Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium Azide: Access to 1 H-[1,2,3]Triazolo[4,5- c]quinoline Derivatives

Article abstract of DOI:10.1021/acs.joc.8b02476

A practical copper-catalyzed multicomponent reaction has been developed for the synthesis of 1H-[1,2,3]triazolo[4,5-c]quinoline derivatives from commercially available 2-bromobenzaldehydes, aryl methyl ketones, and sodium azide. This protocol integrated consecutive base-promoted condensation, [3 + 2] cycloaddition, copper-catalyzed S_NAr, and denitrogenation cyclization sequences. Preliminary mechanistic studies revealed that CuBr₂ acted as a multifunctional catalyst to streamline this domino process. The mild catalytic system enabled effective construction of one C-C and four C-N bonds in one operation.

Full text of DOI:10.1021/acs.joc.8b02476

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Note
Copper-Catalyzed Multicomponent Domino Reaction of 2-
Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium
Azide: Access to 1H-[1,2,3]Triazolo[4,5-c]quinoline Derivatives
Cheng Xu, Shi-Fen Jiang, Yan-Dong Wu, Feng-Cheng Jia, and An-Xin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02476 • Publication Date (Web): 15 Nov 2018
Downloaded from http://pubs.acs.org on November 15, 2018
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Copper-Catalyzed Multicomponent Domino Reaction of
2-Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium
Azide: Access to 1H-[1,2,3]Triazolo[4,5-c]quinoline
Derivatives
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Cheng Xu,† Shi-Fen Jiang,† Yan-Dong Wu,† Feng-Cheng Jia,*‡and An-Xin Wu*†
†Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, P. R. China
‡School of Chemistry and Environmental Engineering, Wuhan Institute of
Technology, Wuhan 430205, P. R. China
*E-mail: fengcheng-jia@wit.edu.cn; chwuax@mail.ccnu.edu.cn.
TOC Graphic:
N
N
H
CuBr2, L-proline, Cs2CO3
DMSO, 100 o
R
R
N
O
O
C
NaN3
25 examples
up to 86% yield
Ar
N
Ar
Br
Multifunction of the CuBr2 catalyst
NaN3 serves as a dual synthon
Simple and mild conditions
Formation of one C-C and four C-N bonds
Abstract: A practical copper-catalyzed multicomponent reaction has been developed
for the synthesis of 1H-[1,2,3]triazolo[4,5-c]quinoline derivatives from commercially
available 2-bromobenzaldehydes, aryl methyl ketones, and sodium azide. This
protocol integrated consecutive base-promoted condensation, [3+2] cycloaddition,
copper-catalyzed SNAr, and denitrogenation cyclization sequences. Preliminary
mechanistic studies revealed that CuBr2 acted as a multifunctional catalyst to
streamline this domino process. The mild catalytic system enabled effective
construction of one C–C and four C–N bonds in one operation.
The pursuit of concise synthetic methods that enable the rapid, straightforward
construction of multifarious heterocyclic frameworks with structural novelty and
complexity is the key focus of organic synthesis and drug discovery.1 In this context,
catalytic multicomponent reactions2 have proven to be extremely powerful protocols
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that allow the convergent synthesis of complex molecules from relatively simple
substrates through facile formation of multiple covalent bonds in a single operation. A
large number of corresponding methodologies have been established for the
construction of N-containing heterocycles.3 The 1,2,3-triazole nucleus is a privileged
structural motif that has been widely applied in the materials,4 chemical,5 and
biological sciences.6 In particular, triazole-fused polycyclic heterocycles7 are
extremely attractive owing to their remarkable pharmaceutical and biological
functionalities. They have been reported to show good serine protease inhibition
activity,8a antimicrobial effects,8b,c and promising anticancer properties.8d
1H-[1,2,3]Triazolo[4,5-c]quinolines are a class of structurally novel triazole-fused
heterocycles that contain both 1,2,3-triazole and quinoline frameworks. It is assumed
that this novel hybrid skeleton may feature promising bioactivity for screening
considering analogue fused 1,2,3-triazoles and their component units. However, only
a few synthetic approaches toward this novel structure have been reported, involving
preparative substrates and stoichiometric amounts of metal salts.9 Therefore, the
design and assembly of this structurally novel fused N-heterocycle from simple
materials via an elegant catalytic multicomponent strategy remains a fascinating and
desirable challenge.
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Sodium azide (NaN3) has been extensively utilized as an inexpensive and
versatile synthon in numerous organic transformations.10–13,15–18,21 Generally,
synthetic procedures for incorporating an azide moiety into organic molecules mainly
includes the following two types: (i) 1,3-Dipole cycloaddition reactions of NaN3 with
electron-deficient olefins11 or alkynes;12 and (ii) copper-catalyzed coupling reactions
of NaN3 with aryl halides13 involving concomitant N-atom transfer reaction14. Great
achievements have been made in the field of employing NaN3 as a versatile building
block based on the two typical reaction patterns.15,16 However, illustrations for the
construction of N-containing heterocycles using NaN3 as a dual nitrogen source
remain rare. In 2015, we developed an appealing copper-catalyzed domino protocol
for the rapid synthesis of 5-phenyl-[1,2,3]triazolo[1,5-c]quinazoline derivatives from
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readily available (E)-1-bromo-2-(2-nitrovinyl)benzenes, aldehydes, and NaN3
(Scheme 1a).17 Moreover, we have also disclosed an efficient Fe/Cu relay-catalyzed
domino protocol for the synthesis of 2-phenyl-quinazolin-4-amines (Scheme 1b).18 In
conjunction with our ongoing research into developing copper-catalyzed
multicomponent reactions using NaN3 as a dual nitrogen source, herein, we report a
facile and efficient approach for the construction of structurally novel
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1H-[1,2,3]triazolo[4,5-c]quinolines
from
commercially
available
2-bromobenzaldehydes, aryl methyl ketones, and NaN3 (Scheme 1c). Notably, one
C–C and four C–N bonds were formed sequentially in this copper-catalyzed domino
reaction.
