Regioselective synthesis, antitumor and antioxidant activities of some 1,2,4-triazole derivatives based on 4-phenyl-5-(quinolin-8-yloxy)methyl-4H-1,2,4-triazole-3-thiol

Article abstract of DOI:10.1080/10426507.2016.1247087

Regioselective synthesis of some triazole derivatives 4–18 was achieved from the versatile, readily accessible 4-phenyl-5-(quinolin-8-yloxy)methyl-4H-1,2,4-triazole-3-thiol/thione 3. The structures of the newly synthesized products were confirmed and characterized by IR, ¹H NMR, ¹³C NMR, and mass spectral studies. Most of the synthesized compounds were evaluated for their antitumor and antioxidant activities and demonstrated potent to weak activities.

Full text of DOI:10.1080/10426507.2016.1247087

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Regioselective Synthesis, Antitumor and Antioxidant Activities of Some 1,2,4-Triazole
Derivatives Based on 4-Phenyl-5-(quinolin-8-yloxy)methyl-4H-1,2,4-triazole-3-thiol
M. S. Behalo, M. S. Amine, I. M. Fouda
Chemistry Department, Faculty of Science, Benha University, Benha, P. O. Box 13518. Egypt
Corresponding author: mohamed.behalo@fsc.bu.edu.eg
ABSTRACT
Regioselective synthesis of some triazole derivatives 4-19 was achieved from the versatile, readily
accessible 4-phenyl-5-(quinolin-8-yloxy)methyl-4H-1,2,4-triazole-3-thiol/thione 3. The structures
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of the newly synthesized products were confirmed and characterized by IR, H NMR, C
NMR and mass spectral studies. Most of the synthesized compounds were evaluated for their
antitumor and antioxidant activities and demonstrated potent to weak activities.
Keywords: Quinoline; triazole; pyrazole; thiazole; antitumor; antioxidant
INTRODUCTION
In recent years considerable attention has been devoted to the synthesis of triazole and its thione
derivatives, as they possess such diverse pharmacological properties and industrial applications. A
number of these derivatives showed antimicrobial,1-5 anti-inflamatory,6 antioxidant,7 anticancer,8, 9
and anticonvulsant activity.10 In addition, quinolines are well known natural and synthetic products
occur in several natural compounds and pharmacologically active substances displaying a broad
range of biological activity. Quinoline has been found to possess anticancer,11,12 antibacterial,13,14
anti-tuberculosis,15 antimalarial.16,17
In continuation to our research program about the synthesis of heterocyclic compounds having
biological interest,18-21 we report herein the synthesis, antitumor and antioxidant activities of some
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novel structures incorporating both triazole and quinoline heterocycles. This work was suggested by
our group to investigate the effect of such combination on the anticipated pharmaceutical applications
of molecules including both triazole and quinoline moieties.
RESULTS AND DISCUSSION
The synthetic routes adopted for the synthesis of target structures are depicted in (Schemes 1-5).
Treatment of acid hydrazide 1 (prepared from hydrazinolysis of ethyl 2-(quinolin-8-
yloxy)acetate)3 with phenyl isothiocyanate in ethanol afforded compound 2. Heating of the latter
with sodium hydroxide (2M) furnished 4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazole-
3-thiol (3) (Scheme 1). Triazole 3 can exist in two tautomeric forms, thiol 3a and its tautomeric
thione 3b on the basis of its spectral data.22 1H NMR spectrum showed singlet signals
(exchangeable) at 12.81 and 6.33 ppm corresponding to NH and SH respectively. Also, IR
spectrum displayed absorption bands at 3204, 2615 and 1321 cm-1 corresponding to absorptions
of NH, SH and C=S respectively.
Triazole 3 is used as reactive key precursors for synthesis of a number of substituted 1,2,4-
triazole derivatives of expected biological activity through its reactivity towards variety of
electrophilic reagents depending on the reaction conditions. Thus, treatment of triazole 3 with
chloroacetic acid or ethylchloroacetate in absolute ethanol in the presence of potassium hydroxide
afforded 2-((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio) ethanoic acid
(4a) and ethyl 2-((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio) ethanoate
(4b) respectively via thiol toutomer 3a. In addition, the reaction of triazole 3a with methyl iodide
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in the presence of sodium ethoxide gives 8-((5-(methylthio)-4-phenyl-4H-1,2,4-triazol-3-
yl)methoxy) quinoline (5) (Scheme 2).
On the other hand, the treatment of triazole 3 with formaldehyde in ethanol furnished 2-
(hydroxymethyl)-4-phenyl-5-((quinolin-8-yloxy)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
(6) via thione toutomer 3b. Also, N, 4 –diphenyl -3-((quinolin-5-yloxy)methyl) -5-thioxo -4,5-
dihydro -1H-1,2,4-triazole-1-carbothioamide (7) was obtained via the reaction of compound 3b
with phenyl isothiocyanate.
