Synthesis and biological evaluation of isosteric analogs of mandipropamid for the control of oomycete pathogens

Article abstract of DOI:10.1111/j.1747-0285.2011.01093.x

A series of isosteric analogs of mandipropamid were designed and synthesized via 'click chemistry'. The amide bond of mandipropamid was substituted by a 1,2,3-triazole functional group. The bioassay results have indicated that some of the title compounds exhibited moderate fungicidal activity against Pseudoperonospora cubensis, and the activity has been systematically studied as a function of molecular structure. The low activity of the mandipropamid analog that contains a lipid chain is likely due to the presence of a weak hydrogen bond donor in the 1,2,3-triazole. Furthermore, we have performed the molecular modeling and found that N-methylamide could be more effective than amide as the surrogates to 1,2,3-triazole, which ultimately leads to a longer distance (1.1A longer) between the two substitutes in the 1,4-disubstituted 1,2,3-triazole compound.

Full text of DOI:10.1111/j.1747-0285.2011.01093.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01093.x
Chem Biol Drug Des 2011; 78: 101–111
Research Article
Synthesis and Biological Evaluation of Isosteric
Analogs of Mandipropamid for the Control of
Oomycete pathogens
older products because of their increased resistance. At the same
time, there are increased efforts to search for new agrochemicals
with high activity and a favorable environmental profile.
Na Su, Zhen-Jun Wang, Li-Zhong Wang,
Xiao Zhang, Wei-Li Dong, Hong-Xue Wang,
Zheng-Ming Li and Wei-Guang Zhao*
Mandipropamid 1 is a representative of novel compound that pro-
vides outstanding control over foliar diseases caused by oomycetes
(Figure 1). Syngenta et al. have reported that mandelamides are
highly active against Phytophthora infestans on tomato (EC80
0.1 ppm) (3). In the following foliar application, a significant propor-
tion of mandipropamid binds immediately to the wax layer of plant
surfaces. The adsorption to the wax layer protects the active ingre-
dient from being washed off by rain as soon as the spray deposit
has dried. From the surface deposit and the material adsorbed to
the epicuticular wax, small amounts of active ingredient migrate
progressively into the plant tissue. Owing to the intrinsic high activ-
ity, the amount taken up into the plant tissue is sufficient to pro-
vide good translaminar activity and curative disease control over
both P. infestans and Plasmopara viticola, even though they are
under severe disease pressures during the incubation period (4).
Blum and colleagues (5) has just now reported that the inhibition of
cellulose synthesis is the primary effect of mandipropamid and that
one recessive mutation in PvCesA3 causes inheritable resistance to
mandipropamid.
National Pesticide Engineering Research Center (Tianjin), State Key
Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, China
*Corresponding author: Wei-Guang Zhao, zwg@nankai.edu.cn
A series of isosteric analogs of mandipropamid
were designed and synthesized via ’click chemis-
try’. The amide bond of mandipropamid was
substituted by a 1,2,3-triazole functional group.
The bioassay results have indicated that some of
the title compounds exhibited moderate fungicidal
activity against Pseudoperonospora cubensis, and
the activity has been systematically studied as a
function of molecular structure. The low activity
of the mandipropamid analog that contains a lipid
chain is likely due to the presence of a weak
hydrogen bond donor in the 1,2,3-triazole. Further-
more, we have performed the molecular modeling
and found that N-methylamide could be more
effective than amide as the surrogates to 1,2,3-
triazole, which ultimately leads to a longer dis-
˚
tance (1.1 A longer) between the two substitutes
in the 1,4-disubstituted 1,2,3-triazole compound.
'Click chemistry', introduced by Sharpless and coworkers (6) a cou-
ple of years ago, has recently drawn considerable attention as a
powerful and efficient way to synthesize desired compounds in high
yields using a simple and benign procedure.
Key words: 1,2,3-Triazole, mandipropamid, click chemistry, Oomyce-
te pathogens, synthesis
Received 14 June 2010, revised 8 January 2011 and accepted for publi-
cation 27 January 2011
Among those carefully selected reactions, Cu(I)-catalyzed variant of
the Huisgen's 1,3-dipolar cycloaddition of azides and alkynes to
afford 1,2,3-triazoles (7,8) is generally regarded as the quintessen-
tial example of click chemistry owing to its reliability, specificity,
and biocompatibility. It has been lately explored as a novel ligation
tool for drug design and screening. This reaction has also been
termed as the 'cream of the crop' in click reactions (9).
Oomycetes fungi are biologically and biochemically distinctive from
ascomycetes (1), and it can cause several destructive diseases of
important crop plants. Typical foliar diseases include late blight on
potatoes, blue mold on tobacco, grape downy mildew, plus a wide
range of other foliar blights and downy mildews on cereals, fruits,
vegetables, and ornamentals. Soilborne Phytophthora and Pythium
spp., equally widespread as soybeans and avocados, are another
major cause of losses of crops. In addition, Phytophthora and Pythi-
um spp. are responsible for many pre- and postharvest problems of
fruits and vegetables, including late blight of potato tubers, brown
rot of citrus, and black pod of cocoa (2). Controlling most of these
diseases is generally achieved by the repeated application of chem-
ical fungicides. Thereby, much of the pressure has been laid on
Further interest in this reaction stems from the interesting biological
activity of 1,2,3-triazoles. 1,2,3-Triazoles are a promising candidate
for small-molecule drugs and have found wide application in medic-
inal, agricultural, and industrial applications (7).
Replacement of amide bonds with appropriate isosteres is very
common in medicinal chemistry. Among various bioisosteres of the
amide moiety, 1,2,3-triazoles can mimic the structural and electronic
101

Su et al.
OR2
Cl
O
O
H
N
O
O
N
N
OR1
n
N
O
Cl
2 n = 2
3 n = 1
1
Figure 1: Lead compound and general structure of mandipropamid analogs containing 1,2,3-triazole moiety.
features of an amide bond, which have gained increasing attention
in drug discovery (7,10–13). The value of 1,2,3-triazole as an amide
bond surrogate (the oxygen lone pair, the acidic N–H bond, and the
polarized carbonyl carbon) in peptidomimetic structures has also
been suggested experimentally (14,15). There are also many exam-
ples on non-peptidic mimics where 1,2,3-triazoles replace amides
(16–23). When amide mimics amprenavir, these were co-crystallized
with HIV-1 protease, the 1,2,3-triazole unit revealed itself as an
effective surrogate for the amide bond (15).
solution of tosyl chloride (16.8 mmol) in dichloromethane (10 mL)
was added and this mixture was stirred for 2 h at room tempera-
ture. Subsequently, the reaction mixture was diluted with water.
The organic layer was dried over MgSO4 and evaporated. The resi-
due was purified by chromatography on a silica gel using petroleum
ether and ethyl acetate as the eluent to afford the compounds
11a–11d.
2-(3-Methoxy-4-benzyloxyphenyl)ethyl tosylate
11a
The compound was obtained in 48.8% yield as a yellow oil. 1H
NMR (CDCl3): 2.42 (s, 3H, CH3), 2.88 (t, J = 7.0 Hz, 2H, CH2), 3.81
(s, 3H, OCH3), 4.17 (t, J = 7.0 Hz, 2H, CH2), 5.12 (s, 2H, PhCH2),
6.56–6.77 (m, 3H, Ph), 7.24–7.68 (m, 9H, Ph).
Given these considerations, we decided to replace an amide bond
of mandipropamid with the 1,2,3-triazole functional group. Here, we
present the synthesis, as well as the preliminary evaluation on a
series of 1,2,3-triazole containing mandipropamid analogs of general
structure 2 and 3, in which the lipid chain lengths were varied (Fig-
ure 1).
2-(3,4-Dimethoxy phenyl)ethyl tosylate 11b
The compound was obtained in 65.2% yield as a yellow oil. 1H
NMR (CDCl3): 2.43 (s, 3H, CH3), 2.90 (t, J = 7.0 Hz, 2H, CH2), 3.81
(s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.20 (t, J = 7.0 Hz, 2H, CH2),
6.55–6.77 (m, 3H, Ph), 7.26–7.69 (m, 4H, Ph).
