Synthesis and fungicidal evaluation of 2-arylphenyl ether-3-(1 H-1,2,4-triazol-1-yl)propan-2-ol derivatives

Article abstract of DOI:10.1021/jf900222s

A series of novel 2-arylphenyl ether-3-(1H-1,2,4-triazol-1-yl)propan-2-ol derivatives were designed and synthesized as candidate fungicides. The new compounds were identified by ¹H NMR spectroscopy and element analysis. Their antifungal activit

Full text of DOI:10.1021/jf900222s

4854 J. Agric. Food Chem. 2009, 57, 4854–4860
DOI:10.1021/jf900222s
Synthesis and Fungicidal Evaluation of 2-Arylphenyl
Ether-3-(1H-1,2,4-triazol-1-yl)propan-2-ol Derivatives
†
G
UAN-PING
Y
U
,
‡,§,† LIANG-ZHONG
X
U
,*,† X
U
Y
I
†
,† WEN-ZHAO
B
I
,† Q
I
Z
HU
,
AND
Z
HI-WEI
Z
HAI
†College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, China, ‡Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy
of Sciences, Urumqi 830011, China, and §Graduate School of the Chinese Academy of Sciences,
Beijing 100039, China
A series of novel 2-arylphenyl ether-3-(1H-1,2,4-triazol-1-yl)propan-2-ol derivatives were designed
and synthesized as candidate fungicides. The new compounds were identified by 1H NMR
spectroscopy and element analysis. Their antifungal activities were evaluated. They exhibited
excellent antifungal activities against five common pathogens in comparison with the commercial
fungicides tebuconazole and difenoconazole. The antifungal activities of three new triazole alcohol
compounds were compared with those of tebuconazole and difenoconazole at a concentration of
1 μg/mL.
KEYWORDS: Triazole alcohol; aryl ether; fungicides; synthesis
optimization of V was focused on varying the substituents R1 and
R2 while retaining the arylphenyl ether group. In this paper, we
describe the synthesis and antifungal activities of some novel
triazole alcohol compounds containing an arylphenyl ether group
(Schemes 1-3 and Table 1).
INTRODUCTION
Many 1,2,4-triazole derivatives possess potent pesticidal (1 ),
herbicidal (2 ), and antifungal (3-5) activities, such as tebucona-
zole, flutriafol, hexaconazole and cyproconazole (Figure 1) (6-9)
and the structure unit “(1H-1,2,4-triazol-1-yl)ethanol” is key to
their bioactivities. These compounds represent the most impor-
tant category of fungicides to date and have long protective and
curative activity against a broad spectrum of foliar, root, and
seedling diseases caused by many ascomycetes, basidiomycetes,
and imperfect fungi (10). In addition, the arylphenyl ether group
is a highly efficient pharmacophore and is widely used in pesticide
and drug molecular design (11, 12). For example, difenoconazole
(Figure 2) (12), discovered by Ciba-Geigy (U.K.) Limited, as
fungicide offers a high level of control against soilborne dwarf
bunt, for which chemical control was not previously available.
Bioisosterism (13 ) is an effective way to design bioactive
compounds. To find some valuable compounds, a series of novel
2-arylphenylether-3-(1H-1,2,4-triazol-1-yl)propan-2-ol derivatives
V were designed by introducing the arylphenyl ether group into the
pharmacophore (1H-1,2,4-triazol-1-yl)ethanol (Figure 2). At first,
compounds V1 and V20-V27 (14, 15) (Figure 3) were synthesized
in our laboratory. The results of preliminary biological tests
against Gibberella zeae, Alternaria solani, Fusarium oxysporum,
Physalospora pircola, and Cercospora arachidicola showed that all
of these compounds, especially V1, possess higher antifungal
activities comparable to those of commercial fungicides.
MATERIALS AND METHODS
Synthetic Procedures. Proton NMR spectra were obtained at
500 MHz using a Bruker AC-500 spectrometer in CDCl3 or DMSO-d6
solution with TMS as internal standard. Chemical shift values (δ) are given
in parts per million. Elemental analyses were determined on a Perkin-
Elmer 240 elemental analyzer. Melting points were taken on a Yanaco-
MP-500 microscopic melting apparatus and are uncorrected. Yields are
not optimized.
General Procedure To Synthesize Intermediate 1-((2-(4-(4-
Halogenated
phenoxy)-2-chlorophenyl)oxiran-2-yl)methyl)-1H-
1,2,4-triazole (IV-1). The intermediates II-1 were prepared according
to a literature procedure (16 ). The substituted acetophenones were reacted
with bromine in anhydrous diethyl ether. Two intermediates II-1 were
prepared in this manner: II-1a, R1 = Cl, yield 95.8%, mp 65-66 °C (lit.
(17) yield 89.1%, mp 64-65 °C); and II-1b, R1 = F, yield 90.1%, mp
44-46 °C, 1H NMR (CDCl3, 500 MHz) δ 6.70-7.77 (m, 7H, Ar-H), 4.54
(s, 2H, CH2Br).