Scheme 1. Copper-Catalyzed Multicomponent Reactions Using Sodium Azide as
a Dual Nitrogen Source
R2
Our previous work:
N
R1
R1
N
NO2
N
CuI, L-proline
(a)
(b)
(c)
NaN3
Ar
O
R2
DMSO, 100 o
C
N
Ar
Br
NH2
N
R
R
R
CN
Br
CuI, FeCl3, L-proline
NaN3
Ar
O
DMF, 110 o
C
N
Ar
This work:
N
N
H
R
N
O
CuBr2, L-proline, Cs2CO3
DMSO, 100 o
O
NaN3
Ar
C
Br
N
Ar
Our initial investigation focused on the model reaction of 2-bromobenzaldehyde
(1a), acetophenone (2a), and NaN3 in the presence of 10 mmol % CuI, 0.2 equiv. of
L-proline, and 3.0 equiv. of K2CO3 in DMSO at 100 °C for 20 h. Gratifyingly, the
reaction
proceeded
to
give
the
desired
product
4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3a) in 26% isolated yield (Table 1, entry
1). Encouraged by this preliminary result, various reaction parameters were
systematically evaluated to further improve the yield, the results are summarized in
Table 1. A range of inorganic and organic bases were first screened in the reaction
(Table 1, entries 2–7), with Cs2CO3 exhibiting the highest efficiency. Then, a series of
copper salts were examined (Table 1, entries 8–14), and the results suggested that the
use of CuBr2 as catalyst gave the best yield and provided the optimum result. This
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transformation was also attempted using several other solvents, such as DMF,
1,4-dioxane, toluene, and CH3CN (Table 1, entries 15–18). However, it proved that
they possess less capacity for the reaction. Subsequent increases or decreases in the
temperature did not enhance the outcome of the reaction any further (Table 1, entries
19–20). We also attempted the reaction under an argon atmosphere, but only a trace
amount of 3a was observed (Table 1, entry 21). This result indicated that this
transformation was assisted by oxygen. Further optimization of the reaction
conditions showed that decrease in the equivalent of NaN3, Cs2CO3, or CuBr2 catalyst
gave lower yields (see the Supporting Information). Eventually, the optimal reaction
conditions were determined as 1a (0.4 mmol), 1.0 equiv of 2a, 4.0 equiv of NaN3, 10
mmol % of CuBr2, 20 mmol % of L-proline, and 3.0 equiv. of Cs2CO3 in 3 mL of
DMSO at 100 °C in a sealed vessel under air.
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Table 1. Optimization of the Reaction Conditionsa
N
O
HN
N
O
Conditions
NaN3
Br
N
2a
1a
3a
yieldb
(%)
entry
catalyst
base
solvent
temp (°C)
1
2
CuI
CuI
K2CO3
Na2CO3
NaHCO3
Cs2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
26
19
21
67
52
trace
18
58
69
43
81
85
72
46
32
3
CuI
4
CuI
5
CuI
6
CuI
KOH
7
CuI
DBU
8
CuCl
CuBr
Cu2O
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
CuBr2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
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1,4-diox
16
CuBr2
Cs2CO3
100
trace
ane
6
7
8
9
17
18
19
20
21c
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
toluene
CH3CN
DMSO
DMSO
DMSO
100
100
90
trace
trace
62
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110
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75
<10
aReactions conditions: 1a (0.4 mmol), 2a (0.4 mmol), NaN3 (1.6 mmol), base (1.2 mmol), catalyst (10
mmol %), and L-proline (20 mmol %) were heated in 3 mL of solvent in a pressure vessel under air for
20 h. bIsolated yields. cReaction was performed under an argon atmosphere.
With the optimized conditions in hand, we proceeded to evaluate the scope and
generality of this copper-catalyzed multicomponent reaction. To our delight, the
reaction demonstrated a wide substrate scope in terms of the aromatic ketone unit
(Scheme 2). Various aryl methyl ketones bearing electronically neutral (4-H, 4-Me),
electron-donating (3-OMe, 4-OMe, 4-OEt, 3,4-OCH2O), and electron-withdrawing
(3-NO2, 4-Ph) substituents were successfully converted to the corresponding products
in good to excellent yields (76–86%; 3a–3h). Furthermore, halogenated aryl methyl
ketones were compatible with the reaction (74–81%, 3i–3l), therefore providing
opportunities for further synthetic elaboration. Sterically hindered (1-naphthyl and
2-naphthyl) methyl ketones also proceeded smoothly to afford the expected products
in 80% and 74% yields, respectively. As compounds bearing multiheterocyclic
scaffolds that might exhibit enhanced biological activity or vagarious properties are
valuable, we also explored the reactivity of heteroaryl methyl ketones, such as
1-(thiophen-2-yl)ethan-1-one and 1-(thiophen-3-yl)ethan-1-one. To our satisfaction,
the optimized conditions proved to be suitable for the conversion to these structurally
novel molecules (65% and 58%; 3o–3p). This transformation was also attempted with
propiophenone and several representative aliphatic methyl ketones, such as
butan-2-one, 3,3-dimethylbutan-2-one and 1-cyclopentylethan-1-one. However, none
of the desired products were observed under the standard conditions.
Scheme 2. Scope of Aryl Methyl Ketones a,b
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N
N
HN
O
CuBr2, L-proline, Cs2CO3
O
NaN3
DMSO, 100 o
C
Ar
Br
N
Ar
2
3
1a
N
N
N
N
HN
N
HN
N
HN
HN
N
N
N
N
N
N
N
N
N
N
N
N
N
OMe
N
Me
OMe
3a 85%
3b 83%
3c 78%
3d 86%
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N
N
N
HN
N
HN
HN
HN
N
O
O
N
N
N
N
OEt
Ph
3g 82%
3h 76%
3e 81%
3f 79%
NO2
N
N
N
N
HN
HN
HN
HN
N
Cl
N
N
N
N
3k 74%
3l 78%
3i 81%
F
3j 77%
Cl
Br
N
N
N
N
HN
HN
HN
HN
N
N
N
N
N
N
S
S
3m 80%
3n 74%
3o 65%
3p 58%
aReaction conditions: 1a (0.4 mmol), 2 (0.4 mmol), NaN3 (1.6 mmol), Cs2CO3 (1.2 mmol), CuBr2 (0.04
b
mmol) and L-proline (0.08 mmol) in DMSO (3 mL) at 100 °C in a pressure vessel for 20 h; Isolated
yields.
The scope of the copper-catalyzed multicomponent reaction was subsequently
extended to different substituted 2-bromobenzaldehydes. The results are displayed in
Scheme 3. Notably, the electronic properties of the substituents on the aromatic ring
system were shown to have little influence on the reaction efficiency. Various
substituted 2-bromobenzaldehydes found to be compatible with the reaction.
2-Bromobenzaldehydes bearing electron-neutral (5-Me, 4-Me) and electron-rich
(5-OMe, 4,5-(OMe)2 , 4,5-OCH2O) phenyl-ring substituents were smoothly
transformed into the corresponding products in good to excellent yields (77–84%;
3q–3u). In addition, halogen-substituted 2-bromobenzaldehydes (5-F, 5-Cl, 3-F, 3-Cl)
were also found to readily undergo the transformation, affording the desired products
in satisfactory yields (67–75%; 3v–3y). Furthermore, the structures of 3u and 3x were
unambiguously determined by X-ray crystallographic analysis (see the Supporting
Information).
