Synthesis of paeonol derivatives linked with 1,2,3-triazole moiety by 1,3-dipolar huisgen-cylcoaddition reaction

Article abstract of DOI:10.3184/174751912X13385686259241

Paeonol is a major phenolic component isolated from Moutan Cortex, a traditional Chinese medicine. An efficient synthesis of paeonol derivatives linked to a 1,2,3-triazole moiety using a 1,3-dipolar Huisgen-cycloaddition reaction is described. The paeonol derivatives are regioselectively obtained in good yields under mild conditions using Cu(OAc)₂·H ₂O/sodium ascorbate as a catalyst system, and t-BuOH/H2O (1:1, v/v) as a co-solvent.

Full text of DOI:10.3184/174751912X13385686259241

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 457
AUGUST, 457–459
Synthesis of paeonol derivatives linked with 1,2,3-triazole moiety by
1,3-dipolar huisgen-cylcoaddition reaction
Yuqin Jiang, Xin Shi, Guiqing Xu and Wei Li*
College of Chemistry and Environmental Science, Henan Normal University, Xinxiang 453007, P. R. China
Paeonol is a major phenolic component isolated from Moutan Cortex, a traditional Chinese medicine. An efficient
synthesis of paeonol derivatives linked to a 1,2,3-triazole moiety using a 1,3-dipolar Huisgen-cycloaddition reaction
is described. The paeonol derivatives are regioselectively obtained in good yields under mild conditions using
Cu(OAc)2·H2O/sodium ascorbate as a catalyst system, and t-BuOH/H2O (1:1, v/v) as a co-solvent.
Keywords: paeonol, Huisgen cycloaddition, Cu(OAc)2·H2O/sodium ascorbate, ultrasound irradiation
Paeonol (2′-hydroxyl-4′-methoxyacetophenone), the major
phenolic component isolated from Moutan Cortex, a tradi-
tional Chinese medicine widely used in clinical treatment of
inflammatory diseases, has various bioactivities such as anti-
neoplastic activity,1–4 anti-inflammatory,5,6 antioxidant,7 and
antithrombotic activities.8 More recent studies have shown that
paeonol could increase levels of cortical cytochrome oxidase
and vascular actin and improve behaviour in the rat model of
Alzheimer’s disease (AD), which indicated that paeonol is a
possible therapeutic measure in slowing down the pathogenic
processes associated with AD.9 Efforts to improve the pharma-
cological and biological activities of paeonol have led to the
development of its derivatives by appropriate modification of
paeonol as mentioned elsewhere.10–13
The 1,2,3-triazole moiety is stable to metabolic degradation
and capable of hydrogen bonding, which could be favourable
in binding of biomolecular targets as well as in increasing solu-
bility.14 Moreover, 1,2,3-triazoles are attractive linker units
which could connect two pharmacophores for constructing
bioactive and functional molecules.15–17 Compounds contain-
ing a 1,2,3-triazole ring show various biological properties,
such as anti-HIV,18 anti-microbial,19 and anti-allergic activi-
ties.20 A simple, quick and useful approach to introducing the
1,2,3-triazole moiety is using the copper(I)-catalysed azide–
alkyne cycloaddition (CuAAC reaction).21,22
As far as we know, the modification of introducing 1,2,3-
triazole groups into paeonol has not been previously reported.
In order to maintain the main chemical structure of paeonol,
the hydrogen atom in the methyl group of paeonol was replaced
by an azide group to form the intermediate, azide-paeonol. The
main targets of this work was to find efficient conditions for
the 1,3-dipolar cycloaddition reaction between azide-paeonol
and terminal alkynes and synthesise a series of paeonol deriva-
tives linked with 1,2,3-moiety. In our previous works,23,24 we
found that ultrasound irradiation could greatly accelerate the
CuAAC reaction at room temperature. In the work described
here, a series of paeonol derivatives linked with 1,2,3-triazoles
were synthesised using the CuAAC reaction between azide-
paeonol and terminal alkynes, which could be successively
carried out in t-BuOH/H2O (1:1, v/v) using Cu(OAc)2·H2O/
sodium ascorbate as the catalyst system under the help of
ultrasound irradiation at room temperature.
Results and discussion
The title compounds were synthesised in three steps and the
synthetic routine is shown in Scheme 1. Paeonol (1) was firstly
selectively α-brominated by CuBr2 in CHCl3/EtOAc at reflux
to form compound 2,25 which could be converted to azide-
paeonol (3)26 by reacting with sodium azide in DMF at 0 °C.
