Synthesis and fungicidal activity of 1-(alpha-tert-butylcinnamoyl)imidazoles.

Article abstract of DOI:10.1271/bbb.66.2243

Several 1-(alpha-tert-butylcinnamoyl)imidazoles were prepared to examine their fungicidal activity. The (Z)-4-chlorocinnamoyl derivative was prepared from (anti)-2-tert-butyl-3-(4-chlorophenyl)-3-hydroxypropanoic acid by treating with 1,1'-carbonyldiimidazole and a subsequent beta-elimination reaction at an elevated temperature. The (Z)-isomer of the 4-chlorocinnamoyl derivative showed good fungicidal activity against Erysiphe graminis and Botrytis cinerea in pot tests, whereas the corresponding (E)-isomer derived from the (Z)-isomer through photoisomerization was much less active.

Full text of DOI:10.1271/bbb.66.2243

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Synthesis and Fungicidal Activity of 1-(α-tert-
Butylcinnamoyl)imidazoles
Akio MANABEa, Hirotaka TAKANOa, Kunihiko FURUZAWAa, Kazunori YANAGIb, Yoshio
HISADAa & Shizuya TANAKAa
a Agricultural Chemicals Research Laboratory, Sumitomo Chemical Co. Ltd. 4-2-1
Takatsukasa, Takarazuka, Hyogo 665-8555, Japan
b Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd. 4-2-1
Takatsukasa, Takarazuka, Hyogo 665-8555, Japan
Published online: 22 May 2014.
To cite this article: Akio MANABE, Hirotaka TAKANO, Kunihiko FURUZAWA, Kazunori YANAGI, Yoshio HISADA & Shizuya
TANAKA (2002) Synthesis and Fungicidal Activity of 1-(α-tert-Butylcinnamoyl)imidazoles, Bioscience, Biotechnology, and
Biochemistry, 66:10, 2243-2246, DOI: 10.1271/bbb.66.2243
To link to this article: http://dx.doi.org/10.1271/bbb.66.2243
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Biosci. Biotechnol. Biochem., 66 (10), 2243–2246, 2002
Note
Synthesis and Fungicidal Activity of 1-(
a
-tert-Butylcinnamoyl)imidazoles
† Hirotaka TAKANO,1 Kunihiko FURUZAWA,1 Kazunori YANAGI
,
1,
2
Akio MANABE
,
Yoshio HISADA,1 and Shizuya TANAKA
1
1Agricultural Chemicals Research Laboratory, Sumitomo Chemical Co. Ltd., 4-2-1 Takatsukasa,
Takarazuka, Hyogo 665-8555, Japan
2Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., 4-2-1 Takatsukasa,
Takarazuka, Hyogo 665-8555, Japan
Received April 1, 2002; Accepted May 30, 2002
Several 1-(
prepared to examine their fungicidal activity. The (
chlorocinnamoyl derivative was prepared from (anti)-2-
tert-butyl-3-(4-chlorophenyl)-3-hydroxypropanoic acid
a
-
tert-butylcinnamoyl)imidazoles were
)-4-
zole was eŠective for the control of phytopathogenic
Z
fungi such as powdery mildew on barley, Erysiphe
graminis
ber, Botrytis cinerea
other azole fungicides such as the stylyl triazole
fungicide, diniconazole3) (S-3308; (
)-(RS)-1-(2,4-
dichlorophenyl)-4,4-dimethyl-2-(1 -1,2,4-triazol-1-
(E. graminis), and the gray mold on cucum-
(
B. cinerea). Presumably, like
by treating with 1,1
?
-carbonyldiimidazole and a subse-
-elimination reaction at an elevated temperature.
)-isomer of the 4-chlorocinnamoyl derivative
quent
The (
b
Z
E
H
showed good fungicidal activity against Erysiphe grami-
nis and Botrytis cinerea in pot tests, whereas the corre-
yl)pent-1-en-3-ol), the 1-acyl imidazole compound
might show its fungicidal activity by inhibiting
ergosterol biosynthesis rather than by acylating reac-
tivity.2) These ˆndings prompted us to search for fun-
sponding (
E )-isomer derived from the (Z )-isomer
through photoisomerization was much less active.
gicidal activity in its cinnamoyl analogues, i.e., 1-(a-
Key words: 1-cinnamoylimidazole;
b
-elimination
tert-butylcinnamoyl)imidazoles, sharing the common
stylyl moiety with diniconazole. We report in this
note their synthesis and fungicidal activity.
reaction; geometrical isomer; azole fungi-
cide; fungicidal activity
The synthetic procedure for 1-[
chlorocinnamoyl]imidazole is illustrated in Fig. 1.
Anti)- -hydroxy acid 1a that was obtained by
stereoselective aldol-type addition under ther-
a-(tert-butyl)-4-
We have reported in the previous papers1–2) that a
sterically-hindered 1-acyl imidazole compound, i.e.,
1-[2-(4-chlorobenzyl)-3,3-dimethylbutanoyl]imida-
(
b
Fig. 1. Synthesis of 1-[a-(tert-Butyl)-4-chlorocinnamoyl]imidazole.
†
To whom correspondence should be addressed. Fax: +81-797-74-2129; E-mail: manabe
＠
sc.sumitomo-chem.co.jp
Abbreviations E. graminis, Erysiphe graminis; B. cinerea, Botrytis cinerea; CDI, 1,1 -carbonyldiimidazole; THF, tetrahydrofuran
:
?

