Microwave-assisted synthesis of some novel 1,2,3-triazoles by click chemistry, and their biological activity

Article abstract of DOI:10.1007/s11164-012-0595-9

Five mandipropamid analogues were designed and synthesized via "click chemistry". The phenyl ring of mandipropamid was substituted by a 1,2,3-triazole functional group. Bioassay results indicated that some of the title compounds had moderate fungicidal activity.

Full text of DOI:10.1007/s11164-012-0595-9

Res Chem Intermed (2013) 39:759–766
DOI 10.1007/s11164-012-0595-9
Microwave-assisted synthesis of some novel 1,2,3-
triazoles by click chemistry, and their biological
activity
Na-Na Su
Xing-Hai Liu
•
Yao Li
•
•
Shu-Jing Yu
Wei-Guang Zhao
•
Xiao Zhang
•
Received: 27 April 2012 / Accepted: 6 May 2012 / Published online: 24 May 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Five mandipropamid analogues were designed and synthesized via
‘‘click chemistry’’. The phenyl ring of mandipropamid was substituted by a 1,2,3-
triazole functional group. Bioassay results indicated that some of the title com-
pounds had moderate fungicidal activity.
Keywords 1,2,3-Triazole ꢀ Mandipropamid ꢀ Click chemistry ꢀ Fungicidal
activity ꢀ Synthesis
Introduction
In recent years, nitrogen-linked heterocyclic compounds have attracted much
attention because of their wide range of applications [1–5]. 1,2,3-Triazoles are used
very often in industrial, medicinal, and agricultural applications. Some, for example
tazobactam and cefatrizine, have been developed as antifungal agents. Because
1
,2,3-Triazoles have other outstanding activity, for example antifungal [6],
antitumor [7], antimalarial [8], antitubercular [9], glycogen phosphorylase inhibition
10], and aromatase inhibition [11], synthesis of a wider range of 1,2,3-triazole
compounds with high biological activity has become a topic of intensive research.
‘Click chemistry’’, introduced by Sharpless and coworkers in 2001, has recently
[
‘
attracted much attention as a powerful and efficient way to synthesize desired
N.-N. Su ꢀ Y. Li ꢀ S.-J. Yu ꢀ X. Zhang ꢀ W.-G. Zhao (&)
State-Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research
Center (Tianjin), Nankai University, Tianjin 300071, China
e-mail: zwg@nankai.edu.cn
X.-H. Liu (&)
College of Chemical Engineering & Materials Sciences, Zhejiang University of Technology,
Hangzhou 310014, China
e-mail: xhliu@zjut.edu.cn
123

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N.-N. Su et al.
R
N
O
H
N
O
H
N
O
O
O
O
N
N
F3C
O
O
Cl
Mandipropamid
Fig. 1 Design strategy of title compounds
compounds in high yields by use of a simple and benign procedure. It has been
explored recently as a novel ligation tool for drug design and screening. This
reaction has also been termed the ‘‘cream of the crop’’ in click reactions [12].
In view of the facts mentioned above, and as a part of our work on the synthesis
of bioactive lead compounds for drug discovery, the title compounds were designed
by replacing the phenyl ring in mandipropamid with the 1,2,3-triazole pharmaco-
phore (Fig. 1). Our original strategy is depicted in Scheme 1.
Results and discussion
Chemistry
The key structure 1,2,3-triazole was used in click chemistry. Ethyl 2-hydroxybut-3-
ynoate, the key starting compound of the ‘‘click’’ cycloaddition, was prepared by
adding ethynylmagnesium bromide to an aldehyde. 2-Hydroxyl acid ethyl ester
becomes yellow at room temperature, so it should be kept under refrigeration. We
encountered difficulties when converting compound 2 into the corresponding alkoxy
compound, because of the high activity of alkynyl. So the alkoxy compound was
obtained as the last step.
To date, many methods have been described for the preparation of amides [13].
The synthetic methods usually used to produce amides involve reaction between an
amine and a carboxylic acid in DCC or reaction between an acyl chloride and an
amine at reflux temperature. However, traditional methods of synthesis of amides
suffer from disadvantages, for example long reaction time and inconvenient
handling. In this paper, the amide was prepared in accordance with Scheme 1. We
synthesized amide derivative 7 by two different methods. In conventional synthesis
a mixture of amine and ester was stirred at 130–140 °C for 10 h, then the product
was obtained by chromatography on silica gel. Microwave irradiation-assisted
synthesis was also used in this work. When one-pot synthesis was conducted with
microwave irradiation the yield was high and the reaction time was short.
Spectra
1
In the H NMR spectra of 7, the –OCH proton signals were observed at d 3.85 and
3
3
.86 ppm and the NCH CH proton signals were observed at 2.76–2.79 ppm and
2 2
1
23

