Copper-catalyzed cascade three-component azide-alkyne cycloaddition/condensation/transesterification: Easy access to 3-triazolylcoumarins

Article abstract of DOI:10.1039/d0nj02100h

A novel and efficient strategy has been developed for the synthesis of 3-triazolylcoumarins in a one-pot, copper-catalyzed multicomponent reaction involving a cascade reaction of salicylaldehydes, ethyl 2-azidoacetate, and arylacetylenes including azide-a

Full text of DOI:10.1039/d0nj02100h

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Copper-catalyzed
cycloaddition/condensation/transesterification: easy access to 3-
triazolylcoumarins
cascade
three-component
azide-alkyne
Received 00th January 20xx,
Accepted 00th January 20xx
Xinwei He,* Ruxue Li, Mengqing Xie, Jiahui Duan, Qiang Tang, Yongjia Shang*
DOI: 10.1039/x0xx00000x
A novel and efficient strategy has been developed for the synthesis catalyzed azide-alkyne cycloaddition (CuAAC) reaction of 3-
of 3-triazolylcoumarins in one-pot, copper-catalyzed azidocoumarins with terminal alkynes is the most widely used
multicomponent reaction involving cascade reaction of and well-studied method to afford a single product under mild
salicylaldehydes, ethyl 2-azidoacetate, and arylacetylenes including conditions (Scheme 1a). The main drawbacks of this method
a azide-alkyne cycloaddition, Knoevenagel condensation and an is that the reaction substrates are obtained through multiple
intramolecular transesterification sequence mediated by base. This steps, the scope of substrates is narrow, and the overall yield is
one-pot procedure provides a convenient and eco-friendly method no more than 50%. Hence, it is necessary to explore novel and
of accessing a wide range of substituted 3-trizolylcoumarins in efficient methods from simple available materials for the
moderate to excellent yields with a broad substrate scope. A synthesis of diversified 3-triazolylcoumarins in one-pot step.
possible mechanism for the reaction pathway was also proposed.
a
a
10
In addition, the fluorescence properties of 3-triazolylcoumarin
derivatives were also evaluated and it displayed a wide range of
fluorescence emission.
Introduction
Coumarin and its derivatives are privileged scaffolds
exhibiting widespread biological, medicinal, and material
1
applications, which have exhibited broad spectrum of
2
pharmacological activities, such as anti-microbial, anti-
Figure 1. Selection of bioactive 3-triazolylcoumarin derivatives.
3
4
depressants, anti-inflammatory, antivirals (including anti-
The transformation of simple starting materials into a library
of complex molecules with structural diversity has led to
tremendous research in the design and production of building
functional chemicals. The use of multicomponent reactions
5
6
7
HIV), anti-oxidants, and anti-coagulants. It has been revealed
that 3-triazolylcoumarins are active pharmaceutical ingredients
and have widely application in biochemistry and fluorogenic
chemistry due to their high emission yield, excellent
(MCRs) is attractive in terms of atom- and step-economy,
8
photostability. For example, compounds I and II showed most
potent inhibition against SKBr-3 and MCF-7 among homologous
operational simplicity, and eco-friendly for the construction of
complex molecular scaffolds and natural products through the
formation of multiple carbon-carbon and carbon-heteroatom
bonds in one-pot.
multicomponent reactions followed by other synthetic
conversions emerged as a powerful tool for designing functional
molecules. Therefore, the development of novel protocol with
MCRs approaches to construct multifunctionalized heterocyclic
skeletons continues to attract the attention of the organic
chemists in the field of modern organic chemistry. As a part of
our interest in the synthesis of heterocyclic compounds by
series with IC50 = 13.16 ± 3.85
5.99 M against SKBr-3 for compound I. Compound II
exhibited a IC50 value of 18.33 ± 4.67 M against MCF-7 and IC50
μM against MCF-7 and IC50 = 21.22
±
μ
1
1
Recently, click chemistry-based
μ
9
=
8.17 ± 0.11 μM against SKBr-3. To date, the copper(I)-
1
2
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui
Laboratory of Molecule-Based Materials (State Key Laboratory Cultivation Base),
College of Chemistry and Materials Science, Anhui Normal University, Wuhu
241002, People’s Republic of China. E-mail: Xinweihe@mail.ahnu.edu.cn,
shyj@mail.ahnu.edu.cn
Electronic Supplementary Information (ESI) available: Experimental procedures,
analytical data, and copies of NMR spectra. CCDC xxxxxx. For ESI and
crystallographic data in CIF or other electronic format See DOI: 10.1039/x0xx00000x
†
13
MCRs protocol, we herein report a novel and efficient eco-
friendly three-component reactions of alicylaldehydes, ethyl 2-
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azidoacetate, and arylacetylenes for the construction of 3-
triazolylcoumarins under mild conditions (Scheme 1b).
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DOI: 10.1039/D0NJ02100H
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68
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c
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EtOH
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EtOH
EtOH
EtOH
EtOH
EtOH
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Reaction conditions: salicylaldehyde 1a (1.0 mmol), ethyl 2-azidoacetate
2a (1.0 mmol), phenylacetylene 3a (1.0 mmol), CuI (5 mol%), base (1.0
equiv.), solvent (3 mL). Isolated yield. c CuBr (5 mol%) was used as
b
Scheme 1 Synthesis of 3-triazolylcoumarin from available salicylaldehydes and
terminal alkynes.
d
e
catalyst. CuI (2 mol%) was used as catalyst. The amount of base was
f
0
.5 equivalent. The amount of base was 1.5 equivalent.