Then 3 was reacted with various kinds of terminal alkynes
4
27–31 to form the title compounds (5). The CuAAC reaction is
a key step in the pathway for preparation of the target mole-
cules. The 1,3-dipolar cycloaddition between 3 and propargyl
phenyl ether was chosen as a model reaction (Table 1) to
optimise the CuAAC reaction conditions. Considering the
solubility of the organic reactants and the inorganic copper salt
catalyst, t-BuOH/H2O (1:1, v/v) was chosen as the reaction
solvent. The model reaction was carried out using compound 3
(0.1 mmol) and propargyl phenyl ether (0.1 mmol) in the
presence of 10 mol% Cu(I) in t-BuOH/H2O (3mL, 1:1, v/v) at
room temperature.
The following experiments were designed to investigate the
acceleration effect of ultrasound on the model reaction. The
model reaction was performed using Cu(OAc)2·H2O/sodium
ascorbate as the catalyst with a magnetic stirring in the absence
of ultrasound irradiation and in the presence of ultrasound
irradiation (Table 1). Tracked by TLC, 36 hours was taken to
complete the reaction in the absence of ultrasound irradiation
in 94% yield at room temperature, whereas only 25 minutes
was needed in the presence of ultrasound irradiation in almost
the same yield, indicating that the cycloaddition rate was
greatly accelerated by ultrasound. The outcome is consistent
with the precious work.23,24
Different copper catalyst systems (10 mol%) were screened
by the model reaction in t-BuOH/water (1:1, v/v) under con-
tinuous sonication at room temperature. As shown in Table 1,
the best catalytic efficiency was observed for Cu(OAc)2·H2O/
sodium ascorbate among the tested catalysts. Most notably, the
Scheme 1 Synthetic routine of the title compounds.
* Correspondent. E-mail: liweigq@163.com

458 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Screening of catalysts for the model reaction in
t-BuOH/H2O under the ultrasonic irradiation a
DMSO-d6 at room temperature (20 2 °C). 1H and 13C chemical shifts
are quoted in parts per million downfield from TMS. ESI MS were
recorded on a Bruker Esquire 3000. High-resolution mass spectra (HR
MS) were performed on a MicrOTOF-Q II mass spectrometer with an
ESI source (Waters, Manchester, UK).
Synthesis of the target molecules (5a–g); general procedure
Substituted terminal alkyne (0.3 mmol) and 3 (0.3 mmol) were sus-
pended in t-BuOH/H2O (3 mL, 1:1, v/v) in a 10 mL round-bottomed
flask followed by Cu(OAc)2·H2O (10 mol%) and sodium ascorbate
(20 mol%). The mixture was sonicated in a laboratory ultrasonic
cleaning bath. After completion of the reaction, as indicated by TLC,
the reaction mixture was diluted with 10 mL water, and the precipitate
was collected and washed with cold water and saturated ammonium
chloride as a grey solid. The crude product was purified by column
chromatography on silica gel using ethyl acetate /petroleum ether
(2:1, v/v) as eluent.
Copper salts
Reductant
Time/min Yield/%b
Cu(OAc)2·H2O
Cu(OAc)2·H2Oc
CuSO4·5H2O
CuBr2
CuCl2·2H2O
CuI
Sodium ascorbate
25
36 (h)
40
95
94
83
68
67
86
71
85
Sodium ascorbate
Sodium ascorbate
Sodium ascorbate
70
Sodium ascorbate
80
–
–
–
55
CuBr
CuCl
55
55
a Reaction conditions: 0.1 mmol azide, 0.1 mmol terminal
alkyne, 30 °C.
1-(2-Hydroxy-4-methoxyphenyl)-2-{4-[(4-chlorophenoxy)methyl]-
1H-1,2,3-triazol-1-yl}ethan-1-one (5a): White solid, m.p. 156–158
°C, IR (KBr, vmax): 2939, 2845, 1631, 1578, 1509, 1202, 1132, 823,
b Isolated yield.
c In absence of ultrasound irradiation condition.