2244
A. MANABE et al.
modynamic control4) was reacted with 3.5 equivalents
of 1,1 -carbonyldiimidazole (CDI) in tetrahydrofu-
ran (THF) under re‰ux to give diimidazole derivative
2a in a 69 yield. Since the reaction is considered to
Fig. 2. As shown in Fig. 1, since (anti)- diimidazole
2a gave mainly ( )-product 3a, the -elimination
reaction may be characterized as involving anti-elimi-
nation rather than pyrolytic syn-elimination: the
necessary conformation of 2a! leading to (E )-
?
Z
b
z
have proceeded with retention of the conˆguration at
two asymmetric carbon atoms, 2a should have the
anti conˆguration like 1a. When 2a was heated at
product 3b was presumably destabilized in this reac-
tion by steric interaction between the bulky tert-butyl
group and the 4-chlorophenyl group. Each of the
190–200
the loss of carbon dioxide and imidazole to give
desired cinnamoyl imidazole 3a having the conˆgu-
ration in a 42 yield as the main product. Its chemi-
9
C, a b-elimination reaction took place with
other (
prepared in a similar way by an analogous procedure.
On the other hand, corresponding ( )-derivative 3b
was obtained by photoisomerization of ( )-deriva-
tive 3a under irradiation by sunlight in acetone.
As shown in Table 1, ( )-4-chloro derivative 3a
Z )-cinnamoyl derivatives 3c-3g (Table 1) was
Z
z
E
cal structure (3a), including the
Z
conˆguration of
Z
the double bond, was conˆrmed by an X-ray struc-
tural analysis. The molecular structure of 3a is shown
Z
showed good activity against E. graminis and B.
cinerea in pot tests. In marked contrast, corre-
sponding (E )-isomer 3b was much less active against
both fungi, suggesting the signiˆcance of the
stereochemistry in eliciting the fungicidal activity of
this class of compounds. In this context, it is interest-
ing to note that the geometrical isomer-fungicidal ac-
tivity relationship is diŠerent between the cinnamoyl
imidazoles (3a vs. 3b) and the stylyl triazoles
(diniconazole vs. its less active geometrical isomer);
i.e., in more active 3a, the phenyl ring and the im-
idazolylcarbonyl moiety are cis, while in more active
diniconazole, the phenyl and triazolyl rings are
trans.3) The bromo (3d) and cyano (3f) analogues of
3a also showed good activity comparable to that of
3a, while the tri‰uoromethyl (3e), methyl (3g) and
unsubstituted (3c) analogues were less active.
Experimental
Melting point (mp) data were determined with
Yanagimoto micro melting point apparatus and are
Fig. 2. Molecular Structure of 3a Determined by an X-ray Anal-
ysis.
Table 1. 1[(a-(tert-Butyl)-4-substituted-cinnamoyl]imidazoles and Their Fungicidal Activity against Erysiphe graminis and Botrytis cinerea
Compound
mp ( C)
Preventive activity
a)
No.
X
Z E
W
9
1H-NMR (CDCL3 TMS)
d
(ppm)
pED50
W
t
-Bu
2-Position of imidazole
E. graminis
B. cinerea
3a
3b
3c
3d
3e
3f
Cl
Cl
H
Br
CF3
CN
Me
Z
E
Z
Z
Z
Z
Z
95.5–96.5
111.5–112.5
88–89
111–111.5
74–74.5
134–135
79–80
1.31
1.20
1.31
1.29
1.31
1.32
1.28
7.82
8.24
7.87
7.82
7.84
7.80
7.63
5.92
3.52
4.17
5.96
4.19
5.89
3.92
4.82
2.92
3.40
4.63
3.04
4.40
3.43
3g
a) Negative logarithm of the molar concentration required for 50
z control in pot tests.

