A Convenient One-Pot Synthesis of Triazolopyridine and Related Heterocycle Fused-Triazole Analogs Through Copper Catalyzed Oxidative Cyclization Strategy

Article abstract of DOI:10.1002/jhet.2331

One-pot synthesis of heterocycle fused-triazole analogs from the corresponding aldehydes and heteroarylhydrazines is demonstrated. Transformation of hydrazones to the desired systems was achieved by employing the oxidative cyclization with catalytic CuBr₂ and oxone. This reaction condition is mild and selective, and a wide range of functional groups were able to sustain. An array of biologically important triazolopyridines, triazolopyridazines, triazolopyrimidines, and triazoloquinolines were obtained in fairly good yield.

Full text of DOI:10.1002/jhet.2331

606
A Convenient One-Pot Synthesis of Triazolopyridine and Related Hetero-
cycle Fused-Triazole Analogs Through Copper Catalyzed Oxidative
Cyclization Strategy
Vol 53
b
a
c
c
R. Srinivasan,a,c J. Sembian Ruso, N. S. Nagarajan, R. Senthil Kumaran, and G. Manickam
*
aDepartment of Chemistry, Gandhigram Rural Institute – Deemed University, Gandhigram 624 302, Tamil Nadu, India
bDepartment of Polymer Science, University of Madras, Maraimalai Campus, Guindy, Chennai 600025, India
cSyngene International Ltd, Bangalore 560099, India
*
E-mail: nsnrajan@yahoo.co.in
Additional Supporting Information may be found in the online version of this article.
Received May 7, 2014
DOI 10.1002/jhet.2331
Published online 11 May 2015 in Wiley Online Library (wileyonlinelibrary.com).
RCHO
2
X
N
X
X
N
10 mol% CuBr2,
X
X
N
X
R
oxone, H2O,
RT, 3 h
EtOH, RT, 3 h
NHNH2
1
N
N
HN
N
R
X = C, N
4
3
One-pot synthesis of heterocycle fused-triazole analogs from the corresponding aldehydes and
heteroarylhydrazines is demonstrated. Transformation of hydrazones to the desired systems was achieved
by employing the oxidative cyclization with catalytic CuBr2 and oxone. This reaction condition is mild
and selective, and a wide range of functional groups were able to sustain. An array of biologically important
triazolopyridines, triazolopyridazines, triazolopyrimidines, and triazoloquinolines were obtained in fairly
good yield.
J. Heterocyclic Chem., 53, 606 (2016).
INTRODUCTION
antibacterial activity [7]. Owing to their broad spectrum of
biological activities, heterocycle fused-triazoles have gained
considerable interest among the researchers and these sys-
tems can be routinely synthesized by constructing the
1,2,4-triazole motif by adopting either dehydrative cycliza-
tion of acyl hydrazides [8] or oxidative cyclization of
heteroaryl hydrazones [9–11]. Although the former method
was used successfully for the efficient preparation of numer-
ous heterocyclic compounds, the latter is the most common,
attractive and widely exploited method. To execute oxidative
cyclization of heteroaryl hydrazones, hazardous reagents
such as Br2, POCl3, and Pb(OAc)4 [9] were used in the past.
Recently, chloramines-T [10a], LiI [6a], PhI(OAc)2 [7,10b],
and PhI(OCOCF3)2 [10c] are being employed for cycliza-
tion. In addition to the synthetic methodologies involving
PS-PPh3/CCl3CN under microwave heating, electrochemi-
cal methods are also developed [11a,11b]. Very recently, a
solvent free approach has also surfaced [11c].
However, the earlier synthetic procedures have some con-
straints such as the employment of hazardous materials or
metal reagents and also their moisture sensitive nature. Further,
the requirement of isolating the intermediate hydrazone prior to
oxidative cyclization invariably adds a step in the synthesis.
Furthermore, the stoichiometric amount of reagent is required
to carry out the oxidative cyclization. Thus, it is highly desired
to find a suitable reagent that should be catalytic, nontoxic, and
also has the capability of performing the reaction in one pot.
In recent years, transition metal catalysis emerged as a
powerful tool to form numerous C–C and C–heteroatom
1,2,4-Triazole represents an important class of heterocyclic
unit found to have wide range of applications in chemistry and
biology [1]. Particularly, heterocycle fused-triazoles re-
ceived a long standing interest due to their medicinal
relevance. [1,2,4]Triazolo[4,3-a]pyridine, a hybrid 1,2,4-
triazole and pyridine, is an important prototype of this
family, and one of the well studied systems of this kind
in literature [2]. This motif embedded compounds are
found to display biological activities such as antibacterial,
antifungal, anti-inflammatory, antiproliferative, antithrom-
botic, anticonvulsant, herbicidal, and anxiolytic activity [3].
Like triazolopyridines, triazolopyridazines, and the diazine
congeners, triazolopyrimidines as well as triazoloquinolines
are other important frameworks that belong to heterocy-
cle fused-triazoles wherein 1,2,4-triazole is fused with
pyridazines, pyrimidines, and quinolines, respectively.
[1,2,4]Triazolo[4,3-b]pyridazine is shown to be a weak
yet selective muscarinic acetylcholine receptor antagonist
[4]. Also, it can act as a highly selective and potent Pim-1
kinase inhibitor where the selectivity is derived from an
unorthodox binding mode to the unique hinge region of
Pim-1, and further, this class of analogs is identified as sub-
type selective ligands for the benzodiazepine binding site of
GABA-A receptors [5]. Interestingly, [1,2,4]triazolo[1,5-c]
pyrimidine is found to display a range of bioactivities like
analgesic, anticancer, antiviral and adenosine A1 receptor an-
tagonistic activity [6a]. In addition to that, it acts as potent in-
hibitor of kinases and Shiga toxin trafficking [6b,6c].
Likewise, [1,2,4]triazolo[4,3-a]quinoline exhibits potent
© 2015 HeteroCorporation

March 2016
A Convenient One-Pot Synthesis of Triazolopyridine and Related Heterocycle
Fused-Triazole Analogs Through Copper Catalyzed Oxidative Cyclization Strategy
607
Scheme 1. Synthesis of heterocycle fused triazole.