Scheme 3. Scope of 2-Bromobenzaldehydes a,b
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N
N
O
HN
R
R
CuBr2, L-proline, Cs2CO3
O
NaN3
DMSO, 100 o
C
Br
N
2a
3
1
6
7
8
N
N
N
N
N
N
HN
HN
N
HN
N
MeO
Me
Me
N
3s 83%
3r 80%
3q 84%
9
N
N
N
N
N
HN
HN
HN
N
MeO
MeO
F
O
O
10
11
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N
N
N
3v 73%
3t 79%
3u 77%
N
N
N
N
N
N
HN
HN
HN
N
Cl
N
N
Cl
3y 67%
F
3w 75%
3x 72%
aReaction conditions: 1 (0.4 mmol), 2a (0.4 mmol), NaN3 (1.6 mmol), Cs2CO3 (1.2 mmol), CuBr2 (0.04
b
mmol) and L-proline (0.08 mmol) in DMSO (3 mL) at 100 °C in a pressure vessel for 20 h; Isolated
yields.
To illustrate the synthetic utility and demonstrate the application prospects of
this reaction, further transformations of the obtained products were investigated. For
example,
product
3a
was
easily
converted
to
2-(4-methylbenzyl)-4-phenyl-2H-[1,2,3]triazolo[4,5-c]quinoline (4) via nucleophilic
substitution with 1-(bromomethyl)-4-methylbenzene (Scheme 4a). Furthermore, 3a
was
successfully
functionalized
to
N-alkylation
product
(5) by
1-phenyl-2-(4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)ethan-1-one
reacting with 1-phenylbutane-1,3-dione in the presence of KOtBu and NBS (Scheme
4b).19 We also conducted a gram-scale synthesis experiment to further make this
reaction more attractive in terms of synthetic practicality. Gratifyingly, the reaction
proceeded well, affording desired product 3a in 67% isolate yield.
Scheme 4. Follow-up Transformations and Gram-Scale Experiments.
Tol
N
N
N
N
HN
N
K2CO3
Br
(a)
DMF, 80 oC, 10 h
Me
N
Ph
N
Ph
4a
3a
4,
73%
Ph
O
N
N
N
N
O
O
HN
N
NBS, KOtBu
(b)
(c)
EtOAc, 60 oC, 12 h
N
Ph
N
Ph
5a
3a
5,
87%
N
O
HN
N
CuBr2, L-proline, Cs2CO3
DMSO, 100 oC, 24 h
O
NaN3
Br
N
Ph
3a
(67%, 0.66 g)
1a
2a
(4 mmol)
(4 mmol)
To shed light on the mechanism of this copper-catalyzed multicomponent
reaction, several control experiments were conducted (Scheme 5). When the reaction
of 2-bromobenzaldehyde (1a), acetophenone (2a), and NaN3 under standard
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conditions was terminated at 3 h, product 3a was obtained in 35% yield, accompanied
by the generation of (E)-3-(2-bromophenyl)-1-phenylprop-2-en-1-one (A) in 18%
yield. After prolonging the reaction to 20 h, A had disappeared, while the yield of 3a
was increased to 84%. In the following experiments, A was isolated to react
independently with NaN3 under the optimized conditions, and was successfully
transformed to the desired product 3a in 67% yield. These results demonstrated that
2-bromochalcone A might be a key intermediate in this transformation. Next,
chalcone 6 was reacted with NaN3 in the presence of a catalytic amount of
CuBr2/L-proline to give expected product 7 in 93% yield, while only a trace amount
of 7 was observed in the absence of CuBr2. These results indicated that the CuBr2
catalyst could accelerate the [3+2] cycloaddition of A with NaN3. Furthermore, after
treatment of the (E)-3-(2-azidophenyl)-1-phenylprop-2-en-1-one (8) with NaN3 under
the optimized conditions for 20 h, no desired product 3a was observed. However,
product 2-phenylquinoline (9) was obtained in 72% yield via an intramolecular
annulation.16d These results showed that 2-azidochalcone 8 was not a possible
intermediate. Additionally, the cyclization sequence of intermediate A in this reaction
was initiated by the [3+2] cycloaddition rather than the cross-coupling of intermediate
A with NaN3.
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Scheme 5. Mechanistic Studies.
N
O
HN
N
O
Ph
O
standard conditions
(1)
NaN3
Ph
Br
Br
N
Ph
2a
3a
1a
A
3h: 18%
20h: trace
35%
84%
N
N
O
O
O
HN
N
Ph
standard conditions
NaN3
(2)
Ph
Br
A
6
3a 67%
N
N
HN
DMSO, 100 oC, 20 h
Ph
Ph
(3)
NaN3
Ph
O
with CuBr2/L-Proline
without CuBr2
7
7
93%
<10%
N
N
HN
standard conditions
(4)
NaN3
N
Ph
N
Ph
N3
9
72%
3a n,d
8
Although the mechanistic details have not been fully elucidated, based on
experimental observations and literature precedence,13–18,20,21 a tentative mechanism
for the copper-catalyzed domino sequence was proposed by using
2-bromobenzaldehyde (1a), acetophenone (2a), and NaN3 as an example, as shown in
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Scheme 6. Initially, 2-bromobenzaldehyde (1a) condensed with acetophenone (2a) to
generate the resultant 2-bromochalcone A in situ. Subsequently, the copper-catalyzed
[3+2] cycloaddition of A with NaN3 proceeded to give triazoline intermediate B,
which was further oxidized under air to give triazole intermediate C.9a,17 Intermediate
C would undergo a copper-catalyzed SNAr with NaN3 to afford intermediate D in the
light of the ortho-substituent effect.13,20 Further coordination of the azide group of D
to copper, concomitant with the release of N2 and reduction with the aid of trace H2O
leaded to the formation of intermediate F.21 Eventually, intramolecular condensation
of F would deliver product 4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3a) as
desired.
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Scheme 6. A Possible Mechanism.
