Chiral γ-aryl-1H-1,2,4-triazole derivatives as highly potential antifungal agents: Design, synthesis, structure, and in vitro fungicidal activities

Article abstract of DOI:10.1021/jf8026843

A novel series of chiral γ-aryl-1H-1,2,4-triazole derivatives as highly potential antifungal agents have been designed and synthesized conveniently by using the chiral auxiliary as a controlling reagent. All of the compounds exhibit moderate to high ee va

Full text of DOI:10.1021/jf8026843

J. Agric. Food Chem. 2008, 56, 11367–11375 11367
Chiral γ-Aryl-1H-1,2,4-triazole Derivatives as Highly
Potential Antifungal Agents: Design, Synthesis,
Structure, and in Vitro Fungicidal Activities
XIUFANG CAO, FEI LI, MING HU, WENCHANG LU, GUANG-AO YU, AND
SHENG HUA LIU*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, People’s Republic of China
A novel series of chiral γ-aryl-1H-1,2,4-triazole derivatives as highly potential antifungal agents have
been designed and synthesized conveniently by using the chiral auxiliary as a controlling reagent.
All of the compounds exhibit moderate to high ee values reaching up to 99%, and the preliminary
bioassay results demonstrated that most of the target compounds take on a significantly wide spectrum
activity against Fusarium oxysporium, Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae,
Dothiorella gregaria, and Colletotrichum gossypii species.
KEYWORDS: Synthesis; chirality; 1,2,4-triazole; antifungal activities
INTRODUCTION
curative, and eradicant power toward a wide spectrum of crop
diseases, and they all have an asymmetrically substituted carbon
atom leading to two enantiomers.
The application of agrochemicals to protect vegetable and
cereal crops is an established part of conventional agriculture.
This has provided healthy crops and increased yields as well
as economic benefits for over many years. The main purpose
of the research for agrochemicals is to develop novel active
compounds with lower application doses, high selectivity, and
reduced undesired environmental impact (1, 2). The azole
fungicides, which were synthesized for the first time in the early
1970s for the protection of various crops, represent an important
class of agrochemicals (3). The introduction of these sterol
biosynthesis inhibitors represented a significant progress in the
chemical control of fungal diseases. This class of pesticide
includes several excellent systemic fungicides with long, protec-
tive, and curative activity against a broad spectrum of foliar,
root, and seedling diseases caused by many ascomycetes,
basidiomycetes, and imperfect fungi (4, 5).
Many of the most widely prescribed pesticides have optical
isomers. At present, there are approximately 650 pesticides in
the market, one-fourth of which have optical enantiomers.
However, an important percentage is produced, marketed, and
used in the form of racemates. The presence of a nonactive or
less active stereoisomer only contributes to the increase of the
levels of pollution without any benefit or relevant purpose.
Therefore, the use of chiral pesticides has given rise to the
research for new and effective methods of resolving enantio-
meric mixtures. Triazole derivatives such as diniconazole,
tebuconazole, hexaconazole, triadimefon, triadimenol, and so
on (Figure 1) represent the most important category of
fungicides to date. These compounds have excellent protective,
It is well-known that enantiomers can display different
biological activities (6-10). Most of the published papers are
focused on the separation of chiral pharmaceutical products as
a result of the more severe guidelines for marketing new chiral
drugs. However, it should be recognized that the same principles
are important for pesticides containing stereogenic centers. A
better knowledge of the individual degradation or toxicological
data of each enantiomer could reduce the amount of pesticide
used, decrease undesired ecological impact, and avoid the
unnecessary stereoisomer. Most of triazole pesticides have
stereogenic centers that can lead to one or two pairs of
enantiomers. These enantiomers can lead to important conse-
quences regarding their bioactivity. For instance, in the case of
the triadimenol (Figure 1), each enantiomer causes a different
biological response (11). The biological activity of the threo
diastereomer is higher than that of the erythro diastereomer
(12, 13). The two enantiomers of a wide range of chiral drugs
show differences in terms of bioavailability, distribution,
metabolic, and excretion behavior (14). Very often, one enan-
tiomer represents the needed activity, while the other one might
be active in a different way, contributing to side effects,
displaying toxicity, or acting as an antagonist. Nevertheless,
most of the triazole pesticides, with the exception of uniconazole
and diniconazole, are commercialized as racemic mixtures (15).
The questions concerning the synthetic method of pure active
enantiomers and the influence of stereochemistry upon biological
activity for chiral triazole pesticides are therefore of particular
interest in this study.
The goal of developing safer and more effective chiral drugs,
including medicine and agrochemicals, encouraged us to produce
* To whom correspondence should be addressed. E-mail: chshliu@
mail.ccnu.edu.cn.
10.1021/jf8026843 CCC: $40.75  2008 American Chemical Society
Published on Web 11/11/2008

11368 J. Agric. Food Chem., Vol. 56, No. 23, 2008
Cao et al.
Figure 1. Some representative structures of triazole fungicides containing an asymmetrical carbon atom.
Scheme 1. Synthesis of γ-Aryl-1,2,4-triazole Derivatives 5a
a Reagents and conditions: (i) NaH, THF, 24 h. (ii) RMgX, THF, -78 °C. (iii) NaBH4, aqueous THF. (iv) CBr4, PPh3, CH2Cl2. (v) 1H-1,2,4-trizaloe, K2CO3,
MeCN, reflux, 5-7 h.
tal analyses were performed on a Vario EL III elemental analysis
instrument. Optical rotations were measured on a JASCO P-1010
polarimeter. Melting points were taken on a Buchi B-545 melting point
apparatus and were uncorrected.
General Synthetic Procedure for N-Enoylsultams 1. The chiral
intermediates 1a-d were prepared following the literature methods,
and their spectral and analytical data were the same as those given in
the literature (16-19).
pure active enantiomers. As part of our agrochemistry program
aimed at researching for active chiral trizole derivatives, we
report in this work our effort to design, distereoselectively
synthesize, and investigate the in vitro fungicidal activities of
novel chiral γ-aryl-1H-1,2,4-triazole derivatives. All of the pure
3R- and 3S-γ-aryl-1H-1,2,4-triazole derivatives 5 were obtained
conveniently by using the chiral auxiliary (Oppolzer’s sultam),
as shown in Scheme 1, with the high ee value of the triazoles
reaching up to 99%. The preliminary in vitro assays showed
that compounds 5e-R, 5f-R, 5i-R, 5i-S, and 5j-R have better
fungicidal activities at the concentration of 100 µg/mL. The
compound 5i-R had a comparably high inhibitory rate and broad
spectrum of activity than Bayleton against all of the fungal
pathogens tested at the concentration of 50 µg/mL. The
structure-activity relationships have been discussed further.
General Synthetic Procedure for the Compounds 2. A solution of
1 (10 mmoL) in anhydrous THF (40 mL) under a nitrogen atmosphere
was cooled to -78 °C, to which alkylmagnesium bromide (10 mL, 22
mmoL) was added dropwise. The mixture was stirred at -78 °C for
3 h. After completion of the reaction, saturated aqueous NH4Cl was
added, and the organic layer was extracted with Et2O (2 × 100 mL).
The combined organic layers were washed with brine (100 mL), dried
over anhydrous MgSO4, and filtered. The filtrate was concentrated under
reduced pressure to obtain crude product. The crude product was
purified by crystallization or by flash chromatography to afford the
desired product. The spectral and analytical data of compounds 2a-R,
2b-R, 2c-R, 2e-R, 2f-R, 2h-R, 2i-R, and 2j-R were the same as those in
the literature (20).
N-[(3S)-3-Phenyl-pentanoyl]bornane-10,2-sultam (2a-S). White solid;
mp 98-100 °C; yield 79%. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J
) 7.6 Hz, 3H), 0.96 (s, 3H), 1.17 (s, 3H), 1.31-1.36 (m, 2H),
1.57-1.69 (m, 2H), 1.87-1.88 (m, 3H), 2.01-2.02(m, 2H), 2.98-3.02
(m, 2H), 3.07-3.12 (m, 1H), 3.40 (d, J ) 13.6 Hz, 1H), 3.48 (d, J )
14.0 Hz, 1H), 3.79-3.82 (m, 1H), 7.18-7.21 (m, 3H), 7.27-7.30 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 11.8, 19.7, 20.7, 26.2, 29.1, 32.6,
38.3, 41.8, 43.0, 44.4, 47.5, 48.1, 52.8, 65.0, 126.2, 127.5, 128.1, 143.5,
MATERIALS AND METHODS
Chemistry. Unless otherwise noted, all materials were commercially
available and were used directly without further purification. All
solvents were redistilled before use. Fusarium oxysporium, Rhizoctonia
solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, and
Colletotrichum gossypii were provided through the courtesy of the
1
Center for Bioassay, Central China Normal University. H NMR and
13C NMR spectra were recorded on a Mercury-Plus 400 spectrometer
at 400 or 600 MHz, respectively. The chemical shifts are reported
relative to CDCl3 with TMS as the internal reference. MS spectra were
determined using a TraceMS 2000 organic mass spectrometer. Elemen-

Fungicidal Activities of Chiral Triazole
J. Agric. Food Chem., Vol. 56, No. 23, 2008 11369
170.4. Anal. calcd for C21H29NO3S: C, 67.17; H, 7.78; N, 3.73; S, 8.54.
Found: C, 66.67; H, 7.31; N, 3.53; S, 8.93.