Experimental
Instruments
1H NMR spectra were obtained on Bruker AC-P500 spectrometer
(300 MHz; Bruker, Fallanden, Switzerland) and Bruker Avance 400
spectrometer (400 MHz; Bruker) using tetramethylsilane (TMS) as
an internal standard and CDCl3 as solvent. 13C NMR spectra were
obtained on Bruker AC-P500 spectrometer (75 MHz) and Bruker
Avance 400 spectrometer (100 MHz) with TMS as an internal stan-
dard. Elemental analyses were performed on a Vario EL elemental
analyzer (Elementar, Hanau, Germany). Chromatograms were
recorded on an Agilent 1100 series liquid chromatograph (Agilent
Technologies Inc., Palo Alto, CA, USA). The percentages of com-
pounds were calculated by the area normalization method without
considering response factors. Melting points were determined on
an X-4 binocular microscope melting point apparatus (Beijing Tech
Instruments Co., Beijing, China) and were uncorrected. High-resolution
mass (HRMS) were recorded on a 7.0-T (Ionspec, Irvine, CA, USA)
Fourier transform ion cyclotron resonance mass spectrometer. All
chemicals or reagents were purchased from standard commercial
suppliers. Petroleum ether, bp 60–90 ꢀC.
2-(3-Methoxy-4-ethoxyphenyl)ethyl tosylate 11c
The compound was obtained in 68.0% yield as a yellow oil. 1H
NMR (CDCl3): 1.44 (t, J = 7.2 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 2.89
(t, J = 7.0 Hz, 2H, CH2), 3.80 (s, 3H, OCH3), 4.06 (q, J = 7.0 Hz, 2H,
CH2), 4.19 (t, J = 7.0 Hz, 2H, CH2), 6.60–6.76 (m, 3H, Ph), 7.26–7.69
(m, 4H, Ph).
2-(3-Methoxy-4-propoxyphenyl)ethyl tosylate
11d
The compound was obtained in 66.0% yield as a yellow oil. 1H
NMR (CDCl3): 1.03 (t, J = 7.4 Hz, 3H, CH3), 1.80–1.88 (m, 2H, CH2),
2.17 (s, 3H, CH3), 2.88 (t, J = 7.0 Hz, 2H, CH2), 3.78 (s, 3H, OCH3),
3.94 (t, J = 6.8 Hz, 2H, CH2), 4.18 (t, 2H, CH2), 6.59–6.75 (m, 3H,
Ph), 7.26–7.68 (m, 4H, Ph).
Synthesis of compounds
General method for the synthesis of 4-((4-
chlorophenyl)(hydroxyl)methyl)-1-(3-methoxy-4-
alkoxyphenethyl)-1H-1,2,3-triazole 16a–16d
Sodium azide (2.9 mmol) was added to a solution of 2-(3-meth-
oxy-4-alkoxyphenyl)ethyl tosylate (11) (2.4 mmol) in 6 mL of DMF.
This mixture was stirred at room temperature for 12 h to afford
General method for the synthesis of 2-(3-
methoxy-4-alkoxyphenyl)ethyl tosylate 11a–11d
2-(3-Methoxy-4-alkoxyphenyl)ethanol 10 (6.47 mmol) and triethyl-
amine (50.4 mmol) was dissolved in dichloromethane (20 mL). A
102
Chem Biol Drug Des 2011; 78: 101–111

Synthesis and Biological Evaluation of Analogs of Mandipropamid
a crude product of 3-methoxy-4-alkoxyphenethyl azide 12. With-
out any further purification, 1-(4-chlorophenyl)prop-2-yn-1-ol
General method for the synthesis of 4-((4-
Chlorophenyl)(hydroxyl)methyl)-1-(3-methoxy-4-
alkoxybenzyl)-1H-1,2,3-triazole 17a–17d
5
(2.9 mmol), sodium ascorbate (0.6 mmol), copper sulfate pentahy-
drate (0.12 mmol), and water (2 mL) was added to this reaction
mixture. The mixture was stirred at 30 ꢀC for a further 2 h. The
reaction mixture was the diluted with water and extracted sev-
eral times with dichloromethane. The combined organic phases
were washed with brine, dried over MgSO4, and evaporated. The
remainder was purified by chromatography on silica gel using
petroleum ether and ethyl acetate as the eluent to afford the
compounds 16a–16d.
Sodium azide (3.6 mmol) was added to a solution of 3-methoxy-4-
alkoxybenzyl bromide 14 (3.0 mmol) in 6 mL of DMF. This mixture
was stirred at room temperature for 12 h to afford a crude product
of 3-methoxy-4-alkoxybenzyl azide 15. Without any further purifica-
tion, 1-(4-chlorophenyl)prop-2-yn-1-ol 5 (3.6 mmol), sodium ascor-
bate (0.9 mmol), copper sulfate pentahydrate (0.18 mmol), and
water (2 mL) was added to this reaction mixture. The mixture was
stirred at 30 ꢀC for a further 2 h. The reaction mixture was diluted
with water and extracted several times with dichloromethane. The
combined organic phases were washed with brine, dried over
MgSO4, and evaporated. The remainder was purified by chromatog-
raphy on silica gel using petroleum ether and ethyl acetate as the
eluent to afford the compounds 17a–17d.
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3-
methoxy-4-benzyloxyphenethyl)-1H-1,2,3-
triazole 16a
The compound was obtained in 74.5% yield as a white solid; m.p.
93–95 ꢀC; 1H NMR (CDCl3): 3.07 (t, J = 7.0 Hz, 2H, CH2), 3.42 (s,
1H, OH), 3.77 (s, 3H, OCH3), 4.48 (t, J = 7.0 Hz, 2H, CH2N), 5.11 (s,
2H, CH2), 5.95 (s, 1H, CH), 6.50–6.76 (m, 3H, Ph), 6.93 (s, 1H, triaz-
ole), 7.31–7.44 (m, 9H, Ph); HRMS (ESI) m ⁄ z Calcd. for
C25H24ClN3O3Na (M + Na)+ 472.1398, found 472.1396.
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3-
methoxy-4-benzyloxybenzyl)-1H-1,2,3-triazole
17a
The compound was obtained in 84.9% yield as a white solid; m.p.
1
109–111 ꢀC; H NMR (CDCl3): 2.95 (s, 1H, OH), 3.83 (s, 3H, OCH3),
5.14 (s, 2H, OCH2), 5.38 (s, 2H, CH2N), 5.97 (s, 1H, CH), 6.73–6.85 (m,
3H, Ph), 7.15 (s, 1H, triazole), 7.27–7.43 (m, 9H, Ph). HRMS (ESI) m ⁄ z
Calcd. for C24H22ClN3O3Na (M + Na)+ 458.1242, found 458.1239.
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3,4-
dimethoxyphenethyl)-1H-1,2,3-triazole 16b
The compound was obtained in 73.0% yield as a yellow oil; 1H
NMR (CDCl3): 2.89 (d, J = 3.7 Hz, 1H, OH), 3.10 (t, J = 7.1 Hz, 2H,
CH2), 3.77 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.50 (t, J = 7.1 Hz, 2H,
CH2N), 5.95 (d, J = 3.7 Hz, 1H, CH), 6.47–6.74 (m, 3H, Ph), 6.90 (s,
1H, triazole), 7.31 (s, 4H, Ph); HRMS (ESI) m ⁄ z Calcd. for
C19H20ClN3O3Na C 396.1085, found 396.1090.
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3,4-
dimethoxybenzyl)-1H-1,2,3-triazole 17b
The compound was obtained in 79.2% yield as a white solid; m.p.
1
104–105; H NMR (CDCl3): 3.09 (s, 1H, OH), 3.82 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 5.40 (s, 2H, CH2N), 5.98 (s, 1H, CH), 6.76–6.83 (m,
3H, Ph), 7.17 (s, 1H, triazole), 7.30–7.38 (m, 4H, Ph). HRMS (ESI)
m ⁄ z Calcd. for C18H18ClN3O3 (M + H)+ 360.1110, found 360.1113.
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3-
methoxy-4-ethoxyphenethyl)-1H-1,2,3-triazole
16c
The compound was obtained in 60.0% yield as a white solid; m.p.
115–118 ꢀC; H NMR (CDCl3): 1.46 (t, J = 7.0 Hz, 3H, CH3), 3.02 (s,
1H, OH), 3.09 (t, J = 7.0 Hz, 2H, CH2), 3.76 (s, 3H, OCH3), 4.06 (q,
J = 7.0 Hz, 2H, CH2), 4.50 (t, J = 7.0 Hz, 2H, CH2), 5.96 (d, 1H, CH),
6.48–6.74 (m, 3H, Ph), 6.90 (s, 1H, triazole), 7.31 (s, 4H, Ph); HRMS
(ESI) m ⁄ z Calcd. for C20H22ClN3O3Na (M + Na)+ 410.1242, found
410.1241.
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3-
methoxy-4-ethoxybenzyl)-1H-1,2,3-triazole 17c
The compound was obtained in 82.0% yield as a white solid; m.p.