Microwave assistant synthesis and biological activity
761
O
O
H
CHCMgBr
O
O
O
CuSO4,
sodium ascorbate
O
OH
2
N
6
O
1
N
N
F3C
TsCl
NaN3
O
OH
F3C
O
OH
F3C
OTs
F3C
N3
3
4
5
NH2
F3C N N
N
O
O
R
F3C N N
RX
O
O
N
NH
O
NH
O
NaOH/CH2Cl2
O
OH
MW
8
7
8a: R= CH3CH2; 8b: R= CHCCH2; 8c: R= CH2CHCH2; 8d: R= PhCH2
Scheme 1 Synthetic route to compound 8
3.57–3.58 ppm. Signals in the region of 7.74 ppm were the CH signals of 1,2,3-
triazole. The NH proton signals were at 7.06 ppm. For compound 8, the NCH CH
2
2
proton signals were observed at 2.75–2.90 ppm, 3.50–3.58 ppm and 3.66–
.75 ppm, probably because of the effects of both the chiral C and the conversion
of the N atom.
3
Biological activity
The in-vitro fungicidal activity of the title compounds was tested against Alternaria
solani, Gibberella zea, Botryosphaeria berengeriana, Botrytis cinerea, Cercospora
arachidicola, Phytophthora capsici Leonian, and Phytophthora infestans (Mont.) de
Bary. Herbicidal and insecticidal activity was also determined. The primary bioassay
showed the title compounds had low inhibiting activity against Alternaria solani,
Gibberella zea, Botryosphaeria berengeriana, Botrytis cinerea, and Cercospora
arachidicola. Compound 8c had moderate activity (38.5 %) against B. berengeriana
at 50 lg/mL. Compound 8a had moderate activity (31.0 %) against Brassica napus at
1
00 lg/mL. Results from insecticidal activity testing showed all these compounds
had moderate larvicidal activity against the mosquito; mortality was 30–50 %.
In summary, we have described the synthesis of novel 1,2,3-triazoles via ‘‘click
chemistry’’. The compounds had moderate activity against B. berengeriana and
B. napus.
Experimental
Materials and methods
1
H NMR spectra were measured on a Bruker AC-P500 instrument using TMS as
internal standard and CDCl3 and DMSO-d6 as solvents. Melting points were
determined on an X-4 binocular microscope melting point apparatus (Beijing Tech
Instruments, Beijing, China) and were uncorrected. HRMS were recorded on an
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N.-N. Su et al.
Ionspec 7.0 T Fourier-transform ion-cyclotron resonance (FTICR) mass spectrom-
eter. All chemicals and reagents were purchased from standard commercial suppliers.
Synthesis
Synthesis of ethyl 2-hydroxybut-3-ynoate Under an N atmosphere, magnesium
2
powder (1.44 g, 60 mmol) then a single iodine crystal were added to a solution of
ethyl bromide (7.63 g, 70 mmol) in tetrahydrofuran (50 mL). The mixture became
hot and was stirred for 30 min. After cooling, the solution of EtMgBr thus obtained
was transferred under nitrogen to a dropping funnel with an ethyne gas inlet. After
additional stirring at 0 °C for 1 h, the mixture was used at the same temperature for the
next step. Glyoxylic acid ethyl ester was dissolved in anhydrous THF (7.0 mL) under
nitrogen and then added dropwise to the solution of the ethynyl magnesium bromide
in THF under nitrogen. After stirring at -40 °C for 2 h, the mixture was warmed to
room temperature. Saturated NH Cl was added with stirring to achieve weakly acidic
4
pH. After additional stirring at room temperature for 15 min, Et O (ca. 20 mL) was
2
added and organic phases were separated. The aqueous phase was extracted with Et O
2
(
3 9 30 mL), and the collected organic layers were washed with brine to ca neutral
pH and eventually dried over Na SO , and evaporated. The residue was evaporated
2
4
(
5 mmHg, 78–82 °C) to give crude product 2 (1.84 g, yield 24 %).
2
,2,2-Trifluoroethyl 4-methylbenzenesulfonate (4) 2,2,2-Trifluoroethanol
3
(
(
6.47 mmol) and triethylamine (50.4 mmol) were dissolved in dichloromethane
20 mL). A solution of tosyl chloride (16.8 mmol) in dichloromethane (10 mL) was
added and this mixture was stirred for 2 h at room temperature. Subsequently the
reaction mixture was diluted with water. The organic layer was dried over MgSO and
evaporated. The residue was left overnight. White solid 4 was obtained, yield 81.3 %.
4
2
-Azido-1,1,1-trifluoroethane (5) Sodium azide (2.9 mmol) was added to a
solution of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate 4 (2.4 mmol) in 6 mL
DMF. This mixture was stirred at 120 °C for 6 h to afford crude 2-azido-1,1,1-
trifluoroethane 5, b.p. 54–55 °C, which was used without further purification.
Ethyl 2-hydroxy-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)acetate
Azido-1,1,1-trifluoroethane 5 (3.85 g, 30.7 mmol), ethyl 2-hydroxybut-3-ynoate 2
3.28 g, 25.6 mmol), sodium ascorbate (1.27 g, 6.4 mmol), copper sulfate pentahy-
6
2-
(
drate (0.32 g, 1.28 mmol), and water (2 mL) were mixed added to the reaction
mixture obtained as described above. The mixture was stirred at 30 °C for a further
2
combined organic phases were washed with brine, dried over MgSO , and evaporated.
h then diluted with water and extracted several times with dichloromethane. The
4
The residue was purified by chromatography on silica gel, using petroleum ether
60–90 °C) and ethyl acetate as eluents, to afford compound 6 in 92.6 % yield as a
(
1
white solid; m.p. 114–115 °C; H NMR (DMSO-d ): 1.16 (t, 3H, J = 7.03 Hz,
6
H
CH CH O), 4.11–4.16 (m, 2H, CH CH O), 5.31 (s, 1H, COCH), 5.52 (q, 2H,
JH1 = 9.04 Hz, JH2 = 9.08 Hz, CF CH ), 8.22 (s, 1H, triazole).
3
2
3
2
3
2
1
23