Table 1. ee Value Properties of Compounds 5
compound
R
Ar
configuration
yielda
ee (%)b
N-[(3S)-3-(4-Fluorophenyl)pentanoyl]bornane-10,2-sultam (2b-S).
White solid; mp 108-110 °C; yield 83%. 1H NMR (400 MHz, CDCl3):
δ 0.77 (t, J ) 7.6 Hz, 3H), 0.96 (s, 3H), 1.15 (s, 3H), 1.31-1.36 (m,
2H), 1.58-1.68 (m, 2H), 1.84-1.89 (m, 3H), 2.01-2.02 (m, 2H),
2.99-3.14 (m, 2H), 3.40 (d, J ) 14.0 Hz, 1H), 3.48 (d, J ) 13.6 Hz,
5a-R
5a-S
5b-R
5b-S
5c-R
5c-S
5d-R
5d-S
5e-R
5e-S
5f-R
5f-S
5g-R
5g-S
5h-R
5h-S
5i-R
Et
Et
Et
Et
Et
Et
Et
Et
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
68
75
87
79
69
80
78
79
80
75
74
76
73
63
75
77
78
78
72
74
98
98
82
85
84
80
>99
70
92
95
82
84
72
86
80
88
86
84
96
97
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
Ph
1H), 3.78-3.80 (m, 1H), 6.94-6.98 (m, 2H), 7.14-7.18 (m, 2H). 13
C
NMR (100 MHz, CDCl3): δ 11.7, 19.6, 20.6, 26.2, 29.1, 32.5, 38.2,
41.8, 42.2, 44.3, 47.5, 48.1, 52.7, 64.9, 114.8, 128.9, 139.1, 161.1, 170.1.
Anal. calcd for C21H28FNO3S: C, 64.10; H, 7.17; N, 3.56; S, 8.15.
Found: C, 64.36; H, 7.09; N, 3.46; S, 8.37.
Ph
N-[(3S)-3-(4-Chlorophenyl)pentanoyl]bornane-10,2-sultam (2c-S).
White solid; mp 100-102 °C; yield 82%. 1H NMR (400 MHz, CDCl3):
δ 0.77 (t, J ) 7.2 Hz, 3H), 0.97 (s, 3H), 1.16 (s, 3H), 1.31-1.34 (m,
2H), 1.65-1.68 (m, 2H), 1.85-1.89 (m, 3H), 2.01-2.02 (m, 2H),
3.01-3.13 (m, 2H), 3.40 (d, J ) 14.0 Hz, 1H), 3.49 (d, J ) 13.6 Hz,
1H), 3.78-3.81 (m, 1H), 7.15 (d, J ) 8.4 Hz, 2H), 7.24 (d, J ) 8.4
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 11.8, 19.7, 20.7, 26.2, 29.1,
32.6, 38.2, 41.5, 43.1, 44.4, 47.5, 48.1, 52.8, 64.9, 128.3, 129.1, 131.8,
141.8, 170.3. Anal. calcd for C21H28ClNO3S: C, 61.52; H, 6.88; N,
3.42; S, 7.82. Found: C, 61.88; H, 7.02; N, 3.36; S, 8.06.
4-FC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
5i-S
5j-R
5j-S
a Isolated yields. b Determined by HPLC analysis (Chiralcel OJ-H or OD-H).
N-[(3R)-3-(4-Methoxyphenyl)pentanoyl]bornane-10,2-sultam (2d-R).
White solid; mp 130-132 °C; yield 79%. 1H NMR (400 MHz, CDCl3):
δ 0.76 (t, J ) 7.2 Hz, 3H), 0.96 (s, 3H), 1.16 (s, 3H), 1.30-1.36 (m,
2H), 1.63-1.66 (m, 3H), 1.87-1.88 (m, 3H), 2.01-2.02 (m, 2H),
2.97-3.09 (m, 3H), 3.41 (d, J ) 14.0 Hz, 1H), 3.45 (d, J ) 14.0 Hz,
1H), 3.77 (s, 3H), 3.80-3.82 (m, 1H), 6.81-6.83 (m, 2H), 7.11-7.13
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 11.7, 19.7, 20.7, 26.2, 29.2,
32.6, 38.3, 42.0, 42.3, 44.4, 47.5, 48.1, 52.7, 54.9, 65.0, 113.4, 128.4,
135.6, 157.8, 170.5. Anal. calcd for C22H31NO4S: C, 65.15; H, 7.70;
N, 3.45; S, 7.91. Found: C, 64.88; H, 7.62; N, 3.56; S, 8.22.
7.2 Hz, 3H), 0.96 (s, 3H), 1.17 (s, 3H), 1.12-1.35 (m, 6H), 1.63-1.65
(m, 2H), 1.86-1.88 (m, 3H), 2.0-2.02 (m, 2H), 3.05-3.07 (m, 2H),
3.21-3.23 (m, 1H), 3.40 (d, J ) 14.0 Hz, 1H), 3.48 (d, J ) 13.6 Hz,
1H), 3.78-3.81 (m, 1H), 7.18-7.21 (m, 3H), 7.26-7.29 (m, 2H). 13
C
NMR (100 MHz, CDCl3): δ 13.8, 19.7, 20.7, 22.4, 26.2, 29.2, 32.5,
35.9, 38.2, 41.4, 42.1, 44.3, 47.5, 48.1, 52.7, 64.9, 126.1, 127.4, 128.1,
143.8, 170.4. Anal. calcd for C23H33NO3S: C, 68.45; H, 8.24; N, 3.47;
S, 7.95. Found: C, 68.57; H, 8.16; N, 3.31; S, 8.09.
N-[(3S)-3-(4-Methoxyphenyl)pentanoyl]bornane-10,2-sultam (2d-S).
Yield 74%. The spectroscopic data were the same as those of 2d-R.
N-[(3S)-3-Phenyl-hexanoyl]bornane-10,2-sultam (2e-S). White solid;
N-[(3S)-3-(4-Fluorophenyl)heptanoyl]bornane-10,2-sultam (2i-S). White
solid; mp 93-95 °C; yield 82%. 1H NMR (400 MHz, CDCl3): δ
0.79-0.84 (m, 3H), 0.96 (s, 3H), 1.16 (s, 3H), 1.05-1.38 (m, 6H),
1.54-1.63 (m, 2H), 1.85-1.89 (m, 3H), 2.0-2.01 (m, 2H), 3.0-3.03
(m, 2H), 3.20-3.21 (m, 1H), 3.42 (d, J ) 13.6 Hz, 1H), 3.49 (d, J )
13.6 Hz, 1H), 3.78-3.81 (m, 1H), 6.93-6.98 (m, 2H), 7.15-7.18 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 13.8, 19.7, 20.7, 22.4, 26.2, 29.2,
32.6, 36.1, 38.2, 40.7, 42.2, 44.4, 47.5, 48.1, 52.8, 65.0, 114.8, 129.0,
139.5, 161.2, 170.2. Anal. calcd for C23H32FNO3S: C, 65.53; H, 7.65;
N, 3.32; S, 7.61. Found: C, 65.46; H, 7.66; N, 3.22; S, 7.95.
1
mp 108-109 °C; yield 85%. H NMR (400 MHz, CDCl3): δ 0.83 (t,
J ) 7.2 Hz, 3H), 0.96 (s, 3H), 1.12 (s, 3H), 1.14-1.20 (m, 1H),
1.30-1.36 (m, 2H), 1.56-1.62 (m, 3H), 1.84-1.88 (m, 3H), 2.01-2.02
(m, 2H), 2.98-3.10 (m, 2H), 3.23-3.26 (m, 1H), 3.40 (d, J ) 13.6
Hz, 1H), 3.49 (d, J ) 14.0 Hz, 1H), 3.78-3.81 (m, 1H), 7.17-7.21
(m, 3H), 7.26-7.29 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 13.8,
19.7, 20.2, 20.7, 26.2, 32.5, 38.2, 38.4, 41.2, 42.1, 44.4, 47.5, 48.1,
52.7, 64.9, 126.1, 127.4, 128.1, 143.8, 170.4. Anal. calcd for
C22H31NO3S: C, 67.83; H, 8.02; N, 3.60; S, 8.23. Found: C, 68.09; H,
8.30; N, 3.55; S, 8.53.