To the solution of 2-bromo-1-(2-chloro-4-(4-halogenated phenoxy)
phenyl)ethanone (II-1) (0.1 mol) and 1H-1,2,4-triazole (8.28 g, 0.12 mol)
in ethyl acetate (70 mL) was added potassium carbonate (16.56 g,
0.12 mol); the resulting mixture was refluxed for 6 h and filtered, and the
filtrate was condensed. The residual was recrystallized with ethyl acetate to
give intermediate III-1: III-1a, R1 = Cl, yield 67.3%, mp 151-153 °C,
1H NMR (CDCl3, 500 MHz) δ 8.43 (s, 1H, triazole-H), 8.01 (s, 1H,
triazole-H), 6.68-7.69 (m, 7H, Ar-H), 4.89 (s, 2H, CH2); III-1b, R1 = F,
yield 60.5%, mp 125-126 °C, 1H NMR (CDCl3, 500 MHz) δ 8.23 (s, 1H,
triazole-H), 7.99 (s, 1H, triazole-H). 6.76-7.81 (m, 7H, Ar-H), 4.92
(s, 2H, CH2).
To further amplify the structure-activity relationship (SAR)
between R1 and R2 of V and the resulting activity and to find
valuable lead compounds with high antifungal activity, subsequent
*Author to whom correspondence should be addressed [telephone:
+86-(0)532-84023177; fax: +86-(0)532-84023177; e-mail: qknhs@
yahoo.com.cn].
pubs.acs.org/JAFC
Published on Web 05/07/2009
© 2009 American Chemical Society

Article
J. Agric. Food Chem., Vol. 57, No. 11, 2009 4855
Figure 1. Structures of hexaconazole, cyproconazole, flutriafol, and tebuconazole.
Figure 2. Design strategy of the title compounds.
sulfate, and filtered. The solvent was evaporated, and the residue was
recrystallized from acetone to give IV-3. The melting points and yields of
intermediate II-3 and IV-3 are listed in Table 2, and their1H NMR data are
listed in Table 3.
General Procedure for Target Compounds V1-V27. A mixture of
epoxide IV (5 mmol), potassium carbonate (0.69 g, 5 mmol), and ring
cleavage (6 mmol) was refluxed for 5-6 h in 20 mL of DMF. The organic
phase was separated and condensed, and the residual was purified by
vacuum column chromatography on silica gel to afford the desired
compounds V1-V27.
Figure 3. Structures of V1 and V20-27.
Data for V1: see ref (14)
Data for V2: yield 71.5%; white solid, mp 85-88 °C; 1H NMR (CDCl3,
To the mixture of III-1 (0.1 mol), trimethylsulfoxonium iodide (26.4 g,
0.12 mol), and triethylbenzylammonium chloride (0.3 g) in 100 mL toluene
was added dropwise the aqueous sodium hydroxide (20%, 80 g). After the
resulting mixture had been stirred at 60 °C for 3-4 h, the organic phase
was separated and condensed. The residual was recrystallized with
ethyl acetate to afford intermediate IV-1: IV-1a, R1 = Cl, yield 80%,
mp 70-71 °C, 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H, triazole-H),
500 MHz) δ 8.12 (s, 1H, triazole-H), 7.96 (s, 1H, triazole-H), 6.70-7.49
2
(m, 10H, Ar-H, imidazole-H), 5.50 (s, 1H, OH), 5.40 (d, 1H, JHH
=
14.2 Hz, triazole-CH2), 4.64 (d, 1H, 2JHH = 14.1 Hz, imidazole-CH2),
4.53 (d, 1H, 2JHH = 14.1 Hz, imidazole-CH2), 4.31 (d, 1H, 2JHH = 14.2
Hz, triazole-CH2). Anal. Calcd for C20H17Cl2N5O2 (Mr = 430.29):
C, 55.83; H, 3.98; N, 16.28. Found: C, 55.78; H, 3.90; N, 16.11.
7.65 (s, 1H, triazole-H), 6.55-7.22 (m, 7H, Ar-H), 4.64 (d, 1H, 2JHH
=
Data for V3: yield 51.3%; white solid, mp 100-103 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.08 (s, 1H, triazole-H), 7.98 (s, 1H, triazole-H),
6.87-7.47 (m, 7H, Ar-H), 5.23 (d, 1H, 2JHH = 14.5 Hz, triazole-CH2),
4.79 (d, 1H, 2JHH = 14.5 Hz, triazole-CH2), 4.52 (d, 1H, 2JHH = 14.1 Hz,
15 Hz, triazole-CH2), 4.63 (d, 1H, 2JHH = 15 Hz, triazole-CH2), 2.72 (d,
2
2
1H, JHH = 4.5 Hz, O-CH2), 2.66 (d, 1H, JHH = 4.5 Hz, O-CH2);
IV-1b, R1 = F, yield 75.2%, mp 93-94 °C, 1H NMR (CDCl3, 500 MHz) δ
7.87 (s, 1H, triazole-H), 7.65 (s, 1H, triazole-H), 6.58-7.42 (m, 7H,
2
morpholine-CH2), 4.38 (d, 1H, JHH = 14.1 Hz, morpholine-CH2),
Ar-H), 4.63 (d, 1H, 2JHH = 15 Hz, triazole-CH2), 4.62 (d, 1H, 2JHH
=
3.49-4.26 (m, 8H, morpholine-H). Anal. Calcd for C21H22Cl2N4O3
(Mr = 449.33): C, 56.13; H, 4.94; N, 12.47. Found: C, 56.01; H, 4.52;
N, 12.41.
15 Hz, triazole-CH2), 2.72 (d, 1H, 2JHH =4.5 Hz, O-CH2), 2.67 (d, 1H,
2JHH = 4.5 Hz, O-CH2).