Furthermore, the reaction of compound 3b with ethylchloroacetate in boiling pyridine as a weak
base furnished ethyl 2-(4-phenyl-3-((quinolin-8-yloxy)methyl)-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-1-yl)acetate (8) (Scheme 3) .
Mannich base derivatives are one of the most important compounds that have potent applications
in pharmaceutical chemistry. Thus, treatment of 1,2,4-triazole derivative 3b with several amines
namely, piperidine, p-toludine, morpholine and p-aminobenzoic acid in the presence of
formaldehyde afforded new Mannich base derivatives 9a-d in moderate to good yields (Scheme
3).
An extension of this synthetic approach, ethyl 2-((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-
1,2,4-triazol-3-yl)thio) ethanoate (4b) reacted with hydrazine hydrate in boiling ethanol to furnish
hydrazide 10 which was used as reactive starting material to construct a series of heterocyclic
systems as potential antimicrobial agents. Thus, treatment of hydrazide 10 with carbon disulfide,
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in ethanol containing potassium hydroxide afforded 5-(((4-phenyl-5-((quinolin-8-yloxy)methyl)-
4H-1,2,4-triazol-3-yl)thio)methyl)-1,3,4-oxadiazole-2-thiol (11).
Also, the reaction of hydrazide 10 with phenyl isothiocyanate in dry benzene containing few
drops of triethylamine afforded 4-phenyl-5-(((4-phenyl-8-((quinolin-5-yloxy)methyl)-4H-1,2,4-
triazol-3-yl)thio) methyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (12) (Scheme 4).
The biological activity of pyrazoles as antibacterials, antifungals, and anticancers,23-25 prompted
us to utilize the amino functionality of hydrazide 10 in the design of new heterocyclic systems
incorporating pyrazole nucleus. Thus, hydrazide derivative 10 has been allowed to react with
acetylacetone to afford pyrazole derivative 13. On the other hand, heating of hydrazide 10 with
glacial acetic acid afforded monoacetyl derivative 14 (Scheme 4).
Moreover, the triazole derivative 15 was synthesized through refluxing hydrazide 10 with
phthalic anhydride in glacial acetic acid, whereas Schiff base 16 was prepared by condensation of
10 with benzaldehyde in ethanol (Scheme 5).
Also, treatment of hydrazide derivative 10 with benzoic acid in the presence of phosphorous
oxychloride furnished oxadiazole derivative 17. Oxadiazole 17 can be prepared also by refluxing
benzoylchloride in pyridine, the melting point and IR spectra of the products are consistent.
Finally, treatment of hydrazide derivative 10 with D-glucose in ethanol containing few drops of
acetic acid furnished glucosazone 18 (Scheme 5).
Antitumor Activity
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Treatment of cell lines, hepatocellular carcinoma (HePG-2), mammary gland (MCF-7), Colorectal
carcinoma (HCT-116) and Human prostate cancer cell line (PC3) with some of the synthesized
products using MTT assay showed different cytotoxic effect as shown in (Table S 1, Supplemental
Materials). It was observed that, triazolethione 7 showed the most potent cytotoxic effect against
Colorectal carcinoma (HCT-116) and mammary gland (MCF-7) concluded from their IC50 values
8.4 and 7.7 µg/mL and strong activity against the other two cell lines. Also, Mannich base 9b showed
very strong activity against hepatocellular carcinoma (HePG-2) and Human prostate cancer cell line
(PC3) (IC50 = 9.1, 8.8 µg/mL). The rest of compounds showed moderate activity against all cell
lines while triazole derivative 17 showed weak cytotoxicty.
Antioxidant Activity
Antioxidant activity of the synthesized products and their ability to inhibit oxidation in rat brain and
kidney homogenates were evaluated using (ABTS) inhibition. It was observed from data in (Table S
2, Supplemental Materials) that most of the tested compounds showed potent antioxidant activities
especially triazoles 7 and 9d showed higher activity in comparison to the standard ascorbic acid.
CONCLUSION
We used 4-phenyl-5-(quinolin-8-yloxy)methyl-4H-1,2,4-triazole-3-thiol/thione 3 as a reactive
starting material to synthesize a novel series of triazole derivatives through its reactions with variety
of chemical reagents. Most of the synthesized products were evaluated for their antitumor and
antioxidant activities and exhibited potent to moderate activity.