92–93 ꢀC; 1H NMR (CDCl3): 1.45 (t, J = 7.0 Hz, 3H, CH3), 3.05 (s,
1H, OH), 3.79 (s, 3H, OCH3), 4.07 (q, J = 7.0 Hz, 2H, OCH2), 5.37 (s,
2H, CH2N), 5.96 (s, 1H, CH), 6.74–6.82 (m, 3H, Ph), 7.16 (s, 1H,
triazole), 7.28–7.36 (m, 4H, Ph). HRMS (ESI) m ⁄ z Calcd. for
C19H20ClN3O3 (M + H)+ 374.1266, found 374.1267.
1
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3-
methoxy-4-propoxyphenethyl)-1H-1,2,3-triazole
16d
4-((4-Chlorophenyl)(hydroxyl)methyl)-1-(3-
methoxy-4-propoxybenzyl)-1H-1,2,3-triazole 17d
The compound was obtained in 60.3% yield as a white solid; m.p.
78–80 ꢀC; H NMR (CDCl3): 1.03 (t, J = 7.4 Hz,3H, CH3), 1.81–1.90
The compound was obtained in 69.3% yield as a white solid; m.p.
97–99 ꢀC; H NMR (CDCl3): 0.98 (t, J = 7.4 Hz, 3H, CH3), 1.73–1.85
1
1
(m, 2H, CH2), 3.07 (t, J = 7.1 Hz, 2H, CH2), 3.61 (s, 1H, OH), 3.75 (s,
3H, OCH3), 3.92 (t, J = 6.9 Hz, 2H, CH2), 4.48 (t, J = 6.9 Hz, 2H,
CH2N), 5.95 (s, 1H, CH), 6.47–6.74 (m, 3H, Ph), 6.92 (s, 1H, triazole),
7.30 (s, 4H, Ph); HRMS (ESI) m ⁄ z Calcd. for C21H24ClN3O3 (M + H)+
402.1579, found 402.1538.
(m, 2H, CH2), 3.03 (s, 1H, OH), 3.74 (s, 3H, OCH3), 3.89 (t,
J = 6.8 Hz, 2H, OCH2), 5.32 (s, 2H, CH2N), 5.91 (s, 1H, CH), 6.68–
6.78 (m, 3H, Ph), 7.08 (s, 1H, triazole), 7.19–7.31 (m, 4H, Ph). Ele-
mental Anal. (%), Calcd: C, 61.93; H, 5.72; N, 10.83; found: C,
61.78; H, 5.48; N, 10.70.
Chem Biol Drug Des 2011; 78: 101–111
103

Su et al.
General method for the synthesis of 4-((4-
chlorophenyl)(alkoxy)methyl)-1-(3-methoxy-4-
alkoxyphenethyl)-1H-1,2,3-triazole 2a–2d
Alkyl halide (7.56 mmol) was added to a mixture of 4-((4-chlorophe-
nyl)(methoxy)methyl)-1-(3-methoxy-4-alkoxyphenethyl)-1H-1,2,3-triaz-
ole 16 (3.78 mmol), 30% aqueous sodium hydroxide solution
(18.9 mmol), and catalytic amount of hexadecyl trimethyl ammonium
bromide (0.4 mmol) in 6 mL of CH2Cl2 at room temperature. The
reaction mixture was heated at reflux for 24 h. Subsequently, the
mixture was diluted with water and extracted several times with di-
chloromethane. The combined organic phases were washed with
brine, dried over MgSO4, and evaporated. The remainder was puri-
fied by chromatography on silica gel using petroleum ether and
ethyl acetate as the eluent to afford the title compounds 2a–2d.
Alkyl halides were C2H5Br (2a, 2c), Me2SO4 (2b), propargyl bro-
mide (2d).
4-((4-Chlorophenyl) (propargyloxy)methyl)-1-(3-
methoxy-4-propoxyphenethyl)-1H-1,2,3-triazole
2d
The compound was obtained in 61.8% yield as a yellow oil; 1H
NMR (CDCl3): 1.04 (t, J = 7.4 Hz, 3H, CH3), 1.82–1.91 (m, 2H, CH2),
2.45 (t, J = 2.3 Hz, 1H, CCH), 3.10 (t, J = 7.1 Hz, 2H, CH2), 3.74 (s,
3H, OCH3), 3.93 (t, J = 6.9 Hz, 2H, OCH2), 4.13 (dd, JAB = 15.8 Hz
and J = 2.3 Hz, 2H, OCH2C”), 4.49–4.53 (m, 2H, CH2N), 5.82 (s, 1H,
CH), 6.48–6.74 (m, 3H, Ph), 7.07 (s, 1H, triazole), 7.31–7.31 (m, 4H,
Ph); HRMS (ESI) m ⁄ z Calcd. for C24H26ClN3O3Na (M + Na)+
462.1555, found 462.1562.
General method for the synthesis of 4-((4-
chlorophenyl)(alkoxy)methyl)-1-(3-methoxy -4-
alkoxybenzyl)-1H-1,2,3-triazole 3a–3p
Alkyl halide (8.0 mmol) was added to a mixture of 4-((4-chlorophe-
nyl)(methoxy)methyl)-1-(3-methoxy-4-alkoxybenzyl)-1H-1,2,3-triazole
17 (4.0 mmol), 30% aqueous sodium hydroxide solution
(20.0 mmol), and catalytic amount of hexadecyl trimethyl ammonium
bromide (0.4 mmol) in 6 mL of CH2Cl2 at 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 MgSO4, and evaporated. The remainder was
purified by chromatography on silica gel using petroleum ether and
ethyl acetate as the eluent to afford the compounds 3a–3p.
4-((4-Chlorophenyl)(ethoxy)methyl)-1-(3-
methoxy-4-benzyloxyphenethyl)-1H-1,2,3-
Triazole 2a
VThe compound was obtained in 62.8% yield as a white solid; m.p.
1
99–101 ꢀC; H NMR (CDCl3): 1.11 (t, J = 7.0 Hz, 3H, CH3), 3.08 (t,
J = 7.1 Hz, 2H, CH2), 3.51 (q, J = 7.0 Hz, 2H, OCH2), 3.76 (s, 3H,
OCH3), 4.49 (t, J = 7.1 Hz, 2H, CH2N), 5.11 (s, 2H, OCH2), 5.56 (s,
1H, CH), 6.50–6.76 (m, 3H, Ph), 7.02 (s, 1H, triazole), 7.30–7.45 (m,
9H, Ph); 13C NMR (75 MHz, CDCl3): d149.80, 149.19, 147.20,
139.46, 137.10, 133.39, 130.16, 128.56, 128.45, 128.07, 127.80,
127.24, 122.00, 20.59, 114.39, 112.49, 75.76, 71.09, 64.66, 55.86,
51.79, 36.24, 15.21; Elemental Anal. (%), Calcd: C, 67.85; H, 5.90;
N, 8.79; found: C, 67.70; H, 5.68; N, 8.64.
4-((4-Chlorophenyl)(ethoxy)methyl)-1-(3-
methoxy-4-benzyloxybenzyl)-1H-1,2,3-triazole
3a
The compound was obtained in 56.4% yield as a white solid; purity
99.02%; m.p. 99–103 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.21 (t,
J = 7.0 Hz, 3H, CH3), 3.82 (s, 3H, OCH3), 3.89 (q, J = 7.0 Hz, 2H,
OCH2), 5.15 (s, 2H, CH2), 5.38 (AB, JAB= 14.6 Hz, 2H, CH2N), 5.57 (s,
1H, CH), 6.74–6.85 (m, 3H, Ph), 7.22 (s, 1H, triazole), 7.28–7.44 (m, 9H,
Ph); 13C NMR (75 MHz, CDCl3): d 150.06, 148.55, 139.29, 136.76,
133.57, 128.69, 128.61, 128.14, 128.97, 127.31,127.22, 121.15, 120.72,
113.89, 111.68, 75.99, 70.98, 64.78, 56.04, 54.08, 15.23; HRMS (ESI)
m ⁄ z Calcd. for C25H24ClN3O3 (M + H)+ 464.1735, found 464.1730.
4-((4-Chlorophenyl)(methoxy)methyl)-1-(3-
methoxy-4-ethoxyphenethyl)-1H-1,2,3-triazole
2b
The compound was obtained in 75.3% yield as a white solid; m.p.
74–76 ꢀC; 1H NMR (CDCl3): 1.46 (t, J = 7.0 Hz, 3H, CH3), 3.09 (t,
J = 7.1 Hz, 2H, CH2), 3.35 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 4.06 (q,
J = 7.10 Hz, 2H, OCH2), 4.50 (t, J = 7.1 Hz, 2H, CH2N), 5.44 (s, 1H,
CH), 6.49–6.74 (m, 3H, Ph), 6.99 (s, 1H, triazole), 7.27–7.33(m, 4H,
Ph); Elemental Anal. (%), Calcd: C, 62.76; H, 6.02; N, 10.46; found:
C, 62.68; H, 6.10; N, 10.27.