N-[(3S)-3-(4-Chlorophenyl)heptanoyl]bornane-10,2-sultam
(2j-S).
White solid; mp 116-117 °C; yield 87%. 1H NMR (400 MHz, CDCl3):
δ 0.81 (t, J ) 7.2 Hz, 3H), 0.96 (s, 3H), 1.15 (s, 3H), 1.05-1.39 (m,
6H), 1.54-1.63 (m, 2H), 1.85-1.89 (m, 3H), 2.0-2.01 (m, 2H),
3.0-3.03 (m, 2H), 3.18-3.20 (m, 1H), 3.41 (d, J ) 13.6 Hz, 1H),
3.49 (d, J ) 13.6 Hz, 1H), 3.77-3.80 (m, 1H), 7.14 (d, J ) 8.4 Hz,
2H), 7.24 (d, J ) 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 13.8,
19.7, 20.6, 22.3, 26.2, 29.1, 32.5, 35.9, 38.2, 40.7, 41.9, 44.4, 47.5,
48.1, 52.7, 64.9, 128.2, 128.8, 131.6, 142.4, 170.0. Anal. calcd for
C23H32ClNO3S: C, 63.07; H, 7.36; N, 3.20; S, 7.32. Found: C, 63.32;
H, 7.42; N, 3.17; S, 7.52.
N-[(3S)-3-(4-Fluorophenyl)hexanoyl]bornane-10,2-sultam (2f-S). White
solid; mp 96-98 °C; yield 86%. 1H NMR (400 MHz, CDCl3): δ 0.83
(t, J ) 7.2 Hz, 3H), 0.96 (s, 3H), 1.13-1.14 (m, 2H), 1.15 (s, 3H),
1.30-1.36 (m, 2H), 1.54-1.61 (m, 2H), 1.84-1.88 (m, 3H), 2.0-2.01(m,
2H), 2.98-3.03 (m, 2H), 3.22-3.24 (m, 1H), 3.40 (d, J ) 14.0 Hz,
1H), 3.49 (d, J ) 13.6 Hz, 1H), 3.77-3.80 (m, 1H), 6.93-6.98 (m,
2H), 7.15-7.18 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 13.8, 19.7,
20.2, 20.7, 26.2, 32.6, 38.2, 38.5, 40.4, 42.1, 44.4, 47.5, 48.1, 52.8,
65.0, 114.9, 128.8, 139.5, 161.2, 170.2. Anal. calcd for C22H30FNO3S:
C, 64.84; H, 7.42; N, 3.44; S, 7.87. Found: C, 64.96; H, 7.38; N, 3.42;
S, 7.96.
(3R)-3-(4-Methoxyphenyl)hexanoyl]bornane-10,2-sultam (2g-R). White
solid; mp 108-109 °C; yield 88%. 1H NMR (600 MHz, CDCl3): δ
0.84 (t, J ) 7.2 Hz, 3H), 0.96 (s, 3H), 1.13-1.18 (m, 5H), 1.31-1.35
(m, 2H), 1.55-1.59 (m, 2H), 1.84-1.88 (m, 3H), 2.0-2.04 (m, 2H),
2.94-3.06 (m, 2H), 3.18-3.19 (m, 1H), 3.40 (d, J ) 13.8 Hz, 1H),
3.48 (d, J ) 13.8 Hz, 1H), 3.75-3.81 (m, 4H), 6.82 (d, J ) 8.4 Hz,
2H), 7.12 (d, J ) 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 13.8,
19.7, 20.2, 20.7, 26.2, 32.6, 38.3, 38.6, 40.4, 42.4, 44.4, 47.5, 48.1,
52.8, 54.9, 65.0, 113.5, 128.3, 135.9, 157.7, 170.5. Anal. calcd for
C23H33NO4S: C, 65.84; H, 7.93; N, 3.34; S, 7.64; Found: C, 65.96; H,
7.88; N, 3.36; S, 7.87.
General Synthetic Procedure for the Compounds 3. A solution of
sodium borohydride (40 mmol; 4 equivalents) in water (10 mL) was
added dropwise to a cooled (ice water) solution of 2 (10 mmol) in
THF (30 mL). The mixture was stirred at room temperature, and the
completion of the reaction was monitored by TLC. To the reaction
mixture was added 2 mol/L HCl at a rate to maintain the internal
temperature at 20-25 °C. The reaction mixture was extracted with ethyl
acetate (2 × 50 mL). The combined organic layers were washed with
brine (50 mL), concentrated, and purified by silica gel chromatography
to obtain the desired products. The spectral and analytical data of
compounds 3a-R (21), 3b-R, 3c-R, 3e-R, 3f-R, 3h-R (22-24), 3i-R,
and 3j-R were the same as those given in the literature (22-24).
1
(3S)-3-Phenylpentan-1-ol (3a-S). Colorless oil; yield 87%. H NMR
(400 MHz, CDCl3): δ 0.78 (t, J ) 7.6 Hz, 3H), 1.12 (s, 1H), 1.56-1.59
(m, 1H), 1.61-1.71 (m, 1H), 1.79-1.83 (m, 1H), 1.94-1.98 (m, 1H),
2.57-2.61 (m, 1H), 3.48-3.53 (m, 2H), 7.15-7.21 (m, 3H), 7.23-7.31
(m, 2H). Anal. calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.28;
N-[(3S)-3-(4-Methoxyphenyl)hexanoyl]bornane-10,2-sultam (2g-S).
Yield 87%. The spectroscopic data were the same as those of 2g-R.
N-[(3S)-3-Phenyl-heptanoyl]bornane-10,2-sultam (2h-S). White solid;
mp 63-64 °C; yield 83%. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J )

11370 J. Agric. Food Chem., Vol. 56, No. 23, 2008
Cao et al.
(3S)-3-(4-Fluorophenyl)heptan-1-ol (3i-S). Colorless oil; yield 87%.
1H NMR (400 MHz, CDCl3): δ 0.82 (t, J ) 7.2 Hz, 3H), 1.05-1.29
(m, 5H), 1.51-1.64 (m, 2H), 1.73-1.77 (m, 1H), 1.90-1.93 (m, 1H),
2.65-2.69 (m, 1H), 3.44-3.52 (m, 2H), 6.95-7.0 (m, 2H), 7.09-7.13
(m, 2H). Anal. calcd for C13H19FO: C, 74.25; H, 9.11. Found: C, 74.33;
H, 9.37.
(3S)-3-(4-Chlorophenyl)heptan-1-ol (3j-S). Colorless oil; yield 90%.
1H NMR (600 MHz, CDCl3): δ 0.82 (t, J ) 7.2 Hz, 3H), 1.08-1.28
(m, 5H), 1.53-1.62 (m, 2H), 1.74-1.75 (m, 1H), 1.91-1.93 (m, 1H),
2.67-2.68 (m, 1H), 3.43-3.44 (m, 1H), 3.51-3.52 (m, 1H), 7.10 (d,
J ) 8.4 Hz, 2H), 7.26 (d, J ) 8.4 Hz, 2H). Anal. calcd for C13H19ClO:
C, 68.86; H, 8.45. Found: C, 68.72; H, 8.63.
General Synthetic Procedure for the Compounds 4. A solution of
(0.027 mmoL) triphenylphosphine in methylene chloride (15 mL) was
added dropwise to a cooled (ice water) methylene chloride (10 mL)
solution of 3 (0.01moL) and carbon tetrabromide (0.027 moL). The
mixture was stirred 10-15 h at room temperature. After completion
of the reaction, the solution was filtered to remove the triphenylphos-
phine oxide. The filtrate was evaporated under reduced pressure to give
crude product. The crude product was purified by column chromatog-
raphy to give pure product as a colorless oil.
Figure 2. Molecular structure of compound 5d-R.
H, 9.98. All spectroscopic data were in agreement with those reported
in the literature (25, 26).
(3S)-3-(4-Fluorophenyl)pentan-1-ol (3b-S). Colorless oil; yield 88%.
1H NMR (600 MHz, CDCl3): δ 0.77 (t, J ) 7.2 Hz, 3H), 1.16 (s, 1H),
1.56-1.60 (m, 1H), 1.67-1.68 (m, 1H), 1.74-1.77 (m, 1H), 1.94-1.95
(m, 1H), 2.59-2.60 (m, 1H), 3.45 (s, 1H), 3.53 (s, 1H), 6.97-7.00
(m, 2H), 7.10-7.12 (m, 2H). Anal. calcd for C11H15FO: C, 72.50; H,
8.30. Found: C, 72.34; H, 8.58.
(3S)-3-(4-Chlorophenyl)pentan-1-ol (3c-S). Colorless oil; yield 90%.
