New N-(Aryl)-5-((quinolin-8-yloxy)methyl)-1,3,4-oxa/Thiadiazol-2-amines and 4-Aryl-5-((quinolin-8-yloxy)methyl)-2H-1,2,4-triazole-3(4H)-thiones, synthesis and characterization

Article abstract of DOI:10.1002/jhet.1817

Figure presented In this study, methyl 2-(quinolin-8-yloxy) acetate (2) obtained by reaction of 8-hydroxyquinoline (1) with methyl chloroacetate was condensed with hydrazine hydrate to afford the carbohydrazide (3). Thio/semicarbazide derivatives (4a-g) w

Full text of DOI:10.1002/jhet.1817

September 2014 New N-(Aryl)-5-((quinolin-8-yloxy)methyl)-1,3,4-oxa/Thiadiazol-2-amines
and 4-Aryl-5-((quinolin-8-yloxy)methyl)-2H-1,2,4-triazole-3(4H)-thiones,
Synthesis and Characterization
1357
a
a
a
b
*
Aamer Saeed, Naeem Abbas, Aliya Ibrar, and Michael Bolte
aDepartment of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
bInstitut für Anorganische Chemie, J.W.-Goethe-Universität, Max-von-Laue-Str.7D-60438 Frankfurt/Main, Germany
*
E-mail: aamersaeed@yahoo.com
Received May 29, 2012
DOI 10.1002/jhet.1817
Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
In this study, methyl 2-(quinolin-8-yloxy) acetate (2) obtained by reaction of 8-hydroxyquinoline (1) with
methyl chloroacetate was condensed with hydrazine hydrate to afford the carbohydrazide (3). Thio/semicarbazide
derivatives (4a–g) were obtained by treatment of the 3 with substituted phenyl iso/thioisocyanates. The 4a–g
on acidic and basic intramolecular cyclization led to N-(aryl)-5-((quinolin-8-yloxy)methyl)-1,3,4-oxa/thiadiazol-
2-amines (5a–g) and 4-aryl-5-((quinolin-8-yloxy)methyl)-2H-1,2,4-triazole-3(4H)-thiones (6a–g), respectively.
All the synthesized compounds were characterized by spectroscopic techniques and elemental analyses.
The thiosemicarbazide (4c) was also confirmed by X-ray crystallography.
J. Heterocyclic Chem., 51, 1357 (2014).
INTRODUCTION
The inhibitory effect of benzoyl thiadiazole derivatives on
C-steel has been studied by electrochemical measurements
such as open circuit potential, Tafel polarization, and
electrochemical impedance spectroscopy [19]. A number
of methods are available for synthesis of oxadiazoles/
thiadiazoles including the solid-phase synthesis of substituted
1,3,4-thiadiazoles through resin-bound thiosemicarbazide
synthesis [20]. A green protocol has been reported for
the synthesis of 3,5-disubstituted 1,2,4-thiadiazoles from
thiobenzamides using N-benzyl-DABCO-tribromide in
aqueous media [21].
The triazole ring existing in 1,2,3-triazole and 1,2,4-triazole
isomeric forms [22] is found in a number of antifungal
drugs such as isavuconazole [23], voriconazole [24], and
plants protection fungicides such as paclobutrazol [25],
epoxiconazole, tebuconazole, flusilazole, propiconazole,
and cyproconazole [22].
The synthesis of new compounds and evaluation of their
biological and pharmacological activities are the major
goals of drug improvement projects. Quinoline alkaloids
are extensively distributed in nature and exhibit significant
biological activities [1,2]. Compounds containing quino-
line nucleus are the key building blocks for synthesis of a
huge variety of compounds of vital importance in drug in-
dustry; therefore, structural modifications in this structural
motif leading to the molecular diversity is important in
drug designing [3–5]. The quinoline derivatives have
been used as immuno-suppressive [6], hypocholesterole-
mic [7], and nonnucleoside anti-Hepatitis B virus agents
[8]. Effect of a natural quinoline alkaloid, skimmianine, in
histamine release from rat mast cells has been studied [9],
and 2-mercapto/2-selenobenzoquinoline-3-carbaldehydes
have shown wound healing, antibacterial, DNA binding,
and in vitro antioxidant activities [10].
Similarly, oxa/thiosemicarbazides are the key intermediate
for the synthesis of a number of heterocyclic systems such as
diazoles, triazoles, and imino thiazolidinones [11,12].
Oxa/thiadiazole is another versatile heterocyclic scaffold
of tremendous interest because of its significant contribution
in the biological and pharmaceutical fields [13,14] with
prominent potential as antituberculosis [15], antidepressant,
[16] and antiproliferative agents [17]. The Cefozopran, a
fourth-generation cephalosporin, shows remarkable activity
against Gram negative and Gram positive bacteria [18].
Taking the drug-like properties and synthetic accessibility
of individual heterocyles into account, some hybrid struc-
tures of 1,3,4-oxa/thiadiazol-2-amines and 1,2,4-triazole-3
(4H)-thiones with quinoline were prepared and reported in
this article.