EXPERIMENTAL
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Melting points were determined on a capillary point apparatus equipped with a digital thermometer
and Gallen Kamp melting point apparatus and are uncorrected. IR-Spectra (KBr disk) were recorded
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on FT/IR-BRUKER, Vector 22. 1H NMR and C NMR spectra were recorded in DMSO-d6 with
TMS for (300 and 50 MHz) as an internal reference. Mass spectrometry was done on Thermo
Finnegan (San Jose, CA) LCQ spectrophotometer with electro spray ionization (ESI) and on
Shimadzu GCMS-QP-1000EX mass spectrophotometer at 70 e.v. Elemental analyses were
performed on a Carlo Erba-1106 instrument. The pharmaceutical applications of the products were
carried out at Faculty of Pharmacy, Mansura University, Egypt. The Supplemental Materials
contains sample IR, mass and 1H NMR spectra of the products (Figures S 1 – S 24)
Synthesis of N-phenyl-2-(2-(quinolin-8-yloxy)acetyl)hydrazine-1-carbothioamide (2)
A mixture of hydrazide 1 [prepared from the reaction of ethyl 2-(quinolin-8-yloxy)acetate with
hydrazine hydrate in ethanol according to reported procedures]3 (0.01 mol) and phenyl
isothiocyanate (0.01 mol) in absolute ethanol (30 mL) was refluxed for 4 h then cooled to room
temperature. The product solid was collected by filtration, dried and crystallized from ethanol. Yield,
1
79 %; Pale yellow, m.p. 195-197 ◦C. IR ( KBr, ν cm−1), 3320-3190 (NH), 1677 (CO), 1315 (CS); H
NMR (DMSO-d6, δ ppm): 10.42, 9.74, 5.31 (3S, 3H, 3NH exchangeable) , 8.91 (d,1H,C-2 quin.),
8.32 (d, 1H, C-4 quin.), 7.61 – 7.13 (m, 9H, 1H C-3 quin., and 8H Ar-H) , 4.92 (s, 2H, OCH2); 13C
NMR δ: 198.3 (C=S), 168.3 (C=O), 155.1, 148.2, 142.4, 140.3, 136.2, 130.3, 128.5, 128.2, 127.1,
125.7, 120.5, 118.3, 108.2, (aromatic carbons), 65.8 (CH2); Anal. calcd. for C18H16N4O2S (352.41)
:C, 61.35; H, 4.58; N, 15.90 Found:C, 61.24; H, 4.35; N, 15.76.
Synthesis of 4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazole-3-thiol/ thione (3) 26
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A mixture of compound 2 (0.01 mol) and 10% sodium hydroxide solution (20 mL) was refluxed for
3 h, cooled to room temperature, poured over crushed ice and acidified with conc. HCl to pH 5. The
precipitate was collected by filtration, washed with water, dried and crystallized from ethanol to
afford triazole 3. Yield, 85%, Pale yellow, m.p. 219-221 ◦C. IR spectrum (KBr, ν, cm-1): 3204 (NH),
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2615 (SH), 1637 (C=N), 1321(C=S). H NMR (DMSO-d6, δ ppm): 12.82 (s, 1H, SH or NH
13
exchangeable), 7.17-8.37 (m, 11H, Ar-H), 6.33 (s, 1H, SH, exchangeable) 4.91 (s, 2H, OCH2); C
NMR δ: 169.2 (C=S), 156.3, 155.2, 148.3, 141.2, 134.8, 133.7, 132.5, 128.4, 128.1, 127.2, 125.5,
120.2, 116.3, 106.1(aromatic carbons), 73.2 (CH2); MS: m/z 334 (M+,18.67%), 336 ((M+2,
11.32%), 145 (100%). Anal. calcd. for C18H14N4OS (334.09): C, 64.65; H, 4.22; N, 16.75 Found: C,
64.89; H, 4.36; N, 16.70 .
Synthesis of 2-(4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio) acetic acid
(4a)
A mixture of compound 3 (0.01 mol) and chloroacetic acid (0.01 mol) was dissolved in ethanol (20
mL) containing potassium hydroxide (0.015 mol). The mixture was heated at reflux on water bath
for 6 h. The crude solid product that deposited was collected, dried and recrystallized from ethanol to
afford crystalline solid 4a. Yield, 88%, Yellow, m.p. 178-180 ◦C. IR spectrum (KBr, ν, cm-1): 3422
1
(OH), 2915, 2850 (CH aliphatic), 1701(C=O), 1598(C=N). H NMR (DMSO-d6, δ ppm): 11.23 (s,
1H, OH, exchangeable), 8.42-7.02 (m, 11H, Ar-H), 4.89 (s, 2H, OCH2), 4.20 (s, 2H, SCH2); 13C
NMR δ 173.5 (C=O), 155.8, 152.8, 148.2, 142.3, 134.2, 132.9, 132.2, 128.8, 128.3, 127.5, 126.2,
121.1, 117.2, 107.3, (aromatic carbons), 68.2 (OCH2), 42.6 (SCH2); MS: m/z 392 (M+, 7.65 %), 77
(100%). Anal. calcd. for C20H16N4O3S (392.43): C, 61.21; H, 4.11; N, 14.28 Found: C, 61.17; H,
4.01; N, 14.22.