1H NMR (600 MHz, CDCl3): δ 0.77 (t, J ) 7.2 Hz, 3H), 1.22 (s, 1H),
1.55-1.56 (m, 1H), 1.67-1.69 (m, 1H), 1.75-1.77 (m, 1H), 1.92-1.96
(m, 1H), 2.59-2.60 (m, 1H), 3.43-3.45 (m, 1H), 3.52-3.54 (m, 1H),
7.10 (d, J ) 8.4 Hz, 2H), 7.26 (d, J ) 8.4 Hz, 2H). Anal. calcd for
C11H15ClO: C, 66.49; H, 7.61. Found: C, 66.21; H, 7.56. All
spectroscopic data were in agreement with those reported in the
literature (27).
1
(3R)-3-Phenyl-1-bromopentane (4a-R). Colorless oil; yield 87%. H
NMR (400 MHz, CDCl3): δ 0.80 (t, J ) 7.2 Hz, 3H), 1.60-1.71 (m,
2H), 2.08-2.22 (m, 2H), 2.64-2.69 (m, 1H), 3.08-3.15 (m, 1H),
3.26-3.32 (m, 1H), 7.16-7.33 (m, 5H). All spectroscopic data were
in agreement with those reported in the literature (31, 32).
(3S)-3-Phenyl-1-bromopentane (4a-S). Colorless oil; yield 83%. The
spectroscopic data were the same as those of 4a-R.
(3R)-3-(4-Fluorophenyl)-1-bromopentane (4b-R). Colorless oil; yield
88%. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J ) 7.2 Hz, 3H),
1.55-1.70 (m, 2H), 2.02-2.07 (m, 1H), 2.15-2.18 (m, 1H), 2.66-2.69
(m, 1H), 3.07-3.10 (m, 1H), 3.26-3.32 (m, 1H), 7.0 (t, J ) 8.4 Hz,
2H), 7.10-7.14 (m, 2H).
(3S)-3-(4-Fluorophenyl)-1-bromopentane (4b-S). Colorless oil; yield
90%. The spectroscopic data were the same as those of 4b-R.
(3R)-3-(4-Chlorophenyl)-1-bromopentane (4c-R). Colorless oil; yield
76%. 1H NMR (600 MHz, CDCl3): δ 0.78 (t, J ) 7.2 Hz, 3H),
1.55-1.70 (m, 2H), 2.01-2.05 (m, 1H), 2.15-2.18 (m, 1H), 2.66-2.69
(m, 1H), 3.05-3.09 (m, 1H), 3.27-3.31 (m, 1H), 7.11 (d, J ) 8.4 Hz,
2H), 7.25-7.29 (m, 2H).
(3S)-3-(4-Chlorophenyl)-1-bromopentane (4c-S). Colorless oil; yield
71%. The spectroscopic data were the same as those of 4c-R.
(3R)-3-(4-Methoxyphenyl)-1-bromopentane (4d-R). Colorless oil; yield
82%. 1H NMR (600 MHz, CDCl3): δ 0.78 (t, J ) 7.2 Hz, 3H),
1.55-1.59 (m, 1H), 1.64-1.67 (m, 1H), 2.0-2.05 (m, 1H), 2.14-2.17
(m, 1H), 2.60-2.63 (m, 1H), 3.08-3.11 (m, 1H), 3.27-3.30 (m, 1H),
3.81 (s, 3H), 6.85 (d, J ) 6.6 Hz, 2H), 7.07 (d, J ) 7.2 Hz, 2H).
(3S)-3-(4-Methoxyphenyl)-1-bromopentane (4d-S). Colorless oil; yield
78%. The spectroscopic data were the same as those of 4d-R.
(3R)-3-Phenyl-1-bromohexane (4e-R). Colorless oil; yield 85%. 1H
NMR (400 MHz, CDCl3): δ 0.85 (t, J ) 7.2 Hz, 3H), 1.14-1.22 (m,
2H), 1.55-1.63 (m, 2H), 2.07-2.17 (m, 2H), 2.77 (m, 1H), 3.09-3.13
(m, 1H), 3.25-3.29 (m, 1H), 7.15-7.22 (m, 2H), 7.28-7.32 (m, 3H).
All spectroscopic data were in agreement with those reported in the
literature (33).
(3R)-3-(4-Methoxyphenyl)pentan-1-ol (3d-R). Colorless oil; yield 92%.
1H NMR (400 MHz, CDCl3): δ 0.77 (t, J ) 7.2 Hz, 3H), 1.32 (s, 1H),
1.50-1.79 (m, 3H), 1.88-1.95 (m, 1H), 2.51-2.55 (m, 1H), 3.42-3.55
(m, 2H), 3.78 (s, 3H), 6.84 (d, J ) 8.8 Hz, 2H), 7.07 (d, J ) 8.8 Hz,
2H). Anal. calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 73.98; H,
9.38. All spectroscopic data were in agreement with those reported in
the literature (27).
(3S)-3-(4-Methoxyphenyl)pentan-1-ol (3d-S). Colorless oil; yield 90%.
The spectroscopic data were the same as those of 3d-R.
1
(3S)-3-Phenylhexan-1-ol (3e-S). Colorless oil; yield 92%. H NMR
(600 MHz, CDCl3): δ 0.84 (t, J ) 7.2 Hz, 3H), 1.14-1.19 (m, 3H),
1.57-1.61 (m, 2H), 1.80-1.81 (m, 1H), 1.92-1.93 (m, 1H), 2.69-2.70
(m, 1H), 3.45-3.46 (m, 1H), 3.52-3.53 (m, 1H), 7.16-7.20 (m, 3H),
7.26-7.30 (m, 2H). Anal. calcd for C12H18O: C, 80.85; H, 10.18. Found:
C, 80.68; H, 9.98. All spectroscopic data were in agreement with those
reported in the literature (28, 29).
(3S)-3-(4-Fluorophenyl)hexan-1-ol (3f-S). Colorless oil; yield 89%.
1H NMR (600 MHz, CDCl3): δ 0.84 (t, J ) 7.2 Hz, 3H), 1.13-1.18
(m, 3H), 1.52-1.62 (m, 2H), 1.74-1.76 (m, 1H), 1.91-1.93 (m, 1H),
2.70-2.71 (m, 1H), 3.43-3.44 (m, 1H), 3.52-3.53 (m, 1H), 6.96-7.0
(t, J ) 8.4 Hz, 2H), 7.10-7.13 (m, 2H). Anal. calcd for C12H17FO: C,
73.44; H, 8.73; Anal. calcd for C12H17FO: C, 73.44; H, 8.73. Found:
C, 73.18; H, 8.47.
(3R)-3-(4-Methoxyphenyl)hexan-1-ol (3g-R). Colorless oil; yield 92%.
1H NMR (400 MHz, CDCl3): δ 0.84 (t, J ) 7.2 Hz, 3H), 1.12-1.15
(m, 2H), 1.27 (s, 1H), 1.53-1.57 (m, 2H), 1.73-1.75 (m, 1H),
1.88-1.91 (m, 1H), 2.64 (m, 1H), 3.44-3.50 (m, 2H), 3.78 (s, 3H),
6.83 (d, J ) 8.4 Hz, 2H), 7.07 (d, J ) 8.8 Hz, 2H). Anal. calcd for
C13H20O2: C, 74.96; H, 9.68. Found: C, 74.85; H, 9.81.
(3S)-3-Phenyl-1-bromohexane (4e-S). Colorless oil; yield 89%. The
spectroscopic data were the same as those of 4e-R.
(3R)-3-(4-Fluorophenyl)-1-bromohexane (4f-R). Colorless oil; yield
79%. 1H NMR (400 MHz, CDCl3): δ 0.85 (t, J ) 7.2 Hz, 3H),
1.12-1.20 (m, 2H), 1.53-1.61 (m, 2H), 2.01-2.16 (m, 2H), 2.76-2.79
(m, 1H), 3.03-3.09 (m, 1H), 3.26-3.31 (m, 1H), 6.97-7.01 (m, 2H),
7.11-7.14 (m, 2H).
(3S)-3-(4-Methoxyphenyl)hexan-1-ol (3g-S). Colorless oil; yield 88%.
The spectroscopic data were the same as those of 3g-R.
(3S)-3-(4-Fluorophenyl)-1-bromohexane (4f-S). Colorless oil; yield
85%. The spectroscopic data were the same as those of 4f-R.