At the outset, we focused our attention on
triazolopyridines to optimize the reaction conditions. Ini-
tially, a mixture of 2-pyridyl hydrazine 1a and benzalde-
hyde 2a was stirred in ethanol at room temperature for
3 h to afford the hydrazone of aldehyde 3a whose for-
mation and conversion was confirmed by TLC. Without
isolating the hydrazone 3a, a direct oxidative cycliza-
tion was planned by screening under various reagents
and oxidant sources to obtain 4a (Table 1). Palladium
diacetate without oxidant showed no desired cyclization
whereas in the presence of silver carbonate provided
triazolopyridine 4a in low yield. Ruthenium trichloride
hydrate with or without oxidant did not afford 4a. With
0.1 equivalent of cupric bromide, 4a was obtained in
poor yield. CuCl2 with DDQ as an oxidant also gave
low yield. Various oxidants such as Ag2CO3, K2S2O8,
BQ, and DDQ with catalytic CuBr2 showed gradual in-
crease in the yield. The best yield was obtained with 0.1
equivalent of cupric bromide and 1 equivalent of oxone
(entry 12–15). In order to find the efficiency of this ox-
idant, experiments were conducted using CuCl2, Pd
(OAc)2 and RuCl3∙H2O with oxone as well as oxone
without metal catalyst provided very low yield.
After identification of the optimized condition, 1a was
treated with various aldehydes 2 to produce triazolopyridines
4x (Table 2). Halo substituted aryl aldehydes furnished the
desired compounds without affecting the halo units 4b–4d
(entry 2–4). It is noteworthy that in general, bromo and chloro
substituents are labile to copper condition but remained
unreactive in the present condition. Multi substituted aryl alde-
hydes also underwent the cyclization smoothly. Olefin unit
was preserved when an aldehyde containing olefin was used
4f–4g (entry 6 and 7). 3-Cyanobenzaldehyde gave the desired
product in high yield (91%). The same was the case with
heterocyclic aryl aldehydes 4i–4m (entry 9–11). Alicyclic
aldehydes provided the products 4n–4o in moderate yield
(entry 12).
Having demonstrated the protocol for the synthesis of
triazolopyridines, attention was directed toward the synthe-
sis of triazolopyridazines by taking pyridazine derived
hydrazine 1b as the starting material (Table 3). Hydrazone
formation was realized by following the routine procedure,
and those derivatives were further subjected to oxidative
cyclization to give 5x. Aryl aldehydes having bromo,
methoxy, allyl, and cyano substituents furnished the corre-
sponding products 5a–5f in good yield (entry 1–6). It is to
be noted that the electronic influence of substituents in the
aryl has played insignificant role as the yields were almost
comparable. Further, the reactive chloro unit in the pyridazine
moiety was remaining intact during the reaction condition.
Heterocyclic aryl aldehydes were found to undergo smooth
cyclization to form 5g–5k in good yield (entry 7–9). Cyclo-
propane carboxaldehyde and n-heptanal were able to form
the triazolopyridazines 5l and 5m, respectively (entry 10).
A similar protocol was employed for the synthesis of
triazolopyrimidines 6x as shown in Table 4. Aryl
hydrazone
formation
oxidative
+
RCHO
N
N
N
N
cyclization
R
2
HN
N
N
NHNH2
R
1
4
3
bonds efficiently. Among the various metal catalyzed
reactions, there is a growing interest in copper catalyzed
reactions as they are less toxic and inexpensive. In practical
point of view, copper salts are not only less moisture sensitive
and hence less difficult to store but also easy to handle, and
they can be readily be obtained by commercial sources. A sin-
gle report describes the synthesis of heterocycle fused-triazole
using CuCl2, but stoichiometric amount of copper was needed
[12]. However, catalytic version based oxidative cyclization is
a more attractive approach to heterocycle fused triazoles.
Notably, although numerous specific fused triazole synthesis
were reported, reports dealing with the combined synthesis
of triazolopyridines, triazolopyridazines, triazolopyrimidines,
and triazoloquinolines have been less documented in literature
[12]. In this context, we disclose the synthesis of heterocycle
fused triazoles using catalytic amount of copper catalyst.
The general scheme wherein the treatment of heterocy-
clic hydrazine 1 with aldehyde 2 to produce aldehyde
derived hydrazone 3, which on oxidative cyclization leads
to heterocycle fused triazole 4, is given in Scheme 1.
Table 1
Reagent and oxidant sources used in the synthesis of triazolopyridine.
Temp.
(°C)
Time
(h)
Yield
(%)c
Entry
Reagenta
Oxidantb
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
RuCl3∙H2O
RuCl3∙H2O
CuBr2
CuCl2
CuBr2
CuBr2
CuBr2
—
Ag2CO3
—
Ag2CO3
—
DDQ
80
80
80
80
80
80
80
80
80
80
80
RT
RT
RT
80
80
RT
RT
12
12
12
12
12
12
6
12
5
3
3
3
3
7
12
12
12
12
—
10
—
—
10
26
42
32
35
38
68
90
72
82
7
DDQ
Ag2CO3
K2S2O8
BQ
9
10
11
12
13
14
15
16
17
18
CuBr2
CuBr2
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
CuBr2
d
CuBr2e
CuBr2
—
CuCl2
Pd(OAc)2
RuCl3∙H2O
40
18
12
Reactions were carried out in EtOH:water (4:1).
a0.1 equiv. of reagent was used.
b1 equiv. of oxidant was used.
cIsolated yield.
d0.2 equiv. of reagent was used.
e0.05 equiv. of reagent was used.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

608
R. Srinivasan, J. Sembian Ruso, N. S. Nagarajan, R. Senthil Kumaran, and G. Manickam
Vol 53
Table 2
Synthesis of triazolopyridines.
Entry
R
Yield
Entry
7
R
Yield
1
4a, 90%
4g, 80%
2
4b, 87%
4c, 89%
4d, 85%
4e, 84%
8
9
4h, 91%
4i, 76%
3
4
5
10
11
R = 2-furyl;
R = 2-thiophenyl;
R = 3-thiophenyl;
4j, 70%
4k, 84%
4l, 86%
4m, 85%
6
4f, 87%
12
R = cyclohexyl;
R = cyclopropyl;
4n, 78%
4o, 74%
aldehydes as well as alicyclic aldehydes provided the cor-
responding products 6a–6d although in moderate yield.
Finally, triazoloquinolines 7x were obtained from the
hydrazine 1d and aldehyde derivative 2x (Table 5). A
range of aryl, heteroaryl, and aliphatic aldehydes
underwent the oxidative cyclization to form the products
7a–7k in good yield.
this protocol, a focused library involving the synthesis of
triazolopyridine, triazolopyridazine, triazolopyrimidine, and
triazoloquinoline derivatives has been established.
EXPERIMENTAL
General methods.
All the reagents were purchased
commercially and used without further purification. Solvents were
used without drying. H and 13C NMR spectra were recorded on
1
CONCLUSION
300 or 400 MHz Brucker spectrometers in CDCl3/CD3OD/
DMSO-d6. The chemical shifts were reported in δ ppm relative to
TMS. IR Spectra were recorded on Nicolet 6700 instrument using
a universal ATR sampling unit. Mass Spectra were obtained on
LC-MS Agilent 1100 series instrument, and UPLC was recorded
on Acquity ultra performance LC instrument. Melting point was
measured in BÜCKI-B545 instrument.
