Synthesis of 2,1-Benzoisoxazole-Containing 1,2,3-Triazoles through Copper-Catalyzed Three-Component Domino Reactions of o-Bromoacetophenones, Aldehydes, and Sodium Azide

Article abstract of DOI:10.1021/acs.joc.9b02865

We herein describe an efficient copper-catalyzed three-component domino protocol used to prepare 2,1-benzoisoxazole-containing 1,2,3-triazoles from commercially available o-bromoacetophenones, aldehydes, and sodium azide. This domino process involves Aldol condensation, copper-catalyzed azide-chalcone oxidative cyclization, 1,2,3-triazole-assisted azidation, and denitrogenative cyclization sequences. The formed compounds could be considered as benzo[c]isoxazole-functionalized combretastatin A-4 triazole analogues, which might be potential applications in the discovery of a new anticarcinogen.

Full text of DOI:10.1021/acs.joc.9b02865

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Note
Synthesis of 2,1-Benzoisoxazole-Containing 1,2,3-Triazoles
through Copper-Catalyzed Three-Component Domino Reactions
of o-Bromoacetophenones, Aldehydes and Sodium Azide
Yuwei Wang, Pei Yu, Qingyun Ren, Feng-Cheng Jia, Yunfeng Chen, and An-Xin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02865 • Publication Date (Web): 03 Jan 2020
Downloaded from pubs.acs.org on January 3, 2020
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Synthesis of 2,1-Benzoisoxazole-Containing 1,2,3-Triazoles through
Copper-Catalyzed Three-Component Domino Reactions of
o-Bromoacetophenones, Aldehydes and Sodium Azide
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Yuwei Wang,† Pei Yu,† Qingyun Ren,§ Fengcheng Jia*,†, Yunfeng Chen*,† and Anxin
Wu‡
†School of Chemistry and Environmental Engineering, Wuhan Institute of
Technology, Wuhan 430073, P. R. China
‡Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, P. R. China
§The State Key Laboratory of Anti-Infection Drug Development, HEC Pharma Group,
Dongguan 523871, P. R.China
O
Ar
CuO, K2CO3, air
DMSO, 100oC
O
N
NH
NaN3
R
Ar
O
N
N
R
31 examples
up to 76% yield
Br
(Ar = aryl and heteroaryl)
NaN3 as dual nitrogen source
Broad substrate scopes
Five new bonds formation
Construction of two N-heterocycles
ABSTRACT: We herein describe an efficient copper-catalyzed three-component
domino protocol used to prepare 2,1-benzoisoxazole-containing 1,2,3-triazoles from
commercially available o-bromoacetophenones, aldehydes and sodium azide. This
domino process involves Aldol condensation, copper-catalyzed azide-chalcone
oxidative cyclization, 1,2,3-triazole-assisited azidation and denitrogenative
cyclization sequences. The formed compounds could be considered as
benzo[c]isoxazole-functionalized combretastatin A-4 triazole analogs, which might be
potential applications in the discovery of new anticarcinogen.
1,2,3-triazoles are ubiquitous structural motifs in bioactive molecules due to their
good biocompatibility1 and marked stability under hydrolytic, oxidative and reductive
conditions.2–3 Among these compounds, 4,5-diarylsubstituted 1,2,3-triazoles have
been reported to possess a wide range of biological activities4–5 including Anti-mitosis
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(I),5b–5c Antitumor (II)5d and Anticancer activity (III and IV) (Figure 1).5d Different
modification of the aryl moieties, especially the tuning of aromatic skeleton lead to
diverse biological activities. As a new heteroaromatic ring building block,
benzo[c]isoxazole could also construct novel 4,5-di(hetero)aryl-1,2,3-triazoles (Figure
1 V) (Figure 1), which may feature promising bioactivity in terms of its structural
similarity. However, no synthetic approaches toward this novel structure have been
reported. Therefore, it is fascinating and desirable to assemble this structurally novel
N-heterocycles from simple materials via a multicomponent domino strategy.
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Figure
1.
Selected
Biologically
Active
Compounds
Related
to
4,5-Diarylsubstituted 1,2,3-Triazoles
OCH3
OCH3
OCH3
OCH3
H3CO
OCH3
OCH3
H3CO
H
S
N
H3CO
NH
N
NH
N
NH
N
N
N
N
I
II
III
MDA-MB-435
GI50/uM=0.337
NCI 60 screen
Mean GI50/uM<0.01
BT-549 GI50/uM=0.028
MDA-MB-435 GI50/uM=0.014
R
H3CO
OCH3
H
N
N
O
BT-549 GI50/uM=0.017
NCI-H522 GI50/uM=0.013
MDA-MB-435 GI50/uM=0.010
NH
N
NH
N
N
N
IV
V
(this work)
Aryl azides are important synthetic intermediates with a variety of application in
organic and bioorganic chemistry. Besides acting as building blocks for the
construction of 1,2,3-triazoles, aryl azides could also serve as one-nitrogen source
driven by the irreversible denitrogenation to form other N-containing compounds.6
Among these transformations, reactions related to aryl azides have also developed by
combining copper-catalyzed coupling of haloarenes and NaN3 with denitrogenative
N-X (X = N, C) bond formation reactions.7-11 Various N-containing heterocycles were
efficiently constructed by this synthesis strategy. For instance, Lee’s group described
an efficient synthesis of 2H-indazole and benzimidazoles with the in situ generated
aryl azido group as electrophile or nucleophile to form N-N or C-N bond, respectively
(Scheme 1).9 Ramana and Jiao developed a new strategy to construct intramolecular
C-N bonds by catalytic nitrene (arised from azides) insertion into C-H bonds, which
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enabled the synthesis of indoles and carbazoles (Scheme 1).10 Recently, we also
disclosed an elegant procedure to generate intramolecular or intermolecular C-N bond
via copper-catalyzed aza-Witting-type reaction of aryl azides and carbonyl group
(Scheme 1).11 However, to our knowledge, methods utilizing aryl azides for the N-O
bond formation is rare. Herein, we report a copper-catalyzed three-component domino
reaction which involving N-O bond formation related to in situ generate aryl azides
for the synthesis of structurally novel 2,1-benzoisoxazole-containing 1,2,3-triazoles.