Fungicidal 1-Cinnamoyl Imidazoles
2245
1
uncorrected. Proton (1H) NMR spectra were meas-
ured with a Hitachi R-24B (60 MHz) spectrometer or
JEOL JNM-AL400 spectrometer.
H, 5.93; N, 9.70; Cl, 12.28z. H-NMR (60 MHz)
d(CDCl3 TMS): 1.31 (9H, s), 6.81 (1H, s), 6.91 (1H,
m), 7.12 (4H, s), 7.32 (1H, m), 7.82 (1H, s). IR nmax
W
(nujol) cm„1: 1697 (C O).
＝
(Anti)-2-tert-butyl-3-(4-chlorophenyl)-3-hydroxy-
propanoic acid (1a). To a stirred solution of di-
isopropylamine (40.48 g) in dry THF (200 ml) was
Compounds 3c-3g were prepared by a similar
method to that just described.
added dropwise butyllithium (1.6
250 ml) at below 0 C. After stirring at 0
10 min, tert-butylacetic acid (20.91 g) in dry THF
(50 ml) was added dropwise at below 0 C, and the
M
in hexane,
X-ray analysis. A single crystal of 3a, which had
9
9C for
been obtained by recrystallization from diisopropyl
ether, was monoclinic, space group C2 c, with a
＝
W
＝
＝
＝
9
33.303 (4) Å, b 6.047 (1) Å, c 16.492 (2) Å,
b
3
„3
＝ ＝
3061.4 Å , and dcalcd 1.253 g cm
mixture was stirred at room temperature for 1 hr.
To the mixture was added 4-chlorobenzaldehyde
(25.30 g) in dry THF (50 ml) at „509C. The mixture
112.80 (1)
9,
V
＝
＝
for Z 8 (C16H17N2OCl, mol. wt. 288.78). The in-
tensity data were measured by an Enraf-Nonius CAD
4 diŠractometer with Cu Ka radiation. The structure
was resolved by the direct method and reˆned by the
full-matrix least-squares method. The ˆnal dis-
was allowed to rise to room temperature, and stirred
for 2 days. The resulting mixture was poured into ice-
cooled water and acidiˆed with HCl aq. The organic
layer was separated, and the aqueous layer was ex-
tracted with ether. The combined organic layer was
dried and concentrated. The residue was triturated
with acetonitrile-hexane to give a solid, which was
recrystallized from acetonitrile to give 1a (10.20 g,
＝ ＝
0.040 and Rw 0.058.
crepancy indices are
R
(E)-1-[
a-(tert-butyl)-4-chlorocinnamoyl]imidazole
3b). )-derivative 3a (1.0 g) was placed in a Pyrex
(
(Z
glass ‰ask and dissolved in acetone (500 ml). After al-
lowing the resulting solution to stand for 20 hr under
irradiation with sunlight, the solvent was evaporated.
The residue was crystallized from diisopropyl ether
21
z 9
), mp165–166 C (its (syn)- isomer has been
reported to have a melting point of 194–1959C4)).
Anal.Found: C, 60.82; H, 6.77; Cl, 13.73
z
. Calcd.
1
for C13H17O3Cl: C, 60.82; H, 6.77; Cl, 13.81
NMR (400 MHz)
2.64 (1H, 4.8 Hz, d), 5.04 (1H,
7.3–7.45 (4H, m)
z
. H-
to give (
112.5 C. Anal. Found: C, 66.43; H, 5.83; N, 9.66;
Cl, 12.35 . Calcd. for C16H17N2OCl: C, 66.55; H,
5.93; N, 9.70; Cl, 12.28
1H-NMR (60 MHz)
z
E )-derivative 3b (0.24 g, 24 ), mp111.5–
d
(acetone-d6 TMS): 1.06 (9H, s),
9
W
J
＝
J
＝
4.8 Hz, d),
z
z.
d
(CDCl3 TMS): 1.20 (9H, s), 6.80 (1H, s), 7.15–7.50
(5H, m), 7.60 (1H, m), 8.24 (1H, s). IR nmax (nujol)
W
(Anti)-1-(4-chlorophenyl)-2-(1-imidazolylcar-
bonyl)-3,3-dimethylbutyl imidazole-1-carboxylate
2a). A mixture of 1a (8.99 g) and CDI (19.73 g) in
cm„1: 1700 (C O).
＝
(
The preventive activity of compounds 3a-3g
against a) powdery mildew on wheat, E. graminis,
and b) gray mold on cucumber, B. cinerea, was deter-
mined by pot tests.