Under the optimum conditions, a variety of salicylaldehydes
and arylacetylenes were investigated to examine the substrate
scope. As shown in Table 2, salicylaldehydes bearing either
moderate electron-withdrawing (e.g. -F, -Cl, -Br) or electron-
donating (e.g. –Me, -OMe) groups showed moderated to good
reactivity toward the desired products 4b-4d and 4f-4i in 80-90%
and 68-88% yields, respectively. The electronic nature of the
substituents on benzene ring of salicylaldehydes had somewhat
effect on the reaction efficiency, in which the strong electron-
withdrawing and strong electron-donating, such as nitro and
diethylamino group, led trace yield of the desired products (4e
and 4k) even prolonging the reaction time to 24 h. As an
exception, salicylaldehydes having a hydroxyl group at the para-
position of formyl group afforded the product 4j in 60% yield.
Intriguingly, salicylaldehydes bearing with a bulky tert-butyl
group or bulky atom (-Br) at the ortho- and para-position to the
hydroxyl was also tolerated in the reaction to give the
corresponding products 4l and 4m in 65% and 68% yields,
respectively. In addition, when 2-hydroxy-1-naphthaldehyde
was employed as substrate, the reaction proceeded smoothly
to generate the desired product 4n in 78% yield. For
arylacetylenes, halide substituents (e.g. -Cl, -Br) were
compatible to give the corresponding products 4o-4v in good
yields (67-82%), which makes this transformation particularly
attractive in terms of increasing the molecular complexity via
transition metal-catalyzed coupling reactions.
Results and discussion
Initially, salicylaldehyde 1a
phenylacetylene 3a were selected as the model substrates to
screen the optimal experimental conditions in the presence of
copper(I) iodide as catalyst (Table 1). We first screened various
bases (Table 1, entries 1-7); to our delight, the expected
, ethyl 2-azidoacetate 2a,
3 4 3 4
transformation could occur in the presence of K PO or Na PO
in THF (tetrahydrofuran) at room temperature, and the desired
compound 4a was obtained in 53% and 48% yield, respectively
(Table 1, entries 5,6). Gratifyingly, the yield was notably
increased when the reaction was performed at 50 °C (Table 1,
entry 8). The subsequent solvent screening revealed that MeCN,
2
CH Cl
2
,
DMF
(N,N-dimethylformanide),
DMSO
(dimethylsulfoxide), toluene, and 1,4-dioxane did not give
better results than that obtained with ethanol (Table 1, entries
9-15). Changing catalyst to copper(I) bromide resulted in a
similar yield 84% with almost no yield declined (Table 1, entry
16). By decreasing the catalyst loading to 2 mol%, the yield of
the product reduced to 70% (Table 1, entry 17). In addition, the
effect of temperature, reaction time and loading of base were
also investigated (Table 1, entries 18-23). It was found that
neither
increasing
nor
decreasing
the
reaction
temperature/loading of base could improve the yield (Table 1,
entries 18, 19, 22, 23), and the highest yield was obtained when
the reaction was performed for 5 h (Table 1, entry 21).
Table
2 CuI-catalyzed three-component reaction for the formation of 3-
Table 1 Optimization of reaction conditions.a
triazolylcoumarin derivatives.a,b
Entry
Base
Et
Solvent
THF
THF
THF
THF
THF
THF
THF
THF
Temp./°C Time/h
Yield/% b
trace
30
1
2
3
4
5
6
7
8
9
3
N
rt
rt
48
24
48
24
24
24
24
15
15
15
piperidine
NaOAc
rt
rt
rt
rt
20
30
53
48
30
73
62
65
K
K
Na
2
CO
PO
3
3
4
3
PO
4
NaOH
rt
K
K
K
3
3
3
PO
4
PO
4
PO
4
50
50
50
MeCN
1
0
CH
Cl
2 2
2
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To further expand the efficiency and utility of this strategy, a
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DOI: 10.1039/D0NJ02100H
gram-scale synthesis was performed by using salicylaldehydes
(
1a, 5 mmol), ethyl 2-azidoacetate (2a, 5 mmol), and
phenylacetylene (3a, 5 mmol) as substrates under the standard
conditions (Scheme 3). To our delight, the reaction proceeded
smoothly to give the corresponding product 4a in 83% yield
1.20 g). The result demonstrated the efficiency and practical
applicability of this facile approach for the synthesis of
functional molecules and medicinally important molecules.
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Scheme 3 Gram-scale synthesis.
To get insight into the mechanism of this transformation, we
conducted some control experiments as depicted in Scheme 4.
Treatment of ethyl 2-azidoacetate 2a in ethanol with
arylacetylene 3a or 3c in the presence of copper(I) iodide led to
almost quantitative conversion to ethyl 2-(4-aryl-1H-1,2,3-
5 in 1 h (Scheme 4a). In comparison, only a
trace of conversion to 3-azidocoumarin was detected after 5 h
when salicylaldehydes 1a reacted with ethyl 2-azidoacetate 2a
triazol-1-yl)acetate
in the presence of K
salicylaldehydes 1a and ethyl 2-(4-aryl-1H-1,2,3-triazol-1-
yl)acetate were treated with K PO in ethanol at 50 °C for 5 h,
the desired products 5a 5c were obtained in 89%, 87% yield,
respectively (Scheme 4c). These results clearly showed that
ethyl 2-(4-aryl-1H-1,2,3-triazol-1-yl)acetate was the possible
3 4
PO as base (Scheme 4b). In addition, when
5
3
4
a
Reaction conditions: salicylaldehydes
1
(1.0 mmol), ethyl 2-
(1.0 mmol), CuI (5
,
azidoacetate 2a (1.0 mmol), arylacetylenes
3
b
3
mol%), and K PO
Isolated yield.