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Scheme 1. Synthesis of N-Heterocycles via Copper-Catalyzed Domino Reactions
of ortho-Functionalized Aryl Halides and NaN3
Previous works for N-N or N-C bond formation involving in situ generated aryl azides
R
R
N
N
C
+
N
N
H
R
NaN3
FG
Br
[Cu]
Lee's works
R
+
Solvent
N
other components
R
N
N
C
C
N
N
H
Our previous work
Ramana's & jiao's
works
This work for N-O bond formation involving in situ generated aryl azides
O
N
O
R
Ar
NH
R
CuO, K2CO3
+
NaN3
+
Ar CHO
DMSO, 100 o
C
Br
N
N
We commenced the study with o-bromoacetophenone 1a, benzaldehyde 2a and
sodium azide as model substrates to explore the reaction conditions, and the results
were summarized in Table 1. Initially, the reaction was conducted in the presence of
o
50 mol% CuI and 2 equivalent of Cs2CO3 in DMSO at 100 C, and a 21% yield of
target product 3aa was isolated after 24 h (entry 1). Inspired by this result, various
reaction parameters were systematically evaluated to further improve the yield, Firstly,
a series of copper salts were screened, and CuO showed the highest activity (entries
2–9). Then, several inorganic bases were examined, K2CO3 was found to provide a
more promising outcome (entries 10–12). Next, this transformation was also
performed in different solvents, and DMSO was proved to be the most effective
solvent (entries 13–16). Increasing or decreasing the temperature of the reaction did
not lead to any further improvements in the yield (entries 17–18). Further
optimization of the reaction conditions showed that a decrease in the equivalents of
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NaN3, benzaldehyde or K2CO3 gave lower yields (see the Supporting Information).
We also attempted to reduce the catalyst loading, and 20 mol% CuO distinctly
decreased the yield to 24%, which indicated the loading of CuO was key factor for
this reaction (entry 19). The poor reactivity observed when the reaction was
conducted under inert atmosphere, which meant the O2 may be involved in the
reaction process (entry 20). Eventually, the optimized reaction conditions were
identified as o-bromoacetophenone 1a (1.0 equiv.), benzaldehyde 2a (1.5 equiv.),
NaN3 (3.0 equiv.), K2CO3 (2.0 equiv.) and CuO (50 mol %) in 3 mL of DMSO at 100
°C in an open vessel.
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Table 1. Optimization of the Reaction Conditionsa
O
CHO
N
O
Conditions
+
+
NaN3
NH
N
Br
N
1a
3aa
2a
temp
(oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
yieldb
(%)
21
entry
catalyst
base
solvent
1
2
CuI
CuBr
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
<10
trace
trace
0
3
CuCl
4
Cu2O
Cu(OTf)2
Cu(OAc)2
CuO
5
6
23
7
69
8
CuCl2
CuBr2
CuO
27
9
<10
68
10
11
12
13
14
CuO
K2CO3
NaOH
75
CuO
67
CuO
K2CO3
K2CO3
18
CuO
DMF
65
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CuO
CuO
K2CO3
K2CO3
1,4-dioxane
Ethylene
glycol
100
100
trace
trace
9
17
18
CuO
CuO
CuO
CuO
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
80
36
67
10
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DMSO
120
100
100
19c
20d
DMSO
24
DMSO
trace
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), NaN3 (1.5 mmol),
base (1.0 mmol) and catalyst (50 mol%) were heated in 3 mL solvent in
an open vessel for 24 h. bIsolated yield. cCatalyst was 20 mol%.
dReaction was performed under nitrogen atmosphere.
With the optimized conditions in hand, we then examined the substrate scope of
this reaction, and different aromatic aldehydes were first evaluated (Scheme 2). It was
found that aromatic aldehydes containing electron-donating groups (2-OCH3, 4-OCH3,
3,4-(OCH3)2, 3-Br-4-OCH3, 4-CH3) could be successfully converted into target
products in medium yields (57–71%, 3ab–3af). Moreover, halogen groups (F, Cl and
Br) were well tolerated, affording the corresponding products in good yields (62–76%;
3ag–3ao), which enabled a potential application in further functionalizations.
Fortunately, the electron-withdrawing substituents were also suitable for this
conversion (2-NO2, 3-NO2, 4-NO2, 3-CN, 4-CN), and the target products were
obtained in satisfactory yields (67–72%; 3ap–3at). In addition, 1-naphthaldehyde and
2-naphthaldehyde only proceeded to give products (3au, 3av) in 53% and 58% yield,
respectively.
Heteroaryl
aldehydes
such
as
furan-2-carbaldehyde,
thiophene-2-carbaldehyde and thiophene-3-carbaldehyde were also tolerated under
the optimal conditions, leading to the polyheterocyclic products (63−67%, 3aw−3ay).
Furthermore, the structure of 3af was unambiguously determined by X-ray
crystallographic analysis (see Supporting Information).
Scheme 2. Scope of Aromatic Aldehydea,b
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O
N
O
Ar
NH
CuO, K2CO3
Ar CHO
+
+
NaN3
OCH3
DMSO, 100oC
Br
N
N
1a
2
3
OCH3
Br
OCH3
OCH3
N
N
O
N
N
O
O
O
OCH3
NH
NH
N
NH
N
NH
N
10
11
12
13
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N
N
N
N
N
3ac
3ad
3ae
, 65%
, 62%
, 57%
3ab
, 61%
F
F
N
N
N
O
O
O
F
NH
NH
Cl
NH
N
N
N
N
N
N
3ag
3ai, 75%
Cl
, 76%
3ah
3af
, 72%
, 71%
Cl
N
N
N
N
O
O
O
O
Cl
Cl
NH
NH
NH
NH
N
N
N
N
N
N
N
N
3am
, 69%
3aj
3ak
3al
, 64%
, 62%
, 67%
Br
Br
NO2
N
N
N
N
O
O
O
O
NO2
NH
NH
NH
NH
N
N
N
N
N
N
N
N
3an
3ao
3ap
3aq
, 67%
, 68%
, 71%
, 68%
CN
NO2
CN
N
N
N
N
O
O
O
O
NH
N
NH
NH
N
NH
N
N
N
N
N
N
3ar
3as, 69%
3at
3au, 53%
, 72%
, 71%
S
O
S
N
O
N
N
O
N
O
O
NH
N
NH
N
NH
NH
N
N
N
N
N
N
3aw
3ax
3ay
, 63%
3av
, 67%
, 65%
, 58%
aReaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), NaN3 (1.5
mmol), CuO (50 mol%) and K2CO3 (1.0 mmol) were heated in
DMSO (3 mL) at 100 oC in an open vessel for 24 h. bIsolated yield.