(3R)-3-(4-Methoxyphenyl)-1-bromohexane (4g-R). Colorless oil; yield
89%. 1H NMR (600 MHz, CDCl3): δ 0.85 (t, J ) 7.2 Hz, 3H),
1.14-1.20 (m, 2H), 1.54-1.58 (m, 2H), 2.0-2.04 (m, 1H), 2.12-2.17
(m, 1H), 2.71-2.73 (m, 1H), 3.07-3.11 (m, 1H), 3.26-3.30 (m, 1H),
3.80 (s, 3H), 6.85 (d, J ) 8.4 Hz, 2H), 7.08 (d, J ) 8.4 Hz, 2H).
(3S)-3-(4-Methoxyphenyl)-1-bromohexane (4g-S). Colorless oil; yield
90%. The spectroscopic data were the same as those of 4g-R.
(S)-3-Phenylheptan-1-ol (3h-S). Colorless oil; yield 93%. 1H NMR
(600 MHz, CDCl3): δ 0.83 (t, J ) 7.2 Hz, 3H), 1.08-1.18 (m, 3H),
1.20-1.29 (m, 2H), 1.60-1.65 (m, 2H), 1.78-1.82 (m, 1H), 1.93-1.96
(m, 1H), 2.66-2.69 (m, 1H), 3.46-3.47 (m, 1H), 3.52-3.53 (m, 1H),
7.16-7.21 (m, 3H), 7.26-7.30 (m, 2H). Anal. calcd for C13H20O: C,
81.20; H, 10.48. Found: C, 81.05; H, 10.61. All spectroscopic data
were in agreement with those reported in the literature (30).

Fungicidal Activities of Chiral Triazole
J. Agric. Food Chem., Vol. 56, No. 23, 2008 11371
Figure 3. Packing diagram of the unit cell of compound 5d-R.
Table 2. In Vitro Fungicidal Activities of Compounds 5a-j (100 mg L-1, Inhibitory Rate Percent)a
inhibitory rate (%)
compound
R
Ar
configuration
F. oxysporium
R. solani
B. cinereapers
G. zeae
D. gregaria
C. gossypii
5a-R
5a-S
5b-R
5b-S
5c-R
5c-S
5d-R
5d-S
5e-R
5e-S
5f-R
Et
Et
Et
Et
Et
Et
Et
Et
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
60 ( 2
55 ( 3
50 ( 2
60 ( 3
91 ( 2
80 ( 1
65 ( 3
40 ( 3
80 ( 2
55 ( 3
82 ( 1
73 ( 2
90 ( 1
75 ( 2
66 ( 3
74 ( 3
100 ( 1
96 ( 1
82 ( 2
78 ( 2
97 ( 1
80 ( 3
75 ( 3
82 ( 2
85 ( 2
85 ( 2
83 ( 2
60 ( 4
73 ( 3
97 ( 1
78 ( 2
90 ( 2
86 ( 3
78 ( 2
90 ( 3
90 ( 3
87 ( 2
100 ( 1
100 ( 1
91 ( 1
84 ( 2
100 ( 1
52 ( 3
52 ( 4
36 ( 5
52 ( 4
94 ( 2
84 ( 3
30 ( 5
30 ( 5
98 ( 1
44 ( 4
71 ( 3
94 ( 2
60 ( 3
92 ( 1
91 ( 2
91 ( 1
100 ( 1
96 ( 1
88 ( 2
94 ( 1
96 ( 1
60 ( 2
63 ( 2
63 ( 3
56 ( 3
76 ( 2
73 ( 3
66 ( 3
42 ( 4
83 ( 3
52 ( 3
85 ( 2
83 ( 2
66 ( 3
76 ( 2
71 ( 3
71 ( 3
95 ( 1
83 ( 2
73 ( 3
69 ( 3
76 ( 2
81 ( 2
60 ( 3
82 ( 2
75 ( 2
93 ( 1
80 ( 2
82 ( 2
45 ( 4
100 ( 1
67 ( 2
100 ( 1
83 ( 2
90 ( 2
93 ( 1
100 ( 1
96 ( 1
100 ( 1
97 ( 1
100 ( 0
97 ( 1
71 ( 3
70 ( 2
50 ( 3
78 ( 2
65 ( 3
97 ( 1
85 ( 2
55 ( 4
50 ( 5
92 ( 1
75 ( 2
95 ( 1
90 ( 2
80 ( 3
90 ( 2
87 ( 2
82 ( 2
100 ( 1
95 ( 1
85 ( 2
85 ( 2
100 ( 1
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
4-FC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
Ph
5f-S
5g-R
5g-S
5h-R
5h-S
5i-R
5i-S
5j-R
5j-S
bayleton
Ph
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
a The mean value for relative inhibition was calculated from at least three determinations.
1
(3R)-3-Phenyl-1-bromoheptane (4h-R). Colorless oil; yield 91%. H
NMR (400 MHz, CDCl3): δ 0.82 (t, J ) 7.2 Hz, 3H), 1.04-1.31 (m,
4H), 1.55-1.65 (m, 2H), 2.03-2.20 (m, 2H), 2.71-2.78 (m, 1H),
3.06-3.13 (m, 1H), 3.24-3.28 (m, 1H), 7.15-7.31 (m, 5H). All
spectroscopic data were in agreement with those reported in the
literature (34).
mL), dried over anhydrous Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure to give crude product. The crude
product was purified by column chromatography to give compounds
5.
1-[(3R)-3-Phenylpentyl]-1H-1,2,4-triazole (5a-R). Colorless oil; yield
68%. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J ) 7.2 Hz, 3H),
1.58-1.68 (m, 2H), 2.07-2.09 (m, 1H), 2.30-2.39 (m, 2H), 3.93-4.0
(m, 2H), 7.12-7.13 (m, 2H), 7.23-7.24 (m, 1H), 7.29-7.35 (m, 2H),
7.89 (s, 1H), 7.96 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 11.9, 29.9,
35.6, 44.7, 47.7, 126.6, 127.5, 128.6, 143.2, 152.0. MS: m/z: 215. Anal.
calcd for C13H17N3: C, 72.52; H, 7.96; N, 19.52. Found: C, 72.38; H,
(3S)-3-Phenyl-1-bromoheptane (4h-S). Colorless oil; yield 85%. The
spectroscopic data were the same as those of 4h-R.
(3R)-3-(4-Fluorophenyl)-1-bromoheptane (4i-R). Colorless oil; yield
77%. 1H NMR (400 MHz, CDCl3): δ 0.83 (t, J ) 7.8 Hz, 3H),
1.09-1.28 (m, 4H), 1.55-1.64 (m, 2H), 2.03-2.04 (m, 1H), 2.15-2.17
(m, 1H), 2.74-2.77 (m, 1H), 3.05-3.10 (m, 1H), 3.27-3.30 (m, 1H),
6.97-7.01 (m, 2H), 7.10-7.14 (m, 2H).
(3S)-3-(4-Fluorophenyl)-1-bromoheptane (4i-S). Colorless oil; yield
88%. The spectroscopic data were the same as those of 4i-R.
(3R)-3-(4-Chlorophenyl)-1-bromoheptane (4j-R). Colorless oil; yield
85%. 1H NMR (400 MHz, CDCl3): δ 0.83 (t, J ) 7.6 Hz, 3H),
1.09-1.28 (m, 4H), 1.54-1.62 (m, 2H), 2.01-2.03 (m, 1H), 2.15-2.16
(m, 1H), 2.74-2.77 (m, 1H), 3.03-3.09 (m, 1H), 3.25-3.29 (m, 1H),
7.09-7.11 (m, 2H), 7.27-7.29 (m, 2H).
(3S)-3-(4-Chlorophenyl)-1-bromoheptane (4j-S). Colorless oil; yield
86%. The spectroscopic data were the same as those of 4j-R.
General Procedure for the Synthesis of the Title Compounds 5. A
mixture of 4 (0.05 mmol), K2CO3 (0.25 mmol), and 1H-1,2,4-triazole
(0.06 mmol) in CH3CN (25 mL) was stirred at 60-70 °C for 5-7 h.
After completion of the reaction, the reaction mixture was cooled to
room temperature and filtered. The filtrate was washed with water (5
23
7.86; N, 19.76; [R]D ) -14.0 (c 1.0, CH2Cl2); 98% ee. The
enantiomeric ratio was determined by HPLC on Chiralcel OJ-H column
(hexane/2-propanol ) 90/10, 1 mL/min), tminor ) 24.90 min, tmajor
)33.59 min.
1-[(3S)-3-Phenylpentyl]-1H-1,2,4-triazole (5a-S). Colorless oil; yield
23
75%; [R]D ) 23.3 (c 1.0, CH2Cl2); 98% ee. The enantiomeric ratio
was determined by HPLC on Chiralcel OJ-H column (hexane/2-
propanol ) 90/10, 1 mL/min), tmajor ) 23.53 min, tminor ) 35.04 min.