4
(1.0 mmol) in ethanol (3 mL) at 50 °C for 5 h.
5
intermediate. Therefore, this three-component reaction
involves the click reaction, followed by a Knoevenagel
condensation and intramolecular transesterification sequence.
1
In addition, all of the products were characterized by H NMR,
C NMR and HRMS analysis, and the structure of novel 3-
13
triazolylcoumarin 4c was also unambiguously confirmed by X-
ray crystallographic analysis (Figure 1).
Figure 2 ORTEP drawing of compound 4c (CCDC 1998453).
Next, the feasibility of the developed one-pot protocol with
ferrocenylacetylene was investigated under the standard
conditions (Scheme 2). Likewise, the corresponding products
Scheme 4 Control experiments.
Based on the above observation and previous available
literature reports,13b,14 a plausible mechanism for the formation
of 3-triazolylcoumarins is outlined in Scheme 5 (compound 4a
formation as an example). Initially, the copper(I)-catalyzed
azide-alkyne cycloaddition (CuAAC) reaction of ethyl 2-
azidoacetate 2a with arylacetylene 3a occurred to form the
intermediate 5a containing an active methylene group, which
might easily react with aldehyde group of 1a via Knoevenagel
4w, 4x bearing with a ferrocenyl group were constructed
efficiently and isolated in 85% and 87% yield, respectively,
demonstrated the potential applications of the protocol in the
assembly of molecular diversity and complexity.
condensation to form the intermediate
A in the presence of
Scheme 2 Synthesis of 3-(4-ferrocenyl)-trizaolycoumarins under the standard base rather than converting into ketenimine intermediate from
conditions.
1
,2,3-triazol compounds bearing with a sulfonyl group reported
15
by previous literature. Subsequently, the intermediate
B was
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then generated in the presence of K PO as a base, which could presence of electron-withdrawing groups at the 3,V5ie-wpAorsticitleioOnnlionef
trap the proton of phenol. Finally, the intramolecular the phenyl ring showed a significant pDoOsIi:t1iv0e.10e39ff/eDc0tNJo0n210th0He
nucleophilic addition of intermediate
transesterification to afford the target product 4a via 4b-4d
intermediate by releasing ethanol.
3 4
B
,
followed by fluorescence of compound 4m
(λem = 487 nm). The fluorophores
4q, and 4r exhibited a red shift in the emission
,
C
wavelength of 470-472 nm when excited at 346-350 nm with a
change of electron-donating substituents to electron-
withdrawing substituents at 5-position of the phenyl ring. For
these results, we can say that 3-triazolylcoumarin derivatives
showed a wide range of fluorescence emission (422-487 nm),
thus inciting the possibility of a huge scope in materials
chemistry and bioimaging field.
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Table 3 Fluorescent data of all compounds.
UV-Vis
λabs max (nm)
338
Fluorescence
λex (nm)
Compound
λem (nm)
450
470
470
472
445
452
439
423
424
425
487
438
449
448
471
471
436
422
427
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442
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4a
b
340
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340
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340
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340
365
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340
340
365
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346
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c
348
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g
4
4
h
i
340
352
4j
4l
348
336
348
4
m
4
4
4
n
o
p
376
336
336
Scheme 5 Proposed mechanism for the formation of 3-triazolylcoumarins.
Wang and co-workers previous reported a Cu(I)-catalyzed
,3-dipolar cycloaddition of nonfluorescent 3-azidocoumarins
4q
4r
348
350
1
4
4
s
t
344
350
and terminal alkynes to construct intense fluorescent 1,2,3-
1
0a
triazole products, which has potential in bioconjugation and
bioimaging applications. Therefore, the fluorescent properties
of 3-triazolylcoumarins were evaluated to expedite their
applications in materials science as ligands and chemosensors.
Most of the 3-triazolylcomarin products have good fluorescent
properties in dichloromethane (DCM) under 365 nm irradiation
with a hand-held UV lamp (Figure 3).
4
u
306
4v
4w
4x
378
336
344
Conclusions
In summary, we have developed an operationally simple one-
pot strategy for the synthesis of various 3-triazolylcoumarins
from salicyaldehydes, ethyl 2-azidoacetate, and arylacetylenes
via copper-catalyzed click reaction, Knoevenagel condensation
and an intramolecular transesterification process under mild
reaction conditions. This reaction characterizes the formation
of four new bonds (one C=C, one C-O, and two C-N) in a single
operation and features with broad substrate scope with easily
accessible starting materials with good functional group
tolerance. More importantly, the gram scale synthesis was
accomplished and this protocol has potential applications in the
preparation of natural products, medicinal and functional
molecules. In addition, the excellent fluorescence properties of
3-triazolylcoumarin derivatives provide huge scope in materials
chemistry and bioimaging field.
Figure 3 The fluorescent colours of 3-triazolylcoumarin derivatives in DCM (5.0
μ
M) under UV irradiation (365 nm).