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Synthesis of ethyl 2-(4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate
(4b)
A mixture of compound 3 (0.01 mol), ethyl chloroacetate (0.04 mol) and anhydrous potassium
carbonate (0.04 mol) in dry acetone (30 mL) was heated under reflux on water bath for 20h. The
reaction mixture was allowed to cool, poured into water. The solid so formed was filtered off,
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washed, dried and crystallized. Yield, 81%, Pale yellow, m.p. 112-114 C IR spectrum (KBr, ν, cm-
1): 2984, 2850 (CH aliphatic), 1742(C=O), 1595 (C=N). 1H NMR (DMSO-d6, δ ppm): 8.91-6.86 (m,
11H, Ar-H), 5.05 (s, 2H, OCH2), 4.104 (s, 2H, SCH2), 4.18 (q, 2H, CH2), 1.21 (t, 3H, CH3). MS: m/z
420 (M+, 24.92 %), 264 (100%). Anal. calcd. for C22H20N4O3S, (420.13): C, 62.84; H, 4.79; N,
13.32 Found: C, 62.80; H, 4.72; N, 13.27.
Synthesis of 5-((5-(methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy) quinoline (5)
A compound 3 (0.01 mol) in ethanol (20 mL) containing sodium ethoxide was refluxed for 2h.
Methyl iodide (0.01 mol) was then added and the mixture was refluxed for an additional 3h. The
solvent was evaporated under reduced pressure, and the solid obtained by adding water was filtered
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off and recrystallized from ethanol to afford 5. Yield, 78 %, Pale yellow, m.p. 123-125 C IR
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spectrum (KBr, ν, cm-1): 3014(CH aromatic), 2907, 2850 (CH aliphatic) , 1604 (C=N). H NMR
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(DMSO-d6, δ ppm): 8.80-6.97 (m, 11H, Ar-H) , 5.25 (s, 2H, OCH2), 3.87 (s,3H,CH3); C NMR δ
156.3, 152.6, 149.5, 144.6, 133.3, 132.7, 131.5, 127.3, 127.9, 126.8, 126.1, 120.5, 118.5, 110.3,
(aromatic carbons), 66.5 (OCH2), 15.1 (CH3); Anal. calcd. for C19H16N4OS (348.42): C, 65.50; H,
4.63; N, 16.08 Found: C, 65.45; H, 4.60; N, 16.15 .
Synthesis of 2-(hydroxymethyl)-4-phenyl-5-((quinolin-8-yloxy)methyl)-2,4-dihydro-3H-1,2,4
triazole-3-thione (6)
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A mixture of 3 (0.01 mol) and formaldhyde (0.02 mol) in ethanol (20 mL) was refluxed for 5 h. The
solid that separated after concentration and cooling was recrystallized from ethanol to give 6. Yield,
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76 %, Yellow, m.p. 134-136 C. IR spectrum (KBr, ν, cm-1): 3424 (OH), 1598 (C=N) and 1313
1
(C=S). H NMR (DMSO-d6, δ ppm): 8.92-6.97 (m, 11H, Ar-H) , 5.53, 4.92 (2s, 4H, 2OCH2), 4.18
(s, 1H, OH, exchangeable); 13C NMR δ 170.6 (C=S), 156.2, 154.3, 147.5, 142.6, 135.3, 132.6, 131.7,
128.5, 127.3, 126.8, 126.1, 121.6, 118.4, 108.2 (aromatic carbons), 72.2 (OCH2), 70.3 (OCH2).
Anal. calcd. for C19H16N4O2S (364.42): C, 62.62; H, 4.43; N, 15.37 Found: C, 62.45; H, 4.27; N,
15.30.
Synthesis of N,4-diphenyl-3-((quinolin-8-yloxy)methyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole
-1-carbothioamide (7)
To a solution of 4-phenyl-5-((quinolin-5-yloxy)methyl)-4H-1,2,4-triazole-3-thiol 3 (0.01 mol) in
ethanol (20 mL), phenyl isothiocyanate (0.01 mol) was added. The mixture was refluxed for 3h. The
solid product was filtered off, recrystallized from ethanol to afford 7 as a yellow solid. Yield, 85 %,
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Yellow, m.p. 182-184 C. IR spectrum (KBr, ν, cm-1): 3205 (NH), 2918, 2840 (CH aliphatic), 1597
(C=N), and 1321 (C=S). 1H NMR (DMSO-d6, δ ppm): 11.03 (s, 1H, NH, exchangeable), 8.90-7.12
(m, 16H, Ar-H), 4.92 (s, 2H, OCH2); 13C NMR δ 192.3, 185.6 (2C=S) 154.4, 151.2, 148.5, 144.2,
133,7, 132.6, 132.1, 131.5, 130,5, 128.5, 127.2, 127.6, 126.3, 125.7, 122.4, 117.8, 112.5, 108.5,
(aromatic carbons), 68.5 (OCH2); MS: m/z 469 (M+, 13.25 %), 471 (M+2, 7.23 %), 93(100%). Anal.
calcd. for C25H19N5OS2 (469.58): C, 63.95; H, 4.08; N, 14.91 Found: C, 63.87; H, 3.98; N, 14.85.