Microwave assistant synthesis and biological activity
763
N-(3,4-Dimethoxyphenethyl)-2-hydroxy-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-
-yl)acetamide (7) Method A: To a solution of 2-(3,4-dimethoxyphenyl)ethyla-
4
mine (0.43 g, 2.37 mmol) in a microwave vial, ethyl 2-hydroxy-2-(1-(2,2,2-
trifluoroethyl)-1H-1,2,3-triazol-4-yl)acetate 6 (0.5 g, 1.97 mmol) was added. The
vial was sealed and irradiated in a microwave reactor at 125 °C (10 bar) for 30 min.
The reaction mixture was diluted with water and extracted several times with
dichloromethane. The combined organic phases were washed with brine, dried over
MgSO , and evaporated. The residue was purified by chromatography on silica gel,
4
using petroleum ether (60–90 °C) and ethyl acetate as eluents, to afford 7 in 91.3 %
1
yield as a white solid; m.p. 66–67 °C; H NMR (CDCl ): 2.76–2.79 (m, 2H,
3
ArCH CH ), 3.56–3.58 (m, 2H, ArCH CH ), 3.85 (s, 3H, OCH ), 3.86 (s, 3H,
OCH ), 4.98 (q, 2H, J = 7.81 Hz, JH2 = 15.87 Hz, CF CH ), 5.25 (s, 1H,
2
2
2
2
3
3
H1
3
2
COCH), 6.67–6.71 (m, 2H, Ar–H), 6.78–6.80 (m, 1H, Ar–H), 7.05 (br, 1H, NH),
.74 (s, 1H, triazole). Method B: A mixture of 2-(3,4-dimethoxyphenyl)ethylamine
0.43 g,128 2.37 mmol) and ethyl 2-hydroxy-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-
7
(
triazol-4-yl)acetate (0.5 g, 1.97 mmol) was stirred at 130–140 °C for 10 h, then the
product was purified by chromatography on silica gel to afford 7 in 25 % yield.
General process for title compounds 8 RX (7.56 mmol) was added to a mixture of 7
(3.78 mmol), 30 % aqueous sodium hydroxide solution (18.9 mmol), and a catalytic
amount of hexadecyltrimethylammonium bromide (0.4 mmol) in 6 mL CH Cl at
2
2
room temperature. The reaction mixture was heated at reflux for 24 h. Subsequently
the mixture was diluted with water and extracted several times with dichloromethane.
The combined organic phases were washed with brine, dried over MgSO , and
4
evaporated. The residue was purified by chromatography on silica gel, using
petroleum ether (60–90 °C) and ethyl acetate as eluents, to afford the title compounds
2
PhCH Br.
a–2d. The alkyl halides were C H Br, CH:CCH Br, CH =CHCH Br, and
2
5
2
2
2
2
N-(3,4-Dimethoxyphenethyl)-2-ethoxy-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-
-yl)acetamide (8a) The compound was obtained in 46.6 % yield as a light yellow
4
1
solid; m.p. 112–113 °C; H NMR (CDCl ): 1.21 (t, 3H, J = 7.0 Hz, CH CH O),
3
3
2
2
CH CH O), 3.84(s, 3H, OCH ), 3.87 (s, 3H, OCH ), 4.91–4.96 (m, 2H, CF CH O),
.75–2.90 (m, 2H, ArCH CH ), 3.53–3.61 (m, 2H, ArCH CH ), 3.63–3.73 (m, 2H,
2 2 2 2
3
2
3
3
3
2
4
triazole); HRMS (ESI) m/z Calcd. for C H F N O Na (M ? Na)
.97 (s, 1H, COCH), 6.75–6.84 (m, 3H, Ar–H), 6.96 (br, 1H, NH), 7.42 (s, 1H,
?
439.1564,
1
8 23 3 4 4
found 439.1569.
N-(3,4-dimethoxyphenethyl)-2-(prop-2-yn-1-yloxy)-2-(1-(2,2,2-trifluoroethyl)-1H-
,2,3-triazol-4-yl)acetamide (8b) The compound was obtained in 54.9 % yield as a
1
1
light yellow solid; m.p. 130–131 °C; H NMR (CDCl ): 2.49 (t, 1H, J = 2.37 Hz,
3
H
CHCCH O), 2.75–2.90 (m, 2H, ArCH CH ), 3.51–3.57 (m, 1H, ArCH CH ),
.65–3.72 (m, 1H, ArCH CH ), 3.84(s, 3H, OCH ), 3.87 (s, 3H, OCH ), 4.10–4.14
2 2 3 3
2
2
2
2
2
3
(
m, 1H, COCH), 4.24–4.38 (m, 2H, CHCCH O), 4.92–5.00 (m, 2H, CF CH ),
2 3 2
6
z Calcd. for C H F N O Na (M ? Na) 449.1407, found 449.1413.
.75–6.84 (m, 3H, Ar–H), 6.92 (br, 1H, NH), 7.50 (s, 1H, triazole); HRMS (ESI) m/
?
1
9 21 3 4 4
123

