Synthesis and fungicidal activities of silicon-containing derivatives of 2-aryl-3-(1H-1,2,4-triazol-1-yl)propanenitriles

Article abstract of DOI:10.1248/cpb.49.909

A new series of silicon-containing derivatives of 2-aryl-3- (1H-1,2,4-triazol-1-yl)propanenitriles were synthesized and evaluated for fungicidal activities against rice sheath blight and powdery mildew on cucumber. These derivatives exhibited higher efficacy than reference fungicides.

Full text of DOI:10.1248/cpb.49.909

July 2001
Notes
Chem. Pharm. Bull. 49(7) 909—911 (2001)
909
Synthesis and Fungicidal Activities of Silicon-Containing Derivatives of
2-Aryl-3-(1H-1,2,4-triazol-1-yl)propanenitriles
b
Hiroyuki ITOH, ,a Harukazu TANAKA,a Hiroshi OHTA,a and Hideo TAKESHIBA
*
Agroscience Research Laboratories, Sankyo Co., Ltd.,a 1041 Yasu, Yasu-cho, Shiga 520–2342, Japan and Medicinal
Chemistry Research Laboratories, Sankyo Co., Ltd.,b 2–58 Hiromachi-1-chome, Shinagawa-ku, Tokyo 140–8710, Japan.
Received November 21, 2000; accepted March 21, 2001
A new series of silicon-containing derivatives of 2-aryl-3-(1H-1,2,4-triazol-1-yl)propanenitriles were synthe-
sized and evaluated for fungicidal activities against rice sheath blight and powdery mildew on cucumber. These
derivatives exhibited higher efficacy than reference fungicides.
Key words fungicidal activity; 1H-1,2,4-triazole; cyano; silicon; synthesis
In a previous paper,1) we reported synthesis and antifungal
activity of triazole compounds 1 with a trimethylsilylmethyl
moiety (Fig. 1). The antifungal activity of these triazoles was
presumed to arise from a potential ability to inhibit the
biosynthesis of ergosterol, an important constituent of the
fungal membrane.2) Since remarkably potent activity was ob-
served in this series of derivatives, the trimethylsilylmethyl
moiety of the common structure 1 has been identified as a
key structural element for the antifungal potency. On the
other hand, in azole fungicides, the hydroxy group of 3 plays
a biologically isosteric role to the cyano group of 4. For ex-
ample, the cyano groups of myclobutanil3) and fenbucona-
zole,4) two agents successfully introduced as agricultural
fungicides by Rohm and Haas Co., were interchangeable
with the hydroxy groups of hexaconazole5) and tebucona-
zole,6) respectively (Fig. 2). In our research program, new de-
rivatives 2 containing the cyano group instead of the hydroxy
group were synthesized and evaluated for fungicidal activi-
ties (Fig. 1).
alkylations of substituted phenylacetonitriles 5 with chloro-
methylsilanes 6 and chloromethyltriazole hydrochloride 8
prepared by the methods described in the literature.7) The se-
quential alkylation of substituted phenylacetonitriles 5 was
achieved using sodium hydride in N,N-dimethylformamide to
give 2 in 11—32% yield (2 steps) and another styrene 9 in
5—11% yield (2 steps). The yields, physical data, and spec-
troscopic data of 2 are summarized in Tables 1 and 2.
The derivatives 2 obtained above were evaluated for fungi-
cidal activities against rice sheath blight and powdery
mildew on cucumber in comparison with diclomezine,8)
a
popular fungicide for rice sheath blight, and buthiobate,9) a
popular fungicide for powdery mildew on cucumber (Fig. 3).
The results are shown in Table 1. Among several mono- and
di-substituted phenyl derivatives, 2- or 4-halogen-substituted
derivatives 2a, 2b, 2f, 2h were more active for rice sheath
blight than methyl-substituted derivative 2e and 3-halogen-
substituted derivatives 2g, 2i. On the other hand, non-substi-
tuted derivative 2c and 4-methoxy-substituted derivative 2d
showed fungicidal activities for both diseases. The deriva-
tives having the dimethylphenylsilyl group instead of the
trimethylsilyl group 2j, 2k exhibited fungicidal activity only
against powdery mildew. 3-Phenoxy-substituted derivative 2l
lost fungicidal activity.
The preparation of the target compounds 2 involves double
In summary, we have found that the biological isosterism
between 3 and 4 was applicable to a series of novel silicon-
containing azole derivatives that have fungicidal activities
against rice sheath blight and powdery mildew. Most notably,
2c, 2d, 2h were more active against both diseases than refer-
ence fungicides. Further evaluation of these derivatives as
fungicides is underway.
