Synthesis of 2-aryl-2H-[1,2,4]triazoloquinolin-3-one and 2-aryl-2H-[1,2,4]triazoloisoquinolin-3-one derivatives from α-chloroformylarylhydrazines hydrochloride

Article abstract of DOI:10.1016/j.tet.2009.11.095

The reaction of α-chloroformylarylhydrazines hydrochloride with quinoline under air provided the corresponding 2-aryl-2H-[1,2,4]triazoloquinolin-3-ones 3a-3d in 33-42% yields and unexpected isomeric 2-aryl-2H-[1,2,4]triazoloisoquinolin-3-ones 4a-4d in 30-42% yields. These two isomers were isolated and fully characterized by spectroscopic methods including X-ray crystallography. By employing 3-methylquinoline as the starting material under the same condition, the reaction only gave compound 3e-3h as sole products in 70-82% yields without the formation of isomers. A plausible mechanism was proposed through electrophilic aromatic reaction, the tandem ring cyclization and ring-opening, and oxidation for the generation of 2-aryl-2H-[1,2,4]triazoloisoquinolin-3-ones (4). Crown Copyright

Full text of DOI:10.1016/j.tet.2009.11.095

Tetrahedron 66 (2010) 930–934
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-aryl-2H-[1,2,4]triazoloquinolin-3-one and 2-aryl-2H-
[1,2,4]triazoloisoquinolin-3-one derivatives from a-chloroformylarylhydrazines
hydrochloride
,
Jiann-Jyh Huang b, Kun-Lung Chen c d, Yu-Shiang Lin b, Sheng-Chuan Yang b, Shih-Hsien Chuang b,
,
,
e,
*
Kuo-Chen Chiang c d, Wen-Che Tseng a, Fung Fuh Wong a , Mou-Yung Yeh
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Rd., Taichung, Taiwan 40402, ROC
b Development Center for Biotechnology, No. 101, Lane 169, Kangning St., Xizhi City, Taipei County, Taiwan 221, ROC
c Department of Resources Engineering, National Cheng Kung University, No. 1, Ta Hsueh Rd., Tainan, Taiwan 70101, ROC
d Sustainable Environment Research Center, National Cheng Kung University, No. 500, Sec. 3, An-ming Rd., Tainan, Taiwan 709, ROC
e Department of Chemistry, National Cheng Kung University, No. 1, Ta Hsueh Rd, Tainan, Taiwan 70101, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 March 2009
Received in revised form 12 November 2009
Accepted 24 November 2009
Available online 27 November 2009
The reaction of
a-chloroformylarylhydrazines hydrochloride with quinoline under air provided the
corresponding 2-aryl-2H-[1,2,4]triazoloquinolin-3-ones 3a–3d in 33–42% yields and unexpected iso-
meric 2-aryl-2H-[1,2,4]triazoloisoquinolin-3-ones 4a–4d in 30–42% yields. These two isomers were
isolated and fully characterized by spectroscopic methods including X-ray crystallography. By employing
3-methylquinoline as the starting material under the same condition, the reaction only gave compound
3e–3h as sole products in 70–82% yields without the formation of isomers. A plausible mechanism was
proposed through electrophilic aromatic reaction, the tandem ring cyclization and ring-opening, and
oxidation for the generation of 2-aryl-2H-[1,2,4]triazoloisoquinolin-3-ones (4).
Keywords:
a
-Chloroformylarylhydrazine hydrochloride
Quinoline
Triazoloquinolin-3-one
Triazoloisoquinolin-3-one
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction
the anticipated product 2-aryl-2H-[1,2,4]triazoloquinolin-3-one,
the reaction gave isomeric 2-aryl-2H-[1,2,4]triazoloisoquinolin-3-
Trazodone is a heterocyclic compound widely used as an anti-
depressant drug with clinical success.1 It shows medium to high
affinity for several serotonin receptor, in particular for 5HT2A and
one in nearly equal yields. The two isomers were isolated and fully
characterized by spectroscopic methods including X-ray crystal-
lography. When using 3-methylquinoline as the starting material,
the reaction only provided the corresponding 2-aryl-2H-[1,2,4]tri-
azoloquinolin-3-one as a single product. A plausible mechanismwas
proposed for the generation of the isomers.