RESULTS AND DISCUSSION
As shown in Scheme 1, commercially available quinolin-
8-ol (1) was treated with methyl chloroacetate using K2CO3
in DMF to afford methyl 2-(quinolin-8-yloxy)acetate (2)
© 2014 HeteroCorporation

1358
A. Saeed, N. Abbas, A. Ibrar, and M. Bolte
Vol 51
Scheme 1. Synthetic route to quinolinyloxy 1,3,4-oxa/thiadiazol amines and 1,2,4-triazolone/thiones.
that was smoothly converted into 2-(quinolin-8-yloxy)
acetohydrazide (3) by refluxing with hydrazine hydrate
in ethanol. Treatment of 3 with ethanolic solutions of
arylisocyanates or aryl isothiocyanates at reflux afforded
quinolinyloxythiosemicarbazides (4a–4e) and quinolinyloxy
semicarbazides (4f–4h), respectively, in excellent yields.
In the FTIR spectrum of a typical thiasemicarbazide (4c),
appearance of peaks for NH stretchings in the range
3332–3257, C-H stretching of methylenic group at
2948 cmÀ1, and carbonyl and thiocarbonyl at 1688 and
1232 cmÀ1, respectively, was observed. In 1H NMR, the NH
peaks appeared at 14.35, 10.12, and 9.45 ppm, aromatic pro-
tons in the range of 8.85–7.79, and singlets for methylenic
and methoxy protons at 4.88 ppm and 3.91 ppm. In 13C
NMR, the thiocarbonyl and carbonyl carbons were noted at
174.8 and 167.6 ppm, respectively, whereas the methylenic
and the methoxy carbons appeared at 68.2 and 55.4 ppm.
In GC–MS, the molecular ion peak was observed at m/z
382 and base peak at m/z 145, whereas the other important
peaks appeared at m/z 107, 77, and 31. The structure was
finally confirmed unambiguously by X-ray crystallography.
The crystal structure of 1-(2-(quinolin-8-yloxy)acetyl)-4-
(2-methoxyphenyl)thiosemicarbazide (4c) is shown in
Figure 1. It crystallizes in the monoclinic space group
P 21/n with unit cell dimensions at a = 8.1506(4)Å, a = 90ꢀ,
b = 13.8190(4), b = 101.669(4), c = 19.2381(10) Å, g = 90ꢀ.
Data were collected on a STOE IPDS II two-circle diffrac-
tometer with graphite-monochromated MoKa radiation. An
empirical absorption correction was performed using the
MULABS [26] option in PLATON [27]. The structure
was solved by direct methods using the program SHELXS
[28] and refined against F2 with full-matrix least-squares
techniques using the program SHELXL-97 [29]. There were
26,385 reflections measured, 1548 unique (Rint = 0.0660)
that were used in all calculations. Final R values:
R1 = 0.0452, wR(F2) = 0.1176 (I > 2 (I)); R1 = 0.0524, wR
(F2) = 0.1219 (all data). The molecular conformation is
stabilized by an N-H. . .O hydrogen bond. An ethanol mol-
ecule is bonded to 4c by an N-H. . .O and an O-H. . .N
hydrogen bonds. Molecules of 4c form centrosymmetric
dimers connected by N-H. . .O hydrogen bonds [30].
Acid-catalyzed intramolecular cyclization of quinolinyloxy
thiosemicarbazide (4a–4e) and quinolinyloxy semicarbazides
(4f–4h) using polyphosphoric acid afforded quinolinyloxy
1,3,4-oxadiazole amines (5a–4e) and 1,3,4-thiadiazole amines
(5f–5h), respectively. The absorption bands associated with
different functional groups appeared in the expected regions.
Considering compound (5g), the structure was supported by
FTIR with stretching for NH group at 3292 and methylenic
Figure 1. Crystal structure of 1-(2-(quinolin-8-yloxy)acetyl)-4-(2-
methoxyphenyl)thiosemicarbazide (4c). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014 New N-(Aryl)-5-((quinolin-8-yloxy)methyl)-1,3,4-oxa/Thiadiazol-2-amines and 4-Aryl-5-
((quinolin-8-yloxy)methyl)-2H-1,2,4-triazole-3(4H)-thiones, Synthesis and Characterization
1359
CH2 at 2930 cmÀ1. In 1H NMR spectrum, one NH signal at
10.88 ppm instead of three NH protons was noted besides
the singlet for methylenic protons at 5.84 ppm. In 13C NMR,
the methylenic carbon appeared at 65.3 ppm, and disap-
pearance of carbonyl carbon was noted.
The intramolecular cyclization in basic medium led to
the synthesis of quinolinyloxy1,2,4-triazolones (6a–6e) or
1,2,4-thiones derivatives (6f–6h). In FTIR spectrum of 6b,
appearance of NH stretching at 3258 cmÀ1, CH stretching at
2929 cmÀ1, and thiocarbonyl stretching at 1254 cmÀ1 was
observed. 1H NMR signals at 5.57 ppm, and 2.36 ppm signal
was assigned to methylenic and aromatic methyl protons.
Furthermore, disappearance of two NH signals and presence
of only one NH signal at 9.75 ppm was observed. 13C NMR
spectrum indicated thiocarbonyl at 168.4, and methylenic
and methyl carbon at 67.9 and 21.4 ppm, respectively.