O
O
Cs2CO3
H2
CuBr2, NaN3
O
Ph
[3+2] cycloaddition
Br
Br
O
1a
2a
A
Ph
Ph
Ph
O
O
O
N
N
N
N
N
N
oxidation
CuBr2, NaN3
N
N
N
Na
Na
Na
copper-catalyzed SNAr
Br
Br
N3
C
B
D
Ph
O
Ph
O
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N
N
HN
N
N
N
N
CuBr2, L-Proline
H2
O
N
H
CuII
N
Ph
N
N2
NH2
H2
O
N2
E
F
3a
Conclusion
In summary, we have developed an efficient and practical copper-catalyzed
multicomponent domino protocol for the synthesis of
1H-[1,2,3]triazolo[4,5-c]quinoline derivatives from simple and readily available
2-bromobenzaldehydes, aryl methyl ketones, and NaN3 under mild conditions. CuBr2
was used as a multifunctional catalyst to streamline [3+2] cycloaddition/SNAr and the
subsequent denitrogenation cyclization cascades. Further studies into the development
of new copper-catalyzed domino reactions employing NaN3 as a dual nitrogen source
to construct other fascinating N-heterocycles are underway in our laboratory.
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Experimental Section
General Methods.
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Unless otherwise stated, all starting materials and catalysts were obtained from
commercial suppliers and used without further purification. All new compounds were
fully characterized. TLC analysis was performed using precoated glass plates.
Column chromatography was performed using silica gel (200–300 mesh). IR spectra
were recorded on a PerkinElmer PE-983 infrared spectrometer as KBr pellets with
absorption in cm–1. 1H NMR spectra were recorded in DMSO-d6 or CDCl3 on 400/600
MHz NMR spectrometers, and resonances (δ) are given in parts per million relative to
tetramethylsilane (internal standard). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quadruple),
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coupling constants (Hz), and integration. C spectra were recorded in DMSO-d6 or
CDCl3 on 100/150 MHz NMR spectrometers, and resonances (δ) are given in ppm.
HRMS were obtained on a Bruker 7-T FT-ICR MS equipped with an electrospray
source. The X-ray crystal structure determinations of 3u and 3x were obtained on a
Bruker SMART APEX CCD system. Melting points were determined using an XT-4
apparatus and not corrected.
General Procedures for the Synthesis of Products 3 (3a as an example).
A mixture of 2-bromobenzaldehyde 1a (74.0 mg, 0.4 mmol), acetophenone 2a
(48.1 mg, 0.4 mmol), NaN3 (104.0 mg, 1.6 mmol), CuBr2 (8.9 mg, 0.04 mmol),
Cs2CO3 (391.0 mg, 1.20 mmol), L-proline (9.2 mg, 0.08 mmol) and DMSO (3.0 mL)
was added in a pressure vessel and then stirred at 100 °C for 20 h. After
disappearance of the reactant (monitored by TLC), then added 50 mL water to the
mixture, extracted with EtOAc 3 times (3 × 50 mL). The extract was washed with
30% NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc = 3/1) to afford the desired 3a as a light yellow solid.
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Experimental Procedure for the Synthesis of Compound 4.
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A mixture of 4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline 3a (98.5 mg, 0.4
mmol), 1-(bromomethyl)-4-methylbenzene 4a (74.0 mg, 0.4 mmol), K2CO3 (110.6 mg,
0.8 mmol) and DMF (3.0 mL) was added in a pressure vessel and then stirred at 80 °C
for 10 h. After disappearance of the reactant (monitored by TLC), then added 50 mL
water to the mixture, extracted with EtOAc 3 times (3 × 50 mL). The extract was
washed with 30% NaCl solution (V/V), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (eluent: petroleum ether/EtOAc = 10/1) to afford the
desired product 4.
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2-(4-methylbenzyl)-4-phenyl-2H-[1,2,3]triazolo[4,5-c]quinoline (4). White solid;
102.3 mg (yield 73%); mp 146-148 °C; IR (KBr): 3434, 1625, 1515, 1493, 1466,
1
1445, 1431, 1359, 780, 768, 727, 690, 645 cm-1; H NMR (400 MHz, CDCl3) δ
8.73-8.70 (m, 2H), 8.41 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.72-7.67 (m,
1H), 7.61-7.49 (m, 4H), 7.34 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 5.89 (s,
2H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.0, 145.8, 144.4, 138.5,
138.3, 136.9, 131.5, 130.3, 130.1, 129.5, 129.3, 129.0, 128.5, 128.2, 127.1, 122.5,
119.1, 60.2, 21.0; HRMS (ESI): m/z [M + H]+ calcd for C23H19N4: 351.1604; found:
351.1606.
Experimental Procedure for the Synthesis of Compound 5.
According to the related literature,19 4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline
3a (98.5 mg, 0.4 mmol), 1-phenylbutane-1,3-dione 5a (64.9 mg, 0.4 mmol),
N-bromosuccinimide (NBS) (85.4 mg, 0.48 mmol), KOtBu (89.8 mg, 0.8 mmol) and
EtOAc (4 mL) were added to a flask with a magnetic stirring bar. The resulting
mixture was stirred for 12 h at 60 °C. After cooling to room temperature, the mixture
was diluted with ethyl acetate and filtered. The filtrate was removed under reduced
pressure to get the crude product, which was further purified by silica gel
chromatography (eluent: petroleum ether/EtOAc = 5/1) to give product 5.
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1-phenyl-2-(4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)ethan-1-one (5). Light
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6
yellow solid; 126.8 mg (yield 87%); mp 169-171 °C; IR (KBr): 3551, 3476, 3414,
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8
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3236, 1702, 1617, 1449, 1325, 1225, 1156, 950, 767, 726, 692, 631 cm-1; H NMR
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(400 MHz, DMSO-d6) δ 8.75 (d, J = 6.8 Hz, 2H), 8.44 (d, J = 7.6 Hz, 1H), 8.26 (d, J
= 8.4 Hz, 1H), 8.17 (d, J = 7.2 Hz, 2H), 7.87 (t, J = 7.2 Hz, 1H), 7.81-7.75 (m, 2H),
7.68-7.61 (m, 5H), 6.91 (s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 192.0, 149.8,
145.1, 143.8, 137.8, 136.2, 134.5, 133.9, 130.7, 130.0, 129.6, 129.02, 128.95, 128.6,
128.4, 127.9, 122.3, 118.4, 62.8; HRMS (ESI): m/z [M + H]+ calcd for C23H17N4O:
365.1397; found: 365.1400.
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Procedure for the Scale-Up Synthesis of Product 3a.
2-bromobenzaldehyde 1a (0.74 g, 4.0 mmol), acetophenone 2a (0.48 g, 4.0
mmol), NaN3 (1.04 g, 16.0 mmol), CuBr2 (89 mg, 0.4 mmol), Cs2CO3 (3.91 g, 12.0
mmol), L-proline (92 mg, 0.8 mmol) and DMSO (25 mL) was added subsequently to
a 50 mL dry glass reaction tube equipped with a magnetic stirrer. The mixture was
stirred at 100 °C. The reaction was completed after 24h as monitored by TLC (eluent:
3:1 petroleum ether/ethyl acetate). The resulting reaction mixture was filtered. Then,
it was extracted with EtOAc three times (3 × 100 mL). The extract was washed with
30% NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel
(eluent: 3:1 petroleum ether/ethyl acetate) to afford 3a as a solid (0.66 g, 67%).