Synthesis of ethyl 2-(4-phenyl-3-((quinolin-8-yloxy)methyl)-5-thioxo-4,5-dihydro -1H 1,2,4-
triazol-1-yl)acetate (8)
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A mixture of compound 3 (0.01 mol) and ethyl chloroacetate (0.01 mol) in pyridine (15 mL) was
refluxed for 4h. After cooling, the reaction mixture was poured into crushed ice and neutralized with
dil HCl. The resulting solid product was filtered off and recrystallized from ethanol to give crystals
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of compound 8.Yield, 73 %, Pale yellow, m.p.194- 196 C. IR spectrum (KBr, ν, cm-1): 2987 (CH
1
aliphatic), 1743(C=O), 1641(C=N), 1316(C=S). H NMR (DMSO-d6, δ ppm): 8.08-6.93 (m, 11H,
Ar-H) , 5.03 (s, 2H, OCH2) , 4.99 (s, 2H, CH2), 4.10 (q, 2H, CH2), 1.23 (t, 3H, CH3). 13C NMR δ
190.5 (C=S),172.3 (CO), 155,5, 152.5, 148.3, 144.6, 133.5, 132.2, 131.5, 129.2, 128.5, 126.3, 125.8,
121.5, 117.5, 107.8 (aromatic carbons), 70.5, 67.3 (2OCH2), 48.5 (NCH2), 16.5 (CH3). Anal. calcd.
for C22H20N4O3S (420.13): C, 62.84; H, 4.79; N, 13.32 Found: C, 62.77; H, 4.65; N, 13.21.
General procedure for the synthesis of compounds (9a-d)
A mixture of 3 (0.01 mol) and the corresponding amine (0.02 mol) such as pipredine, p-toludine,
morpholine, and 4 amino benzoic acid in ethanol (20 mL) was refluxed for 4h in the presence of
formaldehyde (37%, 0.02 mol). After cooling and addition of water, the mixture was kept overnight
in cold conditions. The solid that separated was collected by filtration and recrystallized from ethanol
to yield the target compounds (9a-d).
4-Phenyl-2-(piperidin-1-ylmethyl)-5-((quinolin-5-yloxy)methyl)-2,4 dihydro-3H-1,2,4-triazole-
3-thione (9a)
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Yield, 72 %, Yellow, m.p. 169 - 171 C. IR spectrum (KBr, ν, cm-1): 3059 (CH aromatic), 2932-
2851 (CH aliphatic), 1617 (C=N), 1315 (C=S). 1H NMR (DMSO-d6, δ ppm): 8.81-7.02 (m, 11H, Ar-
13
H), 4.85 (s, 2H, OCH2), 4.23 (s, 2H, NCH2), 3.65 (t, 4H, CH2NCH2), 3.23-3.11 (m, 6H, 3CH2); C
NMR δ 184.5 (C=S), 153.7, 152.2, 144.5, 142.3, 133.3, 132.8, 131.6, 129.4, 127.3, 126.5, 124.2,
122.5, 118.3, 111.5 (aromatic carbons), 69.5, (OCH2), 56.6, 52.5, 48.5 (3NCH2), 23.5, 22.7 (3CH2);
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MS: m/z 431 (M+, 15.21 %), 433, (M+2, 9.10), 98 (100%). Anal. calcd. for C24H25N5OS (431.56): C,
66.80; H, 5.84; N, 16.23 % Found: C, 66.72; H, 5.77; N, 16.17 %.
4-Phenyl-5-((quinolin-8-yloxy)methyl)-2-((p-tolylamino)methyl)-2,4-dihydro-3H-1,2,4-triazole-
3-thione (9b)
◦
Yield, 74 %, Yellow, m.p. 177- 179 C. IR spectrum (KBr, ν, cm-1): 3289 (NH) , 2920, 2850
1
(CH aliphatic), 1616(C=N), 1275(C=S). H NMR (DMSO-d6, δ ppm): 10.93 (s, 1H, NH,
exchangeable), (8.36-6.98 (m, 15H, Ar-H), 4.72 (s, 2H, OCH2), 3.96 (s, 2H, NCH2). Anal. calcd. for
C26H22N5OS (452.56): C, 68.85; H, 5.11; N, 15.44 Found: C, 68.80; H, 5.05; N, 15.23 %.