Next, the substrate scope with regard to the o-bromoacetophenone moiety was
examined (Scheme 3). To our delight, o-bromoacetophenones bearing
electron-withdrawing substituents (4-Cl, 5-F, 5-Cl) were successfully converted to the
desired products in good yields (68–71%; 3ba–3da). It is noteworthy that a prolonged
time and elevated temperature were required to accomplish the conversion of
electron-rich
1-(2-bromo-4-methoxyphenyl)ethan-1-one
(1e)
and
1-(2-bromo-6-methoxyphenyl)ethan-1-one (1f), albeit in lower yields (43% and 51%,
3ea and 3fn).
Scheme 3. Scope of o-Bromoacetophenonesa,b
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O
N
O
Ar
R
CuO, K2CO3
R
+
Ar CHO
NaN3
+
NH
N
DMSO, 100oC
Br
N
6
1
2
3
7
Cl
8
9
N
N
N
O
O
O
Cl
Cl
10
11
12
13
14
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16
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19
20
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NH
N
, 71%
NH
N
NH
N
N
N
N
F
3ba
3bl
3ca
, 70%
O
, 69%
Br
N
N
N
O
O
H3CO
NH
N
NH
N
NH
N
N
OCH3
N
N
Cl
3da
3eac, 51%
3fnc
, 43%
, 68%
aReaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), NaN3 (1.5
mmol), CuO (50 mol%) and K2CO3 (1.0 mmol) were heated in
DMSO (3 mL) at 100 oC in an open vessel for 24 h. bIsolated yield.
cThe reaction was performed at 120 oC for 48 h.
To illustrate the synthetic value of this domino reaction, further transformations of
the obtained products were explored. For example, 3aa was easily converted to
N2-substituted product 3-(2-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole
(5) via nucleophilic substitution with benzyl bromide (Scheme 4a).3b In addition,
2,1-benzisoxazoles are also versatile building blocks in organic synthesis12. In our
case 3aa could directly lead to the ring opening of benzisoxazole with CF3COOH12d
as
a
proton
donor
in
the
presence
of
CuI,
and
(2-aminophenyl)(5-phenyl-1H-1,2,3-triazol-4-yl)methanone (6) was obtained in 60%
yield (Scheme 4b).
Scheme 4. Follow-up Transformations
N
N
O
O
KI (10 mol %), K2CO3
DMF, rt, 12 h
Br
(a)
(b)
+
NH
N
N
N
N
N
4a
3aa
Ph
5
, 79%
NH2
N
O
CuI (10 mol %), CF3COOH (2 eq)
DMF, 110 oC, N2, 12 h
O
NH
N
N
NH
N
N
3aa
6
, 60%
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To gain insight into the mechanistic details of this domino reaction, a series of
5
6
control
experiments
were
performed
(Scheme
5).
Initially,
when
7
8
9
o-bromoacetophenone (1a) and benzaldehyde (2a) were reacted only in the presence
of K2CO3 in DMSO at 100 oC, (E)-1-(2-bromophenyl)-3-phenylprop-2-en-1-one (7)13
could be obtained in a high yield of 93% (Scheme 5a). In the following experiments,
2-bromochalcone (7) could react with NaN3 under optimized conditions smoothly to
afford the desired product (3aa) in 79% yield (Scheme 5b). These results indicated
that 2-bromochalcone (7) might be a key intermediate in this transformation process.
To investigate the directing effect of NH-free 1,2,3-triazole group,
o-bromoacetophenone (1a) and the preparative substrate (8)14 were tested under the
standard conditions, and the expected product could not be observed (Scheme 5c and
5d). These control experiments meant that the in situ generated NH-1,2,3-triazole
moiety could be used as an intrinsic ligand to promote the formation of C-N bond.
10
11
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43
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Scheme 5. Control Experiments
O
O
CHO
K2CO3
Ph
(a)
+
DMSO, 100oC
Br
Br
, 93%
N
1a
2a
7
O
standard
Conditions
O
Ph
NH
Ph
(b)
(c)
NaN3
+
Br
7
N
N
3aa
, 79%
O
standard
Conditions
N
O
+
NaN3
Br
1a
O
Ph
N
standard
Conditions
O
Ph
(d)
N
+
NaN3
N
N
N
Ph
Br
Ph
N
N
8
On the basis of the above experimental results and literature reports,4d,6e,15–17
a
reasonable reaction mechanism was proposed using o-bromoacetophenone (1a),
benzaldehyde (2a) and sodium azide as an example (Scheme 6). Initially,
o-bromoacetophenone (1a) was condensed with benzaldehyde (2a) to form
2-bromochalcone
(7).
Subsequently,
(2-bromophenyl)(5-phenyl-4,5-dihydro-1H-1,2,3-triazol-4-yl)methanone (A) was
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produced by a [3+2] cyclization reaction of 7 and NaN3,4d which was further oxidized
5
6
in
the
presence
of
CuO
or
air
to
deliver
7
8
9
(2-bromophenyl)(5-phenyl-1H-1,2,3-triazol-4-yl)methanone (B). Intermediate B
would undergo a copper-catalyzed SNAr16 with NaN3 to afford D with the assistant of
the intramolecular NH-1,2,3-triazole moiety. Finally, the target product
3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3aa) was formed by
intramolecular denitrogenative cyclization.6e,17
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Scheme 6. A Plausible Reaction Mechanism
O
O
NaN3
K2CO3
Ph
O
+
3+2 cycloaddition
H2O
Br
Br
1a
2a
7
Cu(II)+Cu(0)
O
Ph
NH
O
Ph
NH
NaN3, Cu(I)
CuO or Air
oxidation
Cu-catalyzed SNAr
N
N
N
N
N
Br
Br
A
B
N
N
N
Ph
O
Ph
NH
O
Ph
O
N
NH
N
NH
N
N
N
N
N2
Cu(III)
Br
N3
C
3aa
D
CONCLUSIONS
In summary, we have developed an efficient copper-catalyzed three-component
domino protocol for the synthesis of 2,1-benzoisoxazole-containing 1,2,3-triazoles
derivatives from commercially available o-bromoacetophenones, aromatic aldehydes
and sodium azide under mild conditions. This elegant domino process integrated
consecutive Aldol condensation, copper-catalyzed oxidative [3+2] cycloaddition,
copper-catalyzed SNAr, along with unusual denitrogenative cyclization. Notably,
copper catalyst together with the internal directing group of NH-free 1,2,3-triazole
moiety could synergistically promote the formation of 2,1-benzoisoxazole skeleton.