a) A plastic pot was ˆlled with sandy loam soil, and
wheat (var., Norin No. 73) was sown and cultivated
in a greenhouse. Each of the test compounds in the
form of an emulsiˆable concentrate was diluted with
water and foliar-sprayed on to the young seedlings in
the ˆrst true leaf stage to run-oŠ. The seedlings were
cultivated in a greenhouse for one day and inoculated
with the spores of E. graminis. The seedlings were
cultivated for 10 days more in the greenhouse, and
the controlling activity was examined.
THF (100 ml) was heated under re‰ux for 4 hr while
stirring. After evaporating the solvent, the residue
was diluted with ether, washed with water, dried and
concentrated. The residue was chromatographed on
silica gel (eluent, hexane-acetone (1:1,v v)) to give 2a
W
(9.7 g, 69
H, 5.37; N, 13.70
C, 59.93; H, 5.28; N, 13.98
(60 MHz) (CDCl3 TMS): 1.02 (9H, s), 3.53 (1H,
8 Hz, d), 6.30 (1H, 8 Hz, d), 6.98 (1H, s), 7.09
＝
z
), mp 69–71
. Calcd. for C20H21N4O3Cl:
1H-NMR
9C. Anal. Found: C, 59.50;
z
z
.
＝
J
d
W
J
(1H, s), 7.12(1H, s), 7.37 (4H, s), 7.46 (1H, s), 7.87
(1H, s), 8.13 (1H, s). IR nmax (nujol) cm„1: 1758
＝
＝
(C O), 1728 (C O)
b) A plastic pot was ˆlled with sandy loam soil,
and cucumber (var., Sagamihanjiro) was sown and
cultivated in a greenhouse. Each of the test com-
pounds in the form of an emulsiˆable concentrate
was diluted with water and foliar-sprayed on to the
young seedlings in the cotyledonous stage to run-oŠ.
The seedlings were cultivated in the greenhouse for
one day and inoculated with agar gel containing B.
(Z)-1-[
3a). Anti)-diimidazole 2a (48.23 g) was heated at
190–200 C while stirring until the gas (carbon di-
a-(tert-butyl)-4-chlorocinnamoyl]imidazole
(
(
9
oxide) evolution ceased. After cooling, the mixture
was dissolved in ether, washed twice with water,
dried and concentrated. The residue was chro-
matographed on silica gel (eluent, hexane-acetone
(5:1, v v)) to give a solid, which was recrystallized
cinerea. The seedlings were cultivated at 209C for 4
W
from diisopropyl ether to give 3a (14.6 g, 42
95.5–96.5 C. Anal. Found: C, 66.84; H, 5.99; N,
9.71; Cl, 12.38 . Calcd. for C16H17N2OCl: C, 66.55;
z
), mp
days more in humid and dark conditions, and the
controlling activity was examined.
The preventive activity was evaluated by measur-
9
z

2246
A. MANABE et al.
Chem., 50, 3215–3217 (1986).
ing the degree of fungal infection of the controlled
vs. untreated control, and is expressed as the ED50
value, the negative logarithm of the molar concentra-
tion required for 50 control.
2) Manabe, A., Kirino, O., Furuzawa, K., Takano, H.,
Hisada, Y., and Tanaka, S., Structure-activity
relationships in fungicidal 1-(2-benzyl-3,3-dimethyl-
butanoyl)imidazoles and related compounds. Agric.
Biol. Chem., 51, 1959–1965 (1987).
p
z
Acknowledgment
3) Funaki, Y., Ishiguri, Y., Kato, T., and Tanaka, S.,
Structure-activity relationships of vinyl triazole fungi-
cides. J. Pesticide Sci., 9, 229–236 (1984).
We thank the late Dr. Osamu Kirino for his helpful
comments.
4) Mulzer, J., Zippel, M., Bru
ä
ntrup, G., Segner, J., and
uredianion-
Finke, J., Zur Stereochemie der Carbonsa
ä
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