2
a1 adrenergic receptor.3 Many molecules related to trazodone have
been studied4 and used for therapy, examples include etoperidone5
and nefazodone.6 As structural analogs to trazodones, 1,2,4-tri-
azoloquinolinones were more effective and safer antiepileptic
agents,7,8 which demonstrated comparable anticonvulsant potency
to that of phenobarbital in the corresponding tests.9,10
2. Result and discussion
In our previous study, we found a-chloroformylarylhydrazines
We reacted a-chloroformylphenylhydrazines hydrochloride 1a
hydrochloride 1 react with pyrimidine, pyridazine, pyridine, 1,4,5,6-
tetrahydropyrimidine, and 1,3,5-triazine under air to give the corre-
sponding1,2,4-trazodonesassingleproducts, exceptforpyrimidine.11
Furthermore, treatment of compound 1 with isoquinoline under the
same conditions also provides 1,2,4-trazodone compounds in 76–81%
yields as the sole products.11
with quinoline 2a at 80 ꢀC under air for 2.0 h, 2-phenyl-[1,2,4]tri-
azoloquinolin-3-one 3a and 2-phenyl-[1,2,4]triazoloisoquinolin-3-
one 4a were isolated in 42% yield and 32% yields, respectively (see
Scheme 1 and Table 1). When applying the same reaction condi-
tions to substituted
a-chloroformylarylhydrazines hydrochloride
1b–1d, which equipped p-methyl, p-fluoro, and p-chloro on the
phenyl group, the reaction also provided the corresponding two
isomers in 63–75% total yields (Table 1). 1,2,4-Triazoloquinolin-3-
ones 3 and 1,2,4-triazoloisoquinolin-3-ones 4 were fully charac-
terized by spectroscopic methods including single-crystal X-ray
diffraction study. The ORTEP drawing of compound 3c and 4d was
shown in Figures 1 and 2.
In this work, we reported the reaction of a-chloroformylarylhy-
drazines hydrochloride (1) with quinoline. In addition to providing
* Corresponding authors. Tel.: þ886 4 220 53366x5603; fax: þ886 4 220 78083.
E-mail address: wongfungfuh@yahoo.com.tw (F.F. Wong).
0040-4020/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.095

J.-J. Huang et al. / Tetrahedron 66 (2010) 930–934
931
O
N
Ar
+
N
N
O
+
Cl
NH2 HCl
N
80 °C
N
N
N
N
O
Ar
Ar
1a Ar = Ph
2a
3
4
1b Ar = p-MePh
1c Ar = p-FPh
1d Ar = p-ClPh
Scheme 1.
When using 3-methylquinoline 2b as the substrate to react with
-chloroformylarylhydrazines hydrochloride 1a–1d under the
Table 1
a
Reaction of a-chloroformylarylhydrazine hydrochloride with quinoline
same conditions, we only obtained the corresponding 2-aryl-2H-
[1,2,4]triazoloquinolin-3-ones 3e–3h in 70–82% yields as sole
products (see Scheme 2 and Table 2).
a
-Chloroformylarylhydrazine
The yield (%)
of isomersa
Total isolated yield
(%) of 3 and 4
hydrochloride
1
Ar
3a–3d
4a–4d
1a
1b
1c
1d
Ph
42 (3a)
40 (3b)
33 (3c)
39 (3d)
32 (4a)
35 (4b)
30 (4c)
35 (4d)
74
75
63
74
Table 2
p-MePh
p-FPh
p-ClPh
Yields of 2-aryl-2H-[1,2,4]triazoloquinolin-3-one 3e–3h from the reaction of
a
-chloroformylarylhydrazines hydrochloride 1a–1d with 3-methylquinoline (2b)
a
Yielda (%)
The isolation yield.
2-Aryl-2H-[1,2,4]triazoloquinolin-3-one 3e–3h
3
Ar
3e
3f
3g
3h
Ph
82
76
72
70
p-MePh
p-FPh
p-ClPh
a
The isolation yield.
Scheme 3 illustrated a proposed mechanism for the generation
of 1,2,4-triazoloquinolin-3-one 3 and 1,2,4-triazoloisoquinolin-3-
one 4 from the reaction of -chloroformylarylhydrazine hydro-
a
chloride 1 with quinoline 2. For the generation of compound 3, the
electrophilic species 1 reacted with compound 2 to provide cation 5
through N-acylation,11 followed by intramolecular neutralization to
form intermediate 6. In the presence of oxygen from air, oxidation
reaction took place to convert 6 to compound 3 as the final product
(see the path A of Scheme 3).