1
807, 777 cm−1. H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3H, CH3),
5.23 (s, 2H, CH2), 5.80 (s, 2H, CH2), 6.47 (d, J = 2.0 Hz, 1H, ArH),
6.52 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, ArH), 6.92 (d, J = 12 Hz, 2H,
ArH), 7.23 (d, J = 12 Hz, 2H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH),
7.78 (s, 1H, CH), 11.90 (s, 1H, OH). 13C NMR (100 MHz, CDCl3):
δ = 54.3, 55.8, 62.2, 101.2, 108.9, 111.1, 116.1, 124.8, 126.2, 129.4,
130.3, 144.2, 156.8, 165.8, 167.2, 192.9. ESI MS m/z: 374 [M + H]+.
1,3-dipolar cycloaddition reaction catalysed by Cu(OAc)2·H2O/
sodium ascorbate was completed in 25 minutes in 95% yield
(Table 1). In comparison to Cu(OAc)2·H2O/sodium ascorbate,
lower catalytic efficiencies were observed for other catalysts,
among which CuCl2·2H2O/sodium ascorbate showed the
lowest (67% yield) in 80 minutes and CuSO4·5H2O/sodium
ascorbate the highest (83% yield). Therefore, Cu(OAc)2·H2O/
sodium ascorbate was chosen as the catalyst.
Under the optimised reaction conditions mentioned above,
more paeonol derivatives linked with 1,2,3-triazoles ring were
synthesised by using various substituted terminal alkynes. As
can be seen from Table 2, in all cases, a series of new paeonol
derivatives linked with 1,2,3-triazoles moiety were obtained in
good yields.
HR MS m/z: 374.0904 [M
374.0908).
+
H]+, (Calcd for C18H17ClN3O4
1-(2-Hydroxy-4-methoxyphenyl)-2-{4-[(3-methylphenoxy)methyl]-
1H-1,2,3-triazol-1-yl}ethan-1-one (5b): White solid, m.p. 116–
118 °C, IR (KBr, vmax): 2946, 2920, 2843, 1638, 1625, 1583, 1504,
1205, 1132, 831, 801, 748 cm−1. 1H NMR (400 MHz, CDCl3): δ = 2.33
(s, 3H, CH3), 3.87 (s, 3H, CH3), 5.25 (s, 2H, CH2), 5.79 (s, 2H, CH2),
6.47 (d, J = 2.4 Hz, 1H, ArH), 6.52 (d, J = 8.0 Hz, 1H, ArH), 6.79
(t, J = 8.0 Hz, 3H, ArH), 7.16 (t, J = 8.0 Hz, 1H, ArH), 7.64 (d, J =
8.0 Hz, 1H, ArH), 7.78 (s, 1H, CH), 11.92 (s, 1H, OH). 13C NMR
(100 MHz, CDCl3): δ = 21.5, 54.3, 55.8, 61.9, 101.2, 108.8, 111.1,
111.6, 115.6, 122.1, 129.3, 130.4, 139.6, 158.2, 165.7, 167.2, 193.1.
ESI MS m/z: 354 [M + H]+. HR MS m/z: 354.1462 [M + H]+, (Calcd
for C19H20N3O4 354.1454).
2-(4-Cyclopropyl-1H-1,2,3-triazol-1-y)-1-(2-hydroxy-4-methoxyphenyl)-
ethan-1-one (5c): White solid, m.p. 148–150 °C, IR (KBr, vmax): 2951,
2826, 2850, 1643, 1623, 1572, 1518, 1185, 819 cm−1. 1H NMR
(400 MHz, CDCl3): δ = 0.89 (m, 2H, CH2), 0.95 (m, 2H, CH2), 1.96
(m, 1H, CH), 3.87 (s, 3H, CH3), 5.72 (s, 2H, CH2), 6.46 (d, J = 2.4 Hz,
1H, ArH), 6.51 (dd, J1 = 2.4 Hz, J2 = 8.0 Hz, 1H, ArH), 7.40 (s, 1H,
CH) 7.64 (d, J = 8.0 Hz, 1H, ArH), 11.96 (s, 1H, OH). 13C NMR
(100 MHz, CDCl3): δ = 6.7, 7.8, 54.2, 55.7, 101.2, 108.8, 111.2, 121.7,
130.5, 150.6, 165.7, 167.1, 193.5. ESI MS m/z: 274 [M + H]+. HR MS
m/z: 274.1190 [M + H]+, (Calcd for C14H16N3O3 274.1192).
1-(2-Hydroxy-4-methoxyphenyl)-2-[4-(4-propylphenyl)-1H-1,2,3-
triazol-1-yl]ethan-1-one (5d): White solid, m.p. 163–164 °C, IR (KBr,
vmax): 2950, 2867, 2843, 1633, 1581, 1507, 1464, 1213, 829, 813 cm−1.