General Procedure To Synthesize Intermediate 2-(4-(4-Haloge-
nated phenoxy)-2-chlorophenyl)-2-methyloxirane (IV-2). According
to the above procedure from III-1 to IV-1, compound IV-2 was synthe-
sized from I: IV-2a, R1 = Cl, yield 86.5%, mp 46-48 °C, 1H NMR
(DMSO-d6, 500 MHz) δ 6.97-7.47 (m, 7H, Ar-H), 3.02 (d, 1H, 2JHH = 5
Data for V4: yield 61.6%; canary yellow solid, mp 112-115 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.55 (s, 1H, triazole-H), 8.01 (s, 1H, triazole-
2
H), 6.64-7.85 (m, 11H, Ar-H, aziminobenzene), 5.52 (d, 1H, JHH
=
14 Hz, triazole-CH2), 5.36 (d, 1H, aziminobenzene-H, 2JHH = 14.5 Hz),
5.34 (d, 1H, 2JHH = 14.5 Hz, aziminobenzene-H), 4.53 (d, 1H, 2JHH
=
2
Hz, O-CH2), 2.77 (d, 1H, JHH = 5 Hz, O-CH2), 1.55 (s, 3H, CH3);
14 Hz, triazole-CH2). Anal. Calcd for C23H18Cl2N6O2 (Mr = 481.33):
C, 57.39; H, 3.77; N, 17.46. Found: C, 57.33; H, 3.67; N, 17.55.
Data for V5: yield 43.5%; white solid, mp 138-140 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.47 (s, 1H, triazole-H), 8.01 (s, 1H, triazole-H),
IV-2b, R1 = F, yield 76.2%, orange liquid, 1H NMR (CDCl3, 500 MHz) δ
2
6.95-7.57 (m, 7H, Ar-H), 3.04 (d, 1H, JHH = 5 Hz, O-CH2), 2.79
(d, 1H, 2JHH = 5 Hz, O-CH2), 1.58 (s, 3H, CH3).
2
General Procedure To Synthesize Intermediate IV-3. The inter-
mediates II-3 were prepared according to the method given in ref (18).
Intermediate II-3 (10 mmol) and trimethylsulfonium methylsulfate (2.26 g,
12 mol) were dissolved in 20 mL of ethyl ether; potassium hydroxide (2.24
g, 40 mmol) powder was added to the solution at 0 °C, and then the
mixture was heated to boiling (5 h). The mixture was cooled, poured into
water, acidified with 30% H2SO4 to pH 7-8, and extracted with ethyl
ether. The organic extract was washed with water twice, dried with sodium
6.78-7.64 (m, 7H, Ar-H), 5.29 (d, 1H, JHH = 14 Hz, triazole-CH2),
4.88 (d, 1H, 2JHH = 14 Hz, triazole-CH2), 4.23 (s, 1H, OH), 4.36 (d, 1H,
2JHH = 12 Hz, HO-CH2), 3.90 (d, 1H, 2JHH = 14 Hz, HO-CH2). Anal.
Calcd for C17H15Cl2N3O3 (Mr = 380.23): C, 53.70; H, 3.98; N, 11.05.
Found: C, 54.01; H, 3.89; N, 11.12.
Data for V6: yield 86.2%; white solid, mp 119-120 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.18 (s, 1H, triazole-H), 8.01 (s, 1H, triazole-H),
2
6.78-7.64 (m, 7H, Ar-H), 4.74 (d, 1H, JHH = 14 Hz, triazole-CH2),

4856 J. Agric. Food Chem., Vol. 57, No. 11, 2009
Scheme 1. Compounds V1-V17a
Yu et al.
a Compounds V1-V13: R1 = Cl. R2 = triazole; imidazole; morpholine; benzotriazole; OH; N(CH3)2; NCH2CH3; NCH3; OCH3; NH-cyclo-C6H11; SCH3; NCH2CH2OH; NCH2OH.
Compounds V14-V17: R1 = F. R2 = OCH3; NCH3; imidazole; triazole.
Scheme 2. Compounds V18 and V19a
a R1 = Cl; F.
Scheme 3. Compounds V20-V27a
a R1 = Cl. R3 = H; 4-Cl; 2,4-Cl2; 2,6-Cl2; 4-CH3; 4-CH3O; 3,4-Cl2; 2-F.
2
4.71 (d, 1H, 2JHH = 14 Hz, triazole-CH2), 3.41 (d, 1H, 2JHH = 13.5 Hz,
CH2N(CH3)2), 2.70 (d, 1H, 2JHH = 13.5 Hz, CH2N(CH3)2), 2.13 (s, 6H, N
(CH3)2). Anal. Calcd for C19H20Cl2N4O2 (Mr = 407.29): C, 56.03; H,
4.95; N, 13.76. Found: C, 55.94; H, 4.90; N, 13.69.
CH2OCH3), 3.80 (d, 1H, JHH = 9.5 Hz, CH2OCH3), 3.35 (s, 3H,
O-CH3). Anal. Calcd for C18H17Cl2N3O3 (Mr = 394.25): C, 54.84; H,
4.35; N, 10.66. Found: C, 54.88; H, 4.29; N, 10.72.