4-((4-Chlorophenyl)(propargyloxy)methyl)-1-(3-
methoxy-4-benzyloxybenzyl)-1H-1,2,3-triazole
3b
4-((4-Chlorophenyl)(ethoxy)methyl)-1-(3-
methoxy-4-ethoxyphenethyl)-1H-1,2,3-Triazole
2c
The compound was obtained in 60.3% yield as a yellow oil; purity
1
97.92%; H NMR (300 MHz, CDCl3): d 2.43 (t, J = 2.3 Hz, 1H, CCH),
The compound was obtained in 31.4% yield as a white solid; m.p.
88–89 ꢀC; 1H NMR (CDCl3): 1.19–1.24 (t, J = 7.0 Hz, 3H, CH3),
1.44–1.48 (t, J = 6.9 Hz, 3H, CH3), 3.07–3.12 (t, J = 7.1 Hz, 2H,
CH2), 3.48–3.55 (q, J = 6.9 Hz, 2H, OCH2), 3.75 (s, 3H, OCH3), 4.02–
4.09 (q, J = 7.0 Hz, 2H, OCH2), 4.48–4.52 (m, 2H, CH2N), 5.56(s, 1H,
CH), 6.49–6.74 (m, 3H, Ph), 7.01 (s, 1H, triazole), 7.30 (s, 4H, Ph);
Elemental Anal. (%), Calcd: C, 63.53; H, 6.30; N, 10.10; found: C,
63.31; H, 6.28; N, 9.91.
3.83 (s, 3H, OCH3), 4.15 (dd, JAB = 15.8 Hz and J = 2.4 Hz, 2H,
OCH2C”), 5.15 (s, 2H, CH2), 5.39 (AB, JAB = 14.6 Hz, 2H, CH2N),
5.84 (s, 1H, CH), 6.74–6.86 (m, 3H, Ph), 7.26(s, 1H, triazole), 7.23–
7.44 (m, 9H, Ph); 13C NMR (75 MHz, CDCl3): d 150.08, 148.96,
148.60, 137.81, 137.75, 134.06, 128.82, 128.62, 127.99, 127.24,
121.51, 120.79, 113.92, 111.73, 79.04, 75.18, 74.56, 70.99, 56.06,
55.99, 54.14; HRMS (ESI) m ⁄ z Calcd. for C27H24ClN3O3 (M + H)+
474.1579, found 474.1580.
104
Chem Biol Drug Des 2011; 78: 101–111

Synthesis and Biological Evaluation of Analogs of Mandipropamid
4-((4-Chlorophenyl)(methoxy)methyl)-1-(3-
methoxy-4-methoxybenzyl)-1H-1,2,3-triazole 3c
J = 7.0 Hz, 2H, OCH2), 5.39 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.46 (s,
1H, CH), 6.74–6.82 (m, 3H, Ph), 7.22 (s, 1H, triazole), 7.27–7.32 (m,
4H, Ph); 13C NMR (75 MHz, CDCl3): d 149.65, 149.61, 148.76,
138.73, 133.69, 128.72, 128.22, 126.67, 121.14, 120.83, 112.56,
111.42, 77.79, 64.35, 57.019, 55.96, 54.11, 14.73; HRMS (ESI) m ⁄ z
Calcd. for C20H22ClN3O3Na (M + Na)+ 410.1242, found 410.1244.
The compound was obtained in 57.1% yield as a white solid; purity
1
99.68%; m.p. 86–88 ꢀC; H NMR (300 MHz, CDCl3): d 3.29 (s, 3H,
OCH3), 3.75 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 5.34 (s, 2H, CH2N),
5.39 (s, 1H, CH), 6.68–6.76 (m, 3H, Ph), 7.16 (s, 1H, triazole), 7.19–
7.25 (m, 4H, Ph); 13C NMR (75 MHz, CDCl3): d 149.62, 149.48,
149.46, 138.63, 133.77, 128.77, 128.21, 126.68, 121.13, 120.88,
111.27, 111.17, 77.73, 57.06, 55.95, 54.21; HRMS (ESI) m ⁄ z Calcd.
for C19H20ClN3O3Na (M + Na)+ 402.1579, found 402.1581.
4-((4-Chlorophenyl)(ethoxy)methyl)-1-(3-
methoxy-4-ethoxybenzyl)-1H-1,2,3-triazole 3h
The compound was obtained in 61.9% yield as a white solid; purity
99.18%; m.p. 100–102 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.23 (t,
J = 7.0 Hz, 3H, CH3), 1.48 (t, J = 7.0 Hz, 3H, CH3), 3.54 (q,
J = 7.0 Hz, 2H, OCH2), 3.82 (s, 3H, OCH3), 4.11 (q, J = 7.0 Hz, 2H,
OCH2), 5.41 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.59 (s, 1H, CH), 6.76–
6.86 (m, 3H, Ph), 7.24 (s, 1H, triazole), 7.28–7.37 (m, 4H, Ph); 13C
NMR (75 MHz, CDCl3): d 149.99, 149.66, 148.79, 139.22, 133.60,
128.71, 128.13, 126.55, 121.17, 120.87, 112.50, 111.41, 75.90,
64.81, 64.36, 55.98, 54.21, 15.22, 14.73; HRMS (ESI) m ⁄ z Calcd. for
C21H24ClN3O3Na (M + Na)+ 424.1398, found 424.1394.
4-((4-Chlorophenyl)(ethoxy)methyl)-1-(3-
methoxy-4-methoxybenzyl)-1H-1,2,3-triazole 3d
The compound was obtained in 63.8% yield as a white solid; purity
99.51%; m.p. 70–73 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.21 (t,
J = 7.0 Hz, 3H, CH3), 3.49–3.56 (m, 2H, OCH2), 3.81 (s, 3H, OCH3),
3.88 (s, 3H, OCH3), 5.40 (AB, JAB = 14.7 Hz, 2H, CH2N), 5.57 (s, 1H,
CH), 6.74–6.83 (m, 3H, Ph), 7.23 (s, 1H, triazole), 7.28–7.36 (m, 4H,
Ph); 13C NMR (75 MHz, CDCl3): d 150.05, 149.43, 139.29, 133.57,
128.70, 128.14, 126.80, 121.13, 120.86, 111.24, 111.17, 75.99,
64.79, 55.94, 54.12, 15.24; HRMS (ESI) m ⁄ z Calcd. for C20H22ClN3O3
(M + H)+ 388.1428, found 388.1424.
4-((4-Chlorophenyl)(propoxy)methyl)-1-(3-
methoxy-4-ethoxybenzyl)-1H-1,2,3-triazole 3i
The compound was obtained in 62.3% yield as a white solid; purity
99.62%; m.p. 98–101 ꢀC; 1H NMR (300 MHz, CDCl3): d 0.88 (t,
J = 7.4 Hz, 3H, CH3), 1.46 (t, J = 7.0 Hz, 3H, CH3), 1.56–1.65 (m,
2H, CH2), 3.42 (t, J = 7.0 Hz, 2H, OCH2), 3.80 (s, 3H, OCH3), 4.08 (q,
J = 7.0 Hz, 2H, OCH2), 5.39 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.55 (s,
1H, CH), 6.73–6.84 (m, 3H, Ph), 7.22 (s, 1H, triazole), 7.28–7.34 (m,
4H, Ph); 13C NMR (75 MHz, CDCl3): d 150.06, 149.64, 148.73,
139.40, 133.48, 128.64, 128.14, 126.72, 121.16, 120.80, 112.55,
111.41, 76.06, 71.05, 64.35, 55.94, 54.09, 22.93, 14.73, 10.62;
HRMS (ESI) m ⁄ z Calcd. for C22H26ClN3O3 (M + H)+ 416.1735, found
416.1737.
4-((4-Chlorophenyl)(propoxy)methyl)-1-(3-
methoxy-4-methoxybenzyl)-1H-1,2,3-triazole 3e
The compound was obtained in 55.8% yield as a white solid; purity
99.25%; m.p. 81–85 ꢀC; 1H NMR (300 MHz, CDCl3): d 0.91 (t,
J = 7.2 Hz, 3H, CH3), 1.27–1.68 (m, 2H, CH2), 3.44 (t, J = 7.0 Hz,
2H, OCH2), 3.83 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.17 (AB,
JAB = 14.6 Hz, 2H, CH2N), 5.57 (s, 1H, CH), 6.76–6.87 (m, 3H, Ph),
7.21 (s, 1H, triazole), 7.25–7.37 (m, 4H, Ph); 13C NMR (75 MHz,
CDCl3): d 150.17, 149.42, 139.40, 133.51, 128.65, 128.13, 126.86,
121.08, 120.81, 111.24, 111.14, 76.10, 71.07, 55.93, 54.09, 22.93,
10.61; HRMS (ESI) m ⁄ z Calcd. for C21H24ClN3O3 (M + H)+ 402.1584,
found 402.1579.