1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 6.0 Hz, 3H, CH3), 1.64
(m, 2H, CH2), 2.60 (t, J = 8.0 Hz, 2H, CH2), 3.87 (s, 3H, CH3), 5.82
(s, 2H, CH2), 6.47 (d, J = 8.0 Hz, 1H, ArH), 6.52 (dd, J1 = 4.0 Hz,
J2 = 8.0 Hz, 1H, ArH), 7.24 (s, 1H, CH), 7.26 (s, 1H, CH), 7.67 (d,
J = 8.0 Hz, 1H, ArH), 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.89 (s, 1H, CH),
11.97 (s, 1H, OH). 13C NMR (100 MHz, CDCl3): δ = 13.8, 24.4, 37.8,
54.3, 55.7, 101.2, 108.8, 111.2, 121.2, 125.7, 127.8, 128.9, 130.4,
142.9, 148.3, 165.8, 167.2, 193.2. ESI MS m/z: 352 [M + H]+. HR MS
m/z: 352.1662 [M + H]+, (Calcd for C20H22N3O3 352.1661).
In summary, a highly efficient synthesis of paeonol deriva-
tives linked with 1,2,3-triazole in t-BuOH/H2O was developed
by using Cu(OAc)2·H2O/sodium ascorbate as the catalyst
system with the help of ultrasound irradiation.
Experimental
All the chemicals were obtained from Tianjin Kermel Chemical
Reagent Co., Ltd. and used as received. All melting points were deter-
mined on a YUHUA X-3 melting point apparatus and are reported
uncorrected. Sonication was performed in a Kunshan KQ-250B ultra-
sonic cleaner with a frequency of 40 kHz and a power 150 W. The
reaction flasks were located in the maximum energy area in the
cleaner, and the temperature of the reaction solution was controlled at
30 °C by the addition or removal of the bath water. IR spectra were
recorded on a Bio-rad FTS-40. 1H, 13C spectra were recorded on
a Bruker Avance 400 MHz spectrometer operating at 400.13 and
100.61 MHz, respectively. NMR spectra were recorded in CDCl3 or
Table 2 Paeonol derivatives linked with 1,2,3-triazole moiety
(5a–g)a
2-[4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl]-1-(2-hydroxy-4-methoxy-
Entry
R
Yield/%b
phenyl)ethan-1-one (5e): White solid, m.p. 168–170 °C, IR (KBr, vmax):
1
2934, 2843, 1622, 1566, 1500, 1460, 1199, 847, 813 cm−1. H NMR
5a
5b
5c
5d
5e
5f
4-ClC6H5.O.CH2.
3-CH3C6H5.O.CH2.
C3H5.
85
86
69
89
89
88
88
(400 MHz, CDCl3): δ = 1.24 (t, J = 8.0 Hz, 3H, CH3), 2.66 (dd, J1 =
4.0 Hz, J2 = 8.0 Hz, 2H, CH2), 2.60 (t, J = 8.0 Hz, 2H, CH2), 3.87 (s,
3H, CH3), 5.81 (s, 2H, CH2), 6.47 (d, J = 2.4 Hz, 1H, ArH), 6.52 (dd,
J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, ArH), 7.26 (s, 1H, CH), 7.28 (s, 1H, CH),
7.67 (d, J = 8.0 Hz, 1H, ArH), 7.77 (d, J = 8.0 Hz, 2H, ArH), 7.89 (s,
1H, CH), 11.97 (s, 1H, OH). 13C NMR (100 MHz, CDCl3): δ = 15.5,
28.6, 54.3, 55.7, 101.2, 108.8, 111.2, 121.2, 125.8, 127.8, 128.3,
130.4, 144.5, 148.3, 165.8, 167.2, 193.2. ESI MS m/z: 338 [M + H]+.
HR MS m/z: 338.1500 [M + H]+, (Calcd for C19H20N3O3 338.1505).
4-CH3CH2CH2C6H5.
4-CH3CH2C6H5.
3-NH2C6H5.
5g
4-CH3C6H5.
a Reaction conditions: 0.3 mmol azide, 0.3 mmol terminal
alkyne, 30 °C.
b Isolated yields.

JOURNAL OF CHEMICAL RESEARCH 2012 459
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Received 10 April 2012; accepted 12 May 2012
Paper 1201250 doi: 10.3184/174751912X13385686259241
Published online: 8 August 2012
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