Data for V10: yield 82.7%; white solid, mp 106-107 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.16 (s, 1H, triazole-H), 7.85 (s, 1H, triazole-H),
Data for V7: yield 80.0%; white solid, mp 109-110 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.15 (s, 1H, triazole-H), 7.84 (s, 1H, triazole-H),
2
6.82-7.45 (m, 7H, Ar-H), 4.85 (d, 1H, JHH = 14 Hz, triazole-CH2),
2
6.82-7.74 (m, 7H, Ar-H), 4.84 (d, 1H, JHH = 14 Hz, triazole-CH2),
4.67 (d, 1H, 2JHH = 14 Hz, triazole-CH2), 3.43 (d, 1H, 2JHH = 12.5 Hz,
4.74 (d, 1H, 2JHH = 14 Hz, triazole-CH2), 3.48 (d, 1H, 2JHH = 12.5 Hz,
CH2NHC2H5), 2.97 (d, 1H, 2JHH = 12.5 Hz, CH2NHC2H5), 2.54 (q, 2H,
3JHH = 7 Hz, NHCH2CH3), 1.00 (t, 3H, 3JHH = 7 Hz, NHCH2CH3), 1.62
(s, 1H, CH2NHC2H5). Anal. Calcd for C19H20Cl2N4O2 (Mr = 407.29):
C, 56.03; H, 4.95; N, 13.76. Found: C, 56.13; H, 4.89; N, 13.72.
CH2NH), 3.04 (d, 1H, JHH = 12.5 Hz, CH2NH), 0.91-2.21 (m, 11H,
CH2NHC6H11). Anal. Calcd for C22H24Cl2N4O2 (Mr = 447.36): C, 59.87;
2
H, 5.68; N, 12.14. Found: C, 59.78; H, 5.72; N, 12.20.
Data for V11: yield 90.5%; yellowish solid, mp 143-144 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.05 (s, 1H, triazole-H), 7.84 (s, 1H, triazole-H),
Data for V8: yield 85.3%; white solid, mp 110-112 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.47 (s, 1H, triazole-H), 8.01 (s, 1H, triazole-H),
6.78-7.64 (m, 7H, Ar-H), 5.25 (d, 1H, 2JHH = 14.1 Hz, triazole-CH2),
4.81 (d, 1H, 2JHH = 14.1 Hz, triazole-CH2), 3.85 (d, 1H, 2JHH = 10 Hz,
6.81-7.67 (m, 7H, Ar-H), 5.07 (d, 1H, JHH = 14 Hz, triazole-CH2),
2
4.81 (d, 1H, 2JHH = 14 Hz, triazole-CH2), 3.65 (d, 1H, 2JHH = 14 Hz,
CH2SCH3), 2.97 (d, 1H, 2JHH = 14 Hz, CH2SCH3), 1.96 (s, 3H, S-CH3).
Anal. Calcd for C18H17Cl2N3O2S (Mr = 410.32): C, 52.69; H, 4.18;
N, 10.24. Found: C, 52.64; H, 4.11; N, 10.32.
2
CH2NHCH3), 3.73 (d, 1H, JHH = 10 Hz, CH2NHCH3), 3.12 (s, 3H,
NH-CH3), 2.26 (s, 1H, NH-CH3). Anal. Calcd for C18H18Cl2N4O2 (Mr
= 393.27): C, 54.97; H, 4.61; N, 14.25. Found: C, 54.89; H, 4.69; N, 14.18.
Data for V9: yield 83.4%; white solid, mp 149-150 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.15 (s, 1H, triazole-H), 7.80 (s, 1H, triazole-H),
6.74-7.60 (m, 7H, Ar-H), 5.05 (d, 1H, 2JHH = 14.5 Hz, triazole-CH2),
4.74 (d, 1H, 2JHH = 14.5 Hz, triazole-CH2), 3.92 (d, 1H, 2JHH = 9.5 Hz,
Data for V12: yield 91.6%; white solid, mp 100-101 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.10 (s, 1H, triazole-H), 7.84 (s, 1H, triazole-H),
6.80-7.71 (m, 7H, Ar-H), 5.29 (s, 1H, NH), 4.86 (d, 1H, 2JHH = 14 Hz,
triazole-CH2), 4.82 (d, 1H, JHH = 14 Hz, triazole-CH2), 3.60 (t, 2H,
Hz, CH2CH2OH), 3.50 (d, 1H, JHH
CH2NHCH2CH2), 3.01 (d, 1H, JHH = 12.5 Hz, CH2NHCH2CH2),
2
2
3JHH
=
5
=
12.5 Hz,
2

Article
J. Agric. Food Chem., Vol. 57, No. 11, 2009 4857
Table 1. Compounds V1-V27
Table 2. Yields and Melting Points of Intermediates II-3 and IV-3a
Hz, CH2OCH3), 3.81 (d, 1H, JHH = 9.5 Hz, CH2OCH3), 3.45 (s, 3H,
2
OCH3). Anal. Calcd for C18H17ClFN3O3 (Mr = 377.8): C, 57.22; H,
4.54; N, 11.12. Found: C, 57.13; H, 4.49; N, 11.24.
compd
R3
yield (%) mp (°C) compd
R3
yield (%) mp (°C)
Data for V15: yield 65%; yellowish solid, mp 143-145 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.17 (s, 1H, triazole-H), 8.00 (s, 1H, triazole-H),
6.67-7.55 (m, 7H, Ar-H), 5.25 (d, 1H, 2JHH = 13.5 Hz, triazole-CH2),
4.71 (d, 1H, 2JHH = 13.5 Hz, triazole-CH2), 3.63 (s, 1H, OH), 3.55 (d, 1H,
2JHH = 10 Hz, CH2NHCH3), 3.27 (d, 1H, 2JHH = 10 Hz, CH2NHCH3),
3.10 (m, 1H, NH), 2.25 (s, 3H, CH2NHCH3). Anal. Calcd for
C18H18ClFN4O2 (Mr = 376.81): C, 57.37; H, 4.81; N, 14.87. Found: C,
57.23; H, 4.71; N, 14.70.