Experimental Procedure for the Preparation of 8.
According to the related literature,16d acetophenone (0.82 g, 6.8 mmol) was
added dropwise to a solution of sodium hydroxide (0.3 g) in water (10 ml) and ethanol
(5 ml) cooled in an ice bath. A solution of o-azidobenzaldehyde (1.0 g, 6.8 mmol) in
ethanol (1 ml) was added. After 10 min the reaction solution was removed from the
ice bath and stirred at room temperature for 16 h. Filtration gave the crude product.
Recrystallization from ethanol gave 8.
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(E)-3-(2-azidophenyl)-1-phenylprop-2-en-1-one (8).16d Yellow solid; 1.14 g (yield
67%); mp 68-70 °C; IR (KBr): 2126, 1661, 1594, 1571, 1482, 1318, 1215, 1032, 976,
865, 751, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.00 (t, J = 6.8 Hz, 3H), 7.68 (d, J
= 7.6 Hz, 1H), 7.60-7.47 (m, 4H), 7.42 (t, J = 7.6 Hz, 1H), 7.21-7.14 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 190.5, 139.5, 139.1, 138.0, 132.7, 131.4, 128.54, 128.49,
128.4, 126.4, 124.9, 123.7, 118.8; HRMS (ESI): m/z [M + H]+ calcd for C15H12N3O:
250.0975; found: 250.0977.
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Analytical Data for Products 3a-3y, A, 7 and 9.
4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3a).9b Light yellow solid; 83.7 mg
(yield 85%); mp 219-221 °C; IR (KBr): 3429, 3063, 2687, 1630, 1568, 1518, 1490,
1
1462, 1414, 1135, 1025, 976, 955, 914, 764, 730, 697 cm-1; H NMR (600 MHz,
DMSO-d6) δ 16.98 (s, 1H), 8.92 (s, 2H), 8.45 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 7.8 Hz,
1H), 7.88 (t, J = 6.6 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.71 (t, J = 7.2 Hz, 2H), 7.66 (t,
13
J = 6.6 Hz, 1H); C{1H} NMR (150 MHz, DMSO-d6) δ 149.4, 144.0, 137.2, 136.5,
130.4, 129.7, 129.3, 128.6, 127.3, 122.7, 115.3; HRMS (ESI): m/z [M + H]+ calcd for
C15H11N4: 247.0978; found: 247.0977.
4-(p-tolyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3b).9b Light yellow solid; 86.4 mg
(yield 83%); mp 210-212 °C; IR (KBr): 3379, 3020, 2920, 2861, 2662, 2552, 1637,
1
1611, 1509, 1359, 1235, 1207, 1023, 989, 829, 763, 735 cm-1; H NMR (600 MHz,
DMSO-d6) δ 16.95 (s, 1H), 8.82 (s, 2H), 8.43 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.8 Hz,
1H), 7.87 (t, J = 7.2 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 2.46
(s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 149.5, 144.2, 140.5, 137.5, 133.9,
129.9, 129.7, 129.4, 127.3, 122.8, 115.3, 21.2; HRMS (ESI): m/z [M + H]+ calcd for
C16H13N4: 261.1135; found: 261.1136.
4-(3-methoxyphenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3c). White solid; 86.2 mg
(yield 78%); mp 180-182 °C; IR (KBr): 3136, 3097, 2937, 2870, 2830, 2725, 1639,
1
1598, 1518, 1432, 1286, 1261, 1154, 1088, 1049, 956, 894, 784, 763 cm-1; H NMR
(600 MHz, DMSO-d6) δ 16.83 (s, 1H), 8.42 (s, 2H), 8.29 (d, J = 5.4 Hz, 1H), 8.13 (d,
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J = 7.2 Hz, 1H), 7.72-7.63 (m, 2H), 7.48 (d, J = 6.6 Hz, 1H), 7.09 (d, J = 6.0 Hz, 1H),
3.87 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 159.4, 149.0, 143.9, 137.9,
137.4, 129.7, 129.6, 127.2, 122.6, 121.8, 116.0, 115.2, 114.5, 55.2; HRMS (ESI): m/z
[M + H]+ calcd for C16H13N4O: 277.1084; found: 277.1086.
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4-(4-methoxyphenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3d).9b Yellow solid; 95.0
mg (yield 86%); mp 145-147 °C; IR (KBr): 3267, 2846, 2178, 1605, 1509, 1363,
1259, 1233, 1208, 1033, 982, 835, 763 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 16.83
(s, 1H), 8.84 (s, 2H), 8.32 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 7.2
13
Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H); C{1H}
NMR (150 MHz, DMSO-d6) δ 161.3, 149.1, 144.2, 137.3, 131.0, 129.7, 129.5, 129.1,
126.9, 122.7, 115.1, 114.0, 55.4; HRMS (ESI): m/z [M + H]+ calcd for C16H13N4O:
277.1084; found: 277.1088.
4-(4-ethoxyphenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3e). Yellow solid; 94.1 mg
(yield 81%); mp 217-219 °C; IR (KBr): 3468, 2915, 2872, 1638, 1605, 1511, 1452,
1359, 1295, 1189, 1042, 924, 841, 764 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 16.93
(s, 1H), 8.91 (s, 2H), 8.41 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 7.8
Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 9.0 Hz, 2H), 4.19-4.14 (m, 2H), 1.42 (t,
13
J = 7.2 Hz, 3H); C{1H} NMR (150 MHz, DMSO-d6) δ 160.6, 149.1, 144.2, 137.4,
136.5, 131.0, 129.7, 129.4, 128.9, 126.8, 122.7, 114.8, 114.3, 63.3, 14.7; HRMS
(ESI): m/z [M + H]+ calcd for C17H15N4O: 291.1240; found: 291.1239.
4-(benzo[d][1,3]dioxol-5-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3f). Yellow solid;
91.7 mg (yield 79%); mp 215-217 °C; IR (KBr): 3095, 2869, 1637, 1498, 1452, 1248,
1039, 995, 821, 763, 736 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 16.94 (s, 1H), 8.65
(s, 1H), 8.39 (d, J = 7.8 Hz, 2H), 8.20 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H),
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7.76 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.20 (s, 2H); C{1H} NMR (100
MHz, DMSO-d6) δ 148.9, 148.1, 147.3, 143.6, 136.8, 130.4, 129.2, 129.1, 126.5,
124.2, 122.3, 114.7, 108.3, 108.0, 101.4; HRMS (ESI): m/z [M + H]+ calcd for
C16H11N4O2: 291.0877; found: 291.0875.