The biological activities of the structurally novel heterocyclic compounds and
reactions utilizing NaN3 as a simple nitrogen donor are underway in our laboratory.
EXPERIMENTAL SECTION
General Methods Unless otherwise stated, all starting materials, catalysts and
solvents were obtained from commercial suppliers and used without further
purification. All new compounds were fully characterized. Reactions were monitored
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by thin-layer chromatography (TLC), which was performed using precoated glass
plates. Column chromatography was performed using silica gel (200–300 mesh).
Petroleum ether (PE) (60–90 °C) and ethyl acetate (EA) were used as eluents for
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silica gel chromatography. H spectra were recorded in DMSO-d6 or CDCl3 on
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400/600 MHz spectrometers, and resonances (δ) are given in ppm relative to TMS
(internal standard). Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, q = quadruple), coupling constants (Hz),
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and integration. C spectra were recorded in DMSO-d6 or CDCl3 on 100/150 MHz
NMR spectrometers. High-resolution mass spectra (HRMS) were acquired on Waters
Acquity UPLC Class I/Xevo G2Q-TOF. The X-ray crystal structuredetermination of
3af was obtained on a Bruker SMART APEX CCDsystem. Melting points were
determined using an XT-4 apparatus and not corrected. Characterization data for new
1
compounds are given below, and copies of H and 13C NMR spectra for all new
compounds are given in the Supporting Information.
General Procedures for the Synthesis of the Products 3 (3aa as an Example).
To a solution of o-bromoacetophenone 1a (99.5 mg, 0.50 mmol) and benzaldehyde 2a
(79.5 mg, 0.75 mmol) in 3 mL of DMSO was added NaN3 (97.5 mg, 1.50 mmol),
K2CO3 (138.2 mg, 1.00 mmol) and CuO (19.9 mg, 0.25 mmol) successively. The
resulting mixture was stirred in an oil bath at 100 °C under open air conditions for 24
h. After disappearance of the reactant (monitored by TLC), 50 mL of water was
introduced, which was then extracted with EtOAc for 3 times (3 × 50 mL). The
extract was washed with 30% NaCl solution, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (eluent: PE/EA = 3/1) to yield the desired product 3aa
(98.3 mg, yield: 75%).
A Larger Scale for the Synthesis of 3aa.
To a solution of o-bromoacetophenone 1a (0.50 g, 2.50 mmol) and benzaldehyde 2a
(0.40 g, 3.75 mmol) in 12 mL of DMSO was added NaN3 (0.50 g, 7.50 mmol), K2CO3
(0.69 g, 5.00 mmol) and CuO (99.4 mg, 1.25 mmol) successively. The resulting
mixture was stirred in an oil bath at 100 °C under open air conditions for 24 h. Refer
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to the general procedure above to get 3aa (0.39 g, yield: 59%) as a yellow solid.
Experimental Procedure for the Synthesis of Compound 5.
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To a solution of 3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole 3aa (131.0 mg,
0.50 mmol) and (bromomethyl)benzene 4a (102.6 mg, 0.60 mmol) in 3 mL DMF was
added KI (8.3 mg, 0.05 mmol) and K2CO3 (138.2 mg, 1.00 mmol). The mixture was
stirred at room temperature for 12 h. After disappearance of the reactant (monitored
by TLC), 50 mL water was introduced, the mixture was extracted with EtOAc for 3
times (3 × 50 mL). The extract was then washed with 30% NaCl solution (V/V), dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained
residue was purified by column chromatography on silica gel (eluent: PE/EA = 8/1, Rf
= 0.28) to afford the desired product 5.
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3-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (5). brown solid (139.1
o
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mg, yield 79%); mp 102–104 C; H NMR (400 MHz, CDCl3) δ 7.81–7.78 (m, 3H),
7.59 (d, J = 9.2 Hz, 1H), 7.49–7.44 (m, 5H), 7.42–7.30 (m, 4H), 7.04–7.00 (m, 1H),
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5.74 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 157.4, 157.2, 147.2, 134.5, 134.3,
131.1, 129.5, 129.2, 128.8, 128.7, 128.6, 128.5, 128.2, 124.6, 121.5, 116.3, 114.9,
59.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H17N4O 353.1397, found
353.1399.
Experimental Procedure for the Synthesis of Compound 6.
The 3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole 3aa (131.0 mg, 0.50 mmol)
and CuI (10 mg, 0.05 mmol) were dissolved in degassed DMF (3 mL) in a Schlenk
tube under N2 atmosphere. CF3COOH (114 mg, 1.00 mmol) were added by injection.
The mixture was stirred in an oil bath at 110 °C. After 12 h, the reaction was
completed (monitored by TLC, eluent = 3:1 PE/EA). Then 50 mL water was
introduced, and extracted with EtOAc for 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: PE/EA = 3/1, Rf = 0.19) to afford the desired
product 6.
(2-aminophenyl)(5-phenyl-1H-1,2,3-triazol-4-yl)methanone (6). yellow solid (79.3
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mg, 60%); mp 129–131 C; H NMR (400 MHz, CDCl3) δ 7.63–7.61 (m, 2H),
7.44–7.38 (m, 6H), 7.30–7.26 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.45 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 190.6, 152.4, 135.2, 134.1, 128.7, 128.4, 128.2, 127.6,
116.8, 116.7, 114.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H13N4O 265.1084,
found 265.1076.
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Experimental Procedure for the Synthesis of Compound 7.