Figure 1. ORTEP diagram of 2-(p-fluorophenyl)-2H-[1,2,4]triazolo-[3,4-a]quinolin-3-
one (3c).12
For compound 4, the reaction followed electrophilic aromatic re-
action to form anion 6.14 Then, the intramolecular bond-rotation oc-
curred to generate intermediate 8 (see the path B of Scheme 3). The
tandem ring cyclization and ring-opening proceeded to give the ni-
trogen atom migration intermediate 9. After the further oxidation by
oxygen from air, compound 9 was successfully converted to the final
product 4. By using 3-methylquinoline as the starting material, the
similar reaction shown in the path B of Scheme 3 did not take place,
possibly due to the steric hindrance at C-3 position. This would ac-
count for the sole product produced from the reaction of
formylarylhydrazine hydrochloride 1 with 3-methylquinoline.
In conclusion, the reaction of -chloroformylarylhydrazines
a-chloro-
a
hydrochloride 1 with quinoline provided two isomers of 2-aryl-
2H-[1,2,4]triazoloquinolin-3-ones 3a–3d and 2-aryl-2H-[1,2,4]
triazoloisoquinolin-3-ones 4a–4d. Their structures were charac-
terized by spectroscopic methods including X-ray crystallography.
Figure 2. ORTEP diagram of 2-(p-chlorophenyl)-2H-[1,2,4]triazolo-[4,3-a]isoquinolin-
3-one (4d).13
Me
O
Me
Ar
+
N
N
Cl
N
NH2 HCl
80 °C
N
N
O
Ar
1a Ar = Ph
3e Ar = Ph
2b
1b Ar = p-MePh
1c Ar = p-FPh
1d Ar = p-ClPh
3f Ar = p-MePh
3g Ar = p-FPh
3h Ar = p-ClPh
Scheme 2.

932
J.-J. Huang et al. / Tetrahedron 66 (2010) 930–934
DMSO-d6 as solvent. Carbon-13 NMR spectra were obtained on
O
a Bruker (125 MHz) spectrometer by using DMSO-d6 as solvent.
Multiplicities are recorded by the following abbreviations: s, sin-
glet; d, doublet; t, triplet; q, quartet; m, multiplet; J, coupling
constant (hertz). Elemental analyses were carried out on a Heraeus
CHN–O RAPID element analyzer.
Ar
+
N
Cl
N
NH2 HCl
2
1
Path A
Path B
3.2. Standard procedure for the synthesis of 2-aryl-2H-
[1,2,4]triazoloquinolin-3-one 3a–3h and 2-aryl-2H-
[1,2,4]triazoloisoquinolin-3-one 4a–4d
N
N
H2N
H2N
To 10 mL of neat quinoline (2a) or 3-methylquinoline (2b) was
N
Ar
O
N
Ar
O
added
a-chloroformylphenylhydrazines hydrochloride (1a–1d,
5
0.60 g, 2.9 mmol). The reaction mixture was heated at 80 ꢀC under
air for 2.0 h. After the reaction was completed, the reaction mixture
was poured into a 1.0 N HCl aqueous solution (100 mL). The re-
sultant precipitate was filtered, purified by column chromatogra-
phy on silica gel (30% EtOAc in n-hexane), and recrystallized from
THF/EtOAc to give 2-phenyl-2H-[1,2,4]triazolo-[3,4-a]isoquinoline-
3-ones 3a–3h and 2-phenyl-2H-[1,2,4]triazolo-[4,3-a]quinoline-3-
ones 4a–4d.
5
N
ArN
NH2
O
7
3.2.1. 2-Phenyl-2H-[1,2,4]triazolo-[3,4-a]isoquinolin-3-one
(3a). Colorless needles; mp 139–140 ꢀC; 1H NMR (DMSO-d6,
Ar
N
500 MHz)
J¼7.7 Hz, 1H), 7.65–7.73 (m, 2H), 7.47–7.58 (m, 3H), 7.25–7.34 (m,
2H); 13C NMR (125 MHz, DMSO-d6)
148.3, 140.9, 137.5, 132.8,
130.8, 129.8, 129.1, 128.7, 125.8, 125.5, 122.8, 119.0, 114.9, 114.0; IR
(KBr) 1703 cmꢁ1; MS m/z (relative intensity) 261 (Mþ, 40), 204 (23),
190 (12), 111 (25), 91 (100), 77 (69); Anal. Calcd for C16H11N3O: C,
73.56; H, 4.21; N, 16.09. Found: C, 73.50; H, 4.23; N, 16.01.