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4-(3-nitrophenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3g).9b Light yellow solid; 95.5
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6
mg (yield 82%); mp 210-212 °C; IR (KBr): 3095, 2869, 2824, 1524, 1348, 1159,
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8
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1084, 995, 814, 767 cm-1; H NMR (600 MHz, DMSO-d6) δ 17.01 (s, 1H), 9.64 (s,
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1H), 9.26 (d, J = 6.6 Hz, 1H), 8.42-8.37 (m, 2H), 8.23 (d, J = 7.8 Hz, 1H), 7.91 (t, J =
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7.8 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H); C{1H} NMR (150
MHz, DMSO-d6) δ 147.7, 147.6, 145.9, 145.6, 143.2, 137.2, 136.6, 134.6, 129.6,
129.5, 127.5, 124.4, 123.0, 122.3, 115.0; HRMS (ESI): m/z [M + H]+ calcd for
C15H10N5O2: 292.0829; found: 292.0830.
4-([1,1'-biphenyl]-4-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3h).9b Light yellow
solid; 98.0 mg (yield 76%); mp 189-191 °C; IR (KBr): 3056, 3017, 2919, 2713, 1607,
1585, 1491, 1356, 1245, 1159, 1002, 949, 841, 763 cm-1; H NMR (600 MHz,
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DMSO-d6) δ 17.00 (s, 1H), 9.01 (s, 2H), 8.44 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 8.4 Hz,
1H), 7.97 (d, J = 7.8 Hz, 2H), 7.88 (t, J = 7.8 Hz, 1H), 7.84-7.78 (m, 3H), 7.55 (t, J =
7.8 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H); C{1H} NMR (150 MHz, DMSO-d6) δ 149.0,
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144.1, 142.0, 139.5, 137.4, 135.5, 130.0, 129.9, 129.7, 129.2, 128.1, 127.4, 126.90,
126.86, 122.8, 115.2; HRMS (ESI): m/z [M + H]+ calcd for C21H15N4: 323.1291;
found: 323.1294.
4-(4-fluorophenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3i).9b Light yellow solid;
85.6 mg (yield 81%); mp 234-236 °C; IR (KBr): 3022, 2936, 2870, 2827, 1603, 1508,
1356, 1234, 1157, 1085, 996, 842, 765 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 16.98
(s, 1H), 8.96 (s, 2H), 8.41 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.2
Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 9.0 Hz, 2H); 13C{1H} NMR (150 MHz,
1
DMSO-d6) δ 163.7 (d, J = 246.0 Hz, JCF), 148.1, 143.9, 137.1, 132.9, 131.6 (d, J =
3
2
9.0 Hz, JCF), 129.6, 129.6, 127.2, 122.7, 115.5 (d, J = 22.5 Hz, JCF), 115.1; HRMS
(ESI): m/z [M + H]+ calcd for C15H10FN4: 265.0884; found: 265.0885.
4-(3-chlorophenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3j). Light yellow solid; 86.5
mg (yield 77%); mp 218-220 °C; IR (KBr): 3045, 2934, 2868, 2824, 1638, 1517,
1478, 1354, 1247, 1085, 996, 836, 782, 763 cm-1; H NMR (600 MHz, DMSO-d6) δ
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1H), 7.74-7.66 (m, 2H), 7.56 (s, 2H); C{1H} NMR (150 MHz, DMSO-d6) δ 147.3,
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143.7, 138.3, 137.0, 133.4, 130.3, 130.1, 129.7, 128.5, 127.7, 127.5, 122.6, 115.2;
HRMS (ESI): m/z [M + H]+ calcd for C15H10ClN4: 281.0589; found: 281.0585.
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4-(4-chlorophenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3k).9b Light yellow solid;
83.1 mg (yield 74%); mp 252-254 °C; IR (KBr): 3456, 3020, 2868, 2824, 1637, 1593,
1
1518, 1354, 1236, 1089, 996, 837, 760, 735 cm-1; H NMR (600 MHz, DMSO-d6) δ
16.96 (s, 1H), 8.89 (d, J = 7.2 Hz, 2H), 8.39 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 7.8 Hz,
1H), 7.86 (t, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H);
13C{1H} NMR (150 MHz, DMSO-d6) δ 147.8, 143.9, 137.1, 135.4, 135.1, 130.8,
129.72, 129.66, 128.6, 127.4, 122.7, 115.2; HRMS (ESI): m/z [M + H]+ calcd for
C15H10ClN4: 281.0589; found: 281.0587.
4-(4-bromophenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3l).9b Yellow solid; 101.5
mg (yield 78%); mp 247-249 °C; IR (KBr): 3380, 3017, 2922, 2661, 2555, 1635,
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1589, 1487, 1357, 1234, 1070, 989, 834, 762, 736 cm-1; H NMR (600 MHz,
DMSO-d6) δ 16.97 (s, 1H), 8.82 (s, 2H), 8.38 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 8.4 Hz,
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1H), 7.84 (d, J = 8.4 Hz, 3H), 7.78 (t, J = 7.2 Hz, 1H); C{1H} NMR (150 MHz,
DMSO-d6) δ 147.9, 143.8, 137.0, 135.4, 131.5, 131.0, 129.6, 127.3, 124.3, 122.6,
115.2; HRMS (ESI): m/z [M + H]+ calcd for C15H10BrN4: 325.0083; found: 325.0085.
4-(naphthalen-1-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3m). Yellow solid; 94.8 mg
(yield 80%); mp 151-153 °C; IR (KBr): 3264, 3056, 2916, 2646, 1633, 1522, 1356,
1207, 1016, 939, 763 cm-1; 1H NMR (600 MHz, CDCl3) δ 13.77 (s, 1H), 8.23 (d, J =
7.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 6.6 Hz,
1H), 7.58 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.30
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(t, J = 7.2 Hz, 1H), 7.23-7.15 (m, 3H); C{1H} NMR (150 MHz, CDCl3) δ 151.8,
143.2, 138.5, 137.2, 133.4, 132.5, 130.9, 130.1, 129.6, 128.7, 128.3, 128.0, 127.5,
126.6, 125.9, 125.1, 124.6, 122.8, 115.8; HRMS (ESI): m/z [M + H]+ calcd for
C19H13N4: 297.1135; found: 297.1132.