Fig. 1. Research Strategy
Experimental
All melting points (mp) were taken on a Yanaco micro melting point ap-
paratus and are uncorrected. IR was recorded on a JASCO A-102 spectrom-
eter and 1H-NMR spectra were recorded on a Varian Gemini 200 spectrome-
ter using tetramethylsilane as an internal standard. MS was obtained on a
JEOL JMS-D300 spectrometer and a VG Auto Spec M mass spectrometer.
TLC was performed on a precoated plate of Silica gel 60 F254 with a layer
Chart 1
Fig. 2. Azole Fungicides
To whom correspondence should be addressed. e-mail: hiroit@yasu.sankyo.co.jp
© 2001 Pharmaceutical Society of Japan

910
Vol. 49, No. 7
Table 1. Synthesis and Fungicidal Activities of Cyano Azole Derivatives 2
Calcd (%)b)
H
Found (%)b)
H
Entry
No.
Yield
(%)a)
mp
(°C)
X
R
S.B.d)
P.M.e)
C
N
C
N
2a
2b
2c
2d
2e
2f
2g
2h
2i
4-F
4-Cl
H
4-MeO
4-Me
2-Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
18
32
23
17
12
11
23
14
26
26
22
19
128—129
120
113—114
120—121
104—105
Oil
109—110
62—64
126
59.57
56.50
63.34
61.11
64.39
6.33
6.01
7.09
7.05
7.43
18.53
17.57
19.70
17.82
18.77
59.57
56.39
63.12
60.95
64.12
6.33
5.94
7.01
6.93
7.15
18.53
17.71
19.70
17.75
18.50
2
2
2
2
0
2
0
2
0
0
0
0
0
0
2
2
2
0
2
2
2
2
2
0
318.106753c)
6.01
318.106743c)
5.87
3-Cl
56.50
50.99
50.99
17.57
15.86
15.86
56.48
51.16
51.17
17.71
15.86
15.92
2,4-Cl2
3,4-Cl2
4-Cl
H
3-PhO
5.14
5.14
5.13
5.09
2j
2k
2l
Oil
81
Oil
380.122404c)
6.40
380.122299c)
6.45
Ph
Ph
69.33
16.12
69.21
16.12
438.187590c)
438.187737c)
a) 2 steps, b) analytical data, c) high-resolution MS spectrum data, d) sheath blight, e) powdery mildew. The activity index given in this table is based on a visual comparison
of plants inoculated with the test agents and a reference fungicide. 0, disease rate was almost the same as that of an untreated plant; 1, disease rate was more severe than that of a
plant treated with reference fungicide; 2, disease rate was less severe than that of a plant treated with reference fungicide.
Table 2. 1H-NMR, IR and MS Spectrum Data on 2
Entry No.
1H-NMR (200 MHz), d (ppm) in CDCl3
IR (cmϪ1
)
MS (m/z)
2a
Ϫ0.24 (9H, s), 1.32 (1H, d, Jϭ14.9 Hz), 1.42 (1H, d, Jϭ14.9 Hz), 4.38 (1H, d,
Jϭ14.1 Hz), 4.54 (1H, d, Jϭ14.1 Hz), 6.95 (2H, t, Jϭ8.9 Hz), 7.23 (2H, dd, Jϭ5.0,
8.9 Hz), 7.72 (1H, s), 7.78 (1H, s)
Ϫ0.09 (9H, s), 1.45 (1H, d, Jϭ14.6 Hz), 1.50 (1H, d, Jϭ14.6 Hz), 4.47 (1H, d,
Jϭ14.1 Hz), 4.61 (1H, d, Jϭ14.1 Hz), 7.30 (2H, d, Jϭ8.9 Hz), 7.39 (2H, d, Jϭ8.9 Hz),
7.88 (1H, s), 7.90 (1H, s)
Ϫ0.12 (9H, s), 1.44 (1H, d, Jϭ14.4 Hz), 1.55 (1H, d, Jϭ14.4 Hz), 4.50 (1H, d,
Jϭ13.9 Hz), 4.65 (1H, d, Jϭ13.9 Hz), 7.39 (5H, s), 7.81 (1H, s), 7.89 (1H, s)
Ϫ0.19 (9H, s), 1.31 (1H, d, Jϭ14.7 Hz), 1.43 (1H, d, Jϭ14.7 Hz), 3.72 (3H, s), 4.37
(1H, d, Jϭ14.1 Hz), 4.53 (1H, d, Jϭ14.1 Hz), 6.81 (2H, d, Jϭ9.0 Hz), 7.21 (2H, d,
Jϭ9.0 Hz), 7.71 (1H, s), 7.79 (1H, s)