Synthesis of N-(substituted phenyl)-5-((quinolin-8-yloxy)
methyl)-1,3,4-oxadiazolamines (5a–e) and 1,3,4-thiadiazolamines
(5f–h): general procedure.
Semicarbazides (4a–e) or
thiosemicarbazides (4f–4h) (0.88 mmol) was stirred at 90ꢀC with
polyphosporic acid (2.65 g) for 24h in a water bath. After
completion, the reaction mixture was poured on crushed ice and
stirred for 10 min. The reaction mixture was extracted with ethyl
acetate two times, and the combined extract was thoroughly
washed with sodium hydrogen carbonate (5%). The organic layer
was dried over anhydrous sodium sulfate and concentrated under
vacuum. The products (4a–h) were recrystallized from ethanol.
Synthesis of 4-(substituted phenyl)-5-((quinolin-8-yloxy)
methyl)-2H-1,2,4- triazolones (6a–e) and 1,2,4-thiones (6f–6h):
general procedure. 1-(2-(Quinolin-8-yloxy)acetyl)-4-substituted
semicarbazides (4a–e) or thiosemicarbazides (4f–4h) (0.51 mmol)
was refluxed in aqueous sodium hydroxide solution (4N, 5 mL).
The reaction progress was monitor by TLC. After completion,
the reaction mixture was cooled to room temperature and filtered.
The filtrate was neutralized by hydrochloric acid (4N) to
precipitate out the product, filtered, washed with distilled water,
and recrystallized by aqueous ethanol.
EXPERIMENTAL
1-(2-(Quinolin-8-yloxy)acetyl)-4-o-tolylthiosemicarbazide
Melting points of all synthesized compounds were determined in
open capillary using a digital Gallenkamp (SANYO) model MPD
(4a). Yield: 65%; mp 253–255ꢀC; IR: 3335–3219 (NH), 2958
1
(CH2), 1738, (C═O), 1238 (C═S), 1178 (C-N) cmÀ1. H NMR
1
BM 3.5 apparatus and are uncorrected. H NMR and 13C NMR
(300 MHz, CDCl3): d 14.35, 10.26, 9.45 (3NH), 8.75–8.69
(m, 1H, ArH), 8.45–8.26 (m, 1H, ArH), 7.76–7.45 (m, 4H, ArH),
7.33–7.25 (m, 4H, ArH), 4.91 (s, 2H, CH2), 2.74 (s, 3H, CH3);
13C NMR (75MHz, CDCl3): d 172.3, 166.5, 155.4, 151.4, 147.6,
139.3, 138.2, 133.8, 131.4, 129.3, 129.0, 128.2, 126.9, 125.2,
122.6, 122.2, 121.3, 67.9, 21.4. Anal. Calcd for C19H18N4O2S:
C, 62.28; H, 4.95; N, 15.29; S, 8.75. Found: C, 62.15; H,
4.77; N, 15.18; S, 8.90.
spectra were determined at 300 MHz using a Bruker AM-300 spec-
trophotometer. FTIR spectra were measured on FTS 3000 MX
spectrophotometer and mass spectra (EI, 70 eV) on a GC–MS
instrument.
Synthesis of methyl 2-(quinolin-8-yloxy) acetate (2). To a
solution of 8-hydroxyquinoline (1.0 mmol) in DMF, methyl
chloroacetate (1.2 mmol) was added dropwise using K2CO3
(1.2mmol) as the base. The reaction was heated on a water bath
for 8h. The reaction mixture was cooled to room temperature and
poured onto ice cold water. The product was precipitated out,
filtered, washed with cold water, and recrystallized by aqueous
ethanol afford (2). Yield: 85%; mp 70–71ꢀC; IR: 2928 (CH2),
1-(2-(Quinolin-8-yloxy)acetyl)-4-m-tolylthiosemicarbazide
(4b). Yield: 63%; mp 142–144ꢀC; IR: 3392–3271 (NH), 2945
1
(CH2), 1687 (C═O), 1258 (C═S), 1184 (C-N) cmÀ1. H NMR
(300 MHz, CDCl3): d 14.11, 10.44, 9.69 (3NH), 8.89–8.88
(m, 2H, ArH), 8.37–8.31 (m, 1H, ArH), 7.61–7.41 (m, 5H, ArH),
7.34–6.97 (m, 2H, ArH), 4.91 (s, 2H, CH2), 2.03 (s, CH3); 13C
NMR (75 MHz, CDCl3): d 169.6, 167.1, 154.3, 153.3, 148.6,
139.4, 139.0, 133.5, 130.4, 129.2, 129.0, 127.1, 126.9, 125.7,
122.4, 121.7, 121.4, 68.2, 21.4. Anal. Calcd for C19H18N4O2S:
C, 62.28; H, 4.95; N, 15.29; S, 8.75. Found: C, 62.33; H,
4.81; N, 15.19; S, 8.61.
1715 (C═O), cmÀ1 1H NMR (300 MHz, CDCl3): d 8.77–8.64
.