2-(Morpholinomethyl)-4-phenyl-5-((quinolin-8-yloxy)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-
thione (9c)
◦
Yield, 71 %, Pale yellow, m.p. 180-182 C. IR spectrum (KBr, ν, cm-1): 3056 (CH aromatic),
1
2956, 2850 (CH aliphatic), 1619 (C=N), 1312 (C=S). H NMR (DMSO-d6, δ ppm): 8.87-7.11 (m,
11H, Ar-H), 4.917 (s, 2H, OCH2), 4.12 (s, 2H, CH2), 3.88 (t, 4H, CH2OCH2), 3.48 (t, 4H,
CH2NCH2); 13C NMR δ 181.2 (C=S), 154.5, 152.1, 148.4, 142.5, 133.6, 131.5, 131.1, 128,5, 127.8,
125.1, 124.5, 121.2, 117.4, 110.2 (aromatic carbons), 71.5, 69.3 (3OCH2), 52.2, 50.7 (3NCH2); Anal.
calcd. for C23H23N5O2S (433.53): C, 63.72; H, 5.35; N, 16.15 Found: C, 63.80; H, 5.33; N, 16.09 %
.4-(((4-Phenyl-3-((quinolin-8-yloxy)methyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)
amino)benzoic acid (9d)
Yield, 73 %, Pale yellow, m.p. 193-195 ◦C. IR spectrum (KBr, ν, cm-1): 3422 (OH), 3205 (NH),
1
1685 (C=O), 1605 (C=N), 1261(C=S). H NMR (DMSO-d6, δ ppm): 12.39 (s, 1H, OH,
exchangeable), 8.89 (s, 1H, NH, exchangeable), 8.21-6.98 (m, 15H, Ar-H), 5.20 (s, 2H, OCH2), 4.92
(s, 2H, CH2); 13C NMR δ 178.4 (C=S), 169.2 (C=O), 155.3, 152.4, 145.5, 142.3, 136.5, 133.3, 132.5,
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131.5, 131.2, 128,2, 127.5, 126.4, 123.4, 121.5, 116.2, 108.5 (aromatic carbons), 68.5 (OCH2), 48.8
(NCH2); Anal. calcd. for C26H21N5O3S (483.55): C, 64.58; H, 4.38; N, 14.48 Found: C, 64.45; H,
4.30; N, 14.40 % .
Synthesis
of
2-(4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio)
acetohydrazide (10)
To a suspension of 4b (0.01 mol) in absolute ethanol (30 mL), hydrazine hydrate (0.015 mol) was
added and the reaction mixture was refluxed for 6 h. The solution was concentrated and allowed to
cool. The resulting solid obtained was filtered after washed with cold water, dried and recrystalized
◦
from ethanol to give brown crystals of 10. Yield, 73 %, Pale yellow, m.p. 197-199 C. IR spectrum
1
(KBr, ν, cm-1): 3405- 3265 (NH, NH2), 2924, 2855 (CH aliphatic), 1671 (C=O), 1593 (C=N). H
NMR (DMSO-d6, δ ppm): 9.35 (s, 1H, NH, exchangeable), 8.86-7.01(m, 11H, Ar-H), 5.27 (s, 2H,
OCH2), 4.35 (s, 2H, NH2, exchangeable), 3.92 (s, 2H, CH2). MS: m/z 406 (M+, 10.05 %), 407, (M+1,
8.21), 145 (100%). Anal. calcd. for C20H18N6O2S (406.46): C, 59.10; H, 4.46; N, 20.68 Found: C,
59.03; H, 4.40; N, 20.59 %.
Synthesis of 5-(((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl) thio) methyl)-
1,3,4-oxadiazole-2-thiol (11)
To a solution of potassium hydroxide (0.15 mol, 1g in 10 mL H2O) in ethanol (20 mL), hydrazide 10
(0.013 mol) and carbon disulphide (0.06 mol, 5 mL) were added. The mixture was heated at reflux
on water bath for 6h. then it was poured into water and neutralized by dilute hydrochloric acid and
the precipitated solid was recrystallized from light petroleum ether / benzene to give 11 as yellow
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crystals. Yield, 76 %, Yellow, m.p. 122-124 C. IR spectrum (KBr, ν, cm-1): 2924, 2853 (CH
1
aliphatic), 2613(SH), 1383(C=S), 1595 (C=N). H NMR (DMSO-d6, δ ppm): 6.91 – 8.36 (m, 11H,
Ar-H) , 5.29 (s, 2H, OCH2), 4.36 (s, 2H, SCH2), 3.76 (s, 1H, SH). MS: m/z 448 (M+, 15.13 %), 51
(100%). Anal. alcd. for C21H16N6O2S2 (448.52): C, 56.24; H, 3.60; N, 18.74 Found: C, 56.17; H,
3.48; N, 18.68 %.
Synthesis of 4-phenyl-5-(((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol -3-yl)thio)
methyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (12).