d
8.98 (d, J¼8.3 Hz, 1H), 8.06 (d, J¼8.2 Hz, 2H), 7.84 (d,
N
HN
N
N
H2N
d
O
Ar
O
6
8
N
3.2.2. 2-(p-Methylphenyl)-2H-[1,2,4]triazolo-[3,4-a]isoquinolin-3-
_
O
one (3b). Colorless needles; mp 152–154 ꢀC; 1H NMR (DMSO-d6,
H2
NH
N
500 MHz)
d
8.93 (d, J¼8.3 Hz, 1H), 7.89 (d, J¼8.4 Hz, 2H), 7.80 (d,
Ar
Ar
9
J¼7.4 Hz, 1H), 7.62–7.79 (m, 2H), 7.45–7.50 (m, 1H), 7.31 (d,
J¼8.3 Hz, 2H), 7.22 (d, J¼9.7 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
_
H2
d
148.2, 142.9, 134.1, 132.7, 130.5, 129.7, 129.1, 128.6, 124.8, 124.5,
122.8, 119.5, 114.7, 113.7, 15.1; IR (KBr) 1706, 1705 cmꢁ1; MS m/z
(relative intensity) 275 (Mþ, 100), 218 (20), 204 (10), 128 (23), 91
(42); Anal. Calcd for C17H13N3O: C, 74.18; H, 4.76; N, 15.26. Found: C,
74.15; H, 4.70; N, 15.31.
N
N
N
O
N
N
N
O
Ar
3
4
3.2.3. 2-(p-Fluorophenyl)-2H-[1,2,4]triazolo-[3,4-a]isoquinolin-3-
one (3c). Colorless needles; mp 168–170 ꢀC; 1H NMR (DMSO-d6,
Scheme 3.
500 MHz)
d
8.96 (d, J¼8.3 Hz, 1H), 8.04–8.11 (m, 2H), 7.84 (d,
We proposed a plausible mechanism for the generation of com-
pound 4 starting from N-substitution, the tandem ring cyclization
and ring-opening, and oxidation. The formation of sole product
from compound 1 with 3-methylquinoline would rationalize the
possible existence of the mechanism shown in Scheme 3.
J¼7.4 Hz, 1H), 7.65–7.73 (m, 2H), 7.47–7.53 (m, 1H), 7.35–7.42 (m,
2H), 7.27 (d, J¼9.7 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d 160.6,
148.2, 145.8, 133.8,132.7,130.2, 129.7, 128.5, 125.5, 122.9, 121.1, 116.1,
115.6, 113.6; IR (KBr) 1715 cmꢁ1; MS m/z (relative intensity) 279
(Mþ, 100), 222 (26), 128 (29), 95 (43); Anal. Calcd for C16H10N3OF: C,
68.82; H, 3.58; N, 15.05. Found: C, 68.80; H, 3.55; N, 15.09.
3. Experimental section
3.1. General procedure
3.2.4. 2-(p-Chlorophenyl)-2H-[1,2,4]triazolo-[3,4-a]isoquinolin-3-
one (3d). Colorless needles; mp 183–185 ꢀC; 1H NMR (DMSO-d6,
500 MHz)
d
8.95 (d, J¼8.4 Hz, 1H), 8.23 (d, J¼8.4 Hz, 2H), 7.85 (d,
Analytical thin-layer chromatography (TLC) was performed on
precoated plates (silica gel 60 F-254), purchased from Merck Inc.
Purification by gravity column chromatography was carried out by
use of Merck Reagents Silica Gel 60 (particle size 0.063–0.200 mm,
70–230 mesh ASTM). Infrared (IR) spectra were measured on
a Bomem Michelson Series FT-IR spectrometer. The wavenumbers
reported are referenced to the polystyrene absorption at
1601 cmꢁ1. Absorption intensities are recorded by the following
abbreviations: s, strong; m, medium; w, weak. Proton NMR spectra
were obtained on a Bruker (500 MHz) spectrometer by use of
J¼7.4 Hz, 1H), 7.52–7.85 (m, 5H), 7.25 (d, J¼9.7 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6)
d 148.5, 143.9, 134.2, 133.7, 131.4, 130.2, 129.1,
128.4, 125.3, 123.9, 120.1, 116.1, 114.9, 113.7; IR (KBr) 1708 cmꢁ1; MS
m/z (relative intensity) 297 (Mþ2, 31), 295 (Mþ, 100), 240 (6), 238
(18), 128 (37), 111 (35); Anal. Calcd for C16H10ClN3O: C, 64.98; H,
3.41; Cl, 11.90; N, 14.21. Found: C, 65.04; H, 3.37; Cl, 11.92; N, 14.24.