4-((4-Chlorophenyl)(propargyloxy)methyl)-1-(3-
methoxy-4-ethoxybenzyl)-1H-1,2,3-triazole 3j
The compound was obtained in 58.6% yield as a white solid; purity
99.19%; m.p. 84–87 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.40 (t,
J = 7.0 Hz, 3H, CH3), 2.37 (t, J = 2.4 Hz, 1H, CCH), 3.75 (s, 3H,
OCH3), 4.08 (dd, JAB = 15.8 Hz and J = 2.4 Hz, 2H, OCH2C”), 4.09
(q, J = 7.0 Hz, 2H, OCH2), 5.34 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.77
(s, 1H, CH), 6.69–6.79 (m, 3H, Ph), 7.19–7.30 (m, 5H, Ph and
triazole); 13C NMR (75 MHz, CDCl3): d 149.62, 148.80, 148.74,
137.87, 133.94, 128.76, 128.62, 126.69, 121.60, 120.86, 112.59,
111.50, 79.06, 75.28, 74.50, 64.33, 55.94, 54.08, 14.74; HRMS (ESI)
m ⁄ z Calcd. for C22H22ClN3O3 (M + H)+ 412.1422, found 412.1425.
4-((4-Chlorophenyl)(propargyloxy)methyl)-1-(3-
methoxy-4-methoxybenzyl)-1H-1,2,3-triazole 3f
The compound was obtained in 60.8% yield as a white solid; purity
99.19%; m.p. 84–86 ꢀC; 1H NMR (300 MHz, CDCl3): d 2.45 (t,
J = 2.4 Hz, 1H, CCH), 3.84 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.16
(dd, JAB = 15.8 Hz and J = 2.4 Hz, 2H, OCH2C”), 5.42 (AB,
JAB = 14.6 Hz, 2H, CH2N), 5.86 (s, 1H, CH), 6.77–6.86 (m, 3H, Ph),
7.27 (s, 1H, triazole), 7.31–7.39 (m, 4H, Ph); 13C NMR (75 MHz,
CDCl3): d 149.513, 149.467, 148.924, 137.734, 134.095, 128.839,
128.618, 126.637, 121.512, 120.942, 111.287, 111.237, 79.003,
75.197, 74.511, 56.001, 55.972, 54.266; HRMS (ESI) m ⁄ z Calcd. for
C21H20ClN3O3 (M + H)+ 398.1266, found 398.1266.
4-((4-Chlorophenyl)(benzyloxy)methyl)-1-(3-
methoxy-4-ethoxybenzyl)-1H-1,2,3-triazole 3k
The compound was obtained in 74.9% yield as a white solid; purity
99.63%; m.p. 76–78 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.39 (t,
J = 7.0 Hz, 3H, CH3), 3.73 (s, 3H, OCH3), 4.02 (q, J = 7.0 Hz, 2H,
OCH2), 4.47 (s, 2H, OCH2), 5.34 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.60
(s, 1H, CH), 6.67–6.77 (m, 3H, Ph), 7.19–7.31 (m, 10H, Ph and
4-((4-Chlorophenyl)(methoxy)methyl)-1-(3-
methoxy-4-ethoxybenzyl)-1H-1,2,3-triazole 3g
The compound was obtained in 59.4% yield as a white solid; purity
99.36%; m.p. 83–84 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.46 (t,
J = 7.0 Hz, 3H, CH3), 3.36 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.09 (q,
Chem Biol Drug Des 2011; 78: 101–111
105

Su et al.
triazole); 13C NMR (75 MHz, CDCl3): d 149.64, 148.74, 139.00, 137.67,
133.65, 128.74, 128.46, 128.42, 127.85, 126.84, 121.53, 120.84,
112.64, 111.49, 75.28, 70.78, 64.34, 65.92, 54.04, 14.78; HRMS (ESI)
m ⁄ z Calcd. for C26H26ClN3O3 (M + H)+ 464.1735, found 464.1728.
112.95, 111.76, 75.23, 70.85, 70.56, 56.01, 54.21, 22.43, 10.42;
HRMS (ESI) m ⁄ z Calcd. for C27H28ClN3O3Na (M + Na)+ 500.1711,
found 500.1720.
4-((4-Chlorophenyl)(propoxy)methyl)-1-(3-
methoxy-4-benzyloxybenzyl)-1H-1,2,3-triazole
3p
4-((4-Chlorophenyl)(ethoxy)methyl)-1-(3-
methoxy-4-propoxybenzyl)-1H-1,2,3-triazole 3l
The compound was obtained in 56.9% yield as a white solid; purity
100%; m.p. 109–112 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.05 (t,
J = 7.4 Hz, 3H, CH3), 1.23 (t, J = 7.0 Hz, 3H, CH3), 1.82–1.94 (m,
2H, CH2), 3.54 (q, J = 7.0 Hz, 2H, OCH2), 3.82 (s, 3H, OCH3), 3.98 (t,
J = 6.9 Hz, 2H, OCH2), 5.41 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.59 (s,
1H, CH), 6.75–6.86 (m, 3H, Ph), 7.24 (s, 1H, triazole), 7.28–7.37 (m,
4H, Ph); 13C NMR (75 MHz, CDCl3): d 150.07, 149.80, 149.04,
139.32, 133.56, 128.69, 128.14, 126.65, 121.11, 120.87, 112.79,
111.66, 76.00, 70.52, 64.78, 56.06, 54.14, 22.42, 15.23, 10.42;
HRMS (ESI) m ⁄ z Calcd. for C22H26ClN3O3 (M + H)+ 416.1735, found
416.1742.
The compound was obtained in 57.2% yield as a white solid; purity
99.26%; m.p. 114–115 ꢀC; 1H NMR (300 MHz, CDCl3): d 0.91 (t,
J = 7.4 Hz, 3H, CH3), 1.57–1.66 (m, 2H, CH2), 3.44 (t, J = 7.0 Hz,
2H, OCH2), 3.83 (s, 3H, OCH3), 5.16 (s, 2H, OCH2), 5.40 (AB,
JAB = 14.6 Hz, 2H, CH2N), 5.57 (s, 1H, CH), 6.75–6.87 (m, 3H, Ph),
7.24–7.42 (m, 10H, Ph and triazole); 13C NMR (75 MHz, CDCl3): d
150.15, 150.09, 148.56, 139.42, 136.78, 133.51, 128.65, 128.60,
128.14, 127.97, 127.41, 127.23, 121.13, 120.69, 113.97, 111.70,
76.11, 71.08, 71.01, 56.03, 54.05, 22.94, 10.62; HRMS (ESI) m ⁄ z
Calcd. for C27H28ClN3O3 (M + H)+ 478.1892, found 478.1895.
4-(2-(4-((4-Chlorophenyl)(hydroxyl)methyl)-1H-
1,2,3-triazol-1-yl)ethyl)-2-methoxyphenol 18
(1-(4-Benzyloxy)-3-methoxyphenethyl)-1H-1,2,3-triazol-4-yl)(4-chlor-
ophenyl)methanol 16a (1.70 g, 3.8 mmol) was dissolved in 20 mL
of absolute ethanol. To this, 10% palladium–carbon (0.33 g) was
added. The mixture was stirred under hydrogen (1 atm) at room
temperature for 3 h. The catalyst was removed by filtration and
washed with ethanol. Evaporation of the filtrate gave a yellow oil.
The crude product was purified by chromatography on silica gel
using petroleum ether and ethyl acetate as the eluent to afford the
4-((4-Chlorophenyl)(propoxy)methyl)-1-(3-
methoxy-4-propoxybenzyl)-1H-1,2,3-triazole 3m
The compound was obtained in 52.9% yield as a white solid; purity
99.67%; m.p. 98–100 ꢀC; 1H NMR (300 MHz, CDCl3): d 0.91 (t,
J = 7.4 Hz, 3H, CH3), 1.05 (t, J = 7.4 Hz, 3H, CH3), 1.57–1.68 (m,
2H, CH2), 1.82–1.94 (m, 2H, CH2), 3.44 (t, J = 7.0 Hz, 2H, OCH2),
3.81 (s, 3H, OCH3), 3.98 (t, J = 6.8 Hz, 2H, OCH2), 5.41 (AB,
JAB = 14.6 Hz, 2H, CH2N), 5.57 (s, 1H, CH), 6.75–6.86 (m, 3H, Ph),
7.24 (s, 1H, triazole), 7.28–7.37 (m, 4H, Ph); 13C NMR (75 MHz,
CDCl3): d 150.06, 149.77, 149.00, 139.39, 133.49, 128.64, 128.13,
126.68, 121.13, 120.83, 112.79, 111.61, 76.06, 71.06, 70.49, 56.08,
54.11, 22.93, 22.40, 10.61, 10.42; HRMS (ESI) m ⁄ z Calcd. for
C23H28ClN3O3 (M + H)+ 430.1892, found 430.1884.