(m, 1H, ArH), 8.458–8.31 (m, 1H, ArH), 7.71–7.55 (m, 3H, ArH),
7.20–7.12 (m, 1H, ArH), 5.04 (s, 2H, CH2), 3.72 (s, 3H, OCH3).
Synthesis of 2-(quinolin-8-yloxy)acetohydrazide (3).
Hydrazine hydrate (1.7mmol) was added to the suspension
of methyl 2-(quinolin-8-yloxy)acetate (1 mmol) in ethanol and
refluxed for 14h. The reaction mixture was cooled to room
temperature and concentrated under vacuum. The product was
precipitated out and recrystallized from ethanol. mp 140–142ꢀC.
IR (cmÀ1): 3326–3257 (N-H, NHNH2), 1062 (C-OC), 1185
(N-N); 1H NMR (DMSO-d6): 8.09 (s, IH, CONH), 7.72–7.47
(m, 6H, ArH), 4.88 (s, 2H, OCH2), 4.45 (s, 2H, NH2); Anal.
Calcd for C11H11N3O2: C, 60.72; H, 5.00; N, 19.29. Found: C,
60.69; H, 5.09; N, 19.41%.
1-(2-(Quinolin-8-yloxy)acetyl)-4-(2-methoxyphenyl)
thiosemicarbazide (4c).
Yield: 70%; mp 250–253ꢀC; IR:
3332–3257 (NH), 2948 (CH2), 1688 (C═O), 1232 (C═S), 1185
(C-N) cmÀ1. 1H NMR (300 MHz, CDCl3): d 14.35, 10.12, 9.74
(3NH), 8.85–8.61 (m, 2H, ArH), 7.86–7.69 (m, 3H, ArH),
7.66–7.41 (m, 4H, ArH), 7.31–7.19 (m, 1H, ArH), 4.88 (s, 2H, CH2),
3.91 (OCH3); 13C NMR (75 MHz, CDCl3): d 174.8, 167.6,
151.4, 149.2, 139.3, 135.4, 133.9, 133.2, 130.6, 129.7, 128.5,
127.4, 126.5, 124.3, 123.7, 123.0, 121.8, 68.2, 55.4. Anal.
Calcd for C19H18N4O3S: C, 59.67; H, 4.74; N, 14.65; S, 8.38.
Found: C, 59.74; H, 4.79; N, 14.78; S, 8.48.
Synthesis of 1-(2-(quinolin-8-yloxy)acetyl)-4-substituted
semicarbazides (4a–e) and thiosemicarbazides (4f–4h): general
procedure.
To a stirred solution of 2-(quinolin-8-yloxy)
acetohydrazide (0.461 mmol) in methanol, suitably substituted
isothiocyanate or isocyanate (0.461mmol) was added slowly with
continuous stirring and refluxed for 10–12 h. The completion of
reaction was monitored by TLC. Reaction mixture was cooled
to room temperature, and methanol was evaporated under
vacuum, crude product washed with distilled water, and
recrystallized by aqueous ethanol or petroleum ether ethyl
acetate (8:2) mixture.
1-(2-(Quinolin-8-yloxy)acetyl)-4-(2-chlorophenyl)
thiosemicarbazide (4d).
Yield: 60%; mp 120–122ꢀC; IR:
3368–3172 (NH), 2951 (CH2), 1683 (C═O), 1244 (C═S), 1182
1
(C-N) cmÀ1. H NMR (300 MHz, CDCl3): d 14.34, 10.67, 9.68
(3NH), 8.56–8.41 (m, 1H, ArH), 8.32–8.11 (m, 1H, ArH),
7.78–7.42 (m, 6H, ArH), 7.33–7.25 (m, 2H, ArH), 4.87 (s, 2H,
CH2); 13C NMR (75 MHz, CDCl3): d 182.6, 162.8, 150.3,
148.5, 147.2, 138.6, 138.1, 131.6, 129.7, 129.2, 128.6, 128.2,
Journal of Heterocyclic Chemistry
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Vol 51
127.4, 126.5, 124.4, 123.3, 115.3, 68.2. Anal. Calcd for
C18H15ClN4O2S: C, 55.88; H, 3.91; N, 14.48; S, 8.29. Found:
155.5, 152.2, 148.8, 140.8, 139.1, 138.8, 137.5, 129.7, 129.4,
127.9, 123.2, 122.7, 121.5, 118.4, 115.1, 112.7, 65.7, 21.7.
EIMS m/z (%): 348 [M+] (20), 145 (100%), 106 (49), 91 (51)
85 (25). Anal. Calcd for C19H16N4OS: C, 65.50; H, 4.63; N,
16.08; S, 9.20. Found: C, 65.37; H, 4.48; N, 16.26; S, 9.07.
N-(2-Methoxyphenyl)-5-((quinolin-8-yloxy)methyl)-1,3,
C, 55.84; H, 3.74; N, 14; S, 8.51.
1-(2-(Quinolin-8-yloxy)acetyl)-4-(3-chlorophenyl)
thiosemicarbazide (4e).