In conclusion, we have developed a convenient one-pot
synthesis of heterocycle fused-triazoles from the readily
available aldehydes and heterocyclic hydrazines. Oxidative
cyclization of the aldehyde derived hydrazone with 10 mol
% of CuBr2 and oxone is the key step in the synthesis of
the desired analogs under mild condition because the
hydrazone formation and oxidative cyclization have taken
place at room temperature while the literature procedures re-
veal that such cyclizations were carried out normally at high
temperatures. Further, the oxidative cyclization is also selec-
tive as the halo substituents remained unaffected. Employing
General experimental procedure for preparation of
triazoles.
To a solution of hydrazine (1.8 mmol) in ethanol
(8 mL) was added the aldehyde (1.8 mmol) at room temperature,
and the mixture was stirred for 3 h. Then water (2 mL) was
added to the reaction mixture followed by the slow addition of
oxone (1.8 mmol) and cupric bromide (0.18 mmol). The reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
A Convenient One-Pot Synthesis of Triazolopyridine and Related Heterocycle
Fused-Triazole Analogs Through Copper Catalyzed Oxidative Cyclization Strategy
609
Table 3
Synthesis of triazolopyridazines.
Entry
1
R
Yield
Entry
6
R
Yield
5a, 80%
5f, 80%
2
5b, 87%
7
5g, 80%
5h, 90%
3
4
5c, 80%
5d, 92%
8
9
R = 2-furyl;
R = 2-thiophenyl;
R = 3-thiophenyl;
5i, 79%
5j, 78%
5k, 75%
5
5e, 85%
10
R = cyclopropyl;
5l, 75%
R = n-hexyl;
5m, 87%
mixture was stirred at RT for another 3 h. Water (5 mL) was
added to the reaction mixture, which was then extracted with
dichloromethane (2 × 20 mL). The combined organic layer was
washed with brine and dried over sodium sulfate. It was
concentrated under reduced pressure, and the residue obtained
was purified either silica gel column chromatography or
crystallization with EtOAc to give the triazoles in good yield.
A similar procedure was followed for all other examples
shown in Tables 2–5. The triazoles obtained were either purified
by column chromatography or crystallization with EtOAc.
(100 MHz, DMSO-d6): δ 155.1, 130.1, 128.7, 128.3, 124.5, 118.8,
117.6, 116.0, 114.8. LCMS: (M + H)+ 246.0.
3-(4-Bromophenyl)-[1,2,4]triazolo[4,3-a]pyridine (4c). mp
191–193°C. IR (neat) 3076, 1633, 1495, 1456, 1398, 1364,
1062, 1002, 981, 815, 752 cmÀ1
.
1H NMR (300 MHz,
CDCl3): δ 8.56 (d, J = 6.96 Hz, 1H), 7.88–7.80 (m, 5H),
7.46–7.41 (m, 1H), 7.02 (t, J = 6.69 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 150.6 (C), 145.8 (C), 132.6 (2CH),
129.6 (2CH), 127.3 (CH), 125.5 (C), 124.6 (CH), 122.5 (C),
116.8 (CH), 114.6 (CH). UPLC: (M + H)+ 274.2. Anal. Calcd
for C12H8BrN3: C, 52.58; H, 2.94; N, 15.33. Found: C,
52.28; H, 2.84; N, 15.13.
Characterization of the triazolo analogs synthesized
3-Phenyl-[1,2,4]triazolo[4,3-a]pyridine (4a). mp 173–175°C
(lit10c: 172–174°C). IR (neat) 1629, 1496, 1061, 750, 696 cmÀ1
.
3-(4-Bromo-2,5-dimethoxyphenyl)-[1,2,4]triazolo[4,3-a]
pyridine (4d). mp 185–187°C. IR (neat) 1638, 1480, 1217, 1020,
1H NMR (400MHz, CDCl3): δ 8.34–8.30 (m, 1H), 7.84–7.82 (m,
3H), 7.60–7.52 (m, 3H), 7.29 (t, J = 6.60 Hz, 1H), 6.87 (t,
J = 6.72Hz, 1H); 13C NMR (100MHz, CDCl3): δ 150.5 (C),
146.8 (C), 130.2 (CH), 129.3 (CH), 128.2 (CH), 127.1 (CH),
126.6 (C), 122.6 (CH), 116.8 (CH), 114.3 (CH). UPLC: (M + H)+
196.2. Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52.
Found: C, 73.63; H, 4.73; N, 21.57.
1
859, 752 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 8.12–8.11 (m,
1H), 7.89–7.87 (m, 1H), 7.56 (s, 1H), 7.49 (t, J = 6.64Hz, 1H),
7.30 (s, 1H), 7.02 (t, J = 6.72 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H);
13C NMR (100MHz, DMSO-d6): δ 151.3, 149.7, 129.8, 125.8,
117.2, 115.4, 114.7, 114.4, 114.2, 56.8, 56.5. UPLC: (M + H)+
334.3. Anal. Calcd for C14H12BrN3O2: C, 50.32; H, 3.62; N,
12.57. Found: C, 50.22; H, 3.32; N, 12.67.
4-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-2-chlorophenol (4b). mp
258–259°C. IR (neat) 1637, 1308, 815, 692 cmÀ1 1H NMR
.
3-(1-Phenylethyl)-[1,2,4]triazolo[4,3-a]pyridine (4e).
124–126°C. IR (neat) 2975, 2922, 1632, 1488, 1263, 1023,
730, 693 cmÀ1 1H NMR (400 MHz, DMSO-d6):
8.13
(d, J = 6.88 Hz, 1H), 7.74 (d, J = 9.24 Hz, 1H), 7.32–7.22
mp
(400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.53–8.51 (m, 1H),
7.85–7.82 (m, 2H), 7.67 (d, J= 8.36 Hz, 1H), 7.41 (t, J=7.28Hz,
1H), 7.18 (d, J= 8.41 Hz, 1H), 7.0 (t, J=6.72Hz, 1H); 13C NMR
.
δ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

610
R. Srinivasan, J. Sembian Ruso, N. S. Nagarajan, R. Senthil Kumaran, and G. Manickam
Vol 53
Table 4
Synthesis of triazolopyrimidines.
Entry
R
Yield
Entry
3
R
Yield
1
6a, 70%
6c, 60%
2
6b, 75%
4
6d, 65%
(m,5H), 7.20 (t, J = 2.04 Hz, 1H), 6.87 (t, J = 6.72 Hz, 1H), 4.79
(q, J = 7.12 Hz, 1H), 1.79 (d, J = 7.08 Hz, 3H ; 13C NMR
(100 MHz, DMSO-d6): δ 142.4, 129.3, 127.8, 127.6, 127.4,
123.8, 115.9, 113.8, 35.7, 21.3. UPLC: (M + H)+ 224.6 Anal.