3.2.5. 2-Phenyl-4-methyl-2H-[1,2,4]triazolo-[4,3-a]quinolin-3-one
(3e). Mp 159–160 ꢀC; 1H NMR (DMSO-d6, 300 MHz)
d
8.95 (d,
J¼8.3 Hz,1H), 8.08 (d, J¼7.8 Hz, 2H), 7.75 (d, J¼7.4 Hz,1H), 7.61–7.68

J.-J. Huang et al. / Tetrahedron 66 (2010) 930–934
933
(m, 1H), 7.49–7.58 (m, 3H), 7.43–7.48 (m, 1H), 7.30–7.36 (m, 1H),
2.37 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
148.5, 141.3, 137.4,
J¼7.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
158.7, 147.2, 140.2,
d
134.1, 131.7, 130.4, 128.9, 127.8, 122.6, 121.0, 120.9, 119.9, 116.1, 112.6;
IR (KBr) 1703 cmꢁ1; MS m/z (relative intensity) 279 (Mþ, 100), 222
(28),128 (40), 95 (62); Anal. Calcd for C16H10N3OF: C, 68.82; H, 3.58;
N, 15.05. Found: C, 68.88; H, 3.49; N, 15.00.
131.7, 129.6, 128.8, 128.5, 127.6, 125.6, 125.2, 122.9, 122.8, 119.0,
114.4, 14.6; IR (KBr) 3011 (s), 1716 (m, C]O) cmꢁ1; MS m/z (relative
intensity) 275 (Mþ, 100), 218 (24), 91 (22), 77 (29); Anal. Calcd for
C17H13N3O: C, 74.18; H, 4.73; N, 15.27. Found: C. 74.20; H, 4.72; N,
15.32.
3.2.12. 2-(p-Chloroprene)-2H-[1,2,4]triazolo-[4,3-a]quinolin-3-one
(4d). Colorless needles; mp 149–151 ꢀC; 1H NMR (DMSO-d6,
3.2.6. 2-(p-Methylphenyl)-4-methyl-2H-[1,2,4]triazolo-[4,3-a]quino-
500 MHz)
d
8.26 (d, J¼7.8 Hz, 1H), 8.24 (d, J¼8.5 Hz, 1H), 7.78 (d,
lin-3-one (3f). Mp 178–180 ꢀC; 1H NMR (DMSO-d6, 500 MHz)
d
8.88
J¼7.7 Hz, 2H), 7.65–7.77 (m, 3H), 7.53 (d, J¼8.3 Hz, 2H), 7.02 (d,
(d, J¼8.3 Hz, 1H), 7.90 (d, J¼8.4 Hz, 2H), 7.69 (d, J¼7.7 Hz, 1H), 7.52–
J¼7.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d 146.6, 141.3, 135.1,
7.59 (m, 1H), 7.37–7.45 (m, 2H), 7.29 (d, J¼8.4 Hz, 2H), 2.34 (s, 3H),
133.5, 132.6, 129.5, 128.7, 126.9, 122.7, 121.3, 120.8, 119.8, 116.2,
112.6; IR (KBr) 1714 cmꢁ1; MS m/z (relative intensity) 297 (Mþ2,
32), 295 (Mþ, 100), 128 (19), 113 (6), 111 (18); Anal. Calcd for
C16H10ClN3O: C, 64.98; H, 3.41; Cl, 11.90; N, 14.21. Found: C, 64.73;
H, 3.42; Cl, 11.88; N, 14.20.
2.31 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
d 147.5, 140.7, 136.9,
130.7, 129.0, 128.4, 128.1, 127.2, 125.8, 125.1,123.6, 122.4, 119.2,114.7,
17.6, 14.5; IR (KBr) 2931 (s), 1715 (m, C]O) cmꢁ1; MS m/z (relative
intensity) 289 (Mþ, 100), 232 (18), 91 (36); Anal. Calcd for
C18H15N3O: C, 74.74; H, 5.19; N, 14.53. Found: C, 74.68; H, 5.18; N,
14.55.
Acknowledgements
3.2.7. 2-(p-Fluorophenyl)-2H-[1,2,4]triazolo[4,3-a]quinolin-3-one
We are grateful to the National Science Council of Republic of
China (98-2221-E-039-003-) and the China Medical University
(CMU98-S-40) for financial support.