Yield: 59%; mp 193–194ꢀC; IR:
3326–3218 (NH), 2956 (CH2), 1666 (C═O), 1257 (C═S), 1178
1
(C-N) cmÀ1. H NMR (300 MHz, CDCl3): d 14.14, 10.52, 9.84
4-thiadiazol-2-amine (5c).
3244 (NH), 2929 (CH2), 1562 (C═C), 1462 (C═N) cmÀ1
Yield: 79%; mp 136–168ꢀC; IR:
(3NH), 8.93–8.86 (m, 1H, ArH), 8.46–8.37 (m, 1H, ArH),
7.65–7.32 (m, 6H, ArH), 7.34–7.22 (m, 2H, ArH), 4.92 (s, 2H,
CH2). 13C NMR (75MHz, CDCl3): d 181.4, 162.9, 153.7, 149.7,
149.3, 148.5, 138.5, 130.6, 129.6, 129.2, 128.5, 127.5, 122.5,
121.4, 112.4, 68.2. Anal. Calcd for C18H15ClN4O2S: C, 55.88; H,
3.91; N, 14.48; S, 8.29. Found: C, 55.95; H, 3.83; N, 14.40; S, 8.41.
1-(2-(Quinolin-8-yloxy)acetyl)-4-(2-chlorophenyl)semicarbazide
(4f). Yield: 66%; mp 204–207ꢀC; IR: 3336–3231 (NH), 2956
.
1H
NMR (300MHz, CDCl3): d 11.01 (NH), 8.59–8.42 (m, 2H,
ArH), 7.89–7.58 (m, 6H, ArH), 7.45–7.26 (m, 2H, ArH), 5.88 (s,
2H, CH2), 3.91 (OCH3); 13C NMR (100 MHz, CDCl3): d 157.2,
153.3, 148.1, 140.2, 139.2, 138.7, 136.8, 129.7, 129.0, 128.6,
127.8, 125.2, 125.1, 123.9, 123.2, 122.6, 118.4, 65.9, 54.9. EIMS
m/z (%): 364 [M+] (22), 206 (11), 145 (100%), 122 (44), 31 (31).
Anal. Calcd for C19H16N4O2S: C, 62.62; H, 4.43; N, 15.37; S,
8.80. Found: C, 62.78; H, 4.59; N, 15.30; S, 8.94.
(CH2), 1692, 1650 (C═O), 1183 (C-N) cmÀ1
.
1H NMR
(300 MHz, CDCl3): d 14.36, 10.87, 9.55 (3NH), 8.69–8.47
(m, 2H, ArH), 7.88–7.65 (m, 5H, ArH), 7.56–7.39 (m, 3H, ArH),
4.87 (s, 2H, CH2); 13C NMR (75MHz, CDCl3): d 167.2, 161.4,
150.0, 145.6, 138.4, 131.8, 130.9, 129.0, 128.7, 127.6, 126.4,
124.9, 124.3, 123.6, 122.7, 121.0, 68.2. Anal. Calcd for
C18H15ClN4O3: C, 58.31; H, 4.08; N, 15.1. Found: C, 58.44; H,
4.26; N, 15.35.
1-(2-(Quinolin-8-yloxy)acetyl)-4-(3-chlorophenyl)semicarbazide
(4g). Yield: 61%; mp 215–217ꢀC; IR: 3309–3221 (NH), 2949
(CH2), 1699, 1677 (C═O), 1181 (C-N) cmÀ1. 1H NMR (300 MHz,
CDCl3): d 14.15, 10.47, 9.68 (3NH), 8.96–8.80 (m, 1H, ArH),
8.28–8.15 (m, 1H, ArH), 7.61–7.31 (m, 5H, ArH), 7.29–7.16
(m, 3H, ArH), 4.92 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3):
d 166.7, 162.7, 154.6, 149.7, 149.1, 148.5, 138.6, 131.4, 130.6,
129.8, 128.1, 127.8, 124.5, 123.3, 121.4, 120.2, 68.3. Anal.
Calcd for C18H15ClN4O3: C, 58.31; H, 4.08; N, 15.11. Found:
C, 58.48; H, 4.21; N, 15.28.
N-(2-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-1,3,
4-thiadiazol-2-amine (5d).
3222 (NH), 2919 (CH2), 1555 (C═C), 1418 (C═N) cmÀ1
Yield: 70%; mp 150–152ꢀC; IR:
.
1H
NMR (300 MHz, CDCl3): d 11.51 (NH), 8.82–8.51 (m, 2H, ArH),
8.22–8.01 (m, 2H, ArH), 7.70–7.58 (m, 4H, ArH), 7.36–7.21
(m, 2H, ArH), 5.66 (s, 2H, CH2); 13C NMR (75MHz, CDCl3):
d 157.2, 151.6, 148.2, 140.4, 130.7, 129.2, 128.4, 126.5, 125.2,
124.3, 123.9, 123.1, 122.0, 121.6, 120.9, 120.4, 117.4, 64.4. EIMS
m/z (%): 368 [M+] (26), 184 (20), 145 (100%), 111 (33). Anal.
Calcd for C18H13ClN4OS: C, 58.61; H, 3.55; N, 15.19; S, 8.69.
Found: C, 58.70; H, 3.51; N, 15.14; S, 8.71.