Calcd for C14H13N3: C, 75.31; H, 5.87; N, 18.82. Found: C,
75.55; H, 5.65; N, 18.56.
CDCl3): δ 149.8, 146.8, 139.8, 128.0, 126.9, 123.8, 120.7, 116.2,
114.6. UPLC: (M + H)+ 275.2.
3-(Furan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (4j).
89–91°C (lit8c: 92°C) . IR (neat) 3116, 1635, 1498, 1370,
1011, 891, 745 cmÀ1 1H NMR (400 MHz, DMSO-d6): δ
mp
.
8.78 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 1.36 Hz, 1H), 7.88
(d, J = 9.28 Hz, 1H), 7.49–7.47 (m, 1H), 7.33 (d, J = 3.48 Hz,
1H), 7.13 (t, J = 6.32 Hz, 1H), 6.83 (dd, J = 3.44, 1.76 Hz,
1H); 13C NMR (75 MHz, DMSO-d6): δ 147.5 (C), 145.2
(CH), 142.2 (C), 128.7 (CH), 125.0 (CH), 118.2 (C), 116.1
(CH), 115.4 (CH), 112.5 (CH), 111.1 (CH). UPLC:
(M + H)+ 186.2.
3-(4-(Allyloxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine (4f). IR
(neat) 3083, 1608, 1501, 1466, 1372, 1245, 1175, 988, 836,
1
752 cmÀ1. H NMR (400 MHz, CDCl3): δ 8.44 (br s, 1H), 7.89
(br s, 1H), 7.77 (d, J = 8.12 Hz, 1H), 7.31 (s, 1H), 7.13
(d, J = 6.9 Hz, 1H), 6.87 (t, J = 6.28 Hz, 1H), 6.15–6.07 (m, 1H),
5.51–5.46 (m, 2H), 5.36 (d, J = 10.48 Hz, 1H), 4.67–4.65
(m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 159.4, 133.4, 129.6,
127.5, 123.9, 119.0, 117.7, 115.7, 115.4, 114.2, 68.3. LCMS:
(M+ H)+ 252.0.
3-(Thiophen-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (4k).
164–166°C. (lit7: 162–163°C). IR (neat) 3066, 1628, 1494,
723 cmÀ1 1H NMR (400 MHz, DMSO-d6):
8.79
mp
.
δ
(E)-3-Styryl-[1,2,4]triazolo[4,3-a]pyridine (4g). mp 167–169°C.
(d, J = 7.04 Hz, 1H), 7.94–7.91 (m, 2H), 7.88 (dd, J = 5.12,
1.00Hz, 1H), 7.58 (dt, J = 6.68, 0.84 Hz, 1H), 7.34 (t, J = 4.4 Hz,
1H), 7.20 (dt, J = 6.78, 0.76 Hz, 1H; 13C NMR (100 MHz,
DMSO-d6): δ 150.4 (C), 141.9 (C), 129.0 (CH), 128.9 (CH),
128.5 (CH), 128.0 (C), 127.1 (CH), 124.7 (CH), 116.2 (CH),
115.3 (CH). UPLC: (M + H)+ 202.2. Anal. Calcd for C10H7N3S:
C, 59.68; H, 3.51; N, 20.88. Found: C, 59.77; H, 3.33; N, 20.93.
(lit10c: 169–171°C). IR (neat) 3028, 1632, 1494, 1065, 964, 755,
.
730, 679 cmÀ1 1H NMR (400MHz, CDCl3): δ 8.18 (d,
J = 6.84Hz, 1H), 7.93 (d, J = 16.06 Hz, 1H), 7.83 (d, J = 9.16Hz,
1H), 7.63 (d, J = 7.2 Hz, 2H), 7.45–7.42 (m, 2H), 7.40–7.36 (m,
1H), 7.32–7.30 (m, 1H), 7.20 (d, J = 16.06Hz, 1H), 6.95 (d,
J = 6.76Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 135.7, 135.2,
129.1, 128.9 (2C), 127.0 (2C), 126.8, 122.0, 116.9, 114.1, 109.3.
UPLC: (M + H)+ 222.3.
3-(Thiophen-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (4l).
mp
170–172°C. IR (neat) 3094, 1628, 1495, 1307, 1063, 824,
1
3-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)benzonitrile (4h). mp
742 cmÀ1. H NMR (300 MHz, CD3OD): δ 8.61 (d, J = 6.18 Hz,
162–163°C. IR (neat) 2217, 1633, 1495, 1372, 1062, 754 cmÀ1
.
1H), 8.18–8.17 (m, 1H), 7.81–7.69 (m, 3H), 7.52 (t, J = 6.78 Hz,
1H), 7.10 (t, J = 6.87 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
127.7 (CH), 127.2 (CH), 127.0 (CH), 126.9 (C), 125.1 (CH),
122.8 (CH), 116.9 (CH), 114.4 (CH). LCMS: (M + H)+ 202.0.
Anal. Calcd for C10H7N3S: C, 59.68; H, 3.51; N, 20.88; Found:
C, 60.00; H, 3.70; N, 20.94.
1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 6.92 Hz, 1H),
8.14 (d, J = 7.72 Hz, 1H), 7.99 (t, J = 7.52 Hz, 1H), 7.95–7.92
(m, 2H ), 7.81 (t, J = 7.46 Hz, 1H), 7.51 (m, 1H), 7.07
(t, J = 6.72 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 151.2,
143.8, 134.9, 134.3, 131.4, 131.1, 129.7, 129.1, 124.6, 117.8,
116.0, 115.1, 112.5. UPLC: (M + H)+ 221.3. Anal. Calcd for
C13H8N4: C, 70.90; H, 3.66; N, 25.44. Found: C, 71.00; H,
3.46; N, 25.24.
3-(5-Fluoro-1H-indol-2-yl)-[1,2,4]triazolo[4,3-a]pyridine
(4m). mp 256–258°C. IR (neat) 3092, 1638, 1592, 1484, 1158,
1
806, 737 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 12.13 (br s,
3-(5-Bromopyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (4i). mp
1H), 8.89–8.8 (m, 1H), 8.42 (d, J = 2.44 Hz, 1H), 7.97–7.94
(m, 1H), 7.85 (d, J = 8.48Hz, 1H), 7.57 (dd, J = 8.88, 4.48Hz,
1H), 7.20 (t, J = 6.68Hz, 1H), 7.14 (t, J = 8.88 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): 157.8, 132.7, 130.4, 128.1, 125.7, 115.7,
114.4, 113.4, 111.1, 105.3, 100.7. LCMS: (M+ H)+ 253.0.
170–172°C. IR (neat) 1632, 1490, 1083, 1014, 846, 757, 687 cmÀ1
.