The spectroscopic data were the same as those of 5a-R.
1-[(3R)-3-(4-Fluorophenyl)pentyl]-1H-1,2,4-triazole (5b-R). Colorless
1
oil; yield 87%. H NMR (400 MHz, CDCl3): δ 0.75 (t, J ) 6.8 Hz,
3H), 1.54-1.59 (m, 1H), 1.65-1.71 (m, 1H), 2.01 (m, 1H), 2.32-2.39
(m, 2H), 3.95-4.02 (m, 2H), 7.01-7.11 (m, 4H), 7.96 (s, 1H), 8.03
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 11.8, 29.6, 35.9, 44.0, 47.9,
115.4, 115.6, 128.9, 128.9, 138.9, 152.1. MS: m/z: 233. Anal. calcd
for C13H16FN3: C, 66.93; H, 6.91; N, 18.01. Found: C, 66.78; H, 6.98;

11372 J. Agric. Food Chem., Vol. 56, No. 23, 2008
Cao et al.
Table 3. In Vitro Fungicidal Activities of Compounds 5i-R and 5i-S Comparison with Bayleton (50 mg L-1, Inhibitory Rate Percent)a
inhibitory rate (%)
compound
R
Ar
configuration
F. oxysporum
R. solani
B. cinereapers
G. zeae
D. gregaria
C. gossypii
5i-R
5i-S
bayleton
n-Bu
n-Bu
4-FC6H4
4-FC6H4
R
S
99 ( 1
88 ( 2
91 ( 1
99 ( 1
88 ( 1
91 ( 1
100 ( 1
81 ( 2
78 ( 2
89 ( 2
70 ( 3
59 ( 2
100 ( 1
71 ( 3
14 ( 3
100 ( 1
85 ( 2
97 ( 1
a The mean value for relative inhibition was calculated from at least three determinations.
Table 4. In Vitro Fungicidal Activities of Compounds 5i-R and 5i-S Comparison with Bayleton Expressed as 50% Effective Concentration (EC50, mM)a
EC50 (mM)
compound
R
Ar
F. oxysporum
R. solani
B. cinereapers
G. zeae
D. gregaria
C. gossypii
5i-R
5i-S
bayleton
n-Bu
n-Bu
4-FC6H4
4-FC6H4
0.112 ( 0.002
0.109 ( 0.003
0.040 ( 0.004
0.036 ( 0.005
0.049 ( 0.001
0.014 ( 0.004
0.061 ( 0.001
0.056 ( 0.004
0.041 ( 0.001
0.066 ( 0.005
0.104 ( 0.004
0.163 ( 0.003
0.015 ( 0.004
0.079 ( 0.001
0.317 ( 0.003
0.061 ( 0.001
0.063 ( 0.003
0.019 ( 0.001
a The mean value for relative inhibition was calculated from at least three determinations.
N, 17.96. [R]D23 ) -10.9 (c 0.99, CH2Cl2); 82% ee. The enantiomeric
1-[(3S)-3-Phenylhexyl]-1H-1,2,4-triazole (5e-S). Colorless oil; yield
75%; [R]D20 ) 16.9 (c 0.99, CH2Cl2); 95% ee. The enantiomeric ratio
was determined by HPLC on Chiralcel OD-H column (hexane/2-
propanol ) 90/10, 1 mL/min), tmajor ) 15.17 min, tminor ) 18.46 min.
The spectroscopic data were the same as those of 5e-R.
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tminor ) 9.80 min, tmajor ) 14.02 min.
1-[(3S)-3-(4-Fluorophenyl)pentyl]-1H-1,2,4-triazole (5b-S). Colorless
23
oil; yield 79%; [R]D ) 17.1 (c 0.98, CH2Cl2); 85% ee. The
enantiomeric ratio was determined by HPLC on Chiralcel OD-H column
1-[(3R)-3-(4-Fluorophenyl)hexyl]-1H-1,2,4-triazole (5f-R). Colorless
1
(hexane/2-propanol ) 90/10, 1 mL/min), tmajor ) 9.75 min, tminor
)
oil; yield 74%. H NMR (400 MHz, CDCl3): δ 0.81 (t, J ) 7.2 Hz,
13.84 min. The spectroscopic data were the same as those of 5b-R.
1-[(3R)-3-(4-Chlorophenyl)pentyl]-1H-1,2,4-triazole (5c-R). Colorless
3H), 1.08-1.15 (m, 2H), 1.52-1.60 (m, 2H), 2.03-2.07 (m, 1H),
2.31-2.36 (m, 1H), 2.42-2.46 (m, 1H), 3.91-3.99 (m, 2H), 6.99-7.04
(m, 2H), 7.07-7.12 (m, 2H), 7.89 (s, 1H), 7.94 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 13.7, 20.2, 36.0, 39.1, 41.7, 47.4, 115.1, 115.3,
128.7, 139.0, 142.7, 142.9, 151.6, 151.8. MS: m/z: 248 (M + 1). Anal.
calcd for C14H18FN3: C, 67.99; H, 7.34; N, 16.99. Found: C, 67.68; H,
1
oil; yield 69%. H NMR (400 MHz, CDCl3): δ 0.74 (t, J ) 7.2 Hz,
3H), 1.54-1.59 (m, 1H), 1.64-1.69 (m, 1H), 2.03-2.09 (m, 1H),
2.29-2.38 (m, 2H), 3.90-4.02 (m, 2H), 7.07 (d, J ) 8.4 Hz, 2H),
7.31 (d, J ) 8.4 Hz, 2H), 7.89 (s, 1H), 7.95 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 11.8, 29.8, 35.7, 44.1, 47.6, 128.8, 128.9, 132.2, 141.7,
142.9, 151.9. MS: m/z: 249. Anal. calcd for C13H16ClN3: C, 62.52; H,
6.46; N, 16.83. Found: C, 62.38; H, 6.52; N, 16.92; [R]D22 ) -16.8 (c
0.99, CH2Cl2); 84% ee. The enantiomeric ratio was determined by
HPLC on Chiralcel OD-H column (hexane/2-propanol ) 90/10, 1 mL/
min), tmajor ) 17.75 min, tminor ) 24.69 min.
22
7.44; N, 17.06. [R]D ) -11.5 (c 0.99, CH2Cl2); 82% ee. The
enantiomeric ratio was determined by HPLC on Chiralcel OD-H column
(hexane/2-propanol ) 90/10, 1 mL/min), tmajor ) 9.62 min, tminor
)
12.69 min.
1-[(3S)-3-(4-Fluorophenyl)hexyl]-1H-1,2,4-triazole (5f-S). Colorless oil;
22
yield 76%; [R]D ) 15.4 (c 1.0, CH2Cl2); 84% ee. The enantiomeric
1-[(3S)-3-(4-Chlorophenyl)pentyl]-1H-1,2,4-triazole (5c-S). Colorless
oil; yield 80%; [R]D22 ) 23.8 (c 1.0, CH2Cl2); 80% ee. The enantiomeric
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tminor ) 17.32 min, tmajor ) 24.32 min.
The spectroscopic data were the same as those of 5c-R.
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tminor ) 9.56 min, tmajor ) 12.64 min.
The spectroscopic data were the same as those of 5f-R.
1-[(3R)-3-(4-Methoxyphenyl)hexyl]-1H-1,2,4-triazole (5g-R). Colorless
1
oil; yield 73%. H NMR (600 MHz, CDCl3): δ 0.82 (t, J ) 7.2 Hz,
1-[(3R)-3-(4-Methoxyphenyl)pentyl]-1H-1,2,4-triazole (5d-R). White
solid; yield 78%. 1H NMR (600 MHz, CDCl3): δ 0.74 (t, J ) 7.2 Hz,
3H), 1.54-1.56 (m, 1H), 1.63-1.65 (m, 1H), 2.02-2.03 (m, 1H),
2.26-2.33 (m, 2H), 3.79 (s, 3H), 3.91-3.97 (m, 2H), 6.86 (d, J ) 7.2
Hz, 2H), 7.03 (d, J ) 6.6 Hz, 2H), 7.85 (s, 1H), 7.92 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 11.9, 30.0, 35.8, 43.7, 47.7, 55.1, 113.9,
128.4, 135.0, 142.9, 151.8. MS: m/z: 245. Anal. calcd for C14H19N3O:
3H), 1.10-1.16 (m, 2H), 1.52-1.57 (m, 2H), 2.01-2.03 (m, 1H),
2.30-2.39 (m, 2H), 3.80 (t, J ) 9.6 Hz, 3H), 3.9-3.99 (m, 2H), 6.87
(d, J ) 8.4 Hz, 2H), 7.04 (d, J ) 8.4 Hz, 2H), 7.86 (s, 1H), 7.93 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 13.8, 20.3, 36.0, 39.3, 41.6, 47.6,
55.1, 113.8, 114.0, 128.2, 128.4, 135.3, 142.8, 151.8. MS: m/z: 258
(M - 1). Anal. calcd for C15H21N3O: C, 69.47; H, 8.16; N, 16.20.