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N.-N. Su et al.
N-(3,4-dimethoxyphenethyl)-2-allyloxy-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-
-yl)acetamide (8c) The compound was obtained in 54.9 % yield as a light yellow
4
1
solid; m.p. 110–111 °C; H NMR (CDCl ): 2.75–2.90 (m, 2H, ArCH CH ), 3.50–3.58
3
2
2
(
OCH ), 4.05–4.19 (m, 2H, CH CHCH O), 4.92–4.98 (m, 2H, CF CH ), 5.05 (s, 1H,
m, 1H, ArCH CH ), 3.66–3.75 (m, 1H, ArCH CH ), 3.84(s, 3H, OCH ), 3.87 (s, 3H,
2 2 2 2 3
3
2
2
3
2
COCH), 5.22–5.27(m, 2H, CH CHCH O), 5.80–5.90(m, 1H, CH CHCH O),
2
2
2
2
6
z Calcd. for C H F N O Na (M ? Na) 451.1538, found 451.1569.
.75–6.84 (m, 3H, Ar–H), 6.96 (br, 1H, NH), 7.42 (s, 1H, triazole); HRMS (ESI) m/
?
1
9 25 3 4 4
2-(Benzyloxy)-N-(3,4-dimethoxyphenethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-tria-
zol-4-yl)acetamide (8d) The compound was obtained in 32.8 % yield as a light
1
yellow solid; m.p. 105–106 °C; H NMR (CDCl ): 2.74–2.88 (m, 2H, ArCH CH ),
3
2
2
3
.44–3.56 (m, 1H, ArCH CH ), 3.63–3.72 (m, 1H, ArCH CH ), 3.81(s, 3H, OCH ),
2 2 2 2 3
3
.86 (s, 3H, OCH ),4.55–4.71 (m, 2H, PhCH O), 4.92–4.98 (m, 2H, CF CH ), 5.06
3
2
3
2
(
H), 7.33–7.34(m, 3H, Ar–H), 7.43 (s, 1H, triazole); HRMS (ESI) m/z Calcd. for
s, 1H, COCH), 6.74–6.70(m, 3H, Ar–H), 6.98 (br, 1H, NH), 7.26–7.24(m, 2H, Ar–
?
C H F N O Na (M ? Na) 501.1720, found 501.1726.
2
3 25 3 4 4
Bioassay
Bioassay of fungicidal activity
Testing of primary biological activity was performed in an isolated culture. Under
sterile conditions, 1 mL of a DMSO solution of title compound was added to the
culture plates, followed by addition of 9 mL culture medium. The final mass
concentration of the title compound was 50 lg/mL. A blank assay was performed
with 1 mL sterile water. A circle of mycelium with a diameter of 4 mm was cut using
a borer. The culture plates were cultivated at 24 ± 1 °C. The extended diameters of
the circles of mycelium were measured after 72 h. The relative inhibition of the circle
of mycelium compared with the blank assay was calculated by use of the equation:
Relative inhibition rate ð%Þ ¼ ½ðCK ꢁ PTÞ=CKꢂ ꢃ 100%
where CK is the extended diameter of the circle of mycelium during the blank
assay; and PT, is the extended diameter of the circle of mycelium during testing.
Bioassay of herbicidal activity
Inhibition of the root-growth of rape (Brassica campestris)
The evaluated compounds were dissolved in water and emulsified by addition of
1
00 lL N,N-dimethylformamide and 0.1 lL Tween 20. Rape seeds were soaked in
distilled water for 4 h before being placed on a filter paper in a 6-cm Petri plate, to
which 2 mL of inhibitor solution had been added in advance. Usually, 15 seeds were
used per plate. The plate was placed in a dark room and left to germinate for 65 h at
2
8 ± 1 °C. The lengths of 10 rape roots selected from each plate were measured
1
23