1H NMR (400 MHz, CDCl3): δ 9.76 (d, J= 4.12 Hz, 1H), 8.78 (s,
1H), 8.47 (d, J= 8.48 Hz, 1H), 8.02 (d, J= 7.80 Hz, 1H), 7.90 (s,
1H), 7.40 (s, 1H), 7.01 (t, J=6.76Hz, 1H); 13C NMR (100 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
A Convenient One-Pot Synthesis of Triazolopyridine and Related Heterocycle
Fused-Triazole Analogs Through Copper Catalyzed Oxidative Cyclization Strategy
611
Table 5
Synthesis of triazoloquinolines.
Entry
R
Yield
Entry
5
R
Yield
1
2
3
4
7a, 90%
R = 4-pyridyl;
R = 5-bromo-2-pyridyl;
7e, 83%
7f, 79%
7b, 87%
7c, 80%
7d, 81%
6
7
8
R = 2-furyl;
R = 3-thiophenyl;
7g, 72%
7h, 70%
7i, 83%
R = n-hexyl;
R = cyclopropyl;
7j, 78%
7k, 75%
3-Cyclohexyl-[1,2,4]triazolo[4,3-a]pyridine (4n). IR (neat)
DMSO-d6): δ 153.4 (C), 152.5 (C), 149.3 (C), 146.9 (C), 127.45
(CH), 123.3 (CH), 118.0 (CH), 117.2 (CH), 115.4 (C), 114.1
(CH), 56.8 (OCH3), 56.2 (OCH3). LCMS: (M+ H)+ 290.0. Anal.
Calcd for C13H11ClN4O2: C, 53.71; H, 3.81; N, 19.27. Found: C,
53.95; H, 3.75; N, 19.70.
1
3386, 2929, 1648, 1447, 1161, 1042, 855, 755 cmÀ1. H NMR
(300 MHz, CD3OD): δ 8.90 (d, J = 6.81 Hz, 1H), 8.15–8.04
(m, 2H), 7.56 (t, J = 6.81 Hz, 1H), 3.46–3.39 (m, 1H), 2.20–2.16
(m, 2H), 1.95–1.90 (m, 2H), 1.85–1.56 (m, 6H); 13C NMR
(100 MHz, CD3OD): δ 138.3 (CH), 126.9 (CH), 119.1 (CH),
112.3 (CH), 34.8 (CH), 31.1 (CH2), 26.7 (CH2), 26.5 (CH2).
LCMS: (M + H)+ 202.2.
6-Chloro-3-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine
(5c). mp 160–162°C. IR (neat) 1524, 1496, 1463, 1324, 1099,
1022, 808, 754 cmÀ1 1H NMR (400 MHz, DMSO-d6): δ 8.43
.
3-Cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (4o). IR (neat)
(dd, J = 9.68, 1.32Hz, 1H), 7.44 (dd, J = 9.64, 1.32Hz, 1H), 7.31–
7.28 (m, 4H), 7.24–7.20 (m, 1H), 4.77 (q, J = 7.24 Hz, 1H), 1.78
(d, J = 7.20 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 151.5
(C), 148.8 (C), 142.9 (C), 141.6 (C), 128.6 (CH), 127.3 (CH),
127.0 (CH), 126.9 (CH), 122.6 (CH), 34.9 (CH), 20.3 (CH3).
UPLC: (M + H)+ 259.3. Anal. Calcd for C13H11ClN4: C, 60.35; H,
4.29; N, 21.66. Found: C, 60.47; H, 4.42; N, 21.72.
1638, 1501, 1369, 1041, 749 cmÀ1
.
1H NMR (400 MHz,
DMSO-d6): δ 8.54 (d, J = 6.92 Hz, 1H), 7.7 (d, J = 9.2 Hz, 1H),
7.34 (m, 1H), 7.00 (t, J = 6.52 Hz, 1H), 2.42–2.36 (m, 1H),
1.15–1.10 (m, 2H), 1.04–1.00 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 143.7 (C), 127.8 (CH), 124.0 (CH), 115.7 (CH),
113.7 (CH), 6.9 (CH2), 4.8 (CH). UPLC: (M + H)+ 160.0.
3-(4-Bromophenyl)-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine
(4-(Allyloxy)phenyl)-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine
(5d). mp 128–132°C. IR (neat) 1606, 1532, 1459, 1313, 1244,
(5a).
mp 190–192°C. IR (neat) 3044, 1651, 1591, 1522,
1458, 1413, 1325, 1108, 1057, 983, 812, 774 cmÀ1
.
1H
1180, 1103, 1053, 939, 832, 811 cmÀ1 1H NMR (400 MHz,
.
NMR (400 MHz, DMSO-d6): δ 8.55 (d, J = 9.64 Hz, 1H),
8.24 (d, J = 8.48 Hz, 2H), 7.83 (d, J = 8.48 Hz, 2H), 7.57 (d,
J = 9.64 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 149.8
(C), 146.4 (C), 144.6 (C), 132.5 (CH), 129.4 (CH), 127.9
(CH), 125.3 (C), 124.4 (C), 123.3 (CH). UPLC: (M + H)+
309.1. Anal. Calcd for C11H6BrClN4: C, 42.68; H, 1.95; N,
18.10. Found: C, 42.83; H, 1.89; N, 18.00.
6-Chloro-3-(2,5-dimethoxyphenyl)-[1,2,4]triazolo[4,3-b]
pyridazine (5b). mp 105–107°C. IR (neat) 3358, 2922, 1487,
1226, 1160, 1042, 816, 754 cmÀ1. 1H NMR (300 MHz, CDCl3): δ
8.13 (d, J = 9.57Hz, 1H), 7.21 (d, J = 2.97 Hz, 1H), 7.16–7.03
(m, 3H), 3.83 (s, 3H), 3.81 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): δ 8.50 (d, J = 9.68Hz, 1H), 8.24 (dd, J = 7.02, 1.8 Hz,
2H), 7.52 (d, J = 9.68Hz, 1H), 7.2 (d, J = 8.0 Hz, 2H), 6.13–6.03
(m, 1H), 5.44 (dd, J = 17.28, 1.6 Hz, 1H), 5.29 (dd, J = 10.5,
1.4 Hz, 1H), 4.67 (d, J = 5.28 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): δ 160.2, 149.5, 147.2, 144.1, 133.8, 129.2, 127.8,
122.8, 118.5, 118.3, 115.5, 68.8. UPLC: (M + H)+ 287.5.