1
compound 18: yellow oil. Yield: 1.30 g 95.5%. H NMR (CDCl3) d:
3.05 (t, J = 7.1 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.95 (s, 1H, OH),
4.46 (t, J = 7.0 Hz, 2H, CH2N), 5.83 (s, 1H, OH), 5.93–5.96 (d, 1H,
CH), 6.40–6.80 (m, 3H, Ph), 6.92 (s, 1H, triazole), 7.28–7.35 (m, 4H,
Ph); Elemental Anal. (%), Calcd: C, 60.29; H, 4.93; N, 11.57; found:
C, 60.09; H, 5.04; N, 11.68.
4-((4-Chlorophenyl)(propargyloxy)methyl)-1-(3-
methoxy-4-propoxybenzyl)-1H-1,2,3-triazole 3n
The compound was obtained in 60.4% yield as a yellow solid; m.p.
4-((4-Chlorophenyl)(propargyloxy)methyl)-1-(3-
methoxy-4-(propargyloxy)phenethyl)-1H-1,2,3-
triazole 2e
Sodium hydroxide (0.40 g, 10.0 mmol), 4-(2-(4-((4-chloro phenyl)(hy-
droxyl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-methoxyphenol
1
89–91 ꢀC; H NMR (CDCl3): 1.05 (t, J = 7.4 Hz, 3H, CH3), 1.82–1.95
(m, 2H, CH2), 2.46 (t, J = 2.2Hz, 1H, CCH), 3.82 (s, 3H, OCH3), 3.98
(t, J = 6.8 Hz, 2H, OCH2), 4.16 (dd, JAB = 15.8 Hz and J = 2.4 Hz,
2H, OCH2C”), 5.42 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.86 (s, 1H, CH),
6.77–6.87 (m, 3H, Ph), 7.28 (s, 1H, triazole), 7.32–7.39 (m, 4H, Ph);
HRMS (ESI) m ⁄ z Calcd. for C23H24ClN3O3 (M + H)+ 426.1579, found
426.1575.
18
(0.51 g, 1.417 mmol) and cetyltrimethylammonium bromide (0.10 g,
0.275 mmol) was dissolved in 6 mL water and 6 mL CH2Cl2. This
mixture was stirred at room temperature for 30 min. Subsequently,
propargyl bromide was added slowly at room temperature. The
reaction mixture was stirred at room temperature overnight. The
reaction mixture was then diluted with water and extracted several
times with dichloromethane. The combined organic phases were
washed with brine, dried over MgSO4, and evaporated. The remain-
der was purified by chromatography on silica gel using petroleum
ether and ethyl acetate as the eluent to afford the compound 2e:
yellow oil. Yield: 0.32 g, 51.6%. 1H NMR (CDCl3) d: 2.45 (t,
J = 2.4 Hz, 1H, CCH), 2.51 (t, J = 2.3 Hz, 1H, CCH), 3.12 (t,
J = 7.1 Hz, 2H, CH2), 3.74 (s, 3H, OCH3), 4.14 (t, J = 7.0 Hz, 2H,
CH2), 4.52 (t, J = 7.1 Hz, 2H, CH2N), 4.73 (d, J = 2.4 Hz, 2H, CH2),
5.82 (s, 1H, CH), 6.49–6.94 (m, 3H, Ph), 7.09 (s, 1H, triazole),
4-((4-Chlorophenyl)(benzyloxy)methyl)-1-(3-
methoxy-4-propoxybenzyl)-1H-1,2,3-triazole 3o
The compound was obtained in 70.6% yield as a white solid; purity
99.80%; m.p. 81–84 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.05 (t,
J = 7.4 Hz, 3H, CH3), 1.82–1.95 (m, 2H, CH2), 3.81 (s, 3H, OCH3),
3.98 (t, J = 6.8 Hz, 2H, OCH2), 4.56 (AB, JAB = 14.6 Hz, 2H, OCH2),
5.42 (AB, JAB = 14.6 Hz, 2H, CH2N), 5.69 (s, 1H, CH), 6.76–6.87 (m,
3H, Ph), 7.28 (s, 1H, triazole), 7.28–7.40 (m, 9H, Ph); 13C NMR
(75 MHz, CDCl3): d 149.87, 149.70, 149.12, 138.89, 137.62, 133.74,
128.76, 128.44, 128.35, 127.85, 127.81, 126.63, 121.36, 120.89,
106
Chem Biol Drug Des 2011; 78: 101–111

Synthesis and Biological Evaluation of Analogs of Mandipropamid
7.31–7.32 (m, 4H, Ph); HRMS (ESI) m ⁄ z Calcd. for C24H22ClN3O3Na
(4-(Benzyloxy(4-chlorophenyl)methyl)-1-(3-
methoxy-4-propoxybenzyl)-1H-1,2,3-triazol-5-
yl)methanol 21b
(M + Na)+ 458.1242, found 458.1562.
The compound was obtained in 25% yield as a clear film; m.p.
136–138 ꢀC; 1HNMR (400MHz, CDCl3) d: 0.94 (t, J = 7.6 Hz, 3H,
CH3), 1.76 (m, 2H, CH2), 3.69 (s, 3H, OCH3), 3.72 (s, 1H, OH), 3.86 (t,
J = 6.8 Hz, 2H, OCH2), 4.44 (AB, J = 13.4Hz, 2H, CH2O), 4.49 (s, 2H,
OCH2), 5.35(s, 2H, CH2N), 5.40 (d, 1H, J = 6.0 Hz, CH), 6.70–6.59
(m, 3H, Ph), 7.22–7.04 (m, 9H, Ph); 13C NMR (100 MHz, CDCl3): d
149.89, 149.23, 137.94, 135.44, 133.47, 131.07, 130.91, 128.42,
128.07, 127.57, 126.35, 125.32, 120.64, 112.87, 111.51, 74.65,
70.55, 56.18, 53.77, 51.91, 49.30, 22.41, 10.40; HRMS (ESI) m ⁄ z
Calcd. for C28H30ClN3O4 (M + H)+: 508.1998, found 508.1993.
2-(4-Chlorophenyl)-2-ethoxy-N-(4-ethoxy-3-
methoxyphenethyl)-N-methyl acetamide 20
2-(4-Chlorophenyl)-2-ethoxy-N-(4-ethoxy-3-methoxyphenethyl) acet-
amide 19 (2 mmol) was dissolved in 10 mL of DMF. Sodium hydride
(2.4 mmol) was added in small portions at 0 ꢀC. This mixture was
stirred for 30 min at room temperature. Then, CH3I (2.4 mmol) was
added dropwise and the resulting mixture was stirred for a further
3 h at room temperature. The reaction mixture was poured into ice
water and extracted three times with ethyl acetate. The combined
organic layer was washed with brine and dried over MgSO4. After
evaporation of the solvent, the residue was purified by chromatog-
raphy on silica gel using petroleum ether and ethyl acetate as the
eluent to afford the compound 20: yellow oil. Yield: 69.7%. 1H
NMR (CDCl3) d: 1.25 (t, J = 6.9Hz, 3H, CH2CH3), 1.45 (t, J = 7.0Hz,
3H, CH2CH3), 2.46–2.65 (m, 1H, NCH2CH2), 2.74–2.76 (m, 1H,
NCH2CH2), 2.79 (s, 2H, NCH3), 3.00 (s, 1H, NCH3), 3.40–3.67 (m, 4H,
NCH2, CH2CH3), 3.82–3.85 (d, 3H, OCH3), 4.03–4.08 (m, 2H, OCH2),
4.91 (s, 0.4H, CH), 5.04 (s, 0.6H, CH), 6.52–6.79 (m, 3H, Ph), 7.31–
7.32 (d, 4H, Ph); HRMS (ESI) m ⁄ z Calcd. for C22H28NO4Na
(M + Na)+ 428.1593, found 428.1599.