(3g). Mp 183–185 ꢀC; 1H NMR (DMSO-d6, 500 MHz)
d 8.93 (d,
J¼8.3 Hz, 1H), 8.05–8.12 (m, 2H), 7.74 (d, J¼7.6 Hz, 1H), 7.61–7.67
(m, 1H), 7.51 (s, 1H), 7.42–7.48 (m, 1H), 7.35–7.41 (m, 2H), 2.36 (s,
3H); 13C NMR (125 MHz, DMSO-d6)
d 148.6,145.8, 141.4,133.8,131.7,
Supplementary data
130.4, 129.8, 128.6, 127.7, 125.3, 122.9, 121.1, 115.6, 114.4, 14.6; IR
(KBr) 3058 (s), 2826 (s), 1718 (m, C]O) cmꢁ1; MS m/z (relative
intensity) 293 (Mþ, 100), 236 (30), 142 (18), 115 (17), 95 (22); Anal.
Calcd for C17H12N3OF: C, 69.62; H, 4.10; N, 14.33. Found: C, 69.60; H,
4.16; N, 14.31.
Supplementary data associated with this article can be found in
the online version at, doi:10.1016/j.tet.2009.11.095.
References and notes
3.2.8. 2-(p-Chlorophenyl)-2H-[1,2,4]triazolo[4,3-a]quinolin-3-one
(3h). Mp 207–209 ꢀC; 1H NMR (DMSO-d6, 500 MHz)
d 8.94 (d,
1. (a) Silvestrini, B. U.S. Patent 3,381,009, 1968; (b) Marek, G. J.; McDougle, C. J.;
Price, H.; Seiden, L. S. Psycopharmacology 1992, 109, 2–11.
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toria, A. Eur. J. Med. Chem. 1993, 28, 969–974.
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J¼8.3 Hz, 1H), 8.20 (d, J¼8.3 Hz, 2H), 7.84 (d, J¼7.4 Hz, 1H), 7.54–
7.87 (m, 5H), 7.23 (d, J¼9.6 Hz, 1H), 2.33 (s, 3H); 13C NMR (125 MHz,
DMSO-d6)
d 148.3, 142.5, 134.1, 133.6, 132.0, 130.4, 129.5, 128.3,
125.8, 124.9, 121.1, 115.9, 114.3, 113.7, 15.1; IR (KBr) 3018 (s), 1716 (m,
C]O) cmꢁ1; MS m/z (relative intensity) 309 (Mþ2, 100), 252 (26),
142 (21), 111 (24); Anal. Calcd for C17H12ClN3O: C, 65.91; H, 3.88; N,
13.57. Found: C, 65.77; H, 3.82; N; 13.56.
5. Palazzo, G. U.S. Patent 3,857,845, 1974.
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8. Jin, H.-G.; Sun, X.-Y.; Chai, K.-Y.; Piao, H.-R.; Quan, Z.-S. Bioorg. Med. Chem. Lett.
2006, 14, 6868–6873.
9. Xie, Z. S.; Chai, K. Y.; Piao, H. R.; Kwak, K. C.; Quan, Z. S. Bioorg. Med. Chem. Lett.
2005, 15, 4803–4805.
10. Cui, L.-J.; Xie, Z.-F.; Piao, H.-R.; Li, G.; Chai, K.-Y.; Quan, Z.-S. Biol. Pharm. Bull.
2005, 28, 1216–1220.
11. Chiu, C.-Y.; Kuo, C.-N.; Kuo, W.-F.; Yeh, M.-Y. J. Chin. Chem. Soc. 2002, 49,
239–249.
3.2.9. 2-Phenyl-2H-[1,2,4]triazolo-[4,3-a]quinolin-3-one
(4a). Colorless needles; mp 132–133 ꢀC; 1H NMR (DMSO-d6,
500 MHz)
d
8.30 (d, J¼7.8 Hz, 1H), 8.11 (d, J¼7.8 Hz, 2H), 7.84 (d,
J¼7.8 Hz, 1H), 7.72–7.78 (m, 2H), 7.65–7.71 (m, 1H), 7.52–7.58 (m,
2H), 7.30–7.35 (m, 1H), 7.03 (d, J¼7.4 Hz, 1H); 13C NMR (125 MHz,
12. Bond lengths (Å) and angles (ꢀ) of 2-(p-Fluorophenyl)-2H-[1,2,4]triazolo-[4,3-
a]quinolin-3-one (3c): F(1)–C(14), 1.364(2); C(14)–C(15), 1.366(2); C(14)–C(13),
1.364(2); C(15)–C(16), 1.382(2); C(11)–C(16), 1.388(2); N(1)–C(11), 1.424(2);
C(11)–C(12), 1.388(2); C(12)–C(13), 1.383(2); N(1)–N(2), 1.388(2); N(1)–C(1), 1.