II-3a
II-3b
II-3c
II-3d
II-3e
II-3f
H
4-Cl
90.0 68-69 IV-3a
81.2 117-118 IV-3b 4-Cl
88.5 124-125 IV-3c 2,4-Cl2
H
94.1
70.5
79.4
86.0
73.3
82.1
65.4
52.8
54-55
118-119
77-79
47-48
84-86
78-81
62-63
81-82
2,4-Cl2
2,6-Cl2
4-CH3
4-CH3O
92.7
73.6
96.0
79-80 IV-3d 2,6-Cl2
86-87 IV-3e 4-CH3
91-93 IV-3f
4-CH3O
II-3 g 3,4-Cl2
II-3 h 2-F
91.2 107-111 IV-3 g 3,4-Cl2
58.6 103-104 IV-3 h 2-F
Data for V16: yield 75%; white solid, mp 167-168 °C; 1H NMR
(CDCl3, 500 MHz) δ 7.93 (s, 1H, triazole-H), 7.81 (s, 1H, triazole-H),
a Intermediates II-3 and IV-3: R1 = Cl.
2
3
6.63-7.52 (m, 10H, Ar-H, imidazole-H), 5.35 (d, 1H, JHH = 14 Hz,
2.68 (t, 2H, JHH = 5 Hz, NHCH2CH2OH), 2.02 (s, 1H, NHCH2-
CH2OH). Anal. Calcd for C19H20Cl2N4O3 (Mr = 423.29): C, 53.91; H,
4.76; N, 13.24. Found: C, 54.02; H, 4.70; N, 13.34.
2
triazole-CH2), 4.63 (d, 1H, JHH = 14.2 Hz, imidazole-CH2), 4.49
2
2
(d, 1H, JHH = 14.2 Hz, imidazole-CH2), 4.29 (d, 1H, JHH = 14 Hz,
triazole-CH2), 2.03 (s, 1H, OH). Anal. Calcd for C20H17ClFN5O2 (Mr =
413.83): C, 58.05; H, 4.14; N, 16.92. Found: C, 58.25; H, 4.10; N, 16.77.
Data for V17: yield 43%; white solid, mp 215-217 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.12 (s, 2H, triazole-H), 7.91 (s, 2H, triazole-H),
6.68-7.54 (d, 7H, Ar-H), 5.34 (d, 2H, 2JHH = 14.5 Hz, triazole-CH2),
Data for V13: yield 60.5%; white solid, mp 124-125 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.01 (s, 1H, triazole-H), 7.71 (s, 1H, triazole-H),
6.17-7.61 (m, 7H, Ar-H), 5.59 (s, 1H, NH), 4.86 (d, 1H, 2JHH = 14.5 Hz,
triazole-CH2), 4.72 (d, 1H, 2JHH = 14.5 Hz, triazole-CH2), 3.62 (d, 1H,
2JHH = 14.5 Hz, CH2NHCH2OH), 3.38 (d, 1H, JHH = 14.5 Hz,
2
2
4.60 (d, 2H, JHH = 14.5 Hz, triazole-CH2), 1.94 (s, 1H, OH). Anal.
CH2NHCH2OH), 3.30 (s, 3H, NHOCH3). Anal. Calcd for
C18H18Cl2N4O3 (Mr = 409.27): C, 52.82; H, 4.43; N, 13.69. Found: C,
52.04; H, 4.39; N, 13.60.
Calcd for C19H16ClFN6O2 (Mr = 414.82): C, 55.01; H, 3.89; N, 20.26.
Found: C, 55.31; H, 3.82; N, 20.33.
Data for V14: yield 61%; white solid, mp 88-89 °C; 1H NMR (CDCl3,
500 MHz) δ 8.10 (s, 1H, triazole-H), 7.82 (s, 1H, triazole-H), 6.65-7.61
(m, 7H, Ar-H), 5.12 (d, 1H, 2JHH = 14 Hz, triazole-CH2), 4.93 (d, 1H,
2JHH = 14 Hz, triazole-CH2), 4.10 (s, 1H, OH), 3.92 (d, 1H, 2JHH = 9.5
Data for V18: yield 87.5%; white solid, mp 133-136 °C; 1H NMR
(CDCl3, 500 MHz) δ 7.97 (s, 1H, triazole-H), 7.87 (s, 1H, triazole-H),
7.66-6.77 (m, 7H, Ar-H), 5.26 (d, 1H, 2JHH = 14.1 Hz, triazole-CH2),
2
4.65 (d, 1H, JHH = 14.1 Hz, triazole-CH2), 4.74 (s, 1H, O-H), 1.73

4858 J. Agric. Food Chem., Vol. 57, No. 11, 2009
Table 3. 1H NMR Data of Intermediates II-3 and IV-3
compd
Yu et al.