N-(3-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-1,3,
4-thiadiazol-2-amine (5e).
3232 (NH), 2941 (CH2), 1548 (C═C), 1444 (C═N) cmÀ1
Yield: 68%; mp 169–171ꢀC; IR:
.
1H
NMR (300 MHz, CDCl3): d 11.47 (NH), 9.09–8.90 (m, 2H, ArH),
7.94–7.69 (m, 6H, ArH), 7.61–7.42 (m, 2H, ArH), 5.76 (s, 2H,
CH2); 13C NMR (75 MHz, CDCl3): d 155.7, 152.1, 148.2,
140.0, 129.2, 126.9, 126.0, 125.6, 124.8, 124.5, 124.0, 123.1,
121.6, 120.6, 120.5, 65.7. EIMS m/z (%): 368 [M+] (21), 145
(100%), 128 (61), 126 (40). Anal. Calcd for C18H13ClN4OS: C,
58.61; H, 3.55; N, 15.19; S, 8.69. Found: C, 58.66; H, 3.50; N,
15.25; S, 8.58.
1-(2-(Quinolin-8-yloxy)acetyl)-4-ethylsemicarbazide
(4h). Yield: 57%; mp 262–265ꢀC; IR: 3314–3220 (NH), 2957
(CH2), 1618, 1580 (C═O), 1195 (C-N) cmÀ1 1H NMR
.
(300 MHz, CDCl3): d 13.63, 10.32, (2NH), 8.87–8.71 (m, 2H,
ArH), 7.88–7.64 (m, 3H, ArH), 7.50–7.42 (m, 1H, ArH), 6.14
(NH), 3.49 (q, 2H, J = 6.8 Hz, CH2), 1.40 (t, 3H, J = 7.0 Hz,
CH3); 13C NMR (75 MHz, CDCl3): d 166.1, 165.0, 150.4,
148.0, 130.3, 128.9, 126.5, 125.4, 123.0, 121.9, 121.1, 67.6,
35.4, 15.0. Anal. Calcd for C14H16N4O3: C, 58.32; H, 5.59;
N, 19.43. Found: C, 58.50; H, 5.73; N, 19.52.
N-(2-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-1,3,
4-oxadiazol-2-amine (5f).
Yield: 75%; mp 201–202ꢀC; IR:
3256 (NH), 2959 (CH2), 1551 (C═C), 1452 (C═N) cmÀ1
.
1H
NMR (300 MHz, CDCl3): d 10.26 (NH), 8.42–8.34 (m, 2H, ArH),
7.92–7.61 (m, 6H, ArH), 7.62–7.43 (m, 2H, ArH), 5.66 (s, 2H,
CH2); 13C NMR (75 MHz, CDCl3): d 155.2, 152.3, 148.3,
146.5, 141.5, 138.4, 134.2, 128.2, 126.7, 126.1, 125.3, 124.8,
124.2, 123.8, 121.1, 65.7. EIMS m/z (%): 352 [M+] (19), 145
(100%), 128 (47), 111 (37). Anal. Calcd for C18H13ClN4O2: C,
61.28; H, 3.71; N, 15.88. Found: C, 61.51; H, 3.42; N, 15.64.
N-(3-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-1,3,
N-(2-Methylphenyl)-5-((quinolin-8-yloxy)methyl)-1,3,4-
thiadiazol-2-amine (5a). Yield: 75%; mp 163–165ꢀC; IR: 3232
1
(NH), 2953 (CH2), 1550, (C═C), 1484 (C═N) cmÀ1. H NMR
(300MHz, CDCl3): d 10.02 (NH), 8.94–8.42 (m, 2H, ArH),
7.71–7.56 (m, 4H, ArH), 7.52–7.32 (m, 3H, ArH), 6.91–6.79
(m, 1H, ArH), 5.55 (s, 2H, CH2), 2.28 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d 157.2, 155.6, 153.5, 148.8, 140.7, 139.1,
138.8, 137.5, 129.5, 129.4, 126.4, 123.6, 122.5, 121.5, 118.7,
115.2, 111.9, 65.7, 21.8. EIMS m/z (%): 348 [M+] (15), 145
(100%), 106 (55), 91 (47), 85 (21). Anal. Calcd for
C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20. Found: C,
65.55; H, 4.48; N, 16.23; S, 9.39.
4-oxadiazol-2-amine (5g).
3292 (NH), 2930 (CH2), 1568 (C═C), 1474 (C═N) cmÀ1
Yield: 70%; mp 218–220ꢀC; IR:
1H
.
NMR (300 MHz, CDCl3): d 10.88 (NH), 8.69–8.57 (m, 2H,
ArH), 7.90–7.64 (m, 6H, ArH), 7.60–7.51 (m, 2H, ArH), 5.84
(s, 2H, CH2); 13C NMR (75 MHz, CDCl3): d 154.2, 152.3,
147.6, 141.1, 131.2, 129.6, 128.2, 126.2, 125.2, 124.6, 123.9,
122.1, 121.4, 120.6, 120.1, 119.8, 115.2, 65.3. EIMS m/z (%):
352 [M+] (14), 184 (11), 145 (100%), 126 (54). Anal. Calcd
for C18H13ClN4O2: C, 61.28; H, 3.71; N, 15.88. Found: C,
61.21; H, 3.84; N, 15.80.