Theoretical calculations
On the basis of the structure of amide and 1,2,3-triazole, selected
as the initial structure, DFT-B3LYP ⁄ 6-31G (d,p) methods in Gaussian
03 package[19] were used to optimize these structure. Vibration
analysis showed that the optimized structures were in accordance
with the minimum points on the potential energy surfaces. All the
convergent precisions were the system default values, and all the
calculations were carried out on the Nankai Stars supercomputer at
Nankai University.
General method for the synthesis of (4-((4-
chlorophenyl)(alkoxy)methyl)-1-(3-methoxy-4-
alkoxybenzyl)-1H-1,2,3-triazol-5-yl)methanol
21a-b
Biological assay
Fungicidal activity against Pseudoperonospora
Cubensis
A solution of triazole 3 (0.314 mmol) in THF (4 mL) was cooled to
)78 ꢀC before being treated dropwise with n-BuLi (152 lL of a
2.5 M solution in hexanes, 0.377 mmol). The solution was allowed
to stir for 5 min at )78 ꢀC before being transferred by cannula
onto p-CH2O (94 mg, 3.14 mmol) at 0 ꢀC. The reaction rapidly
turned brown and then became light yellow. After being allowed to
stir for a further 1 h, the reaction was quenched by the addition of
saturated NH4Cl solution (15 mL) and extracted with DCM. The
combined organic layers were dried over MgSO4 before being con-
centrated under reduced pressure to furnish the crude product. Puri-
fication by flash chromatography (EtOAc: hexanes = 1:1.5) furnished
the title compound.
To determine the efficacy of 1,2,3-triazole-modified mandipropamid
analogs against P. cubensis, the upper leaf surfaces in 3-week-old
cucumber plants were treated with the test compounds in a spray
chamber. Each test compound was prepared at a terminal concen-
tration of 500 and 200 mg ⁄ L, respectively. One day later, the trea-
ted plants were inoculated with P. cubensis by spraying
a
sporangial suspension. Disease incidence was assessed after an
incubation period of 5 days in a greenhouse. Results are presented
in Table 1.
Table 1: Inhibition rate of title compounds
Pseudoperonospora
Pseudoperonospora
cubenis (%)
cubenis (%)
(4-((4-Chlorophenyl)(propoxy)methyl)-1-(4-
ethoxy-3-methoxybenzyl)-1H-1,2,3-triazol-5-
yl)methanol 21a
No.
500 mg ⁄ L
200 mg ⁄ L
No.
500 mg ⁄ L
200 mg ⁄ L
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
30
0
0
0
0
0
3h
3i
20
60
60
95
70
60
20
60
20
99
–
0
50
50
90
50
30
0
50
0
98
60
40
The compound was obtained in 24% yield as a clear film; m.p. 68–
69 ꢀC; 1HNMR (400 MHz, CDCl3) d: 0.84 (t, J = 7.0 Hz, 3H, CH3),
1.37 (t, 3H, J = 6.5 Hz, CH3), 1.61–1.48 (m, 2H, CH2), 3.52 (t,
J = 6.6 Hz, 2H, OCH2), 3.63 (s, 1H, OH); 3.80 (s, 3H, OCH3), 3.99 (q,
J = 7.0 Hz, 2H, OCH2), 4.45 (AB, JAB 14.8 Hz, 2H, CH2O), 5.40 (s,
2H, CH2N), 5.64 (s, 1H, CH), 6.73–6.63 (m, 3H, Ph), 7.27–7.20 (m,
4H, Ph); 13C NMR (75 MHz, CDCl3): d 149.67, 148.52, 146.81,
138.60, 133.69, 133.32, 128.72, 127.95, 126.98, 119.89, 112.50,
110.67, 71.44, 64.34, 55.92, 52.90, 52.26, 22.91, 14.73, 10.61;
HRMS (ESI) m ⁄ z Calcd. for C23H28ClN3O4 (M + H)+: 446.1841, found
446.1843.
3j
–
0
3k
3l
70
75
30
60
60
90
80
–
50
40
0
0
0
60
50
40
3m
3n
3o
3p
19
20
21b
3g
21a
–
Chem Biol Drug Des 2011; 78: 101–111
107

Su et al.
sation reaction (25), were alkylated with halohydrocarbon to give
compound 9; (ii) Compound 6 was firstly alkylated (26) and then
reacted with methylidene-triphenyl-phosphorane to form compounds
9a–d through Wittig reaction (27). Compounds 9a–d were hydrob-
orated with sodium borohydride ⁄ boron trifluoride, followed by oxi-
dation, to afford phenylethanol 10 (28). Azides 12a–d were
obtained in two different methods starting from bromides and tosy-
late derivatives 11a–d, respectively. Bromination of compounds
10, leading to a mixture of a-bromide and b-bromide products,
really bring us some difficulties. To avoid the mixture, we treated
10 with 4-tolylsulfonyl chloride in the presence of triethylamine to
afford corresponding tosylate derivatives 11a–d. Compounds 11a–
d were then transformed into azides 12a–d with sodium azide.
Results and Discussion
Synthesis
For the divergent synthesis of 1,2,3-triazole analogs of mandiprop-
amid, we employed click chemistry. The aryl substituted propargyl
alcohol 5, the key starting compound of the 'click' cycloaddition,
was prepared by adding ethynylmagnesium bromide to an aryl alde-
hyde (24) (Scheme 1).
Azide 12 and 15 were prepared as following (Scheme 2). We have
synthesized the styrene derivative 9 in two different methods: (i) Vi-
nylphenols 7, which were prepared from commercially available
vanillin 6 and malonic acid through classical Knoevenagel conden-
When mandipropamid and its analogs bind to the target receptor, it
is necessary to consider the pharmacophore distance range
between the two phenyl groups. Hence, we have synthesized azides
15a–d according to Scheme 3. The vanillin derivatives 8 were
reduced by sodium borohydride to afford alcohol derivatives 13
(29). The exposure of 13 to phosphorus tribromide at room temper-
ature generated benzyl bromide 14 (30), which were then trans-
formed into azides 15a–d.
OH
O
H
a
Cl
Cl
4
5
Scheme 1: Synthetic route of propargyl alcohol 5. (a)
HCCMgBr, THF, rt.
OR1
OR1
OR1
OR1
OH
O
O
O
O
O
g
e
c
f
OH
a
O
OH
OTs
N3
7
9
12
11
d
10
OR1
OR1
OR1
b
OR1
H
O
O
O
O
O
6
j
i
h
OH
Br
N3
H
O
15
13
14
8
8a-15a: R1 = PhCH2; 8b-15b: R1 = CH3; 8c-15c: R1= C2H5; 8d-15d: R1 = n-C3H7
Scheme 2: General synthetic route of the azides 12 and 15. Reagents and conditions: (a) malonic acid, piperidine, toluene, reflux; (b)
alkyl halide, K2CO3, acetone, reflux; (c) alkyl halide, NaOH ⁄ H2O, cetyltrimethylammonium bromide, CH2Cl2, 80 ꢀC; (d) triphenyl methylphospho-
nium iodide, NaH, DMSO, rt; e) NaBH4, BF3 ⁄ (CH3CH2)2O, NaOH, H2O2, rt; (f) TsCl, Et3N, rt; (g) NaN3, DMF, rt; (h) NaBH4, isopropyl alcohol, rt;
(i) PBr3, CH2Cl2, rt; (j) NaN3, DMF, rt.
OR1
Cl
OH
OR2
Cl
Cl
O
O
O
+
b
a
N
N
N
N
OR1
N
n
OR1
n
n
N
N3
HO
2 n = 2
3 n = 1
16 n = 2
17 n = 1
12 n = 2
15 n = 1
12a, 15a, 16a, 17a: R1= PhCH2;
12c, 15c, 16c, 17c: R
2a: R1 = PhCH2, R2 = Et;
3a: R1 = PhCH2, R2 = Et;
3e: R
1 = Me, R2 = n-C3H7;
3i: R1 = Et, R2 = n-C3H7;
12b, 15b, 16b, 17b: R1 = CH3;
12d, 15d, 16d, 17d: R
1 = C2H5;
1 = n-C3H7
2c: R1= Et, R2 = Et;
3b: R1 = PhCH2, R2 = HCCCH2; 3c: R1 = Me, R2 = Me;
3f: R 3g: R
2b: R1 = Et, R2 = Me;
2d: R1 = n-C3H7, R2 = n-C3H7;
3d: R1 = Me, R2 = Et;
3h: R
1 = Et, R2 = Et;
1 = Me, R2 = HCCCH2;
3j: R1 = Et, R2 = HCCCH2;
1 = Et, R2 = Me;
3k: R1 = Et, R2 = PhCH2;
3l: R1 = n-C3H7, R2 = Et;
3m:R1 = n-C3H7, R2 = n-C3H7; 3n: R1 = n-C3H7, R2 = HCCCH2; 3o: R1 = n-C3H7, R2 = PhCH2; 3p: R1 = PhCH2, R = n-C3H7
Scheme 3: General synthetic route of the title compounds 2 and 3. Reagents and conditions: (a) sodium ascorbate, CuSO4, DMF ⁄ H2O
(3:1), 30 ꢀC; (b) alkyl halide, NaOH ⁄ H2O, cetyltrimethylammonium bromide, CH2Cl2, reflux.
