80, 40.86, 61.18, 116.14, 116.36
(d, J=21.9 Hz), 122.83, 125.88, 128.59, 129.92, 131.98 (d, J=9.6 Hz),
132.52 (d, J=2.5 Hz), 150.79, 151.19, 152.36, 165.77 (d, J=252.2
Hz), 192.24. HRMS (m/z): [M+H]+ calcd for C19 H16 N3O2FSCl2:
440.0397; found: 440.0389.
4.1.3. Synthesis of
2-(2-(2,4-dichlorophenoxy)acetyl)-N-ethylhydrazine-1-carbothioamide
(3)
2-(2,4-Dichlorophenoxy)acetohydrazide (2) (4.914 gr, 0.021 mol)
and isothiocyanatoethane (1.827 gr, 0.021 mol) were dissolved in
ethanol (absolute) (40 mL). The reaction mixture was refluxed for
10 h. After completion of the reaction, the mixture was cooled and
the precipitated compound was filtered and recrystallized from
ethanol. The product was obtained in 83% yield.
4.1.5.4. 1-(4-Bromophenyl)-2-((5-((2,4-dichlorophenoxy)methyl)-
4-ethyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one
%, M.P.: 207.9-209.0 °C. 1H-NMR (300 MHz, DMSO-d6):
1.33 (3H, t, J=7.2 Hz, -CH2CH3), 4.09 (2H, q, J=7.2
(5d). Yield:
88
δ
=
Hz, -CH2CH3), 4.98 (2H, s, -CH2-), 5.41 (2H, s, -CH2-
), 7.42-7.43 (2H, m, 1,2,4-Trisubstituebenzene), 7.61 (1H,
d, J=1.7 Hz, 1,2,4-Trisubstituebenzene), 7.77 (2H, d, J=8.5
Hz, 1,4-Disubstituebenzene), 7.96 (2H, d, J=8.6 Hz, 1,4-
Disubstituebenzene). 13C-NMR (75 MHz, DMSO-d6): δ = 15.51,
30.31, 40.83, 61.18, 116.13, 122.83, 125.88, 128.38, 128.58, 129.93,
130.88, 132.37, 134.77, 150.73, 151.21, 152.36, 192.93. HRMS (m/z):
[M+H]+ calcd for C19 H16 N3O2SCl2Br: 499.9596; found: 499.9583.
4.1.4. Synthesis of
5-((2,4-dichlorophenoxy)methyl)-4-ethyl-4H-1,2,4-triazole-3-thiol (4)
2-(2-(2,4-dichlorophenoxy)acetyl)-N-ethylhydrazine-1-
carbothioamide (3) (5.778 gr, 0.018 mol) was dissolved in ethanol
(absolute) (40 mL). Sodium hydroxide solution (0.840 gr, 0.021
mol) in ethanol and carbon disulfide (1.270 mL, 0.021 mol) were
added to the reaction vial. The reaction mixture was refluxed for
5 h. After completion of the reaction, the mixture was poured in
ice water. The reaction medium is acidified with 20% HCl to pH 2.
The precipitated product was filtered, then dried and recrystallized
from EtOH. The product was obtained in 80% yield.
4.1.5.5. 2-((5-((2,4-Dichlorophenoxy)methyl)-4-ethyl-4H-1,2,4-triazol-
3-yl)thio)-1-(2,4-dihydroxyphenyl)ethan-1-one (5e). Yield: 77 %,
M.P.: 203.7-205.8 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 1.33
(3H, t, J=7.2 Hz, -CH2CH3), 4.09 (2H, q, J=7.2 Hz, -CH2CH3),
6