N-(3-Methylphenyl)-5-((quinolin-8-yloxy)methyl)-1,3,4-
thiadiazol-2-amine (5b). Yield: 72%; mp 142–144ꢀC; IR: 3239
1
(NH), 2918 (CH2), 1556 (C═C), 1488 (C═N) cmÀ1. H NMR
(300MHz, CDCl3): d 10.41 (NH), 8.93–8.55 (m, 2H, ArH),
7.69–7.62 (m, 3H, ArH), 7.53–7.38 (m, 3H, ArH), 7.24–7.19
(m, 1H, ArH), 6.83–6.81 (m, 1H, ArH), 5.67 (s, 2H, CH2),
2.29 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 156.2,
N-Ethyl-5-((quinolin-8-yloxy)methyl)-1,3,4-oxadiazol-2-amine
(5h). Yield: 77%; mp 145–147ꢀC; IR: 3230 (NH), 2951 (CH2),
1
1549 (C═C), 1449 (C═N) cmÀ1. H NMR (300MHz, CDCl3):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014 New N-(Aryl)-5-((quinolin-8-yloxy)methyl)-1,3,4-oxa/Thiadiazol-2-amines and 4-Aryl-5-
((quinolin-8-yloxy)methyl)-2H-1,2,4-triazole-3(4H)-thiones, Synthesis and Characterization
1361
d 9.00 (NH), 8.41–8.11 (m, 2H, ArH), 7.85–7.51 (m, 4H, ArH),
5.53 (s, 2H, CH2), 3.51 (q, 2H, J = 6.9Hz, CH2), 0.97 (t, 2H,
J = 6.8Hz, CH3); 13C NMR (75 MHz, CDCl3): d 155.2, 153.3,
147.5, 140.0, 129.7, 128.2, 128.0, 126.0, 125.2, 124.6, 121.6,
65.6, 36.6, 15.4. EIMS m/z (%): 270 [M+] (15), 184 (17), 145
(100%), 128 (56), 44(19). Anal. Calcd for C14H14N4O2: C, 62.21;
H, 5.22; N, 20.73. Found: C, 62.09; H, 5.16; N, 20.79.
131.5, 130.3, 129.2, 128.6, 126.7, 123.3, 67.8, 14.3. EIMS m/z
(%): 368 [M+] (15), 184 (25), 145 (100%), 128 (65). Anal. Calcd
for C18H13ClN4OS: C, 58.61; H, 3.55; N, 15.19; S, 8.69. Found:
C, 58.61; H, 3.54; N, 15.25; S, 8.60.
4-(2-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-2H-1,2,
4-triazol-3(4H)-one (6f). Yield: 54%; mp 180–182ꢀC; IR:
3229 (NH), 2924 (CH2), 1725 (C═O), 1563 (C═N) cmÀ1
.
1H NMR (300 MHz, CDCl3): d 9.86 (bs, 1H, NH), 8.87–8.66 (m,
2H, ArH), 7.78–7.56 (m, 4H, ArH), 7.49–7.34 (m, 3H, ArH),
7.28–7.16 (m, 1H, ArH), 5.34 (s, 2H, CH2); 13C NMR
(75 MHz, CDCl3): d 156.4, 150.5, 141.3, 138.3, 136.1, 135.7,
134.5, 132.1, 128.6, 128.1, 126.6, 124.9, 121.5, 120.3, 118.8,
67.3. EIMS m/z (%): 352 [M+] (18), 184 (20), 158 (10), 145
(100%), 111 (53). Anal. Calcd for C18H13ClN4O2: C, 61.28; H,
3.71; N, 15.88. Found: C, 61.62; H, 3.43; N, 15.60 %.
4-(2-Methylphenyl)-5-((quinolin-8-yloxy)methyl)-2H-1,2,
4-triazole-3(4H)-thione (6a). Yield: 61%; mp 196–198ꢀC;
IR: 3266 (NH), 2930 (CH2), 1574 (C═N), 1250 (C═S) cmÀ1
.
1H NMR (300 MHz, CDCl3): d 9.89 (bs, 1H, NH), 8.87–8.81
(m, 1H, ArH), 8.35–8.30 (m, 1H, ArH), 7.73–7.65 (m, 3H, ArH),
7.58–7.50 (m, 1H, ArH), 7.47–7.43 (m, 1H, ArH), 7.38–7.11
(m, 3H, ArH), 5.40 (s, 2H, CH2), 2.35 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d 167.4, 151.3, 140.5, 139.2, 136.1, 135.8,
134.9, 133.8, 132.4, 132.0, 130.2, 129.9, 129.1, 128.3, 128.0,
125.4, 118.1, 67.8, 21.3. EIMS m/z (%): 348 [M+] (10), 145
(100%), 91 (45), 15 (39). Anal. Calcd for C19H16N4OS: C,
65.50; H, 4.63; N, 16.08; S, 9.20. Found: C, 65.56; H, 4.69;
N, 16.14; S, 9.28.