A mixture of 1-(2-bromophenyl)ethan-1-one 1a (99.5 mg, 0.50 mmol), benzaldehyde
2a (79.5 mg, 0.75 mmol), K2CO3 (138.2 mg, 1.00 mmol) and DMSO (3mL) was
added to an open tube and then stirred in an oil bath at 100 °C for 4 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: PE/EA = 20/1, Rf = 0.38) to afford the desired product 7 in the yield of 93%.
(E)-1-(2-bromophenyl)-3-phenylprop-2-en-1-one (7):12 yellow oil (133.5 mg, yield:
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93%); H NMR (400 MHz, CDCl3) δ 7.65–7.63 (m, 1H), 7.56–7.53 (m, 2H),
7.45–7.37 (m, 6H), 7.34–7.30 (m, 1H), 7.10 (d, J = 16.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 194.5, 146.5, 141.0, 134.2, 133.3, 131.3, 130.8, 129.0, 128.9, 128.4,
127.2, 126.0, 119.3.
Experimental Procedure for the Synthesis of Compound 8.
An open tube was charged with (E)-1-(2-bromophenyl)-3-phenylprop-2-en-1-one 7
(143.6 mg, 0.50 mmol), (azidomethyl)benzene (199.7 mg, 0.75 mmol) and Cu(NO3)2
(4.6 mg, 0.025 mmol) at room temperature, and then toluene (3 mL) was added. The
resulting mixture was stirred in an oil bath at 100 °C for 8h. After disappearance of
the reactant (monitored by TLC), 50 mL of water was added to the mixture, which
was then 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: PE/EA = 20/1, Rf = 0.27) to obtain the desired product 8.
(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)(2-bromophenyl)methanone (8). white oil
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(154.8 mg, yield: 74%); 1H NMR (400 MHz, CDCl3) δ 7.54–7.51 (m, 1H), 7.48–7.45
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6
(m, 1H), 7.43–7.36 (m, 3H), 7.34–7.30 (m, 1H), 7.27–7.22 (m, 6H), 7.04–7.01 (m,
7
8
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2H), 5.45 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 187.9, 143.1, 141.2, 140.0,
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134.4, 133.0, 131.4, 130.0, 129.7, 129.5, 128.7, 128.5, 128.3, 127.3, 126.9, 125.4,
119.8, 51.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H16N3OBrNa 440.0369,
found 440.0374.
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Analytical Data for Products 3aa–3fn.
3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3aa). yellow solid (98.3 mg,
o
yield: 75%); mp 189–191 C; purification by silica gel chromatography (eluent:
PE/EA = 3:1, Rf = 0.21); 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.0 Hz, 1H),
7.73–7.70 (m, 2H), 7.65 (d, J = 9.2 Hz, 1H), 7.55–7.53 (m, 3H), 7.47–7.43 (m, 1H),
7.16–7.12 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 157.8, 156.6, 131.9, 129.6,
128.8, 128.7, 125.1, 121.4, 115.3, 114.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H11N4O 263.0927, found 263.0930.
3-(5-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ab). slight yellow
solid (89.1 mg, yield: 61%); mp 199–200 oC; purification by silica gel
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chromatography (eluent: PE/EA = 3:1, Rf = 0.20); H NMR (600 MHz, DMSO-d6) δ
7.88 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.54–7.52 (m, 2H), 7.44–7.42 (m, 1H), 7.17 (d,
J = 8.4 Hz, 1H), 7.13–7.10 (m, 2H), 3.50 (s, 3H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 158.6, 157.1, 156.7, 134.2, 132.1, 131.9, 131.2, 125.1, 121.4, 120.9,
115.1, 114.6, 112.0, 55.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H13N4O2
293.1033, found 293.1039.
3-(5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ac). slight yellow
solid (90.5 mg, yield: 62%); mp 205–207 oC; purification by silica gel
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chromatography (eluent: PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ
7.91 (d, J = 9.2 Hz, 1H), 7.66–7.62 (m, 3H), 7.46–7.43 (m, 1H), 7.16–7.08 (m, 3H),
3.82 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.4, 158.0, 156.7, 132.0,
130.1, 125.0, 121.5, 119.1, 115.4, 114.5, 114.4, 114.1, 114.0, 55.4; HRMS (ESI-TOF)
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m/z: [M + H]+ calcd for C16H13N4O2 293.1033, found 293.1039.
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3-(5-(3,4-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ad). yellow
solid (91.8 mg, yield: 57%); mp 175–177 oC; purification by silica gel
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chromatography (eluent: PE/EA = 3:1, Rf = 0.18); H NMR (400 MHz, DMSO-d6) δ
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7.92 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.47–7.43 (m, 1H), 7.34 (d, J = 1.6
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Hz, 1H), 7.30–7.28 (m, 1H), 7.16-7.11 (m, 2H), 3.83 (s, 3H), 3.76 (s, 3H); C{1H}
NMR (100 MHz, DMSO-d6) δ 156.6, 148.6, 131.8, 124.9, 121.5, 121.3, 115.3, 114.4,
112.1, 111.8, 55.6, 55.5; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H14N4O3Na
345.0958, found 345.0952.
3-(5-(3-bromo-4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole
(3ae).
o
yellow solid (120.6 mg, yield: 65%); mp 183–185 C; purification by silica gel
chromatography (eluent: PE/EA = 3:1, Rf = 0.19); 1H NMR (400 MHz, DMSO-d6): δ
7.96–7.92 (m, 2H), 7.73–7.71 (m, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.46–7.42 (m, 1H),
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7.26 (d, J = 8.4 Hz, 1H), 7.16–7.12 (m, 1H), 3.93 (s, 3H); C{1H} NMR (100 MHz,
DMSO-d6) δ 157.7, 156.6, 156.3, 132.8, 131.9, 129.5, 125.0, 121.4, 115.3, 114.4,
112.7, 110.7, 56.5; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H11N4O2BrNa
392.9958, found 392.9952.