δ (500 MHz, DMSO-d6)
II-3a
II-3b
II-3c
II-3d
II-3e
II-3f
7.76 (d, 1H, 3JHH = 3.5 Hz, Ar;CHdCH), 7.66 (d, 1H, 3JHH = 3.5 Hz, Ar;CHdCH), 7.05-7.52 (m, 12H, Ar;H)
7.82 (d, 1H, 3JHH = 3.5 Hz, Ar;CHdCH), 7.67 (d, 1H, 3JHH = 3.5 Hz, Ar;CHdCH), 7.06-7.53 (m, 11H, Ar;H)
8.16 (d, 1H, 3JHH = 3.0 Hz, Ar-CHdCH), 8.14 (d, 1H, 3JHH = 3.0 Hz, Ar;CHdCH), 7.13-7.82 (m, 10H, Ar;H)
7.70 (d, 1H, 3JHH = 4.0 Hz, Ar;CHdCH), 7.57 (d, 1H, 3JHH = 4.0 Hz, Ar;CHdCH), 7.07-7.54 (m, 10H, Ar;H)
7.67 (d, 1H, 3JHH = 8.0 Hz, Ar;CHdCH), 7.64 (d, 1H, 3JHH = 8.0 Hz, Ar;CHdCH), 7.05-7.52 (m, 11H, Ar;H), 2.33 (s, 3H, CH3)
7.71 (d, 1H, 3JHH = 8.0 Hz, Ar-CH=CH), 7.65 (d, 1H, 3JHH = 8.0 Hz, Ar-CH=CH), 7.03-7.55 (m, 11H, Ar-H), 3.63 (s, 3H, CH3)
II-3 g 7.88(d, 1H, 3JHH = 3.5 Hz, Ar;CHdCH), 7.69 (d, 1H, 3JHH = 3.5 Hz, Ar;CHdCH), 7.05-7.54 (m, 11H, Ar;H)
II-3 h 7.97 (d, 1H, 3JHH = 4.0 Hz, Ar;CHdCH), 7.94 (d, 1H, 3JHH = 4 Hz, Ar;CHdCH), 7.06-7.71 (m, 11H, Ar;H)
IV-3a 7.01-7.49 (m, 12H, Ar;H), 6.24 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 6.16 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 3.34 (d, 1H,2JHH = 5 Hz, O;CH2), 3.13 (d, 1H,
2JHH = 5 Hz, O;CH2)
IV-3b 7.03-7.51 (m, 11H, Ar;H), 6.34 (d, 1H, 3JHH = 16.5 Hz, Ar;CHdCH), 6.22 (d, 1H, 3JHH = 16.5 Hz, Ar;CHdCH), 3.33 (d, 1H, 2JHH = 5 Hz, O;CH2), 3.11 (d, 1H,
2JHH = 5 Hz, O;CH2)
IV-3c 7.03-7.57 (m, 10H, Ar;H), 6.32 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 6.27 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 3.35 (d, 1H,2JHH = 5 Hz, O;CH2), 3.15 (d, 1H,
2JHH = 5 Hz, O;CH2)
IV-3d 7.04-7.55 (m, 10H, Ar;H), 6.21 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 6.20 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 3.35 (d, 1H, 2JHH = 5.5 Hz, O;CH2), 3.15(d, 1H, 2JHH
5.5 Hz, O;CH2)
IV-3e 7.02-7.51 (m, 11H, Ar;H), 6.22 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 6.17 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 3.32 (d, 1H,2JHH = 5 Hz, O;CH2), 3.10 (d, 1H,
=
2JHH = 5 Hz, O;CH2), 2.25 (s, 3H, CH3)
IV-3f 7.03-7.54 (m, 11H, Ar;H), 6.26 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 6.19 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 3.75 (s, 3H, CH3), 3.35 (d, 1H,2JHH = 5 Hz, O;CH2),
3.13 (d, 1H,2JHH = 5 Hz, O;CH2)
IV-3 g 7.03-7.68 (m, 10H, Ar;H), 6.31 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 6.23 (d, 1H, 3JHH = 16 Hz, Ar;CHdCH), 3.33 (d, 1H, 2JHH = 5 Hz, O;CH2) 3.16 (d, 1H,
2JHH = 5 Hz, O;CH2)
IV-3 h 7.04-7.65 (m, 11H, Ar;H), 6.41 (d, 1H, 3JHH = 16.5 Hz, Ar;CHdCH), 6.33 (d, 1H, 3JHH = 16.5 Hz, Ar;CHdCH), 3.35 (d, 1H, 2JHH = 5 Hz, O;CH2) 3.15 (d, 1H,
2JHH = 5 Hz, O;CH2)
(s, 3H, CH3). Anal. Calcd for C17H15Cl2N3O2 (Mr = 364.23): C, 56.06; H,
4.15; N, 11.54. Found: C, 56.21; H, 4.10; N, 11.66.
3.85 (s, 3H, O-CH3). Elemental Anal. Calcd for C25H21Cl2N3O3:
C, 62.25; H, 4.39; N, 8.71. Found: C, 62.21; H, 4.42; N, 8.75.
Data for V26: yield 52.2%; yellowish solid, mp 117-120 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.29 (s, 1H, triazole-H), 7.89 (s, 1H, triazole-H),
6.78-7.69 (m, 10H, Ar-H), 6.67-6.69 (q, 2H, CHdCH), 5.27 (d, 1H,
2JHH = 14 Hz, triazole-CH2), 4.77 (d, 1H, 2JHH = 14 Hz, triazole-CH2).
Elemental Anal. Calcd for C24H17Cl4N3O2: C, 55.30; H, 3.29; N, 8.06.
Found: C, 55.31; H, 3.28; N, 8.11.
Data for V19: yield 85%; white solid, mp 125-127 °C; 1H NMR
(CDCl3, 500 MHz) δ 7.97 (s, 1H, triazole-H), 7.86 (s, 1H, triazole-H),
2
6.75-7.63 (m, 7H, Ar-H), 5.28 (d, 1H, JHH = 14 Hz, triazole-CH2),
2
4.73 (s, 1H, OH), 4.52 (d, 1H, JHH = 14.1 Hz, triazole-CH2), 1.73
(s, 3H, CH3). Anal. Calcd for C17H15ClFN3O2 (Mr = 347.77): C, 58.71; H,
4.35; N, 12.08. Found: C, 58.66; H, 4.45; N, 12.28.