4-(3-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-2H-1,2,4-
triazol-3(4H)-one (6g). Yield: 56%; mp 225–227ꢀC; IR: 3289
(NH), 2940 (CH2), 1700 (C═O), 1570 (C═N), 1196 (C-N) cmÀ1
.
1H NMR (300MHz, CDCl3): d 9.65 (bs, 1H, NH), 8.75–8.39
(m, 2H, ArH), 7.81–7.69 (m, 3H, ArH), 7.57–7.50 (m, 2H, ArH),
7.39–7.13 (m, 3H, ArH), 5.47 (s, 2H, CH2); 13C NMR
(75 MHz, CDCl3): d 157.2, 149.4, 142.0, 139.5, 138.2, 137.4,
135.8, 134.7, 133.5, 132.8, 131.5, 130.2, 129.8, 128.6, 128.1,
125.3, 121.7, 66.7. EIMS m/z (%): 352 [M+] (18), 184 (25),
158 (14), 145 (100%), 111 (44). Anal. Calcd for
C18H13ClN4O2: C, 61.28; H, 3.71; N, 15.88. Found: C, 61.33;
H, 3.79; N, 15.92.
4-(3-Methylphenyl)-5-((quinolin-8-yloxy)methyl)-2H-1,2,
4-triazole-3(4H)-thione (6b). Yield: 60%; mp 175–177ꢀC;
IR: 3258 (NH), 2929 (CH2), 1574 (C═N), 1254 (C═S) cmÀ1
.
1H NMR (300 MHz, CDCl3): d 9.75 (bs, 1H, NH), 8.86–8.79
(m, 1H, ArH), 8.47–8.35 (m, 1H, ArH), 7.74–7.55 (m, 3H, ArH),
7.50–7.48 (m, 2H, ArH), 7.30–7.11 (m, 3H, ArH), 5.57 (s, 2H,
CH2), 2.36 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 168.4,
151.4, 140.6, 139.5, 137.3, 135.8, 133.6, 132.9, 132.1, 131.0,
130.6, 129.4, 128.4, 128.0, 125.1, 121.5, 118.1, 67.9, 21.4. EIMS
m/z (%): 348 [M+] (16), 184 (14), 145 (100%), 91 (37). Anal.
Calcd for C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20.
Found: C, 65.40; H, 4.66; N, 16.13; S, 9.34.
4-Ethyl-5-((quinolin-8-yloxy)methyl)-2H-1,2,4-triazol-3(4H)-
one (6h).
(CH2), 1699 (C═O), 1577 (C═N) cmÀ1
Yield: 55%; mp 167–169ꢀC; IR: 3278 (NH), 2934
.
1H NMR (300MHz,
CDCl3): d 9.84 (bs, 1H, NH), 8.83–8.77 (m, 2H, ArH), 7.84–7.65
(m, 2H, ArH), 7.51–7.39 (m, 2H, ArH), 5.42 (s, 2H, CH2), 4.21
(q, 2H, J=6.9Hz, CH2), 0.99 (t, 2H, J=6.9Hz, CH3); 13C NMR
(75 MHz, CDCl3): d 155.3, 151.4, 146.4, 141.0, 130.6, 127.3,
126.5, 125.0, 123.6, 122.6, 121.0, 65.5, 36.4, 15.1. EIMS m/z
(%): 270 [M+] (10), 145 (100%), 128 (26). Anal. Calcd for
4-(2-Methoxyphenyl)-5-((quinolin-8-yloxy)methyl)-2H-1,2,
4-triazole-3(4H)-thione (6c).
3269 (NH), 2948 (CH2), 1579 (C═N), 1256 (C═S) cmÀ1
Yield: 59%; mp 211–213ꢀC; IR:
.
1H
NMR (300 MHz, CDCl3): d 9.79 (bs, 1H, NH), 8.76–8.40 (m, 2H,
ArH), 7.82–7.53 (m, 4H, ArH), 7.58–7.36 (m, 4H, ArH), 5.69 (s,
2H, CH2), 3.91 (s, 3H, OCH3); 13C NMR (75MHz, CDCl3): d
166.8, 150.6, 141.5, 139.6, 137.3, 135.0, 134.4, 133.6, 132.8,
131.3, 130.4, 129.8, 128.7, 127.0, 125.9, 123.9, 118.1, 67.9, 21.9.
EIMS m/z (%): 364 [M+] (14), 145 (100%), 107 (43), 31 (27).
Anal. Calcd for C19H16N4O2S: C, 62.62; H, 4.43; N, 15.37; S,
8.80. Found: C, 62.55; H, 4.44; N, 15.21; S, 8.70.
C
14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C, 62.35; H,
5.41; N, 20.79.
Acknowledgments. NA and AI are grateful to the Higher Education
Commission of Pakistan for the financial support for a PhD program.
4-(2-Chlorophenyl)-5-((quinolin-8-yloxy)methyl)-2H-1,2,
4-triazole-3(4H)-thione (6d). Yield: 54%; mp 189–191ꢀC;
IR: 3261 (NH), 2932 (CH2), 1569 (C═N), 1250 (C═S)
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.
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