We next studied the impact of different substituents on the
absorbance and fluorescent properties of the obtained 3-
triazolylcoumarins. Interestingly, all the products showed a
widespread (λmax = 306-378 nm) of the UV-Vis absorbance
with intense excitation and emission spectra (
Experimental
General experimental method
abs
λ
ex = 320-365 nm,
λ
em = 422-487 nm) of fluorescent properties (Table 3). The
4
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Unless otherwise specified, all reagents and starting materials a white solid in 84% yield (271 mg); mp 163-164 °C; H NMR (300
were purchased from commercial sources and used as received, MHz, DMSO-d ) δ 9.07 (s, 1H), 8.72 (s, 1H), 8.06 (s, 1H), 7.96 (d,
6
and the solvents were purified and dried using standard J = 6.6 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H),
procedures. The chromatography solvents were technical grade 7.47 (d, J = 6.3 Hz, 2H), 7.39 (d, J = 6.6 Hz, 1H); C NMR (125
and distilled prior to use. Flash chromatography was performed MHz, DMSO-d ) δ 156.3, 151.9, 147.5, 134.3, 133.2, 130.6,
using 200-300 mesh silica gel with the indicated solvent system 129.9, 129.3, 129.2, 126.3, 124.9, 122.8, 120.6, 119.2; HRMS
3 2
according to standard techniques. The H and C NMR data (APCI-TOF) m/z: [M+H] calcd for C17H11ClN O 324.0540; found
were recorded on 300 MHz NMR spectrometers, unless 324.0531.
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
otherwise specified. Chemical shifts (δ) in parts per million are
6-Bromo-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
4d). This compound was purified by column
reported relative to the residual signals of chloroform (7.26 one
(
1
13
13
ppm for H and 77.16 ppm for C), and all C NMR were chromatography (ethyl acetate/petroleum ether = 1:6) to afford
1
recorded with proton broadband decoupling and indicated as a white solid in 80% yield (294 mg); mp 170-171 °C; H NMR (300
13
1
C{ H}NMR. Multiplicities are described as s (singlet), d MHz, DMSO-d
6
): δ 9.08 (s, 1H), 8.73 (s, 1H), 8.21 (s, 1H), 7.98 (d,
(doublet), t (triplet), q (quartet), or m (multiplet), and the J = 6.9 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.47-7.55 (m, 3H), 7.41
13
6
coupling constants (J) are reported in Hertz. HRMS analysis with (d, J = 6.9 Hz, 1H); C NMR (125 MHz, DMSO-d ): δ 156.3, 152.4,
a quadrupole time-of-flight mass spectrometer yielded ion 147.5, 136.0, 134.2, 132.2, 130.6, 129.9, 129.2, 126.3, 124.9,
mass/charge (m/z) ratios in atomic mass units. IR spectra were 122.8, 121.0, 119.4, 117.7; HRMS (ESI-TOF) m/z: [M+H] calcd
+
measured as dry films (KBr), and the peaks are reported in terms for C17
H
11BrN
3
O
2
368.0035; found 368.0038.
6-Methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
one 4f). This compound was purified by column
-
1
of wave number (cm ). The melting points were measured
using SGWX-4 melting point apparatus.
(
General procedure for the synthesis of 3-triazolylcoumarins 4
.
chromatography (ethyl acetate/petroleum ether = 1:6) to afford
1
A mixture of salicylaldehydes
(1.0 mmol), arylacetylenes
0.05 mmol), and tripotassium orthophosphate (1.0 mmol) in 2H), 7.69 (s, 1H), 7.42-7.54 (m, 4H), 7.38 (d, J = 6.6 Hz, 1H), 2.37
1
(1.0 mmol), ethyl 2-azidoacetate a white solid in 88% yield (266 mg); mp 136-137 °C; H NMR (300
3 (1.0 mmol), copper(I) iodide MHz, DMSO-d ) δ 9.04 (s, 1H), 8.67 (s, 1H), 7.95 (d, J = 7.5 Hz,
6
2
a
(
13
6
ethanol (3 mL) was heated to 50 °C in an oil bath. After the (s, 3H); C NMR (125 MHz, DMSO-d ) δ 156.8, 151.5, 147.4,
reaction was complete (as determined by TLC), the mixture was 136.2, 135.6, 134.8, 130.7, 129.9, 129.2, 126.3, 123.9, 123.0,
+
cooled to room temperature, extracted with CH
and washed with brine. The organic layers were combined,
dried over anhydrous Na SO , filtered, and then evaporated
under vacuum. The residue was purified using flash column one
2
Cl
2
(3 × 10 mL), 118.7, 116.9, 21.1; HRMS (ESI-TOF) m/z: [M+H] calcd for
C
18
H
14
N
3
O
2
304.1086; found 304.1090.
8-Methoxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
4g). This compound was purified by column
2
4
(
chromatography with a silica gel (200-300 mesh), using ethyl chromatography (ethyl acetate/petroleum ether = 1:8) to afford
acetate and petroleum ether (1:6, v/v) as the elution solvent to a white solid in 69% yield (220 mg); mp 142-143 °C; H NMR (300
1
give the desired product
-(4-Phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one
This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:6) to afford a white solid in 87% 124.1, 122.9, 121.4, 119.6, 116.0, 57.1; HRMS (ESI-TOF) m/z:
4
.
MHz, DMSO-d
4a). 2H), 7.37-7.47 (m, 6H), 3.94 (s, 3H); C NMR (125 MHz, DMSO-
) δ 156.4, 147.4, 147.3, 136.2, 130.7, 129.9, 129.2, 126.3,
6
) δ 9.06 (s, 1H), 8.75 (s, 1H), 7.97 (d, J = 7.2 Hz,
1
3
3
(
d
6
1
+
yield (251 mg); mp 198-199 °C; H NMR (300 MHz, DMSO-d
6
) δ [M+H] calcd for C18
7-Methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.35-7.49 (m, 5H); C NMR (125 one 4h). This compound was purified by column
MHz, DMSO-d ) δ 155.8, 152.6, 148.0, 132.9, 132.7, 129.9, chromatography (ethyl acetate/petroleum ether = 1:6) to afford
14 3 3
H N O 320.1035; found 320.1040.