3-(5-(p-tolyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3af). yellow solid (98.1 mg,
o
yield: 71%); mp 205–206 C; Purification by silica gel chromatography (eluent:
PE/EA = 3:1, Rf = 0.21); 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.8 Hz, 1H),
7.76 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.59–7.55 (m, 1H), 7.46 (d, J = 8.0
Hz, 2H), 7.28–7.24 (m, 1H), 2.62-2.61 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 158.1, 156.9, 139.7, 132.4, 132.2, 129.6, 128.7, 125.3, 125.0, 121.6, 115.6, 114.6,
21.2; HRMS (ESI-TOF) m/z: [M + Na]+ valcd for C16H12N4ONa 299.0903, found
299.0904.
3-(5-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ag). yellow solid
o
(106.4 mg, yield: 76%); mp 203–205 C; purification by silica gel chromatography
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(eluent: PE/EA = 3:1, Rf = 0.24); H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.8
Hz, 1H), 7.73–7.69 (m, 1H), 7.65–7.59 (m, 2H), 7.47–7.38 (m, 3H), 7.17–7.13 (m,
13
1H); C{1H} NMR (100 MHz, DMSO-d6) δ 159.5 (d, J = 254.0 Hz), 157.4, 156.5,
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134.2, 132.0 (d, J = 8.4 Hz), 131.9, 131.6 (d, J = 2.4 Hz), 125.2, 124.8 (d, J = 3.6 Hz),
121.0, 116.0 (d, J = 21.2 Hz), 115.0, 114.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C15H10N4OF 281.0833, found 281.0837.
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3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ah). yellow solid
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(100.8 mg, yield: 72%); mp 174–176 C; purification by silica gel chromatography
1
(eluent: PE/EA = 3:1, Rf = 0.22); H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.4
Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.61–7.56 (m, 3H), 7.47–7.43 (m, 1H), 7.39–7.34
(m, 1H), 7.17–7.13 (m, 1H); C{1H} NMR (100 MHz, DMSO-d6) δ 162.0 (d, J =
13
244.0 Hz), 157.4, 156.6, 131.9, 130.9 (d, J = 8.4 Hz), 125.2, 123.1 (d, J = 364.0 Hz),
116.3 (d, J = 21.2 Hz), 115.5, 115.5 (d, J = 24.0 Hz), 114.5; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C15H10N4OF 281.0833, found 281.0838.
3-(5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ai). slight yellow
solid (105.0 mg, yield: 75%); mp 195–196 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.24); H NMR (600 MHz, DMSO-d6) δ
7.89 (d, J = 9.0 Hz, 1H), 7.78–7.76 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.46–7.43 (m,
1H), 7.40–7.37 (m, 2H), 7.16–7.13 (m, 1H); C{1H} NMR (150 MHz, DMSO-d6) δ
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162.9 (d, J = 248.0 Hz), 157.7, 156.7, 132.0, 131.1 (d, J = 8.8 Hz), 130.3, 125.2,
121.4, 119.6, 115.9 (d, J = 21.6 Hz), 115.4, 114.5; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H10N4OF 281.0833, found 281.0837.
3-(5-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3aj). yellow solid
o
(91.8 mg, yield: 62%); mp 205–207 C; purification by silica gel chromatography
1
(eluent: PE/EA = 3:1, Rf = 0.25); H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 6.8
Hz, 1H), 7.68–7.52 (m, 5H), 7.46–7.42 (m, 1H), 7.16–7.12 (m, 1H); C{1H} NMR
13
(100 MHz, DMSO-d6) δ 156.5, 133.1, 132.3, 131.9, 131.5, 129.8, 127.5, 125.2, 120.9,
114.9, 114.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N4OCl 297.0538,
found 297.0539.
3-(5-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ak). slight yellow
solid (99.2 mg, yield: 67%); mp 207–210 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.23); H NMR (400 MHz, DMSO-d6) δ
7.91 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.70–7.65 (m, 2H), 7.60–7.54 (m,
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2H), 7.48–7.44 (m, 1H), 7.18–7.14 (m, 1H); C{1H} NMR (100 MHz, DMSO-d6) δ
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157.4, 156.6, 133.4, 131.9, 130.6, 129.3, 128.3, 127.3, 125.2, 121.3, 115.4, 114.5;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N4OCl 297.0538, found 297.0539.
3-(5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3al). yellow solid
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o
(94.8 mg, yield: 64%); mp 233–234 C; purification by silica gel chromatography
1
(eluent: PE/EA = 3:1, Rf = 0.25); H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.8
Hz, 1H), 7.76–7.73 (m, 2H), 7.66 (d, J = 9.2 Hz, 1H), 7.63–7.60 (m, 2H), 7.48–7.45
(m, 1H), 7.18–7.15 (m, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 157.6, 156.7,
134.5, 132.1, 130.5, 129.0, 125.4, 121.3, 115.6, 114.6; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C15H10N4OCl 297.0538, found 297.0539.
3-(5-(2,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3am). yellow
solid (114.3 mg, yield: 69%); mp 180–182 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.28); H NMR (400 MHz, DMSO-d6) δ
7.92 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65–7.62
(m, 2H), 7.47–7.43 (m, 1H), 7.19–7.15 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 156.5, 134.2, 133.5, 132.0, 129.4, 127.8, 125.4, 120.9, 114.9, 114.5; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H8N4OCl2Na 352.9967, found 352.9966.
3-(5-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3an). slight yellow
solid (115.6 mg, yield: 68%); mp 209–210 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.24); H NMR (600 MHz, DMSO-d6) δ
7.93 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.73–7.72 (m, 2H), 7.66 (d, J = 9.0
Hz, 1H), 7.52–7.45 (m, 2H), 7.18–7.16 (m, 1H); 13C{1H} NMR (150 MHz, DMSO-d6)
δ 157.4, 156.7, 132.3, 132.0, 131.1, 130.9, 127.7, 125.3, 121.8, 121.3, 115.5, 114.5;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N4OBr 341.0032, found 341.0038.
3-(5-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ao). slight yellow
solid (120.7 mg, yield: 71%); mp 234–235 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.26); H NMR (600 MHz, DMSO-d6) δ
7.89 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.68–7.64 (m, 3H), 7.47–7.44 (m,
1H), 7.17–7.14 (m, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 157.6, 156.8, 132.6,
132.1, 131.9, 130.8, 127.8, 125.3, 123.1, 121.4, 115.5, 114.6; HRMS (ESI-TOF) m/z:
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[M + H]+ calcd for C15H10N4OBr 341.0032, found 341.0023.