(E)-6-Chloro-3-styryl-[1,2,4]triazolo[4,3-b]pyridazine (5e). mp
148–150°C. IR (neat) 3333, 3076, 1635, 1522, 1498, 1450, 1319,
1133, 1048, 964, 813, 753 cmÀ1. 1H NMR (300 MHz, CD3OD): δ
8.27 (d, J= 9.75 Hz, 1H), 8.06 (d, J= 16.50 Hz, 1H), 7.69 (d,
J= 6.87 Hz, 1H), 7.49 (d, J= 16.00 Hz, 1H ), 7.46–7.38 (m, 5H);
13C NMR (75 MHz, DMSO-d6): δ 149.8, 135.9, 135.6, 129.7,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

612
R. Srinivasan, J. Sembian Ruso, N. S. Nagarajan, R. Senthil Kumaran, and G. Manickam
Vol 53
129.4, 127.8, 127.7, 123.1, 110.8. UPLC: (M + H)+ 257.0. Anal.
Calcd for C13H9ClN4: C, 42.68; H, 1.95; N, 18.10. Found: C, 42.83;
H, 1.89; N, 18.00.
(M + H)+ 195.0. Anal. Calcd for C8H7ClN4: C, 49.37; H,
3.63; N, 28.79. Found: C, 49.55; H, 3.54; N, 28.70.
6-Chloro-3-hexyl-[1,2,4]triazolo[4,3-b]pyridazine (5m).
38–40°C. IR (neat) 3079, 2919, 1504, 1464, 1328, 1143, 1074,
824, 754 cmÀ1 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d,
mp
3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)benzonitrile
(5f). mp 160–162°C. IR (neat) 3087, 2228, 1521, 1455, 1318,
.
1
1105, 1059, 810, 768 cmÀ1. H NMR (400 MHz, DMSO-d6): δ
J = 9.64 Hz, 1H), 7.45 (d, J = 9.68Hz, 1H), 3.05 (t, J = 7.48Hz,
2H), 1.82–1.75 (m, 2H), 1.39–1.32 (m, 2H), 1.29–1.19 (m, 4H),
0.85 (t, J = 3.40 Hz, 3H); 13C NMR (100MHz, DMSO-d6): δ
149.9, 149.1, 143.1, 127.5, 122.6, 31.3, 28.7, 26.2, 23.7, 22.4,
14.3. LCMS: (M+ H)+ 239.0.
8.60 (s, 1H), 8.61–8.59 (m, 2H), 8.07 (d, J = 7.68Hz, 1H), 7.86
(d, J = 7.84Hz, 1H), 7.61 (d, J = 9.64Hz, 1H); 13C NMR
(100MHz, DMSO-d6): δ 150.0, 145.6, 144.7, 134.3, 132.1,
130.9, 130.7, 127.9, 127.3, 123.7, 118.7, 112.6. UPLC: (M+ H)+
256.2. Anal. Calcd for C12H6ClN5: C, 45.80; H, 2.05; N, 23.77.
Found: C, 45.70; H, 2.55; N, 23.88.
4-([1,2,4]Triazolo[4,3-a]pyrimidin-3-yl)-2-chlorophenol
(6a). mp 271–272°C. IR (neat) 2921, 1611, 1507, 1430, 1305,
1
6-Chloro-3-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine
(5g). mp 220–222°C. IR (neat) 1601, 1521, 1456, 1114, 1063,
848, 778 cmÀ1. H NMR (300 MHz, DMSO-d6): δ 10.83 (s, 1H),
9.37 (dd, J = 6.75, 1.86 Hz, 1H), 8.83 (d, J = 4.35, 1.92 Hz, 1H),
8.10 (d, J = 2.0 Hz, 2H), 7.99 (d, J = 8.46, 2.10 Hz, 2H), 7.34–7.31
(m, 1H), 7.12 (d, J = 8.49 Hz, 2H); 13C NMR (100MHz,
DMSO-d6): δ 163.7,155.5, 155.4, 155.3, 137.1, 128.3, 127.0,
122.2, 120.2, 117.0, 110.81. LCMS: (M + H)+ 247.0. Anal. Calcd
for C11H7ClN4O: C, 53.56; H, 2.86; N, 22.71. Found: C, 53.90;
H, 2.56; N, 22.90.
1
845, 824, 747, 676cmÀ1. H NMR (400 MHz, CD3OD): δ 8.82
(br s, 2H), 8.48 (d, J = 5.88Hz, 2H), 8.43 (d, J = 9.68 Hz, 1H),
7.58 (d, J = 9.72Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ
150.9, 150.2, 145.2, 133.4, 127.9, 123.9, 121.1. LCMS: (M+ H)+
232.0. Anal. Calcd for C10H6ClN5: C, 51.85; H, 2.61; N, 30.23.
Found: C, 51.98; H, 2.70, N, 30.30.
3-(5-Bromopyridin-2-yl)-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine
(5h). mp 225–227°C. IR (neat) 3021, 2922, 1571, 1514, 1446,
3-(4-Bromophenyl)-[1,2,4]triazolo[4,3-a]pyrimidine (6b). IR
(neat) 3354, 1617, 1594, 1429, 1394, 1066, 1006, 826, 771 cmÀ1
.
1392, 1317, 1062, 999, 824, 776 cmÀ1
.
1H NMR (400 MHz,
1H NMR (400 MHz, DMSO-d6): δ 9.43 (dd, J = 6.50, 1.48Hz,
1H), 8.89 (d, J = 2.64 Hz, 1H), 8.15 (d, J = 8.36Hz, 2H), 7.76 (d,
J = 8.40 Hz, 2H), 7.38 (t, J = 5.48 Hz, 1H); 13C NMR (100MHz,
DMSO-d6): δ 163.6 (C), 155.7 (CH), 155.5 (C), 137.3 (CH),
132.1 (CH), 129.0 (C), 128.8 (CH), 124.2 (C), 111.2 (CH).
LCMS: (M+ H)+ 274.8.
DMSO-d6): δ 8.99 (d, J= 2.2 Hz, 1H), 8.60 (d, J= 9.68 Hz, 1H),
8.36 (dd, J= 8.44, 2.32 Hz, 1H), 8.23 (d, J= 8.44 Hz, 1H), 7.62 (d,
J=9.64Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 151.3, 150.1,
144.7, 144.3, 140.5, 127.7, 125.7, 123.9, 122.1. LCMS: (M + H)+
310.2. Anal. Calcd for C10H5BrClN5: C, 38.68; H, 1.62; N, 22.55.
Found: C, 38.75; H, 1.57; N, 22.36.
3-Cyclohexyl-[1,2,4]triazolo[4,3-a]pyrimidine (6c).
mp
6-Chloro-3-(furan-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine
(5i). mp 130–132°C. IR (neat) 3075, 1516, 1323, 1074, 995, 816,
738 cmÀ1. 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, J = 9.64Hz,
1H), 8.06 (s, 1H), 7.58 (d, J = 9.64 Hz, 1H), 7.41 (d, J = 3.4 Hz, 1H),
6.83–6.82 (m, 1H); 13C NMR (100MHz, DMSO-d6): δ 149.7 (C),
145.3 (CH), 143.2 (C), 140.7 (C), 139.9 (C), 127.2 (CH), 123.0
(CH), 112.5 (CH), 112.1 (CH). Anal. Calcd for C9H5ClN4O: C,
49.00; H, 2.28; N, 25.40. Found: C, 49.45; H, 2.35; N, 25.23.