376(2); O(1)–C(1), 1.219(2); N(3)–C(1), 1.395(2); N(3)–C(2), 1.378(2); N(2)–C(2),
1.300(2); N(3)–C(10), 1.413(2); C(2)–C(3), 1.433(2); C(5)–C(10), 1.404(2); C(9)–
C(10), 1.391(2); C(8)–C(9), 1.379(2); C(7)–C(8), 1.388(2); C(6)–C(7), 1.371(2);
C(5)–C(6), 1.401(2); C(4)–C(5), 1.441(2); C(3)–C(4), 1.339(2); C(3)–H(1), 0.95;
C(4)–H(2), 0.95; C(6)–H(3), 0.95; C(7)–H(4), 0.95; C(8)–H(5), 0.95; C(9)–H(6), 0.
95; C(12)–H(7), 0.95; C(13)–H(8), 0.95; C(15)–H(9), 0.95; C(16)–H(10), 0.95;
N(2)–N(1)–C(1), 112.8(1); N(2)–N(1)–C(11), 119.1(1); C(1)–N(1)–C(11), 128.1(1);
N(1)–N(2)–C(2), 104.2(1); C(1)–N(3)-C(2), 107.8(1); C(1)––N(3)–C(10), 129.1(1);
C(2)–N(3)–C(10), 123.2(1); O(1)–C(1)–N(1), 129.2(1); O(1)–C(1)–N(3), 127.9(1);
N(1)–C(1)–N(3), 102.8(1); N(2)–C(2)–N(3), 112.4(1); N(2)–C(2)–C(3), 128.1(1);
N(3)–C(2)–C(3), 119.5(1); C(2)–C(3)–C(4), 118.5(1); C(3)–C(4)–C(5), 122.3(1);
C(4)–C(5)–C(6), 121.8(1); C(4)–C(5)–C(10), 119.9(1); C(6)–C(5)–C(10), 118.3(1);
C(5)–C(6)–C(7), 120.7(1); C(6)–C(7)–C(8), 120.1(2); C(7)–C(8)–C(9), 120.9(2);
C(8)–C(9)–C(10), 119.1(1); N(3)–C(10)–C(5), 116.5(1); N(3)–C(10)–C(9), 122.
6(1); C(5)–C(10)–C(9), 120.9(1); N(1)–C(11)–C(12), 118.7(1); N(1)–C(11)–C(16),
121.0(1); C(12)–C(11)–C(16), 120.2(1); C(11)–C(12)–C(13), 120.2(1); C(12)–
C(13)–C(14), 118.4(2); F(1)–C(14)–C(13), 118.8(2); F(1)–C(14)–C(15), 118.5(2);
C(13)–C(14)–C(15), 122.7(2); C(14)–C(15)–C(16), 119.3(2); C(11)–C(16)–C(15),
119.1(1); C(4)–C(3)–H(1), 120.8; C(2)–C(3)–H(1), 120.7; C(5)–C(4)–H(2), 118.8;
C(3)–C(4)–H(2), 118.9; C(7)–C(6)–H(3), 119.7; C(5)–C(6)–H(3), 119.6; C(8)–C(7)–
H(4), 119.9; C(6)–C(7)–H(4), 120.0; C(9)–C(8)–H(5), 119.6; C(7)–C(8)–H(5), 119.
5; C(10)–C(9)–H(6), 120.4; C(8)–C(9)–H(6), 120.5; C(13)–C(12)–H(7), 119.9;
C(11)–C(12)–H(7), 119.8; C(14)–C(13)–H(8), 120.8; C(12)–C(13)–H(8), 120.8;
DMSO-d6) d 147.3, 140.2, 137.7, 131.7, 131.4, 129.2, 128.9, 127.8, 125.7,
122.7, 120.1, 119.9, 118.8, 112.0; IR (KBr) 1714 cmꢁ1; MS m/z (relative
intensity) 261 (Mþ, 100), 206 (10), 204 (30), 128 (29), 105 (8), 77
(41); Anal. Calcd for C16H11N3O: C, 73.56; H, 4.21; N,16.09. Found: C,
73.58; H, 4.21; N, 16.13.