Data for V20: yield 68.9%; yellow solid, mp 142-145 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.04 (s, 1H, triazole-H), 7.87 (s, 1H, triazole-H),
6.93-7.74 (m, 12H, Ar-H), 6.76-6.83 (q, 2H, CHdCH), 5.20 (d, 1H,
2JHH = 14.5 Hz, triazole-CH2), 4.76 (d, 1H, 2JHH = 14.5 Hz, triazole-
CH2). Elemental Anal. Calcd for C24H19Cl2N3O2: C, 63.73; H, 4.23;
N, 9.29. Found: C, 63.72; H, 4.28; N, 9.26.
Data for V27: yield 50.3%; white solid, mp 105-107 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.10 (s, 1H, triazole-H), 7.91 (s, 1H, triazole-H),
6.96-7.76 (m, 11H, Ar-H), 6.83-6.85 (q, 2H, CHdCH), 5.27 (d, 1H,
2JHH = 14 Hz, triazole-CH2), 4.77 (d, 1H, 2JHH = 14 Hz, triazole-CH2).
Elemental Anal. Calcd for C24H18Cl2FN3O2: C, 61.29; H, 3.86; N, 8.93.
Found: C, 61.27; H, 3.88; N, 8.96.
Data for V21: yield 81.5%; yellowish solid, mp 116-119 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.23 (s, 1H, triazole-H), 7.91 (s, 1H, triazole-H),
6.96-7.74 (m, 11H, Ar-H), 6.79-6.85 (q, 2H, CHdCH), 5.26 (d, 1H,
2JHH = 14 Hz, triazole-CH2), 4.77 (d, 1H, 2JHH = 14 Hz, triazole-CH2).
Elemental Anal. Calcd for C24H18Cl3N3O2: C, 59.22; H, 3.73; N, 8.63.
Found: C, 59.28; H, 3.71; N, 8.67.
Bioassays. For comparison, the antifungal activities of the title
compounds (V1-V27) and the commercial fungicides (tebuconazole,
difenoconazole) were evaluated according to a procedure described in
our previous work (14, 15). A mixture of the same amount of water,
N-dimethylformamide, and Tween 20 was used as a negative control. The
inhibition rates (%) of V1-V27 are summarized in Table 4.
Data for V22: yield 75.4%; white solid, mp 128-130 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.18 (s, 1H, triazole-H), 7.91 (s, 1H, triazole-H),
6.99-7.77 (m, 10H, Ar-H), 6.79-6.85 (q, 2H, CHdCH), 5.24 (d, 1H,
2JHH = 14.1 Hz, triazole-CH2), 4.78 (d, 1H, 2JHH = 14.1 Hz, triazole-
CH2), 1.77 (s, 1H, OH). Elemental Anal. Calcd for C24H17Cl4N3O2:
C, 55.30; H, 3.29; N, 8.06. Found: C, 55.33; H, 3.35; N, 8.02.
RESULTS AND DISCUSSION
Preparations. The target compounds V1-V27 were synthe-
sized from 1-(4-(4-halogenated phenoxy)-2-chlorophenyl)etha-
none (I) as shown in Schemes 1-3. The substituted
acetophenones (I) were reacted with bromine in anhydrous
diethyl ether to give intermediate II-1 according to a reported
procedure (16), and subsequent reaction with 1H-1,2,4-triazole
yielded compounds III-1; further epoxidation reaction using
trimethylsulfoxonium iodide provided epoxide IV-1 (Scheme 1).
Intermediates IV-2 were prepared by epoxidized compound I
with trimethylsulfonium methylsulfate as shown in Scheme 2. To
obtain intermediate IV-3, we synthesized II-3 according to
method given in ref (18) and then epoxidized II-3 using trimethyl-
sulfonium methylsulfate (Scheme 3). The epoxide IV, in base-
catalyzed ring-opening, was attacked by the 1H-1,2,4-triazole and
other ring cleavages at the less sustituted carbon atom to afford
target compounds V1-27. Intermediates IV-2 and IV-3 can
be epoxidized I and II-3 by trimethylsulfoxonium iodide or
Data for V23: yield 80.6%; yellowish solid, mp 128-130 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.38 (s, 1H, triazole-H), 7.98 (s, 1H, triazole-H),
6.93-7.81 (m, 10H, Ar-H), 6.82-6.87 (q, 2H, CHdCH), 5.24 (d, 1H,
2JHH = 14 Hz, triazole-CH2), 4.92 (d, 1H, 2JHH = 14 Hz, triazole-CH2).
Elemental Anal. Calcd for C24H17Cl4N3O2: C, 55.30; H, 3.29; N, 8.06.
Found: C, 55.28; H, 3.31; N, 8.09.
Data for V24: yield 53%; yellow viscous fluid; 1H NMR (CDCl3,
500 MHz) δ 8.12 (s, 1H, triazole-H), 7.98 (s, 1H, triazole-H), 6.89-7.82
(m, 11H, Ar-H), 6.75-6.79 (q, 2H, CHdCH), 5.16 (d, 1H, 2JHH = 14.5
2
Hz, triazole-CH2), 4.78 (d, 1H, JHH = 14.5 Hz, triazole-CH2), 2.81
(s, 3H, CH3). Elemental Anal. Calcd for C25H21Cl2N3O2: C, 64.39;
H, 4.54; N, 9.01. Found: C, 64.38; H, 4.58; N, 8.87.