108
Chem Biol Drug Des 2011; 78: 101–111

Synthesis and Biological Evaluation of Analogs of Mandipropamid
In the presence of CuSO4 and sodium ascorbate in DMF, Huisgen's
attributed to the presence of a weak hydrogen-bonding donor in
1,2,3-triazole analogs that change the action mode of compounds 3
on Oomycete pathogens. To validate this assumption, we performed
N-methylation on the amide group of 20 by methylation of 19. The
parent compound 19 exhibited excellent fungicidal activity (98%
inhibition at 25 mg ⁄ L) against P. cubenis. However, after N-methyla-
tion on the amide group, fungicidal activity of compound 20 was
equivalent to that of compound 3, only 60% against P. cubenis at
200 mg ⁄ L. We conclude that there is a strong hydrogen bond
formed between the active site of target receptor and the N–H of
amide. The molecular dimension of the 1,4-disubstituted 1,2,3-
triazoles is similar to amide bonds in terms of distance and planar-
ity. The polarized C(5)-H bond can act as a hydrogen bonding donor,
just like the amide N–H bond, to form weaker hydrogen bonds with
the active sites, which ultimately reduces the fungicidal activity.
These results indicated that the hydrogen bond formed at the C-5
position in 1,2,3-triazole might have played a crucial rule for effi-
cient binding to the active-site residues. Therefore, we chose to
install an additional small and polar substituent at the triazole C-5
position by direct quenching of a 5-metalated species. Treatment of
2 with 1.2 equiv of n-BuLi at )78 ꢀC gave the anion, which could
be quenched with paraformaldehyde to produce the 5-hydroxymethyl
triazole 21 as the major product (Scheme 6).
1,3-dipolar cycloaddition between the obtained terminal alkyne 5
and azido compounds 12 or 15 provided the desired 1,4-regioselec-
tive 1,2,3-triazole products 16 or 17 as shown in Scheme 3. The
temperature was kept at 30–40 ꢀC. Alkylation of 16 or 17 with
alkyl halide proceeded smoothly to lead to the final product 2 or 3
(Scheme 3).
Benzyl deprotection of compound 16a followed by alkylation with
3-bromopropyne gave dipropyne compound 2e (Scheme 4).
For the activity study, mandelamide 19 was prepared from vanillin
and mandelic acid according to the established five-step procedure
(31), and N-methylation of compound 19 produced compound 20
(Scheme 5).
Antifungal activities and structure–activity
relationship
The screening data revealed that most of 1,4-disubstituted 1,2,3-
triazole analogs 3a–p retain their activity in some degree at
200 mg ⁄ L, whereas 1,2,3-triazole analogs 2a–d, which have two
carbon atoms between 1,2,3-triazole ring and phenyl ring, lose virtu-
ally all activity. For example, compounds 3f and 3k exhibited 60%
and 90% inhibition effect against Pseudoperonospora cubenis,
respectively, at 200 mg ⁄ L, and compounds 3l and 3o displayed
50% and 50% inhibition rate against Blumeria graminis f.sp. tritici
(data not shown). From the biological data (Table 1), we have
observed that there is no apparent correlation between the struc-
ture and fungicidal activity of 1,2,3-triazole analogs 3. This may be
Unexpectedly, incorporation of small polar groups did not increase
the inhibitory activity: the 5-hydroxymethyl compounds, 21a and
21b, showed almost the same activity as the corresponding 5-
unsubstituted 1,2,3-triazoles. There are potentially two explanations
for this discrepancy. First, compound 21 was unstable in solvent
and therefore formed a variety of degradation compounds. Secondly,
N
N
N
O
N
N
N
N
HO
HO
O
a
N
O
b
N
O
OH
OCH Ph
2
O
Cl
Cl
Cl
2e
16a
18
Scheme 4: Synthetic route of compound 2e. Reagents and conditions: (a) Pd ⁄ C (10%), absolute ethanol, H2, rt; (b) NaOH ⁄ H2O, cetyltrime-
thylammonium bromide, propargyl bromide, CH2Cl2, rt.
Et
Et
Me
N
O
O
H
O
O
N
O
O
NaH,CH3I, DMF, rt
O
O
Cl
Cl
19
20
Scheme 5: Synthetic route of compound 20.
OR2
OR2
Cl
Cl
OH
O
O
BuLi/p-CH2O
THF
N
N
N
N
OR1
N
OR1
N
21a: R1 = C2H5, R2 = n-C3H7;
21b: R1 = n-C3H7, R2 = PhCH2
3i, 3o
Scheme 6: Synthetic route of compound 21.
Chem Biol Drug Des 2011; 78: 101–111
109

Su et al.
the hydrogen could not effectively bind to the active-site residues,
because two atoms (C and O) were inserted onto the C(5) of 1,2,3-
triazole ring.
3. Lamberth C., Cederbaum F., Jeanguenat A., Kempf H., Zeller M.,
Zeun R. (2006) Synthesis and fungicidal activity of N-2-(3-meth-
oxy-4-propargyloxy) phenethyl amides. Part II: anti-oomycetic
mandelamides. Pest Manag Sci;62:446–451.
The structural difference is also an important issue. For instance,
the distance between the two substitutes in 1,2,3-triazole is about
1.1 ꢀ longer than that in amide. While compounds 2 and 3 are dif-
ferent as to the distance between the 1,2,3-triazole ring and vanillin
ring. The former has one more atom than the latter. We therefore
speculate that this is the distance range required between the two
phenyl rings when mandipropamids bind to the target receptor
(Figure S1). As an example, N-ethylacetamide and 1,4-dimethyl-
1,2,3-triazole are aligned to explain how they interact with the
target receptor. The distance between the two methyl of 1,4-
dimethyl-1,2,3-triazole ring is 5.046 ꢀ, whereas the distance
between the two methyl of N-ethylacetamide is 4.874 ꢀ. The
molecular dimension of the 1,4-dimethyl 1,2,3-triazoles is very simi-
lar to N-ethylacetamide in terms of distance and planarity. Our
molecular modeling shows that a 1,4-connected 1,2,3-triazole ring
might be commensurate with the geometry of N-methylamide.
Based on the above molecular structure, an isolated molecule was
selected as the initial structure, while DFT-B3LYP ⁄ 6-31G (d) method
in Gaussian 03 package were used to optimize the structure of the
title compound. Vibration analysis showed that the optimized struc-
tures were in accordance with the minimum points on the potential
energy surfaces. All the convergent precisions were the system
default values, and all the calculations were carried out on the
Nankai Stars supercomputer at Nankai University.
4. Hsu C., McCallister J., Hartung J., Turechek W. (2006) A quanti-
tative PCR assay for detection of Xanthomonas fragariae. A
quantitative PCR assay for detection of Xanthomonas fragariae.
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In summary, we have described the synthesis of isosteric analogs
of mandipropamid via 'click chemistry'. The 1,2,3-triazole-modified
mandipropamid analogs have showed moderate activity against
P. cubenis, and the activity has been systematically studied as a
function of the molecular structure. The low activity of compound 3
is likely due to a weak hydrogen-bonding donor of the 1,2,3-triazole,
which prevents it from acting as a hydrogen bond acceptor. Further-
more, we have performed the molecular modeling and found that
N-methylamide can be more effective than amide as the surrogate
to 1,2,3-triazole, which ultimately leads to a longer distance (1.1ꢀ
longer) between the two substitutes in the 1,4-disubstituted 1,2,3-
triazole compound.
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Acknowledgments
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We gratefully thank the National Natural Science Foundation of
China (grant No. 20772069) and the National Basic Research Sci-
ence Foundation of China (2010CB126105) for financial support of
this research.
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Figure S1. Overlay of energy-minimized structures of 1,4-
dimethyl-1,2,3-triazole and N-ethylacetamide. Representative original
1H NMR, 13C NMR and HPLC of title compounds.
Please note: Wiley-Blackwell is not responsible for the content or
functionality of any supporting materials supplied by the authors.
Any queries (other than missing material) should be directed to the
corresponding author for the article.
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Chem Biol Drug Des 2011; 78: 101–111
111