3.2.10. 2-(p-Methylphenyl)-2H-[1,2,4]triazolo-[4,3-a]quinolin-3-one
(4b). Colorless needles; mp 143–145 ꢀC; 1H NMR (DMSO-d6,
500 MHz)
d
8.25 (d, J¼7.8 Hz, 1H), 7.94 (d, J¼8.5 Hz, 1H), 7.79 (d,
J¼7.7 Hz, 1H), 7.62–7.73 (m, 3H), 7.33 (d, J¼8.3 Hz, 2H), 7.00 (d,
J¼7.4 Hz, 1H), 2.34 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
d 148.2,
141.2, 137.4, 131.6, 131.2, 128.3, 127.9, 127.1, 125.8, 123.7, 121.2, 119.8,
118.9, 113.3, 14.6; IR (KBr) 1706, 1724 cmꢁ1; MS m/z (relative in-
tensity) 275 (Mþ, 100), 233 (4), 218 (17), 138 (4), 128 (37), 105 (74),
91 (64); Anal. Calcd for C17H13N3O: C, 74.18; H, 4.76; N, 15.26.
Found: C, 74.11; H, 4.80; N, 15.31.
3.2.11. 2-(p-Fluorophenyl)-2H-[1,2,4]triazolo-[4,3-a]quinolin-3-one
(4c). colorless needles; mp 193–194 ꢀC; 1H NMR (DMSO-d6,
500 MHz)
d
8.28 (d, J¼7.8 Hz, 1H), 8.08–8.15 (m, 2H), 7.83 (d,
J¼7.8 Hz, 1H), 7.65–7.78 (m, 3H), 7.35–7.42 (m, 2H), 7.03 (d,

934
J.-J. Huang et al. / Tetrahedron 66 (2010) 930–934
C(16)–C(15)–H(9), 120.3; C(14)–C(15)–H(9), 120.3; C(15)–C(16)–H(10), 120.5;
C(11)–C(16)–H(10), 120.5.
120.4(3); C(4)-C(5)–C(6), 120.9(3); C(1)–C(6)–C(5), 118.9(3); N(1)–C(7)–N(2),
102.5(3); N(1)–C(7)–O(7), 130.6(3); N(2)–C(7)–O(7), 126.9(3); C(9)–C(8)–N(2),
118.7(3); C(9)–C(8)–N(3), 129.2(3); N(2)–C(8)–N(3), 112.1(3); C(8)–C(9)–C(10),
117.0(3); C(8)–C(9)–C(16), 122.1(3); C(10)–C(9)–C(16), 120.9(3); C(9)-C(10)–
C(11), 120.6(3); C(9)–C(10)–C(13), 117.8(3); C(11)–C(10)–C(13), 121.6(3); C(10)–
C(11)–C(12), 120.6(3); C(11)–C(12)–N(2), 119.0(4); C(10)-C(13)–C(14), 120.6(4);
C(14)–C(15)–C(16), 119.9(4); C(9)–C(16)–C(15), 119.9(3); C(4)–N(1)–C(7), 127.
5(3); C(4)–N(1)–N(3), 119.6(2); C(7)–N(1)–N(3), 112.9(2); C(7)–N(2)–C(8), 108.
6(2); C(7)–N(2)–C(12), 127.3(3); C(8)–N(2)–C(12), 124.0(3); C(8)–N(3)–N(1),
103.9(2).
13. Bond lengths (Å) and angles (ꢀ) of 2-(p-Chlorophenyl)-2H-[1,2,4]triazolo-[3,4-
a]-isoquinolin-3-one (4d): C(1)–C(2), 1.367(5); C(1)–C(6), 1.388(5); C(1)–Cl, 1.
739(3); C(2)–C(3), 1.376(5); C(3)–C(4), 1.394(5); C(4)–C(5), 1.380(5); C(4)–N(1),
1.413(4); C(5)–C(6), 1.376(5); C(7)–N(1), 1.372(4); C(7)–N(2), 1.390(4); C(7)–
O(7), 1.217(4); C(8)–C(9),1.449(4); C(8)–N(2), 1.371(4); C(8)–N(3), 1.299(4);
C(9)–C(10), 1.407(4); C(9)–C(16), 1.389(5); C(10)–C(11), 1.453(5); C(10)–C(13), 1.
409(5); C(11)–C(12), 1.332(6); C(12)–N(2), 1.392(4); C(13)–C(14), 1.369(7);
C(14)–C(15), 1.384(6); C(15)–C(16), 1.382(5); N(1)–N(3), 1.398(3); C(2)–C(1)–
C(6), 121.0(3); C(2)–C(1)–Cl, 119.2(3); C(6)–C(1)–Cl, 119.9(3); C(1)–C(2)–C(3),
120.0(3); C(2)–C(3)–C(4), 119.9(3); C(3)–C(4)-C(5), 119.3(3); C(3)–C(4)–N(1),
14. Ullah, E.; Rotzoll, S.; Schmidt, A.; Michalik, D.; Langer, P. Tetrahedron Lett. 2005,
46, 8997–8999.