Data for V25: yield 61.8%; yellow solid, mp 121-124 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.31 (s, 1H, triazole-H), 7.92 (s, 1H, triazole-H),
6.82-7.73 (m, 11H, Ar-H), 6.66-6.74 (q, 2H, CHdCH), 5.26 (d, 1H,
2JHH = 14 Hz, triazole-CH2), 4.78 (d, 1H, 2JHH = 14 Hz, triazole-CH2),

Article
J. Agric. Food Chem., Vol. 57, No. 11, 2009 4859
Table 4. Fungicidal Activities of Compounds V1-V27
of compounds V the signals of the two protons of the CH2 group
connecting the triazoles appear as two doublets at around 5.2 and
4.7 ppm. It is believed that this is due to the fact they are attached
to an asymmetrical carbon atom, which makes the magnetic
environments of the two CH2 group protons different.
fungicidal activities (inhibition %)
concn
G.
A.
C.
P.
F.
compd
(μg/mL) zeae solani arachidicoa pircola oxysporum
Structure-Activity Relationship. The antifungal activities for
compound V were tested, and the results are listed in Table 4.
The 1H-1,2,4-triazole compounds’ mode of action is the arrest
of sterol biosynthesis by inhibiting 14R-demethylase (14r-DM), a
specific cytochrome P450. Evidence that sterol biosynthesis
inhibition is linked to the binding of nucleophilic N4 of 1,2,
4-triazole to iron in the ferric state of the heme is an essential
feature of the inhibition action (19). The N1 substituent, which
generally bears one or more hydrophobic groups, binds to a
region normally occupied by the natural sterol substrate. Struc-
tural limitations to binding have been analyzed with computer
graphic approaches (19). As shown in Table 4, all title com-
pounds had a high inhibition rate at 50 μg/mL concentration; V,
with a small size of R2, favorably inhibited the oxidative removal
of sterol C(14) methyl groups by the cytochrome P450 enzyme,
which increased the antifungal activity, especially when the
substituents of R2 were smaller alkylamino/alkoxy groups (such
as methylamino, methoxy) or a triazole group (compounds V1,
V8, V9, V14, V15, V17). It was also found that when the R2 was
modified by a substituted benzyl group, the target molecules
V20-V27 showed excellent inhibitory activities to C. arachidicoa.
When R2 was not changed, the antifungal acitvities for R1 (Cl, F)
were in the same level as the similar hydrophobic parameter of Cl
(0.71) and F (0.14) (20).
V1a
50
5
100
100
99.0
84.2
58.6
100
100
100
91.0
99.0
80.9
62.5
1
82.6
88.1
90.3
V2
V3
V4
V5
50
50
50
50
71.4
78.3
45.4
99.0
99.0
55.2
53.3
99.0
100.0
60.0
99.0
65.2
55.6
99.0
95.0
34.4
48.7
77.1
62.7
100.0
V6
50
1
96.9
4.2
99.1
18.6
97.2
0
100
100
0
27.7
V7
V8
50
56.8
63.8
61.4
75.4
86.9
50
1
98
72.5
99
50.3
99
57.2
100
96
100
0
V9
50
1
98.7 100
63.2
99.1
78.6
100
100
98.7
99.2
89.9
V10
V11
V12
50
50
50
47.5
37.2
37.3
87.3
83.7
98.5
75.2
82.4
72.2
100
100
78.9
78.9
97.7
100
V13
V14
V15
50
1
97.3 100
18.2 61.3
98.4
55.3
100
84.2
100
0
Compounds (V1, V6, V8, V9, V13-V15, V17, V19) with higher
inhibition rates (>90% for all five fungi at 50 μg/mL concentra-
tion) were further bioassayed at a concentration of 1 μg/mL. The
bioassay result showed that compounds V1, V9, and V15 possess
higher antifungal activities comparable to those of commercial
fungicides tebuconazole and difenoconazole.
50
1
100
57.2
100
96.9
100
100
89.5
100
76.2
82.7
50
1
100
100
86.7
100
100
74.6
100
68.7
67.2
72.1
In conclusion, by introducing the arylphenyl ether group in
triazole alcohol compounds, a new type of fungicidal candidate
was synthesized and explored. When the substituents R2 were
smaller alkylamino/alkoxy groups (such as methylamino, meth-
oxy) or a triazole group, the new target compounds showed
higher antifungal activities comparable to those of commercial
fungicides tebuconazole and difenoconazole.
V16
V17
50
84.3
73.2
100.0
87.9
57.1
50
1
95
21.8
97.5
75.0
100
95.9
49.3
100
39.5
90.0
85.3
V18
V19
50
100.0
78.2
100.0
100.0
50
1
98
0
100
99
37.5
100
99
17.9
20.0
48.7
LITERATURE CITED
V20a
V21a
V22a
V23a
V24a
V25a
V26a
V27a
50
50
50
50
50
50
50
50
64.3
77.2
37.2
50.3
51.8
61.4
53.6
61.4
81.2
76.8
54.4
60.7
63.2
55.0
66.7
55.0
100
67.9
64.1
58.7
79.3
59.3
64.5
64.6
52.1
68.7
57.1
50.9
51.8
60.2
55.4
57.1
65.9
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95.0
97.8
92.4
95.0
91.3
100.0
99.3
difenoconazole
tebuconazole
50
1
100
99.2
95
100
100
99.9
53.1
73.9
56.7
69.7
50
1
100
100
65.5
100
100.0
68.2
100.0
65.6
86.9
91.0
a These compounds and their antifungal activities had been reported in refs (14)
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Received January 20, 2009. Revised manuscript received April 16,
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