8
.93 (s, 1H), 8.68 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 7.8
1
3
(
6
1
1
28.9, 128.5, 125.9, 125.6, 123.0, 120.4, 118.1, 116.7; HRMS a white solid in 87% yield (263 mg); mp 124-126 °C; H NMR (300
+
(ESI-TOF) m/z: [M+H] calcd for C17
H
12
N
3
O
2
290.0930; found MHz, DMSO-d
6
) δ 9.03 (s, 1H), 8.71 (s, 1H), 7.96 (d, J = 7.5 Hz,
2H), 7.82 (d, J = 7.5 Hz, 1H), 7.45-7.50 (m, 3H), 7.38 (s, 1H), 7.30
(d, J = 7.8 Hz, 1H), 2.45 (s, 3H); C NMR (125 MHz, DMSO-d ) δ
6
2
6
90.0928.
-Fluoro-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
one 4b). This compound was purified by column 156.9, 153.5, 147.4, 145.1, 136.5, 130.8, 130.1, 129.9, 129.1,
chromatography (ethyl acetate/petroleum ether = 1:6) to afford 127.4, 126.3, 123.0, 122.9, 117.2, 116.5, 22.2; HRMS (APCI-TOF)
13
(
1
+
a white solid in 90% yield (276 mg); mp 156-157 °C; H NMR (300 m/z: [M+H] calcd for C18
MHz, DMSO-d ) δ 9.08 (s, 1H), 8.74 (s, 1H), 7.97 (d, J = 7.2 Hz, 7-Methoxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
H), 7.84 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.40-7.50 (m, 3H), 7.37 one 4i). This compound was purified by column
14 3 2
H N O 304.1086; found 304.1082.
6
2
(
1
3
1
(d, J = 7.2 Hz, 1H); C NMR (125 MHz, DMSO-d
6
) δ 159.3 (d, JCF chromatography (ethyl acetate/petroleum ether = 1:8) to afford
1
=
1
240.3 Hz), 156.4, 149.7, 147.5, 134.5, 133.2, 130.7, 129.9, a white solid in 68% yield (217 mg); mp 137-138 °C; H NMR (300
2
29.2, 126.3, 124.9, 122.8, 120.9 (d, JCF = 24.0 Hz), 120.1, 119.2 MHz, DMSO-d
6
) δ 9.01 (s, 1H), 8.70 (s, 1H), 8.17 (d, J = 7.2 Hz,
2
(
[
d, 3JCF = 8.6 Hz), 115.5 (d, JCF = 25.0 Hz); HRMS (APCI-TOF) m/z: 1H), 7.96 (d, J = 7.2 Hz, 2H), 7.86 (t, J = 8.4 Hz, 2H), 7.61 (t, J =
+
13
M+H] calcd for C17
-Chloro-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
one 4c). This compound was purified by column 132.3, 131.5, 130.9, 130.1, 129.8, 129.1, 126.6, 126.2, 122.9,
H11FN
3
O
2
308.0835; found 308.0835.
7.2 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 3.90 (s, 3H);
C
6
NMR (125 MHz, DMSO-d ) δ 164.3, 157.0, 155.5, 147.3, 137.1,
6
(
chromatography (ethyl acetate/petroleum ether = 1:6) to afford
This journal is © The Royal Society of Chemistry 20xx
New J. Chem., 2020, 00, 1-3 | 5
Please do not adjust margins

Pl eNa es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Page 6 of 9
PAPER
21.0, 114.4, 112.3, 101.6, 57.0; HRMS (APCI-TOF) m/z: [M+H]+
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
View Article Online
DOI: 10.1039/D0NJ02100H
calcd for C18 320.1035; found 320.1030.
H N
14 3
O
3
one
(4p). This compound was purified by column
7
-Hydroxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
chromatography (ethyl acetate/petroleum ether = 1:6) to afford
1
one
(4j). This compound was purified by column a white solid in 82% yield (264 mg); mp 138-139 °C; H NMR (300
chromatography (ethyl acetate/petroleum ether = 1:8) to afford MHz, DMSO-d
6
) δ 9.10 (s, 1H), 8.75 (s, 1H), 7.99 (d, J = 8.7 Hz,
1
a white solid in 60% yield (183 mg); mp 235-236 °C; H NMR (300 2H), 7.95 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 8.4 Hz, 1H), 7.55 (d, J =
1
3
MHz, DMSO-d
6 6
) δ 10.95 (s, 1H), 8.98 (s, 1H), 8.64 (s, 1H), 7.94 (d, 8.4 Hz, 2H), 7.44-7.49 (m, 2H); C NMR (125 MHz, DMSO-d ) δ
J = 7.2 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 156.7, 153.4, 146.4, 136.3, 133.9, 133.7, 130.4, 130.0, 129.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
7
.35 (t, J = 7.2 Hz, 1H), 6.86-6.92 (m, 2H); C NMR (125 MHz, 129.6, 128.0, 126.2, 123.9, 123.3, 119.0, 117.2; HRMS (APCI-TOF)
+
DMSO-d
6
) δ 163.4, 157.2, 155.6, 147.3, 137.6, 131.9, 130.9, m/z: [M+H] calcd for C17
H
11ClN
3
O
2
324.0540; found 324.0545.