A mixture of hydrazide 10 (0.01 mol) and phenyl isothiocyanate (0.01 mol) in absolute ethanol (30
mL) was refluxed for 6 h and then cooled to room temperature then a mixture of new compound
(0.01 mol) and 10% sodium hydroxide solution (20 mL) was refluxed for 5 h, cooled to room
temperature, poured over crushed ice and acidified with conc. HCl to pH 5. The precipitate was
collected by filtration, washed with water, dried and crystallized from ethanol to give 12. Yield, 75
◦
%, Pale yellow, m.p. 113-115 C. IR spectrum (KBr, ν, cm-1): 3286 (NH), 2621(SH), 1598 (C=N),
1
and 1377(C=S). H NMR (DMSO-d6, δ ppm): 9.90 (s, 1H, NH, exchangeable) , 8.84-6.91 (m, 16H,
Ar-H) , 5.23(s, 2H, OCH2), 4.97(s, 1H, SH, exchangeable), and 4.02 (s, 2H, SCH2). MS: m/z 523
(M+, 10.54 %), 93 (100%). Anal. calcd. for C27H21N7OS2 (523.63): C, 61.93; H, 4.04; N, 18.72
Found: C, 61.87; H, 3.95; N, 18.66 %.
Synthesis of 1-(3,5-dimethyl-1H-pyrazol-1-yl)-2-((4-phenyl-5-((quinolin-8-yloxy) methyl)-4H-
1,2,4-triazol-3-yl)thio)ethan-1-one (13)
To a solution of acetohydrazide derivative 10 (0.01 mol) in absolute ethanol (20 mL), acetylacetone
(0.01 mol) was added and the reaction mixture was heated at reflux for 8 h, left to cool. The crude
solid product that deposited was collected, dried and recrystallized from petroleum ether/ benzene to
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afford 13 as a yellow crystalline solid. Yield, 70 %, Yellow, m.p. 121-123 ◦C. IR spectrum (KBr, ν,
1
cm-1): 1691(C=O), 1592(C=N), and 1361(C=S). H NMR (DMSO-d6, δ ppm): 8.87-7.20 (m, 11H,
Ar-H) , 5.26 (s, 2H, OCH2), 4.36 (s, 2H, SCH2), 6.45 (s, 1H, pyrazole-H), 2.01, 2.12 (2s, 6H, 2CH3).
Anal. alcd. for C25H22N6O2S (470.55): C, 63.81; H, 4.71; N, 17.86 Found: C, 63.77; H, 4.55; N,
17.70 % .
Synthesis of N'-acetyl-2-((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl) thio)
acetohydrazide (14).
A solution of acetohydrazide derivative 10 (0.01 mol) in glacial acetic acid (20 mL) was heated at
reflux for 5h, left to cool. The crude solid product that deposited was collected and recrystallized
◦
from ethanol to afford 14 as yellow crystalline solid. Yield, 77 %, Yellow, m.p. 117-119 C. IR
spectrum (KBr, ν, cm-1): 3246 (NH), 2930, 2845 (CH aliphatic), 1690-1675 (C=O), 1628(C=N), and
1
1317 (C=S). H NMR (DMSO-d6, δ ppm): 9.86, 6.32 (2s, 2H, 2NH, exchangeable), 8.38-6.90 (m,
11H, Ar-H) , 5.11 (s, 2H, OCH2), 3.25 (s, 3H, CH3). MS: m/z 448 (M+, 15.39 %), 145 (100%). Anal.
calcd. for C22H20N6O3S (448.50): C, 58.92; H, 4.49; N, 18.74 Found: C, 58.72; H, 4.45; N, 18.64 %.
Synthesis of N-(1,3-dioxoisoindolin-2-yl)-2-((4-phenyl-5-((quinolin-8-yloxy) methyl)-4H-1,2,4-
triazol-3-yl)thio)acetamide (15)
A mixture of 10 (0.01 mol) and phthalic anhydride (0.01 mol) in glacial acetic acid (20 mL) was
heated under reflux for 5 h, after cooling, the reaction mixture was poured over ice-water. The
separated solid was collected by filtration, washed, dried and recrystallized from glacial acetic acid
◦
to give pure product 15. Yield, 75 %, Pale yellow, m.p. 120-122 C. IR spectrum (KBr, ν, cm-1):
1
3236 (NH), 1761-1714 (C=O), 1599 (C=N). H NMR (DMSO-d6, δ ppm): 11.08 (s, 1H, NH,
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13
exchangeable), 8.87-6.93 (m, 15H, Ar-H), 5.29 (s, 2H, OCH2), 4.30 (s, 2H, SCH2); C NMR δ
175.4, 168.7, 155.5, 153.3, 148.4, 143.2, 134.7, 133.1, 132.4, 131.5, 129.3, 128.6, 127.3, 126.8,
123.4, 121.6, 118.5, 108.5, 70.2, 48.3. Anal. calcd. for C28H20N6O4S (536.57): C, 62.68; H, 3.76; N,