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4-(naphthalen-2-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3n).9b Light yellow solid;
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87.7 mg (yield 74%); mp 235-237 °C; IR (KBr): 3365, 2921, 2763, 2557, 1637, 1518,
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1367, 1236, 1022, 937, 818, 747 cm-1; H NMR (600 MHz, DMSO-d6) δ 17.32 (s,
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1H), 9.62 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 7.8
Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 6.6 Hz, 1H),
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7.91 (t, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.67-7.66 (m, 2H); C{1H} NMR
(150 MHz, DMSO-d6) δ 149.1, 144.1, 137.2, 134.0, 133.9, 132.8, 130.2, 130.1, 129.7,
129.1, 128.0, 127.7, 127.4, 127.3, 126.6, 125.7, 122.7, 115.3; HRMS (ESI): m/z [M +
H]+ calcd for C19H13N4: 297.1135; found: 297.1133.
4-(thiophen-2-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3o). Yellow solid; 65.6 mg
(yield 65%); mp 279-281 °C; IR (KBr): 3098, 1629, 1532, 1452, 1363, 1208, 1044,
1
978, 855, 759, 716 cm-1; H NMR (600 MHz, DMSO-d6) δ 16.99 (s, 1H), 8.90 (s,
1H), 8.40 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 4.2 Hz, 1H), 7.86
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(t, J = 7.8 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 4.2 Hz, 1H); C{1H} NMR
(150 MHz, DMSO-d6) δ 145.0, 144.1, 141.6, 136.0, 131.5, 130.7, 129.8, 129.0, 128.8,
127.0, 122.8, 115.1; HRMS (ESI): m/z [M + H]+ calcd for C13H9N4S: 253.0542;
found: 253.0543.
4-(thiophen-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (3p). Yellow solid; 58.5 mg
(yield 58%); mp 272-274 °C; IR (KBr): 3519, 3095, 1638, 1585, 1529, 1412, 1337,
1233, 1070, 953, 874, 761, 730 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 16.82 (s, 1H),
9.08 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 7.8 Hz,
1H), 7.75-7.70 (m, 2H), 7.65 (t, J = 7.8 Hz, 1H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 145.7, 144.2, 139.2, 136.9, 129.73, 129.66, 129.5, 127.4, 127.0, 126.6,
122.7, 115.2; HRMS (ESI): m/z [M + H]+ calcd for C13H9N4S: 253.0542; found:
253.0543.
8-methyl-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3q). Light yellow solid; 87.5
mg (yield 84%); mp 249-251 °C; IR (KBr): 3472, 3068, 3020, 1607, 1564, 1461,
1
1381, 1236, 1023, 958, 821, 767, 726 cm-1; H NMR (400 MHz, DMSO-d6) δ 16.77
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(s, 1H), 8.88 (s, 2H), 8.06 (t, J = 8.8 Hz, 2H), 7.70-7.63 (m, 3H), 7.57 (d, J = 7.6 Hz,
1H), 2.53 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 148.3, 142.3, 136.9, 136.6,
131.2, 130.2, 129.3, 129.2, 128.5, 121.8, 115.1, 21.2; HRMS (ESI): m/z [M + H]+
calcd for C16H13N4: 261.1135; found: 261.1130.
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7-methyl-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3r). Light yellow solid; 83.3
mg (yield 80%); mp 245-247 °C; IR (KBr): 3448, 3020, 2876, 2830, 1639, 1517,
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1492, 1353, 1237, 1090, 995, 851, 770, 692 cm-1; H NMR (600 MHz, DMSO-d6) δ
16.83 (s, 1H), 8.87 (s, 2H), 8.26 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.68 (t, J = 7.8 Hz,
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2H), 7.63 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 2.56 (s, 3H); C{1H} NMR
(150 MHz, DMSO-d6) δ 149.4, 144.3, 139.6, 137.4, 136.7, 135.8, 130.5, 129.4, 129.1,
128.9, 128.7, 122.4, 112.4, 21.5; HRMS (ESI): m/z [M + H]+ calcd for C16H13N4:
261.1135; found: 261.1133.
8-methoxy-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3s). Light yellow solid;
91.7 mg (yield 83%); mp 205-207 °C; IR (KBr): 3411, 2921, 2835, 1618, 1509, 1405,
1261, 1028, 857, 766, 696 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 16.77 (s, 1H), 8.85
(s, 2H), 8.10 (d, J = 9.0 Hz, 1H), 7.76 (s, 1H), 7.67 (t, J = 7.8 Hz, 2H), 7.61 (t, J = 7.2
Hz, 1H), 7.42-7.39 (m, 1H), 3.97 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ
157.9, 146.5, 139.1, 137.5, 136.8, 131.1, 130.0, 129.1, 128.5, 120.0, 116.0, 102.5,
55.5; HRMS (ESI): m/z [M + H]+ calcd for C16H13N4O: 277.1084; found: 277.1087.
7,8-dimethoxy-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3t). Yellow solid; 96.8
mg (yield 79%); mp 243-245 °C; IR (KBr): 3533, 3034, 2835, 1625, 1506, 1471,
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1272, 1175, 1030, 857, 819, 764, 693 cm-1; H NMR (600 MHz, DMSO-d6) δ 16.50
(s, 1H), 8.85 (s, 2H), 7.65 (t, J = 7.8 Hz, 3H), 7.59 (t, J = 7.2 Hz, 1H), 7.54 (s, 1H),
3.98 (s, 3H), 3.97 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 151.3, 149.4, 146.5,
140.1, 136.9, 136.0, 129.9, 129.0, 128.5, 109.5, 108.7, 101.8, 55.67, 55.64; HRMS
(ESI): m/z [M + H]+ calcd for C17H15N4O2: 307.1190; found: 307.1188.
4-phenyl-1H-[1,3]dioxolo[4,5-g][1,2,3]triazolo[4,5-c]quinoline (3u). Light yellow
solid; 89.4 mg (yield 77%); mp 267-269 °C; IR (KBr): 3136, 3037, 2824, 2716, 1641,
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1463, 1352, 1266, 1171, 1036, 986, 861, 763, 690 cm-1; H NMR (600 MHz,
DMSO-d6) δ 16.57 (s, 1H), 8.81 (s, 2H), 7.64 (t, J = 7.2 Hz, 3H), 7.58 (t, J = 7.2 Hz,
1H), 7.53 (s, 1H), 6.25 (s, 2H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 150.0, 147.6,
146.7, 141.4, 136.9, 136.6, 135.8, 130.0, 128.9, 128.5, 109.8, 107.1, 102.4, 99.1;
HRMS (ESI): m/z [M + H]+ calcd for C16H11N4O2: 291.0877; found: 291.0875.