1
29.8, 129.1, 126.2, 123.0, 120.1, 115.2, 111.1, 103.0; HRMS
6-Chloro-3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)-2H-
306.0879; found chromen-2-one 4q). This compound was purified by column
+
(
3
APCI-TOF) m/z: [M+H] calcd for C17
06.0885.
,8-Di-tert-butyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-
chromen-2-one
chromatography (ethyl acetate/petroleum ether = 1:16) to J = 8.1 Hz, 2H), 7.78 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H),
H
11
N
3
O
3
(
chromatography (ethyl acetate/petroleum ether = 1:6) to afford
1
6
a white solid in 80% yield (286 mg); mp 153-154 °C; H NMR (300
6
(4l). This compound was purified by column MHz, DMSO-d ) δ 9.14 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 8.01 (d,
1
13
afford a white solid in 65% yield (261 mg); mp 108-109 °C; H 7.55 (d, J = 8.1 Hz, 2H); C NMR (125 MHz, DMSO-d
6
) δ 156.2,
NMR (300 MHz, DMSO-d ) δ 9.08 (s, 1H), 8.73 (s, 1H), 7.96 (d, J 152.0, 146.5, 134.3, 133.7, 133.3, 129.9, 129.6, 129.2, 128.1,
6
+
=
7
7.5 Hz, 2H), 7.84 (s, 1H), 7.64 (s, 1H), 7.48 (t, J = 7.2 Hz, 2H), 124.9, 123.2, 120.6, 119.2; HRMS (APCI-TOF) m/z: [M+H] calcd
13
.37 (t, J = 6.9 Hz, 1H), 1.49 (s, 9H), 1.33 (s, 9H); C NMR (125 for C17
) δ 156.5, 150.1, 148.0, 147.4, 137.5, 137.0, 6-Bromo-3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)-2H-
30.8, 129.9, 129.2, 128.4, 126.3, 125.3, 123.0, 122.9, 119.1, chromen-2-one 4r). This compound was purified by column
2 3 2
H10Cl N O 358.0150; found 358.0143.
MHz, DMSO-d
6
1
3
C
6
2
(
+
5.5, 35.4, 31.5, 30.4; HRMS (APCI-TOF) m/z: [M+H] calcd for chromatography (ethyl acetate/petroleum ether = 1:6) to afford
1
25
H
28
N
3
O
2
402.2182; found 402.2175.
,8-Dibromo-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2H-chromen- MHz, DMSO-d
-one 4m). This compound was purified by column J = 8.4 Hz, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 3H);
a white solid in 82% yield (271 mg); mp 146-148 °C; H NMR (300
6
) δ 9.14 (s, 1H), 8.72 (s, 1H), 8.20 (s, 1H), 8.01 (d,
(
13
chromatography (ethyl acetate/petroleum ether = 1:6) to afford
6
C NMR (125 MHz, DMSO-d ) δ 156.2, 152.4, 146.5, 136.0,
1
a white solid in 68% yield (302 mg); mp 137-138 °C; H NMR (300 134.3, 133.7, 132.2, 129.9, 129.6, 128.1, 124.8, 123.2, 121.0,
MHz, DMSO-d
6
) δ 9.08 (s, 1H), 8.72 (s, 1H), 8.26 (s, 1H), 8.22 (s, 119.4, 117.7; HRMS (APCI-TOF) m/z: [M+H]+ calcd for
H), 7.99 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 10BrClN 401.9645; found 401.9648.
3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-7-methyl-2H-
40.2, 137.9, 133.5, 133.0, 131.8, 130.5, 129.9, 129.3, 129.2, chromen-2-one 4s). This compound was purified by column
26.4, 126.1, 125.5, 122.7, 122.1, 117.8, 111.0; HRMS (ESI) m/z: chromatography (ethyl acetate/petroleum ether = 1:8) to afford
1
6
1
1
17
C H
3 2
O
13
6
.9 Hz, 1H); C NMR (125 MHz, DMSO-d ) δ 155.7, 149.2, 147.6,
(
+
1
[
M+Na] calcd for C17
-(4-Phenyl-1H-1,2,3-triazol-1-yl)-3H-benzo[f]chromen-3-
one 4n). This compound was purified by column 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H),
9
H Br
N
2 3
O
2
Na 467.8953; found 467.8954.
a white solid in 78% yield (262 mg); mp 132-133 °C; H NMR (300
2
MHz, DMSO-d ) δ 9.10 (s, 1H), 8.72 (s, 1H), 7.99 (d, J = 8.4 Hz,
6
(
13
chromatography (ethyl acetate/petroleum ether = 1:8) to afford 7.30 (d, J = 7.8 Hz, 1H), 2.45 (s, 3H); C NMR (125 MHz, DMSO-
1
a white solid in 78% yield (264 mg); mp 175-176 °C; H NMR (300
6
d ) δ 156.8, 153.5, 146.5, 145.2, 136.6, 134.6, 134.2, 130.5,
MHz, CDCl
3
) δ 9.43 (s, 1H), 9.00 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 130.1, 129.7, 128.4, 128.0, 127.4, 123.3, 122.9, 117.6, 117.2,
.10 (d, J = 9.3 Hz, 1H), 7.96 (d, J = 6.9 Hz, 2H), 7.78 (t, J = 8.1 Hz, 116.5, 22.2; HRMS (APCI-TOF) m/z: [M+H]+ calcd for
H), 7.64 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.47 (t, J = 338.0696; found 338.0700.