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3-(5-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ap). yellow solid
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8
o
(104.4 mg, yield: 68%); mp 218–220 C; purification by silica gel chromatography
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(eluent: PE/EA = 3:1, Rf = 0.19); H NMR (400 MHz, DMSO-d6) δ 8.28–8.26 (m,
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1H), 7.97–7.90 (m, 2H), 7.87–7.79 (m, 2H), 7.61 (d, J = 9.2 Hz, 1H), 7.47–7.43 (m,
1H), 7.19–7.16 (m, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 157.0, 156.6, 148.4,
134.0, 133.0, 132.1, 131.3, 130.0, 128.5, 125.5, 125.0, 124.1, 121.0, 114.9, 114.5;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N5O3 308.0778, found 308.0775.
3-(5-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3aq). slight yellow
solid (102.9 mg, yield: 67%); mp 230–231 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ
8.61 (s, 1H), 8.38–8.35 (m, 1H), 8.21–8.19 (m, 1H), 7.94 (d, J = 8.8 Hz, 1H),
7.87–7.82 (m, 1H), 7.69–7.66 (m, 1H), 7.50–7.46 (m, 1H), 7.21–7.17 (m, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 156.7, 147.9, 135.0, 132.0, 130.4, 125.4, 124.1, 123.1,
121.2, 115.5, 114.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N5O3 308.0778,
found 308.0777.
3-(5-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ar). slight yellow
solid (110.6 mg, yield: 72%); mp 245–246 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.21); H NMR (400 MHz, DMSO-d6) δ
8.38 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.69 (d, J
= 8.8 Hz, 1H), 7.50–7.46 (m, 1H), 7.21–7.17 (m, 1H); 13C{1H} NMR (150 MHz,
DMSO-d6) δ 157.6, 157.3, 148.3, 135.9, 133.6, 132.8, 130.4, 126.2, 124.4, 121.6,
116.2, 115.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N5O3 308.0778, found
308.0777.
3-(4-(benzo[c]isoxazol-3-yl)-1H-1,2,3-triazol-5-yl)benzonitrile (3as). slight yellow
solid (99.1 mg, yield: 69%); mp 205–207 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.25); H NMR (400 MHz, DMSO-d6) δ
8.30 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.93 (d, J
= 8.8 Hz, 1H), 7.78–7.74 (m, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.49–7.45 (m, 1H),
7.20–7.16 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 157.2, 156.6, 133.4, 133.0,
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132.2, 132.0, 130.0, 125.3, 121.2, 119.4, 118.3, 115.4, 114.5, 111.8; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H10N5O 288.0880, found 288.0872.
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4-(4-(benzo[c]isoxazol-3-yl)-1H-1,2,3-triazol-5-yl)benzonitrile (3at). slight yellow
solid (102.0 mg, yield: 71%); mp 185–188 oC; purification by silica gel
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1
chromatography (eluent: PE/EA = 3:1, Rf = 0.24); H NMR (400 MHz, DMSO-d6) δ
8.01 (d, J = 8.4 Hz, 2H), 7.94–7.89 (m, 3H), 7.67 (d, J = 9.2 Hz, 1H), 7.49–7.45 (m,
1H), 7.19–7.16 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 157.1, 156.7, 133.4,
132.6, 132.0, 129.4, 125.4, 121.2, 118.5, 115.6, 114.5, 111.9; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C16H10N5O 288.0880, found 288.0872.
3-(5-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3au). yellow solid
o
(82.7 mg, yield: 53%); mp 163–165 C; purification by silica gel chromatography
1
(eluent: PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.0
Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H),
7.69–7.65 (m, 1H), 7.59–7.54 (m, 3H), 7.47–7.43 (m, 1H), 7.41–7.37 (m, 1H),
7.11–7.07 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 157.6, 156.4, 134.7, 133.2,
131.8, 131.4, 130.1, 128.9, 128.5, 127.1, 126.5, 125.4, 125.0, 124.7, 121.2, 115.0,
114.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H13N4O 313.1084, found
313.1085.
3-(5-(naphthalen-2-yl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3av). yellow solid
o
(90.6 mg, yield: 58%); mp 155–157 C; purification by silica gel chromatography
1
(eluent: PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.0
Hz, 1H), 8.09–8.06 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.74–7.72 (m, 1H), 7.69–7.65
(m, 1H), 7.59–7.54 (m, 3H), 7.48–7.43 (m, 1H), 7.42–7.38 (m, 1H), 7.12–7.08 (m,
1H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 157.6, 156.4, 133.2, 131.8, 131.3, 130.1,
128.9, 128.5, 127.1, 126.4, 125.4, 125.0, 124.7, 121.2, 114.9, 114.3; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H13N4O 313.1084, found 313.1089.
3-(5-(furan-2-yl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3aw). brown solid (84.5
o
mg, yield: 67%); mp 88–90 C; purification by silica gel chromatography (eluent:
PE/EA = 3:1, Rf = 0.21); 1H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 8.4 Hz, 1H),
7.95 (s, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.49–7.47 (m, 1H), 7.26 (s, 1H), 7.20–7.17 (m,
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1H), 6.76 (s, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 156.6, 131.8, 131.6, 128.7,
128.6, 125.0, 121.3, 115.3, 114.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H9N4O2 253.0720, found 253.0724.
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3-(5-(thiophen-2-yl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ax). yellow solid (87.2
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o
mg, yield: 65%); mp 178–180 C; purification by silica gel chromatography (eluent:
PE/EA = 3:1, Rf = 0.23); 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.8 Hz, 1H),
7.76–7.72 (m, 2H), 7.66–7.63 (m, 1H), 7.45–7.40 (m, 1H), 7.23–7.21 (m, 1H),
7.15–7.10 (m, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 157.2, 156.6, 131.9, 129.7,
128.3, 128.1, 125.1, 121.3, 115.6, 114.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H9N4OS 269.0492, found 269.0496.
3-(5-(thiophen-3-yl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ay). yellow solid (84.5
o
mg, yield: 63%); mp 168–170 C; purification by silica gel chromatography (eluent:
1
PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ 8.14–8.10 (m, 1H), 7.96
(d, J = 8.8 Hz, 1H), 7.76–7.74 (m, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.56–7.54 (m, 1H),
7.47–7.43 (m, 1H), 7.17–7.13 (m, 1H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 157.7,
156.6, 134.9, 131.9, 127.6, 127.3, 126.3, 125.0, 121.5, 118.9, 117.2, 115.4, 114.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H9N4OS 269.0492, found 269.0494.