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8-fluoro-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3v). Light yellow solid; 77.2
mg (yield 73%); mp 217-219 °C; IR (KBr): 3396, 2765, 1608, 1502, 1410, 1353,
1259, 1193, 1075, 994, 882, 760, 686 cm-1; H NMR (600 MHz, DMSO-d6) δ 16.83
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(s, 1H), 8.79 (s, 2H), 8.21-8.18 (m, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.67-7.62 (m, 4H);
13C{1H} NMR (150 MHz, DMSO-d6) δ 160.0 (d, J = 244.5 Hz, JCF), 148.7, 140.9,
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3
137.1, 136.2, 132.4 (d, J = 9.0 Hz, JCF), 130.4, 129.1, 128.5, 118.5 (d, J = 24.0 Hz,
2JCF), 116.2, 107.1 (d, J = 24.0 Hz, JCF); HRMS (ESI): m/z [M + H]+ calcd for
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C15H10FN4: 265.0884; found: 265.0885.
8-chloro-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3w). Light yellow solid; 84.2
mg (yield 75%); mp 239-241 °C; IR (KBr): 3441, 3064, 2952, 1564, 1512, 1451,
1417, 1316, 1133, 1083, 977, 823, 754, 688 cm-1; H NMR (600 MHz, DMSO-d6) δ
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16.85 (s, 1H), 8.79 (d, J = 5.4 Hz, 2H), 8.31 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.74 (d,
J = 8.4 Hz, 1H), 7.66-7.63 (m, 3H); C{1H} NMR (150 MHz, DMSO-d6) δ 149.5,
13
142.2, 137.2, 136.1, 131.3, 131.3, 130.5, 129.6, 129.2, 128.4, 121.6, 116.0; HRMS
(ESI): m/z [M + H]+ calcd for C15H10ClN4: 281.0589; found: 281.0586.
6-fluoro-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3x). Yellow solid 76.1 mg
(yield 72%); mp 199-201 °C; IR (KBr): 3395, 2920, 2849, 1643, 1596, 1521, 1466,
1355, 1243, 967, 873, 760, 697 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 17.08 (s, 1H),
8.86 (d, J = 6.6 Hz, 2H), 8.23 (d, J = 6.0 Hz, 1H), 7.78-7.66 (m, 4H), 7.64 (t, J = 6.6
Hz, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 157.9 (d, J = 255.0 Hz, 1JCF), 149.5,
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137.4, 136.2, 133.4 (d, J = 10.5 Hz, JCF), 130.7, 129.4, 128.6, 127.8 (d, J = 9.0 Hz,
3JCF), 118.5, 117.2, 114.6 (d, J = 19.5 Hz, 2JCF); HRMS (ESI): m/z [M + H]+ calcd for
C15H10FN4: 265.0884; found: 265.0887.
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6-chloro-4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3y). Yellow solid; 75.2 mg
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(yield 67%); mp 273-275 °C; IR (KBr): 3394, 1631, 1513, 1492, 1458, 1355, 957,
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927, 762, 693 cm-1; H NMR (600 MHz, DMSO-d6) δ 16.99 (s, 1H), 8.95 (s, 2H),
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8.26 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.2 Hz, 2H), 7.68 (t, J =
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7.2 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H); C{1H} NMR (150 MHz, DMSO-d6) δ 149.4,
139.7, 137.5, 136.2, 133.4, 130.8, 129.8, 129.5, 128.6, 127.5, 121.8, 116.9; HRMS
(ESI): m/z [M + H]+ calcd for C15H10ClN4: 281.0589; found: 281.0588.
(E)-3-(2-bromophenyl)-1-phenylprop-2-en-1-one (A).16d Light yellow solid; mp
39-41 °C; IR (KBr): 3056, 1664, 1607, 1463, 1334, 1312, 1269, 1213, 1160, 1014,
971, 750, 688 cm-1; H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 15.6 Hz, 1H),
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8.03-8.00 (m, 2H), 7.74-7.71 (m, 1H), 7.64-7.56 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H),
7.42 (d, J = 15.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.26-7.21 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 190.2, 143.0, 137.7, 134.9, 133.4, 132.9, 131.3, 128.6, 128.5,
127.8, 127.6, 125.8, 124.9; HRMS (ESI): m/z [M + H]+ calcd for C15H12BrO:
287.0066; found: 287.0068.
phenyl(5-phenyl-1H-1,2,3-triazol-4-yl)methanone (7). Yellow solid; mp 83-85 °C;
IR (KBr): 3145, 2995, 2907, 1658, 1577, 1466, 1295, 1175, 1074, 997, 907, 743, 692
cm-1; 1H NMR (600 MHz, CDCl3) δ 14.50 (s, 1H), 8.00 (d, J = 6.6 Hz, 2H), 7.62 (d, J
= 6.6 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.32-7.27 (m, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 188.3, 140.8, 136.8, 133.4, 130.4, 129.6, 128.7,
128.4, 128.2, 127.1; HRMS (ESI): m/z [M + H]+ calcd for C15H12N3O: 250.0975;
found: 250.0977.
2-phenylquinoline (9).16d White solid; mp 82-84 °C; IR (KBr): 3068, 1595, 1553,
1489, 1445, 1317, 829, 772, 690, 675 cm-1; H NMR (400 MHz, CDCl3) δ 8.19-8.11
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(m, 4H), 7.80 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71-7.66 (m, 1H),
7.52-7.41 (m, 4H); C{1H} NMR (100 MHz, CDCl3) δ 157.2, 148.2, 139.6, 136.7,
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129.6, 129.5, 129.2, 128.7, 127.5, 127.4, 127.1, 126.2, 118.9; HRMS (ESI): m/z [M +
H]+ calcd for C15H12N: 206.0964; found: 206.0967.
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ASSOCIATED CONTENT
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Supporting Information
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Crystallographic data and copies of the H and C NMR spectra are involved. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: fengcheng-jia@wit.edu.cn; chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China
(Grant 21472056, 21602070, and 21772051) and the Fundamental Research
Funds for the Central Universities (CCNU15ZX002 and CCNU16A05002) for
financial support. It was also supported by the 111 Project B17019. We
acknowledge the graduate student educational innovation grant from Central
China Normal University (2018CXZZ033).
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(7) (a) Barve, I. J.; Thikekar, T. U.; Sun, C.-M. Silver(I)-Catalyzed Regioselective
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(9) (a) Upadhyaya, K.; Ajay, A.; Mahar, R.; Pandey, R.; Kumar, B.; Shukla, S. K.;
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