.2 Hz, 3H), 7.38 (t, J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl
) δ 3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2H-
56.1, 153.0, 148.5, 134.6, 131.0, 130.4, 129.5, 129.3, 128.9, chromen-2-one 4t). This compound was purified by column
27.2, 126.3, 122.7, 122.2, 120.8, 116.7, 113.2; HRMS (APCI-TOF) chromatography (ethyl acetate/petroleum ether = 1:6) to afford
8
1
7
1
1
18 3 2
C H13ClN O
3
(
+
1
m/z: [M+H] calcd for C21
H
14
N
3
O
2
340.1086; found 340.1094.
a white solid in 67% yield (236 mg); mp 129-130 °C; H NMR (300
MHz, DMSO-d ) δ 9.07 (s, 1H), 8.69 (s, 1H), 7.99 (d, J = 8.4 Hz,
(4o). This compound was purified by column 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.17 (s, 1H),
3
-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-
6
one
13
chromatography (ethyl acetate/petroleum ether = 1:6) to afford 7.09 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H); C NMR (125 MHz, DMSO-
1
a yellow solid in 80% yield (294 mg); mp 143-144 °C; H NMR
6
d ) δ 164.1, 157.0, 155.5, 146.3, 137.2, 133.6, 131.5, 129.9,
(300 MHz, DMSO-d
6
) δ 9.13 (s, 1H), 8.77 (s, 1H), 7.94 (d, J = 8.1 129.8, 128.0, 123.3, 120.9, 114.5, 112.3, 101.6, 57.0; HRMS
+
Hz, 3H), 7.70 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.56 (d, J (APCI-TOF) m/z: [M+H] calcd for C18
H13ClN
3
O
3
354.0645; found
=
d
1
1
3
8.7 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H); 13C NMR (125 MHz, DMSO- 354.0646.
) δ 156.7, 153.4, 146.4, 136.2, 134.3, 133.9, 133.2, 132.9, 6,8-Di-tert-butyl-3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)-
6
32.8, 130.4, 130.0, 128.3, 126.2, 123.9, 123.3, 122.2, 119.0, 2H-chromen-2-one
(
4u). This compound was purified by
+
17.2; HRMS (APCI-TOF) m/z: [M+H] calcd for C17
H
11BrN
3
O
2
column chromatography (ethyl acetate/petroleum ether = 1:16)
1
68.0035; found 368.0029.
to afford a white solid in 70% yield (304 mg); mp 112-113 °C; H
6
NMR (300 MHz, DMSO-d ) δ 8.77 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H),
6
| New J. Chem., 2020, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
Pl eNa es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
New Journal of Chemistry
PAPER
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1
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+
7
1
1
1
1
.79 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 121.4, 62.3, 50.8, 14.0; HRMS (ESI-TOF) m/z: [M+H] calcd for
.49 (s, 9H), 1.33 (s, 9H); C NMR (125 MHz, DMSO-d
51.0, 148.2, 146.3, 144.5, 137.3, 136.1, 135.0, 134.6, 134.0,
30.2, 130.0, 129.6, 128.7, 128.4, 125.6, 121.6, 119.8, 119.3, This compound was purified by column chromatography (ethyl
View Article Online
DOI: 10.1039/D0NJ02100H
13
6
) δ 156.4,
C
12
H
14
N
3
O
2
232.1086; found 232.1082.
Ethyl 2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetate
(5c).
18.7, 102.9, 76.3, 35.6, 35.4, 31.8, 30.4; HRMS (APCI-TOF) m/z: acetate/petroleum ether = 1:6) to afford a white solid in 97%
+
1
[
M+H] calcd for C25
-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-3H-
benzo[f]chromen-3-one 4v). This compound was purified by 2H), 4.28 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); C NMR (75
H27ClN
3
O
2
436.1792; found 436.1785.
yield (257 mg); mp 115-116 °C; H NMR (300 MHz, CDCl
3
) δ 7.90
2
(s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.19 (s,
13
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
column chromatography (ethyl acetate/petroleum ether = 1:8) MHz, CDCl
to afford a white solid in 80% yield (298 mg); mp 165-166 °C; H 62.5, 50.9, 14.0; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
3
) δ 166.2, 147.1, 133.9, 129.0, 128.8, 127.0, 121.1,
1
NMR (300 MHz, CDCl
3
) δ 9.36 (s, 1H), 9.07 (s, 1H), 8.60 (d, J = 8.4
12 3 2
C H13ClN O 266.0696; found 266.0700.
Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.96 (d,
J = 8.1 Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H),
1
3
Conflicts of interest
There are no conflicts to declare.
7
1
1
3
.52 (d, J = 8.1 Hz, 2H); C NMR (125 MHz, CDCl ) δ 156.8, 153.5,
46.4, 135.4, 133.7, 133.5, 133.4, 130.9, 129.9, 129.8, 129.7,
29.6, 128.0, 127.5, 123.6, 123.5, 123.4, 117.2, 113.3; HRMS
+
(
APCI-TOF) m/z: [M+H] calcd for C21
H
13ClN
3
O
2
374.0696; found
3
3
74.0689.
-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one
4w). This compound was purified by column chromatography
Acknowledgements
The work was partially supported by the National Natural
Science Foundation of China (No. 21772001), the Anhui
Provincial Natural Science Foundation (No. 1808085MB41), and
the Special and Excellent Research Fund of Anhui Normal
University.