Ϫ0.12 (9H, s), 1.38 (1H, d, Jϭ15.1 Hz), 1.51 (1H, d, Jϭ15.1 Hz), 2.36 (3H, s), 4.46
(1H, d, Jϭ14.0 Hz), 4.61 (1H, d, Jϭ14.0 Hz), 7.21—7.32 (4H, m), 7.79 (1H, s),
7.97 (1H, s)
2958, 2249, 1510, 1274,
1240, 1137
302 (Mϩ), 287, 220
2b
3107, 2956, 2248, 1506,
1426, 1274, 1248, 1137,
1099
3108, 2951, 2249, 1507,
1449, 1274, 1249, 1140
2964, 2248, 1618, 1515,
1274, 1251, 1194, 1139
318 (Mϩ), 303, 236
2c
284 (Mϩ), 269, 202
314 (Mϩ), 299, 232
2d
2e
2f
3106, 2956, 2247, 1508,
1438, 1273, 1248, 1140
298 (Mϩ), 283, 216
318 (Mϩ), 283, 236
Ϫ0.13 (9H, s), 1.38 (1H, d, Jϭ14.9 Hz), 2.29 (1H, d, Jϭ14.9 Hz), 4.82 (1H, d,
Jϭ14.3 Hz), 5.22 (1H, d, Jϭ14.3 Hz), 7.21—7.61 (4H, m), 7.79 (1H, s), 7.97 (1H, s)
3122, 2955, 2897, 2239,
1505, 1475, 1434, 1274,
1251, 1138
3222, 3122, 2944, 1511,
1244, 1133, 1022
2g
2h
Ϫ0.10 (9H, s), 1.42 (1H, d, Jϭ14.2 Hz), 1.51 (1H, d, Jϭ14.2 Hz), 4.47 (1H, d,
Jϭ14.2 Hz), 4.61 (1H, d, Jϭ14.2 Hz), 7.26—7.38 (4H, m), 7.89 (1H, s), 7.90 (1H, s)
Ϫ0.10 (9H, s), 1.40 (1H, d, Jϭ14.9 Hz), 2.24 (1H, d, Jϭ14.9 Hz), 4.77 (1H, d,
Jϭ14.3 Hz), 5.20 (1H, d, Jϭ14.3 Hz), 7.20 (1H, dd, Jϭ2.2, 8.5 Hz), 7.44 (1H, d,
Jϭ2.2 Hz), 7.79 (1H, d, Jϭ8.5 Hz), 7.79 (1H, s), 8.03 (1H, s)
Ϫ0.06 (9H, s), 1.44 (1H, d, Jϭ14.2 Hz), 1.50 (1H, d, Jϭ14.2 Hz), 4.47 (1H, d,
Jϭ14.2 Hz), 4.60 (1H, d, Jϭ14.2 Hz), 7.20 (1H, dd, Jϭ2.3, 8.4 Hz), 7.48 (1H, d,
Jϭ2.3 Hz), 7.48 (1H, d, Jϭ8.4 Hz), 7.89 (1H, s), 7.97 (1H, s)
305 (Mϩ), 290, 274,
133
3104, 2953, 2245, 1514,
1476, 1275, 1248, 1150
354 (Mϩϩ2),
352 (Mϩ), 337
2i
3106, 2956, 2248, 1508,
1475, 1280, 1250, 1139
354 (Mϩϩ2),
352 (Mϩ), 337
2j
2k
2l
0.16 (3H, s), 0.33 (3H, s), 1.63 (1H, d, Jϭ14.9 Hz), 1.72 (1H, d, Jϭ14.9 Hz), 4.41
(1H, d, Jϭ14.2 Hz), 4.56 (1H, d, Jϭ14.2 Hz), 7.15 (2H, d, Jϭ9.1 Hz), 7.22 (2H, d,
Jϭ9.1 Hz), 7.26—7.35 (5H, m), 7.85 (1H, s), 7.86 (1H, s)
0.03 (3H, s), 0.31 (3H, s), 1.63 (1H, d, Jϭ14.9 Hz), 1.75 (1H, d, Jϭ14.9 Hz), 4.42
(1H, d, Jϭ14.2 Hz), 4.58 (1H, d, Jϭ14.2 Hz), 7.25—7.35 (10H, m), 7.74 (1H, s),
7.84 (1H, s)
0.12 (3H, s), 0.35 (3H, s), 1.61 (1H, d, Jϭ14.9 Hz), 1.71 (1H, d, Jϭ14.9 Hz), 4.41
(1H, d, Jϭ14.1 Hz), 4.56 (1H, d, Jϭ14.1 Hz), 6.88—7.40 (14H, m), 7.82 (1H, m),
7.87 (1H, s)
3070, 2956, 2240, 1504,
1428, 1274, 1208, 1137,
1113
3097, 2960, 2244, 1509,
1449, 1279, 1252, 1138
380 (Mϩ), 365, 298
346 (Mϩ), 331, 264
438 (Mϩ), 423, 356
3069, 2956, 2240, 1583,
1487, 1428, 1273, 1231,
1138
thickness of 0.25 mm (E. Merck), and spots were made visible by ultraviolet
(UV) irradiation. Silica gel (350—250 mesh, Yamamura Chemical Labora-
tories Co., Ltd.) was used for column chromatography and preparative TLC
was carried out on plates of Silica gel 60 F254 with a layer thickness of 2 mm
(E. Merck). The following abbreviations are used: s, singlet; d, doublet; dd,
doublet of doublet; t, triplet; q, quartet; m, multiplet; br, broad.