6-chloro-3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ba). slight yellow
solid (103.8 mg, yield: 70%); mp 205–207 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ
7.92 (s, 1H), 7.79 (s, 1H), 7.71 (dd, J = 6.4, 2.7 Hz, 3H), 7.53 (s, 4H), 7.14–7.04 (m,
1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 158.8, 156.7, 136.9, 128.8, 128.7, 126.2,
123.6, 113.8, 113.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10ClN4O
297.0538, found 297.0541.
6-chloro-3-(5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3bl). slight
o
yellow solid (114.3 mg, yield: 69%); mp 215–218 C; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.22); H NMR (400 MHz, DMSO-d6) δ
7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz,
2H), 7.16–7.13 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 156.7, 136.9, 130.5,
128.8, 126.5, 123.5, 113.9, 113.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
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C15H8N4OCl2Na 352.9967, found 352.9966.
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5-fluoro-3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ca). slight yellow
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solid (99.4 mg, yield: 71%); mp 181–184 oC; purification by silica gel
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chromatography (eluent: PE/EA = 3:1, Rf = 0.21); H NMR (400 MHz, DMSO-d6) δ
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7.78–7.74 (m, 1H), 7.71–7.69 (m, 2H), 7.54–7.52 (m, 3H), 7.45–7.37 (m, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 158.7 (d, J = 245.6 Hz), 154.8, 129.6, 128.7 (d, J =
14.4 Hz), 124.7 (d, J = 32.0 Hz), 117.8 (d, J = 9.6 Hz), 114.5 (d, J = 13.2 Hz), 102.8
(d, J = 26.0 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10N4OF 281.0833,
found 281.0837.
5-chloro-3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3da). slight yellow
solid (100.9 mg, yield: 68%); mp 182–184 oC; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.20); H NMR (400 MHz, DMSO-d6) δ
7.88 (s, 1H), 7.75-7.71 (m, 3H), 7.55–7.54 (m, 3H), 7.45–7.41 (m, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 157.9, 155.1, 133.1, 129.7, 129.3, 128.8, 128.7, 119.7,
116.9, 115.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H10ClN4O 297.0538,
found 297.0539.
6-methoxy-3-(5-phenyl-1H-1,2,3-triazol-4-yl)benzo[c]isoxazole (3ea). yellow solid
o
(74.5 mg, yield: 51%); mp 162–164 C; purification by silica gel chromatography
1
(eluent: PE/EA = 3:1, Rf = 0.17); H NMR (400 MHz, DMSO-d6) δ 7.75–7.68 (m,
3H), 7.53–7.51 (m, 3H), 6.84 (d, J = 1.6 Hz, 1H), 6.78–6.75 (m, 1H), 3.84 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 161.6, 158.0, 156.9, 132.5, 129.5, 128.7,
128.6, 122.3, 121.6, 112.3, 89.4, 55.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H13N4O2 293.1033, found 293.1026.
3-(5-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)-4-methoxybenzo[c]isoxazole
(3fn).
o
slight yellow solid (79.9 mg, yield: 43%); mp 178–180 C; purification by silica gel
1
chromatography (eluent: PE/EA = 3:1, Rf = 0.18); H NMR (400 MHz, DMSO-d6) δ
8.02 (s, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.46–7.42 (m, 1H),
7.34–7.30 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.66 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 157.2, 132.5, 131.8, 131.2, 130.7, 130.6,
127.7, 124.1, 121.6, 118.4, 110.9, 56.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
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C16H11N4O2BrNa 392.9958, found 392.9952.
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ASSOCIATED CONTENT
9
*Supporting Information
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The Supporting Information is available free of charge on the ACS Publications
website at DOI:
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Crystallographic data for 3af (CIF) and copies of the H and C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: yfchen@wit.edu.cn
*E-mail: fengcheng-jia@wit.edu.cn
ORCID
Yunfeng Chen: 0000-0002-6220-5015
Fengcheng Jia: 0000-0002-1290-3018
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural Science Foundation of
China (21002076), Natural Science Foundation of Hubei Association for Science and
Technology (2018CFB149), Young and middle-aged talent program of Hubei
Provincial Department of Education (Q20181509), and the 10th Graduate's
Innovation of Wuhan Institute of Techonology(CX2018139).
REFERENCES
(1) (a) Chen, Z.; Liu, Z.; Cao, G.; Li, H.; Ren, H. Recent Advances in
Multicomponent Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles. Adv. Synth. Catal.
2017, 359, 202–224; (b) Wan, J. P.; Cao, S.; Liu, Y. Base-Promoted Synthesis of
N-Substituted 1,2,3-Triazoles via Enaminone Azide Cycloaddition Involving Regitz
Diazo Transfer. Org. Lett. 2016, 18, 6034–6037; (c) Liu, Z.; Zhu, D.; Luo, B.; Zhang,
N.; Liu, Q.; Hu, Y.; Pi, R.; Huang, P.; Wen, S. Mild Cu(I)-Catalyzed Cascade
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Reaction of Cyclic Diaryliodoniums, Sodium Azide, and Alkynes: Efficient Synthesis
of Triazolophenanthridines. Org. Lett. 2014, 16, 5600–5603; (d) Kamijo, S.; Jin, T.
N.; Huo, Z. B.; Yamamoto, Y. Synthesis of Triazoles From Nonactivated Terminal
Alkynes via the Three-Component Coupling Reaction Using a Pd(0)-Cu(I) Bimetallic
Catalyst. J. Am. Chem. Soc. 2003, 125, 7786–7787. (e) Zhang, Z.; Zhou, Q.; Yu, W.;
Li, T.; Zhang, Y.; Wang, J. Cu(I)-Catalyzed Three-Component Coupling of
Trifluoromethyl Ketone N-Tosylhydrazones, Alkynes and Azides: Synthesis of
Difluoromethylene Substituted 1,2,3-Triazoles. Chin. J. Chem. 2017, 35, 387–391. (f)
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