Microwave assistant synthesis and biological activity
765
and the mean was calculated. A blank test was carried out in distilled water only.
The inhibition rate was calculated from the root length by use of the equation:
Relative inhibition rateð%Þ ¼ ½ðCK ꢁ PTÞ=CKꢂ ꢃ 100%
where CK is the average root length during the blank assay and PT is the average
root length after treatment during testing.
Inhibition of seedling-growth of Barnyard grass (Echinochloa crusgalli)
The evaluated compounds were dissolved in water and emulsified if necessary. Ten
barnyard grass seeds were placed in a 50-mL cup covered with a layer of glass beads
and a piece of filter paper at the bottom, to which 5 mL inhibitor solution had been
added in advance. The cup was placed in a bright room and the seeds were left to
germinate for 65 h at 28 ± 1 °C. The heights of the above-ground parts of the
plants in the cup were measured and the mean was calculated. A blank test was
carried out in distilled water only. The inhibition rate was calculated from the plant
height by use of the equation:
Relative inhibition rate ð%Þ ¼ ½ðCK ꢁ PTÞ=CKꢂ ꢃ 100%
where CK is the average plant height during the blank assay and PT is the average
plant height after treatment during testing.
Bioassay of insecticidal activity
All bioassays were performed on representative test organisms reared in the
laboratory; they were repeated at 25 ± 1 °C according to statistical requirements.
The detailed procedure was as follows. The immersion method assay was used for
Culex pipiens pallens tests, and concentrations of test compounds were adjusted by
serial dilution of a stock solution of the compounds in acetone. Each compound in
acetone was suspended in distilled water, and 10 early fourth-instar larvae of Culex
pipiens pallens were placed in glass cups (125 mL) containing each test solution
(
100 mL). Larvicidal activity was evaluated 72 h after treatment.
Acknowledgments We gratefully thank the National Natural Science Foundation of China (grant no.
1172124), the National Basic Research Science Foundation of China (2010CB126105), and The
National Key Technology R&D program (2011BAE06B05-3) for financial support of this research.
2
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