6-Chloro-3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine
(5j). mp 155–157°C. IR (neat) 3080, 1519, 1456, 1408, 1314,
118–120°C. IR (neat) 3376, 2923, 1610, 1505, 1461, 1346,
1
1383, 1220, 779 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 9.32
(dd, J = 6.78, 1.88 Hz, 1H), 8.80 (m, 1H), 7.28 (m, 1H),
2.89–2.87 (m, 1H), 2.05–2.01 (m, 2H), 1.81–1.71 (m, 2H),
1.70–1.55 (m, 4H), 1.45–1.23 (m, 4H); 13C NMR (75 MHz,
DMSO-d6): δ 172.7 (C), 155.4 (C), 155.3 (CH), 137.4 (CH),
110.7 (CH), 38.0 (CH), 31.7 (CH2), 26.0 (CH2), 25.9 (CH2).
Anal. Calcd for C11H14N4: C, 65.32; H, 6.98; N, 27.70. Found:
C, 65.43; H, 7.09; N, 27.87.
3-Cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine (6d).
IR
1
1098, 1052, 825 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 8.53
(neat) 3394, 3014, 1612, 1513, 1488, 1381, 1191, 1034, 897,
1
(d, J = 9.64Hz, 1H), 8.12 (d, J = 3.56Hz, 1H), 7.87 (d, J = 5.0 Hz,
779 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 9.25 (dd, J = 6.72,
1H), 7.56 (d, J = 9.64Hz, 1H), 7.33 (d, J = 4.80, 3.96 Hz, 1H); 13
C
1.92 Hz, 1H), 8.76 (dd, J = 4.32, 1.92 Hz, 1H), 7.24 (dd,
J = 6.72, 4.36 Hz, 1H), 2.17–2.12 (m, 1H), 1.09–1.08 (m, 2H),
1.07–1.06 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 170.9
(C), 160.0 (C), 155.1 (CH), 137.0 (CH) , 110.5 (CH), 9.9 (CH),
8.1 (CH2). LCMS: (M + H)+ 274.8.
NMR (100 MHz, DMSO-d6): δ 150.0, 144.0, 129.8, 129.5, 128.4,
127.8, 126.6, 123.2. UPLC: (M + H)+ 237.2. Anal. Calcd for
C9H5ClN4S: C, 45.67; H, 2.13; N, 23.67. Found: C, 45.80; H,
2.12; N, 23.70.
6-Chloro-3-(thiophen-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine
(5k). mp 169–171°C. IR (neat) 1518, 1457, 1341, 1321, 1055,
4-([1,2,4]Triazolo[4,3-a]quinolin-1-yl)-2-chlorophenol (7a). mp
276–282°C. IR (neat) 2976, 2922, 1620, 1534, 1456, 1296, 1188,
1
1
940, 865, 796, 699cmÀ1. H NMR (400 MHz, CD3OD): δ 8.65
1054, 801, 750 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 10.93 (s,
(dd, J = 2.92, 1.12Hz, 1H), 8.34 (d, J = 9.68Hz, 1H), 8.02
(dd, J = 5.14, 1.12Hz, 1H), 7.70 (dd, J = 5.08, 2.92Hz, 1H), 7.50
(d, J = 9.64 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 149.4,
128.7, 128.5, 127.7, 127.2, 126.2, 126.1, 125.9, 122.5. LCMS:
(M+ H)+ 237.0. Anal. Calcd for C9H5ClN4S: C, 45.67; H, 2.13;
N, 23.67. Found: C, 45.75; H, 2.00; N, 23.34.
1H), 8.00–7.98 (m, 1H), 7.83–7.79 (m, 1H), 7.73–7.71 (m, 2H),
7.53–7.45 (m, 4H), 7.2 (d, J=7.76Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 155.4, 132.0, 130.4, 130.3, 130.0,129.7, 126.6, 124.7,
121.5, 120.7, 117.5, 116.4, 115.0. LCMS: (M + H)+ 296.0. Anal.
Calcd for C16H10ClN3O: C, 64.98; H, 3.41; N, 14.21. Found: C,
65.05; H, 3.72; N, 14.56.
6-Chloro-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine
1-(2,5-dimethoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoline
(7b). mp 137–139°C. IR (neat) 1618, 1482, 1220, 1038, 802,
(5l).
mp 115–117°C. IR (neat) 3083, 1530, 1320, 1091,
937, 804, 773 cmÀ1
.
1H NMR (400 MHz, CDCl3): δ 8.04
750 cmÀ1 1H NMR (400 MHz, DMSO-d6): δ 8.0 (d, J=7.2Hz,
.
(d, J = 9.56 Hz, 1H), 7.08 (d, J = 9.48 Hz, 1H), 2.52–2.46
(m, 1H), 1.42–1.38 (m, 2H), 1.28–1.25 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): δ 150.9 (C), 148.8 (C), 142.9 (C),
127.0 (CH), 122.2 (CH), 7.3 (CH2), 4.7 (CH). LCMS:
1H), 7.83 (d, J=9.6Hz, 1H), 7.75 (d, J=9.6Hz, 1H), 7.55–7.48 (m,
2H), 7.37 (d, J= 8.0 Hz, 1H), 7.28–7.20 (m, 3H), 3.78 (s, 3H), 3.53
(s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 153.7, 152.2, 132.1,
130.3, 129.8,126.6, 124.3, 119.5, 117.9, 115.9, 115.0, 113.4,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
A Convenient One-Pot Synthesis of Triazolopyridine and Related Heterocycle
Fused-Triazole Analogs Through Copper Catalyzed Oxidative Cyclization Strategy
613
56.3, 56.2. LCMS: (M + H)+ 306.0. Anal. Calcd for C18H15N3O2:
C, 70.81; H, 4.95; N, 13.76. Found: C, 70.65; H, 4.90; N, 13.69.
1-(4-(Allyloxy)phenyl)-[1,2,4]triazolo[4,3-a]quinoline (7c). mp
91–93°C. IR (neat) 3045, 1611, 1530, 1446, 1398, 1246, 817,
750 cmÀ1. 1H NMR (400 MHz, CDCl3): δ 8.01–7.99 (m, 1H), 7.91
(d, J= 9.56 Hz, 1H), 7.73 (d, J= 9.52 Hz, 1H),7.65–7.62 (m, 2H),
7.54–7.49 (m, 1H), 7.47–7.43 (m, 2H), 7.23–7.19 (m, 2H), 6.17–
6.07 (m, 1H), 5.50–5.44 (m, 1H), 5.32 (dd, J= 10.52, 1.52 Hz, 1H),
4.71 (dt, J= 5.20, 1.32 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
δ 160.1, 133.9, 132.0, 131.9, 130.2, 130.0, 129.5, 126.5, 124.7,
122.1, 118.3, 116.4, 115.7, 115.1, 68.8. LCMS: (M + H)+ 302.0.