15.66 Found: C, 62.59; H, 3.59; N, 15.52 %.
Synthesis of (E)-N'-benzylidene-2-((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-
yl)thio)acetohydrazide (16)
To a hot solution of acetohydrazide derivative 10 (0.01 mol) in ethanol (20 mL), benzaldehyde (0.01
mol) was added and the reaction mixture was heated under reflux for 6 h., left to cool. The crude
solid product that deposited was collected, dried and recrystallized from ethanol to afford 16 as
◦
yellow crystals. Yield, 80 %, Yellow, m.p. 130-132 C. IR spectrum (KBr, ν, cm-1): 3258 (NH),
3058 (CH aliphatic), 1686 (C=O), and 1598 (C=N). 1H NMR (DMSO-d6, δ ppm): 10.26 (s, 1H, NH,
exchangeable), 9.06 (s, 1H, CH=N), 8.65-6.97 (m, 16H, Ar-H), 5.11 (s, 2H, OCH2), 4.63 (s, 2H,
13
SCH2); C NMR δ 173.5, 155.3, 154.2, 148.1, 144.4, 142.3, 134.3, 132.9, 132.2, 131.7, 129.5,
127.8, 127.4, 126.2, 125.7, 125.1, 122.6, 121.3, 119.4, 107.2, 69.8, 50.3. MS: m/z 494 (M+, 8.82 %),
145 (100%). Anal. calcd. for C27H22N6O2S (494.57): C, 65.57; H, 4.48; N, 16.99 Found: C, 65.32; H,
4.72; N, 16.77 %.
Synthesis
of
2-phenyl-5-((4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-
yl)thio)methyl-1,3,4-oxadiazole (17)
A mixture of 10 (0.01 mol) and benzoic acid (0.01 mol) in phosphorous oxychloride (15 mL) was
heated at reflux on water bath for 6 h. left to cool and poured into crushed ice. The solid product that
formed was collected, washed with water, dried and recrystallized from light petroleum ether to
◦
afford 17 as brown crystals. Yield, 78 %, Brown, m.p. 125-127 C. IR spectrum (KBr, ν, cm-1):
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1600 (C=N). H NMR (DMSO-d6, δ ppm): 8.86-7.20 (m, 16H, ArH), 5.28 (s, 2H, OCH2); 4.35 (s,
2H, SCH2). MS: m/z 492 (M+, 11.17 %), 105 (100%). Anal. calcd. for C27H20N6O2S (492.56): C,
65.84; H, 4.09; N, 17.06 Found: C, 65.61; H, 3.98); N, 16.90 %.
Alternative method for synthesis of oxadiazole 17
A mixture of 10 (0.01 mol) and benzoyl chloride (0.03 mol) in pyridine (5 mL) was heated at reflux
on water bath for 6 h. left to cool, neutralized by cooled dilute hydrochloric acid. The solid product
that formed was collected, washed with water, dried and recrystallized from light petroleum ether to
afford 17.
Synthesis of N'-((2S,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexylidene)-2-((4-phenyl-5-((quinolin-5-
yloxy)methyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide (18)
A mixture of acetohydrazide derivative 10 (0.01 mol) and glucose (0.01 mol) in ethanol (30 mL)
was heated under reflux for 4h. The solid product which was separated out after cooling was
collected, dried and recrystallized from ethanol to afford hydrazone 18. Yield, 78 %, Pale yellow,
◦
m.p. 170-172 C. IR spectrum (KBr, ν, cm-1): 3392-3150 (OH, NH), 2850 (CH aliphatic), 1680
1
(C=O), 1632 (C=N). H NMR (DMSO-d6, δ ppm): 10.63 (s, 1H, NH, exchangeable), 8.99 (s, 1H,
CH=N), 8.52-7.12 (m, 11H, ArH), 5.20 (s, 2H, OCH2); 4.26 (s, 2H, SCH2), 4.32-3.68 (brs, 5H,
5OH), 3.43 (m, 2H, CH2), 3.30-3.15 (m, 4H, 4CH). Anal. calcd. for C26H28N6O7S (568.61): C, 54.92;
H, 4.96; N, 14.78 Found: C, 54.82; H, 4.77; N, 14.63 %.
Acknowledgment. Authors wish to thank Chemistry Department, Faculty of Science, Benha
University for the financial support.
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Scheme 1: Synthetic pathway of triazole 3.
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Scheme 2: Synthesis of triazole derivatives 4,5.
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Scheme 3: Synthesis of triazole derivatives 6-9.
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Scheme 4: Synthesis of triazole derivatives 11-14.
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Scheme 5: Synthesis of triazoles derivatives 15.18.
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