(
(
ethyl acetate/petroleum ether = 1:6) to afford a brown solid in
1
8
8
5% yield (337 mg); mp 212-213 °C; H NMR (300 MHz, CDCl
.67 (s, 1H), 8.62 (s, 1H), 7.70 (t, J = 6.9 Hz, 1H), 7.66 (d, J = 7.8
3
) δ
Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.26 (s, 1H), 4.83 (s, 2H), 4.37 (s,
1
3
2
1
6
3
H), 4.13 (s, 5H); C NMR (75 MHz, CDCl ) δ 155.9, 151.4, 147.3,
32.6, 128.9, 125.6, 123.0, 119.6, 118.2, 116.7, 74.9, 69.8, 69.1,
7.0; HRMS (ESI) m/z: [M] calcd for C21
Notes and references
1
+
H
15FeN
3
O
2
397.0513;
(a) M.-K. Jeon, M.-K. Kang and K. H. Park, Tetrahedron, 2012,
, 6038; (b) S. Robert, C. Bertolla, B. Masereel, J. M. Dogné
found 397.0510.
-Chloro-3-(4-ferrocenyl-1H-1,2,3-triazol-1-yl)-2H-chromen-
-one 4x). This compound was purified by column
6
8
6
and M. Pochet, J. Med. Chem., 2008, 51, 3077; (c) A. Maresca,
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2
(
chromatography (ethyl acetate/petroleum ether = 1:6) to afford
a brown solid in 87% yield (375 mg); mp 206-208 °C; H NMR
1
2
019, 119, 10403; (e) R. Nazir, A. J. Stasyuk and D. T. Gryko, J.
(300 MHz, DMSO-d
6
) δ 8.71 (s, 1H), 8.70 (s, 1H), 8.07 (s, 1H),
Org. Chem., 2016, 81, 11104; (f) J. Jiang, Q. Tan, S. Zhao, H.
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.77 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 4.86 (s, 2H), 4.35
1
3
(s, 2H), 4.06 (s, 5H); C NMR (75 MHz, DMSO-d
6
) δ 155.9, 151.4,
1
7
C
46.5, 133.1, 132.6, 129.4, 128.7, 124.6, 121.3, 120.3, 118.7,
5.3, 69.7, 69.1, 67.0; HRMS (ESI) m/z: [M]+ calcd for
14ClFeN 431.0118; found 431.0112.
21
H
3 2
O
17, 5392.
General procedure for the synthesis of ethyl 2-(4-aryl-1H-
2
(a) T. R. Burke Jr, M. Fesen, A. Mazumder, J. Yung, J. Wang, A.
M. Carothers, D. Grunberger, J. Driscoll, Y. Pommier and K.
Kohn, J. Med. Chem., 1995, 38, 4171; (b) K. Kushwaha, N.
1
2
,2,3-triazol-1-yl)acetate 5. A mixture of ethyl 2-azidoacetate
(1.0 mmol), arylacetylenes (1.0 mmol), and copper(I) iodide
a
3
(
0.05 mmol) in ethanol (3 mL) was stirred at room temperature
for 1 h. After the reaction was complete (as determined by TLC),
the mixture was extracted with CH Cl (3 × 10 mL), and washed
with brine. The organic layers were combined, dried over
anhydrous Na SO , filtered, and then evaporated under vacuum.
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1
795; (c) D. A. Ostrov, J. A. Hernández-Prada, P. E. Corsino, K.
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2
2
2
4
The residue was purified using flash column chromatography
with a silica gel (200-300 mesh), using ethyl acetate and
petroleum ether (1:6, v/v) as the elution solvent to give the
3
K. V. Sashidhara, A. Kumar, M. Chatterjee, K. B. Rao, S. Singh,
A. K. Verma and G. Palit, Bioorg. Med. Chem. Lett., 2011, 21
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937.
desired product
5.
4
5
Y. Bansal, P. Sethi and G. Bansal, Med. Chem. Res., 2013, 22
,
Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate
compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:6) to afford a white solid in 98%
yield (226 mg); mp 102-103 °C; H NMR (300 MHz, CDCl
(
5a). This
3049.
(a) J. R. Hwu, S. Y. Lin, S. C. Tsay, E. De Clercq, P. Leyssen and
J. Neyts, J. Med. Chem., 2011, 54, 2114; (b) E. B. B. Ong, N.
Watanabe, A. Saito, Y. Futamura, K. H. A. El Galil, A. Koito, N.
Najimudin and H. Osada, J. Biol. Chem., 2011, 286, 14049; (c)
S. Sardari, S. Nishibe and M. Daneshtalab, Stud. Nat. Prod.
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1
3
) δ 7.91
(s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.38-7.28 (m, 3H), 5.13 (s, 2H),
1
3
4
CDCl
.18 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H); C NMR (75 MHz,
) δ 166.4, 148.0, 130.3, 129.2, 128.8, 128.2, 126.1, 125.7,
3
6
G.-L. Xi and Z.-Q. Liu, J. Agric. Food Chem., 2015, 63, 3516.
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Pl eNa es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
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DOI: 10.1039/D0NJ02100H
Table of Contents
N3
R2
CHO
OH
COOEt
N
N
N
R1
R2
R1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
one-pot three-component
four new bonds formation
mild conditions/eco-friendly
large-scale synthesis
CuI/K PO
EtOH
3
4
A novel and efficient strategy has been developed for the synthesis of 3-triazolylcoumarins in a
one-pot, copper-catalyzed multicomponent reaction involving
salicylaldehydes, ethyl 2-azidoacetate, and arylacetylenes.
a
cascade reaction of