2-(4-Fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-trimetylsilylmethyl-
propanenitrile (2a) Sodium hydride (60% mineral oil dispersion, 500 mg,
12.5 mmol) was added to a solution of 2-(4-fluorophenyl)acetonitrile 5a
Fig. 3. Reference Fungicides

July 2001
911
(1.35 g, 10.0 mmol) in N,N-dimethylformamide (40 ml) and stirred for with a previously cultured strain of Rhizoctonia solani and kept in a moist
30 min at 0 °C. Chloromethyltrimethylsilane 6 (2.45 g, 20.0 mmol) was chamber (relative humidity: 100%) for 4 d at 25—27 °C. The results are
added to the mixture and stirred for 2 h at room temperature. The reaction shown in Table 1.
mixture was poured into ice water, quenched with an aqueous solution of
Preventive Activity against Powdery Mildew on Cucumber Cucum-
ammonium chloride, and extracted with ethyl acetate. The extract was dried ber seedlings (variety Sagamihanpaku) at the first leaf stage grown in pots
over magnesium sulfate and concentrated to give a solid, which was chro- were sprayed with an aqueous suspension of the test compound at a concen-
matographed on silica gel (ethyl acetate–hexane, 9 : 1, v/v) to afford 2-(4-flu- tration of 300 ppm. After the seedlings had been kept in a greenhouse for
orophenyl)-3-trimetylsilylpropanenitrile (7a) (1.2 g, 54%). 7a: 1H-NMR 2 d, they were inoculated with a previously cultured strain of Sphaerotheca
(200 MHz, CDCl3) d: 0.03 (9H, s), 1.19 (1H, dd, Jϭ9.0, 14.7 Hz), 1.39 (1H,
fuliginea and kept in a moist chamber (relative humidity: 100%) for 4 d at
dd, Jϭ9.0, 14.7 Hz), 3.50 (1H, dd, Jϭ7.1, 9.0 Hz), 7.06 (2H, t, Jϭ8.7 Hz), 25—27 °C. The results are shown in Table 1.
7.32 (2H, dd, Jϭ5.1, 8.7 Hz). MS m/z: 221 (Mϩ), 206, 122.
The product 7a (440 mg, 2.0 mmol) was added to a suspension of sodium
Acknowledgements We are grateful to Dr. S. Sugai, the director of our
hydride (60% mineral oil dispersion, 220 mg, 5.5 mmol) in N,N-dimethylfor- laboratories, and to Dr. T. Jojima, the former director, for their encourage-
mamide (10 ml) at 0 °C and stirred for 30 min. 1-Chloromethyl-1H-1,2,4-tri- ment throughout this work. We also would like to thank Dr. K. Sato in our
azole hydrochloride 8 (320 mg, 2.1 mmol) was added to the mixture at room laboratories for his helpful discussion.
temperature and stirred for 1 h. The reaction mixture was poured into ice
water and extracted with ethyl acetate. The extract was washed with a satu- References
rated solution of ammonium chloride and dried over magnesium sulfate. The
solid remaining after evaporation of the solvent was purified by thin layer
chromatography (ethyl acetate–hexane, 1 : 1, v/v) to afford 2a (300 mg, 50%)
as colorless crystals (recrystallized from diisopropyl ether) from more polar
fractions and 1-[2-(4-fluorophenyl)-1-propenyl]-1H-1,2,4-triazole (9a) (30
mg, 20%) as colorless crystals (recrystallized from diisopropyl ether) from
less polar fractions. 9a: mp 42—44 °C. 1H-NMR (200 MHz, CDCl3) d: 2.27
(3H, d, Jϭ1.5 Hz), 7.05 (1H, m), 7.09 (2H, t, Jϭ8.9 Hz), 7.44 (2H, dd,
Jϭ5.3, 8.9 Hz), 8.06 (1H, s), 8.25 (1H, s). MS m/z: 203 (Mϩ), 175, 148, 122.
The other silicon-containing azole derivatives (2b—l) were obtained in a
similar way to that described for the preparation of 2a. The yields, physical
data, spectroscopic data, and elementary analysis data on these derivatives 2
are given in Tables 1 and 2.
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Preventive Activity against Rice Sheath Blight Rice seedlings (variety
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