20
Found: C, 69.07; H, 8.19; N, 16.32. [R]D ) -12.5 (c 1.0, CH2Cl2);
22
C, 68.54; H, 7.81; N, 17.13. Found: C, 68.17; H, 7.92; N, 17.28. [R]D
72% ee. The enantiomeric ratio was determined by HPLC on Chiralcel
OD-H column (hexane/2-propanol ) 90/10, 1 mL/min), tmajor ) 31.45
min, tminor ) 74.06 min.
) -16.2 (c 1.0, CH2Cl2); 99.3% ee. The enantiomeric ratio was
determined by HPLC on Chiralcel OD-H column (hexane/2-propanol
) 90/10, 1 mL/min), tmajor ) 19.77 min, tminor ) 26.65 min.
1-[(3S)-3-(4-Methoxyphenyl)hexyl]-1H-1,2,4-triazole (5g-S). Colorless
1-[(3S)-3-(4-Methoxyphenyl)pentyl]-1H-1,2,4-triazole (5d-S). White
20
22
oil; yield 63%; [R]D ) 15.6 (c 0.49, CH2Cl2); 86% ee. The
solid; yield 79%; [R]D ) 22.3 (c 0.5, CH2Cl2); 71% ee. The
enantiomeric ratio was determined by HPLC on Chiralcel OD-H column
enantiomeric ratio was determined by HPLC on Chiralcel OD-H column
(hexane/2-propanol ) 90/10, 1 mL/min), tminor ) 28.76 min, tmajor
)
(hexane/2-propanol ) 90/10, 1 mL/min), tminor ) 19.22 min, tmajor
)
80.41 min. The spectroscopic data were the same as those of 5g-R.
1-[(3R)-3-Phenylheptyl]-1H-1,2,4-triazole (5h-R). Colorless oil; yield
75%. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J ) 7.2 Hz, 3H),
1.04-1.27 (m, 4H), 1.57-1.64 (m, 2H), 2.07-2.09 (m, 1H), 2.33-2.42
(m, 2H), 3.92-3.98 (m, 2H), 7.13 (d, J ) 7.2 Hz, 2H), 7.23 (m, 1H),
7.33 (m, 2H), 7.85 (s, 1H), 7.94 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ 13.7, 22.4, 29.3, 35.9, 36.6, 42.9, 47.7, 126.5, 127.4, 128.6, 142.8,
143.5, 151.7. MS: m/z: 243, 244 (M + 1). Anal. calcd for C15H21N3:
27.27 min. The spectroscopic data were the same as those of 5d-R.
1-[(3R)-3-Phenylhexyl]-1H-1,2,4-triazole (5e-R). Colorless oil; yield
80%. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J ) 7.2 Hz, 3H), 1.1-1.18
(m, 2H), 1.56-1.61 (m, 2H), 2.06-2.1 (m, 1H), 2.32-2.36 (m, 1H),
2.42-2.45 (m, 1H), 3.9-3.98 (m, 2H), 7.13 (d, J ) 8 Hz, 2H),
7.22-7.27 (m, 1H), 7.31-7.35 (m, 2H), 7.84 (s, 1H), 7.93 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 13.8, 20.3, 35.9, 39.1, 42.6, 47.7,
126.5, 127.4, 128.6, 142.9, 143.5, 151.8. MS: m/z: 229. Anal. calcd
for C14H19N3: C, 73.33; H, 8.35; N, 18.32. Found: C, 73.18; H, 8.42;
N, 18.40. [R]D20 ) -17.1 (c 0.98, CH2Cl2); 92% ee. The enantiomeric
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tminor ) 16.33 min, tmajor ) 24.24 min.
22
C, 74.03; H, 8.70; N, 17.27. Found: C, 73.86; H, 8.81; N, 17.33. [R]D
) -15.9 (c 0.51, CH2Cl2); 80% ee. The enantiomeric ratio was
determined by HPLC on Chiralcel OD-H column (hexane/2-propanol
) 90/10, 1 mL/min), tminor ) 18.92 min, tmajor ) 22.33 min.

Fungicidal Activities of Chiral Triazole
J. Agric. Food Chem., Vol. 56, No. 23, 2008 11373
1-[(3S)-3-Phenylheptyl]-1H-1,2,4-triazole (5h-S). Colorless oil; yield
77%; [R]D22 ) 14.5 (c 0.99, CH2Cl2); 88% ee. The enantiomeric ratio
was determined by HPLC on Chiralcel OD-H column (hexane/2-
propanol ) 90/10, 1 mL/min), tmajor ) 18.58 min, tminor ) 20.95 min.
The spectroscopic data were the same as those of 5h-R.
darkness. The diameter of the mycelium was measured for 48 h. The
inhibition percent was used to describe the control efficiency of the
compounds: inhibition percent (%) ) (hyphal diameter in the control
- hyphal diameter in the treatment)/hyphal diameter in the control.
1-[(3R)-3-(4-Fluorophenyl)heptyl]-1H-1,2,4-triazole (5i-R). Colorless
oil; yield 78%. H NMR (400 MHz, CDCl3): δ 0.81 (t, J ) 7.2 Hz,
RESULTS AND DISCUSSION
1
Synthesis of Chiral γ-Aryl-1H-1,2,4-triazole Derivatives. The
use of chiral pesticides has given rise to the research for new
and effective methods of obtaining pure chiral compounds.
There are two methods used to derive the pure chiral molecules,
namely, chiral-controlling synthesis and resolving the enantio-
meric mixtures. To get the reactions of Grignard reagents to
R,ꢀ-unsaturated carbonyl compounds, we use the chiral auxiliary
under mild reducing reaction to give enantiomerically pure chiral
alcohols (20). Furthermore, we used the chiral auxiliary as
revulsant to obtain the pure chiral 3R- or 3S-γ-aryl-1H-1,2,4-
triazole derivatives. The synthetic route of γ-aryl-1H-1,2,4-
triazoles 5 is outlined in Scheme 1.
3H), 1.02-1.27 (m, 4H), 1.53-1.63 (m, 2H), 2.02-2.05 (m, 1H),
2.31-2.42 (m, 2H), 3.91-3.98 (m, 2H), 7.0-7.04 (m, 2H), 7.07-7.11
(m, 2H), 7.87 (s, 1H), 7.94 (s, 1H). 13C NMR (100 MHz, CDCl3): δ
13.7, 22.3, 29.2, 36.0, 36.6, 42.0, 42.1, 47.5, 47.6, 115.3, 128.6, 128.7,
139.1, 142.7, 151.6, 151.8. MS: m/z: 261, 262 (M + 1). Anal. calcd
for C15H20FN3: C, 68.94; H, 7.71; N, 16.08. Found: C, 68.48; H, 7.60;
22
N, 15.86. [R]D ) -5.6 (c 1.0, CH2Cl2); 87% ee. The enantiomeric
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tmajor ) 8.05 min, tminor ) 11.16 min.
1-[(3S)-3-(4-Fluorophenyl)heptyl]-1H-1,2,4-triazole (5i-S). Colorless
oil; yield 78%; [R]D22 ) 9.9 (c 0.99, CH2Cl2); 84% ee. The enantiomeric
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tminor ) 8.03 min, tmajor ) 11.11 min.
The spectroscopic data were the same as those of 5i-R.
Compounds 5 were prepared from N-enoylsultams 1, which
were readily obtained by acylation of camphorsultam (as well
as their antipode that were readily prepared from camphor on
a kg scale) with NaH/acyl chlorides and purified by crystal-
lization using the two methods (39). The intermediate 1 was
then converted to the chiral amide derivatives 2 by reacting with
Grignard reagents RMgX at -78 °C in anhydrous THF under
a nitrogen atmosphere. Removing the chiral auxiliary camphor-
sultam under mild method using NaBH4 (aqueous THF) (40),
we obtained the various chiral alcohols 3 that were then
bromized with CBr4 in the presence of PPh3 in CH2Cl2. The
bromides 4 were then treated with 1H-1,2,4-triazole in CH3CN
in the presence of K2CO3 at 60-70 °C for 5-7 h to produce
the chiral γ-aryl-1H-1,2,4-triazoles compounds 5. In the ex-
perimental conditions described herein, the pure 3R- and 3S-
γ-aryl-1H-1,2,4-triazole derivatives 5 were obtained conve-
niently by using the chiral auxiliary (Oppolzer’s sultam), with
the ee values of the triazoles reaching up to 99%. The ee value
and optical rotation properties of the target compounds are
shown in Table 1. The structures of all newly compounds are
elucidated by spectroscopic (1H and 13C NMR) data and
elemental analysis. A detailed methodology of obtaining each
of compounds 1-4 is given in the Materials and Methods.