7.35 (td, J = 8.56, 1.32 Hz, 1H), 7.08 (td, J = 9.20, 2.44 Hz, 1H),
6.98 (dd, J = 9.72, 2.36 Hz, 1H), ; 13C NMR (100 MHz,
DMSO-d6): δ 158.0, 133.3, 132.7, 130.2, 130.0, 129.7, 129.5,
127.3, 126.4, 124.8, 116.4, 115.4, 114.1, 111.1, 104.7, 104.2.
LCMS: (M + H)+ 303.0. Anal. Calcd for C18H11FN4: C, 71.51;
H, 3.67; N, 18.53. Found: C, 71.76; H, 3.77; N, 18.67.
1-Hexyl-[1,2,4]triazolo[4,3-a]quinoline (7j). IR (neat) 2928,
2853, 1615, 1465, 1410, 814, 748 cmÀ1 1H NMR (400 MHz,
.
CDCl3): δ 8.19 (d, J = 8.48 Hz, 1H), 7.83 (d, J=7.84Hz, 1H),
7.73–7.69 (m, 1H), 7.68–7.64 (m, 1H), 7.58–7.51 (m, 2H), 3.48 (t,
J= 7.72 Hz, 2H), 2.11–2.03 (m, 2H), 1.64–1.56 (m, 2H), 1.46–1.37
(m, 4H), 0.85 (t, J = 3.40 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6): δ 132.3, 130.1, 129.8, 128.3, 126.3, 124.6, 117.0,
115.1, 31.5, 28.9, 28.8, 26.5, 22.5, 14.4. LCMS: (M + H)+ 254.2.
1-Cyclopropyl-[1,2,4]triazolo[4,3-a]quinoline (7k). mp 85–87°C.
IR(neat)3380,1616,1411,1119,808,760 cmÀ1.1HNMR(400MHz,
CDCl3):δ8.83(d,J = 8.6 Hz,1H),7.86(d,J = 7.56Hz,1H),7.77–7.73
(m, 2H), 7.57 (t, J = 7.52 Hz, 2H), 2.52–2.48 (m, 1H), 1.45–1.39
(m, 4 H); 13C NMR (100MHz, DMSO-d6): δ 132.1, 129.5, 129.3,
129.2, 125.9, 124.1, 116.8, 114.6, 9.4, 6.9. LCMS: (M + H)+
210.2.0. Anal. Calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08.
Found:C,74.56;H,5.24;N, 20.13.
(E)-1-Styryl-[1,2,4]triazolo[4,3-a]quinoline (7d).
157–159°C. IR (neat) 3056, 1613, 1443, 1400, 972, 800,
749, 698 cmÀ1 1H NMR (400 MHz, DMSO-d6): δ 8.33
mp
.
(d, J = 8.37 Hz, 1H), 7.86–7.81 (m, 2H), 7.71–7.67 (m, 4H),
7.59–7.54 (m, 2H), 7.49–7.38 (m, 4H); 13C NMR (100 MHz,
DMSO-d6): δ 149.8, 148.7, 137.4, 136.1, 132.2, 130.5, 130.2,
129.9, 129.6, 129.3, 128.1, 126.7, 124.9, 117.8, 115.1, 115.0.
UPLC: (M + H)+ 272.2. Anal. Calcd for C18H13N3: C, 79.68;
H, 4.83; N, 15.49. Found: C, 79.41; H, 4.67; N, 15.55.
1-(Pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinoline (7e).
204–206°C. IR (neat) 3039, 2921, 1596, 1407, 1217, 1064,
825, 750 cmÀ1 1H NMR (400 MHz, DMSO-d6): δ 8.89 (br s,
mp
.
2H), 8.05 (dd, J = 7.58, 1.80 Hz, 1H), 7.89 (d, J = 9.50 Hz,
1H) 7.82 (d, J = 5.12 Hz, 2H), 7.80 (d, J = 9.56 Hz, 1H), 7.55
(m, 2H), 7.44 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ
150.9, 150.0, 146.9, 138.0, 131.58, 130.9, 130.2, 129.9,
126.9, 124.9, 124.7, 116.8, 114.9. UPLC: (M + H)+ 247.5.
Anal. Calcd for C15H10N4: C, 73.16; H, 4.09; N, 22.75.
Found: C, 73.20; H, 4.45; N, 22.89.
Acknowledgment. One of the authors (R. S.) acknowledges Syngene
and also SAP facility to the department of Chemistry, GRI for
providing necessary facilities to carry out this research work.
CONFLICT OF INTEREST
1-(5-Bromopyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline
(7f). mp 175–177°C. IR (neat) 3068, 1615, 1401, 1082, 1004,
The authors disclose that there is no academic and finan-
cial conflict of interest in this work.
810, 746cmÀ1
. δ 8.96
1H NMR (400 MHz, DMSO-d6):
(d, J = 2.16 Hz, 1H), 8.40 (dd, J = 8.3, 2.36Hz, 1H), 8.03–7.99
(m, 2H), 7.89 (d, J = 9.52Hz, 1H), 7.79 (d, J = 9.48Hz, 1H),
7.62–7.59 (m, 1H), 7.56–7.53 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 151.0, 150.1, 147.8, 147.7, 141.1, 131.4, 131.1,
129.8, 129.7, 128.03, 127.0, 124.7, 122.4, 118.2, 114.8. LCMS:
(M+ H)+ 327.0. Anal. Calcd for C15H9BrN4: C, 55.41; H, 2.79;
N, 17.23. Found: 55.57; H, 2.98; N, 17.09.
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114–116°C. IR (neat) 3112, 1615, 1444, 1399, 1167, 1067,
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.
(s, 1H), 8.03 (d, J = 6.44 Hz, 1H), 7.93 (s, 1H), 7.81–7.84
(m, 1H), 7.61–7.57 (m, 1H), 7.17 (s, 1H), 7.08 (d, J = 7.52 Hz,
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140.7, 131.0, 130.1, 129.7, 129.4, 129.0, 126.4, 126.2, 124.1,
115.8, 115.1, 114.4, 112.1. UPLC: (M + H)+ 236.5.
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744 cmÀ1. H NMR (400 MHz, DMSO-d6): δ 8.14 (dd, J = 2.90,
1.20 Hz, 1H), 8.02 (m, 1H), 7.93 (m, 1H) 7.84 (d, J = 9.48 Hz,
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mp 270–272°C. IR (neat) 3149, 1620, 1579, 1451,
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.
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