As indicated in Table 1, the target molecules have moderate
to high ee values. The ee values of compounds 5a-R, 5a-S, 5d-
R, 5e-S, 5j-R, and 5j-S are more than 95%. The difference of
substitutes and configuration leads to the different ee values.
The configurations of compounds 5 were assigned through the
absolute configuration of compounds 2 and 3 (20).
Crystal Structure Analysis. The crystal structure of target
molecule 5d-R is established using X-ray crystallographic
diffraction analysis as shown in Figures 2 and 3. In compound
5d-R, the bond lengths N(1)-C(1) [1.311(5) Å] and N(3)-C(2)
[1.307(5) Å] are close to the CdN double bond distance (1.34
Å). The bond length C(9)-O(1) is 1.377(3) Å. The benzene
ring [C(6), C(7), C(8), C(9), C(10), C(11)] and the adjacent
carbon atom C(5) are fairly planar, and the deviation from the
least-squares plane through the ring atoms is less than 0.004
Å. The dihedral angle between the plane of benzene and the
plane of the triazole group is 89.51°, and the adjacent carbon
atom C(3) linked to the later is all fairly planar. The deviation
from the least-squares plane through the ring atoms is less than
0.006 Å. As shown in the packing diagram of the compound
5d-R (Figure 3), there exist no classic hydrogen bonds.
However, the weak interactions occurring between intermol-
1-[(3R)-3-(4-Chlorophenyl)heptyl]-1H-1,2,4-triazole (5j-R). Colorless
oil; yield 72%. H NMR (400 MHz, CDCl3): δ 0.81 (t, J ) 7.2 Hz,
1
3H), 1.04-1.25 (m, 4H), 1.55-1.63 (m, 2H), 2.05 (m, 1H), 2.31-2.42
(m, 2H), 3.91-3.98 (m, 2H), 7.05-7.07 (m, 2H), 7.29-7.31 (m, 2H),
7.87 (s, 1H), 7.94 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.8, 22.4,
29.3, 35.9, 36.6, 42.2, 47.5, 128.8, 132.1, 142.0, 142.7, 142.9, 151.8,
152.0. MS: m/z: 277, 278 (M + 1). Anal. calcd for C15H20ClN3: C,
24
64.85; H, 7.26; N, 15.13. Found: C, 64.50; H, 7.21; N, 14.95. [R]D
) -14.4 (c 1.0, CH2Cl2); 96% ee. The enantiomeric ratio was
determined by HPLC on Chiralcel OD-H column (hexane/2-propanol
) 90/10, 1 mL/min), tmajor ) 14.44 min, tminor ) 17.33 min.
1-[(3S)-3-(4-Chlorophenyl)heptyl]-1H-1,2,4-triazole (5j-S). Colorless
oil; yield 74%; [R]D24 ) 16.8 (c 1.0, CH2Cl2); 97% ee. The enantiomeric
ratio was determined by HPLC on Chiralcel OD-H column (hexane/
2-propanol ) 90/10, 1 mL/min), tminor ) 13.73 min, tmajor ) 17.81 min.
The spectroscopic data were the same as those of 5j-R.
X-ray Diffraction Analysis. Colorless blocks of 5d-R (0.30 mm ×
0.20 mm × 0.10 mm) were counted on a quartz fiber with protection
oil. Cell dimensions and intensities were measured at 294 K on a Bruker
SMART CCD area detector diffractometer with graphite monochro-
mated Mo KR radiation (λ ) 0.71073 Å); θmax ) 26.00; 6810 measured
reflections; 1462 independent reflections (Rint ) 0.0787) of which 1251
had I > 2σ(I). Data were corrected for Lorentz and polarization effects
and for absorption (Tmin ) 0.9924; Tmax ) 0.9774). The structure was
solved by direct methods using SHELXS-2001 (35); all other calcula-
tions were performed with Bruker SAINT System and Bruker SMART
programs (36). Full-matrix least-squares refinement based on F2 using
2
the weight of 1/[σ2(Fo ) + (0.0849P)2 + 0.0555P] gave final values
of R ) 0.0472, ωR ) 0.1197, and GOF(F) ) 0.909. Hydrogen atoms
were observed and refined with a fixed value of their isotropic
displacement parameter.
The crystallographic data have been deposited with Cambridge
Crystallographic Data Centre, CCDC No. 691651 for compound 5d-
R. Copies of this information can be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge CB2 IEZ, United
Kingdom (Fax: +44-1123-336033; e-mail: deposit@ccdc.ac.uk or
http://www.ccdc.cam.ac.uk).
Antifungal Activity Determination. The in vitro fungicidal activities
against F. oxysporum, R. solani, B. cinereapers, G. zeae, D. gregaria,
and C. gossypii were tested according to the reported method (37, 38).
The medium was amended with aliquots of each tested compounds
solution to provide concentration of 100 mg/L. The tested compounds
were dissolved in 0.3 mL of DMF and added aseptically to molten
agar after autoclaving, when the agar had cooled to approximately
45-50 °C. The concentration of solvent never exceeded 0.1 mg/L. The
mixed medium without sample was used as the blank control. The
inocula, 5 mm in diameter, were removed from the margins of actively
growing colonies of mycelium, placed in the centers of the above plates.
There were three replate plates of compound concentration, and the
control plates were sealed with parafilm and incubated at 26 °C in

11374 J. Agric. Food Chem., Vol. 56, No. 23, 2008
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ecules of C-H· · ·N and molecules are linked via an intermo-
lecular C-H-π interactions of C(14)-H(14c) to the benzene
ring.
Antifungal Activity. The antifungal activities of compounds
5 were evaluated using in vitro agar diffusion and broth dilution
assay, the results of which are presented in Table 2. Most of
the compounds showed activity in the initial screening against
fungal cultures when tested at 100 µg/mL concentration using
agar diffusion assay. Compounds 5c-R, 5e-R, 5f-R, 5g-S, 5h-R,
5i-R, 5i-S, and 5j-R inhibited the growth of the drug-resistant
species of F. oxysporum, R. solani, B. cinereapers, G. zeae, D.
gregaria, and C. gossypii. They showed significant activity
against all fungal cultures.
In Table 2, the structure-activity relationships clearly suggest
that n-butyl substitution on the γ-position of the triazole ring
in compounds 5h-j is responsible for the broad spectrum and
high antifungal activity. The presence of the groups like 4-Cl
(5c-R, 5j-R, and 5j-S), 4-OMe (5g-S), and 4-F (5f-R, 5i-R, and
5i-S) substitution on the phenyl ring also plays a significant role
in imparting antifungal activity to the compounds.
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assayed. To sum it all, the R-forms were found to be more
active than the S-forms (5c-R, 5e-R, 5f-R, 5h-R, 5i-R, and
5j-R), while the compound 5g-S was more active than the
compound 5g-R.
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Comparison with the Reference Compound Bayleton. Bay-
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fungicide in the year 1976. We used this compound as a
reference to further study the activity of the potential compounds
5i-R and 5i-S at the lower concentration of 50 µg/mL. Tables
3 and 4 show the in vitro activity of compounds 5i-R and 5i-S
against F. oxysporum, R. solani, B. cinereapers, G. zeae, D.
gregaria, and C. gossypii species as compared to those of
Bayleton at the same level. The compound 5i-R had a
comparably high inhibitory activity and broad spectra of activity
as compared to Bayleton against all of the fungal pathogens
tested, especially to the G. zeae and D. gregaria, which reached
the inhibition rate of 89 and 100%, respectively. The values of
EC50 (50% effective concentration) of compounds 5i-R and 5i-S
are shown in Table 4.
In conclusion, a novel series of antifungal agents chiral γ-aryl-
1H-1,2,4-triazole derivatives have been designed and synthesized
conveniently by using the chiral auxiliary as a controlling
reagent. All of the compounds exhibit moderate to high ee values
reaching up to 99%, and the preliminary bioassay results
demonstrated that most of the compounds take on a significantly
wide spectrum activity against F. oxysporum, R. solani, B.
cinereapers, G. zeae, D. gregaria, and C. gossypii species. The
pure optical enantiomer 5i-R showed a better activity against
G. zeae and D. gregaria than the commercial compound
Bayleton, which may be the most potential active compound
for further structure optimization.
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Received for review August 30, 2008. Revised manuscript received
October 12, 2008. Accepted October 13, 2008. We gratefully acknowl-
edge financial support from the National Natural Science Foundation
of China (20572029-20772039) and the Science Foundation of Ministry
of Education for the New Teacher at the University of China
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