2828 J. Agric. Food Chem., Vol. 46, No. 7, 1998
Dekeyser and Davis
Ta ble 1. P h ysica l P r op er ties a n d Sp ectr a l Da ta of Dioxin ca r boxa m id es 4a -g
compd
R
mp (°C)
1H NMR (CDCl3) (ppm)
4a
4b
4c
4d
4e
4f
H
85-87
70-72
71-73
oil
oil
160-163
59-61
8.0 (s, 1H), 7.1-7.6 (m, 5H), 4.0 (s, 4H), 2.2 (s, 3H)
2-CH3
3-CH3
2,3-CH3
2-C6H5
3-CN
8.1 (s, 1H), 7.0-7.7 (m, 4H), 4.0 (s, 4H), 2.3 (s, 3H), 2.2 (s, 3H)
8.0 (s, 1H), 7.1-7.8 (m, 4H), 4.0 (s, 4H), 2.3 (s, 3H), 2.2 (s, 3H)
8.1 (s, 1H), 7.0-7.8 (m, 3H), 4.0 (s, 4H), 2.3 (s, 6H), 2.2 (s, 3H)
8.5 (s, 1H), 7.2-7.7 (m, 9H), 3.8-4.2 (m, 4H), 2.2 (s, 3H)
8.3 (s, 1H), 7.2-7.8 (m, 4H), 4.0 (s, 4H), 2.2 (s, 3H)
4g
4-OCH3
8.1 (s, 1H), 6.9-7.6 (m, 4H), 4.0 (s, 4H), 3.8 (s, 3H), 2.2 (s, 3H)
Ta ble 2. F u n gicid a l Scr een in g Resu lts of
Dioxin ca r boxa m id es 4a -g
refluxed for 1.5 h and then concentrated under reduced
pressure. The resulting acid chloride was dissolved in diethyl
ether (20 mL) and cooled to 10 °C while 20 mmol of an
appropriately substituted aniline dissolved in diethyl ether (20
mL) was added dropwise. After stirring for 2 h at room
temperature, water (50 mL) was added and the mixture was
extracted with diethyl ether. The organic layer was separated
and washed with dilute hydrochloric acid. After drying with
sodium sulfate, the solvent was removed under reduced
pressure, leaving a solid. The products 4a -g were washed
with hexane and filtered, giving yields of 50-68% based on 3.
% inhibition ( SDa of bean rust
compd
4a
4b
4c
4d
4e
4f
4g
R
1000 ppm 500 ppm 250 ppm 100 ppm
H
100 ( 0
100 ( 0
100 ( 0
100 ( 0
50 ( 8
0 ( 0
100 ( 0
79 ( 6
100 ( 0
100 ( 0
17 ( 6
88 ( 8
67 ( 6
100 ( 0
88 ( 6
17 ( 5
67 ( 8
17 ( 3
79 ( 8
75 ( 4
17 ( 4
2-CH3
3-CH3
2,3-CH3
2-C6H5
3-CN
4-OCH3
0 ( 0
carboxin
100 ( 0
100 ( 0
100 ( 0
67 ( 6
RESULTS AND DISCUSSION
a
SD, standard deviation.
Melting points of dioxincarboxamides 4a -g, obtained
by the reaction of 5,6-dihydro-3-methyl-1,4-dioxin-2-
carboxylic acid (3) with various aromatic amines, are
shown in Table 1. Seven compounds were prepared in
which the substituent and its position on the aromatic
ring were varied to determine the effect this would have
on the fungicidal properties of this class of compounds.
Nuclear magnetic resonance spectra of the dioxincar-
boxamides showed the protons of the dioxin ring as a
singlet at 4 ppm in all cases except 4e, in which the
substituent is a phenyl group in the ortho position
(Table 1). In that case, a multiplet at 4 ppm was
observed in the spectrum. Furthermore, a strong
absorption in the infrared spectra of dioxincarboxamides
was observed in the region 1660-1685 cm-1, indicative
of an amide carbonyl group.
Several dioxincarboxamides demonstrated fungicidal
properties. The 3-methyl analogue 4c showed higher
activity against bean rust than the commercial fungi-
cide, carboxin. On the other end of the scale, the 3-CN
and 4-OCH3 analogues (4f and 4g, respectively) both
failed to demonstrate fungicidal activity even at the
highest application rate of 1000 ppm. Replacing O for
S (4a versus carboxin) appears to retain fungicidal
activity.
The substitution of oxygen for sulfur in the hetero-
cyclic ring represents an example of an approach that
is commonly known as bioisosterism. The 1,4-dioxin
ring is a bioisosteric analogue of the 1,4-oxathiin ring.
The idea of bioisosterism is one of the most successful
techniques of bioactive compound design (Lipinski,
1986).
Aside from the expected fungicidal properties, diox-
incarboxamides have also demonstrated usefulness as
plant growth retardants, particularly on wheat and
barley (Dekeyser and Blem, 1991).
(Table 1). Yields of dioxincarboxamides 4a -g were in the
range 50-68%.
Biology. Data on the fungicidal activity of compounds
4a -g are presented in Table 2. The activity of the dioxincar-
boxamides against bean rust was determined by inoculating
7-10-day-old pinto beans with the fungus Uromyces phaseoli
by spraying the leaf surfaces with 85 mg of spores and 10 drops
of Tween 20 surfactant per liter of water. After inoculation,
the plants were immediately placed in a temperature-humid-
ity-controlled chamber at 21 °C for 24 h for infection to occur.
The plants were then placed in the greenhouse for 24 h and
sprayed to runoff with a solution of each compound dissolved
in a minimum volume of acetone and diluted with water
containing a wetting agent. Ten days after treatment, per-
centage disease control was compared to a treatment in the
absence of the experimental compound and estimated with
Abbott’s formula (Abbott, 1925). Four replicates were included
in the evaluation. The commercial fungicide, carboxin, was
tested for comparative purposes under the same conditions as
the dioxincarboxamides.
Melting points were determined in open glass capillaries
and are uncorrected.
1H NMR spectra were recorded on a Varian EM-360L (60
MHz) spectrometer in CDCl3 using TMS as internal reference;
chemical shifts are expressed in parts per million.
2,3-Dih yd r o-5-m eth yl-6-(tr iflu or oa cetyl)-1,4-d ioxin (2).
2-(2-Propynyloxy)ethanol and 5,6-dihydro-2-methyl-1,4-dioxin
(1) were prepared according to the procedure of Bottini et al.
(1965). Trifluoroacetic anhydride (12.64 g, 60.2 mmol) was
added dropwise to a stirred mixture of 1 (3.00 g, 30.0 mmol)
and pyridine (4.87 g, 61.3 mmol) in dichloromethane (20 mL)
at room temperature, and the solution was allowed to stand
for 1 day. After reaction, the mixture was added to an aqueous
10% sodium carbonate solution (20 mL). After washing with
water (2 × 30 mL), the dichloromethane layer was dried with
sodium sulfate, and the solvent was evaported to give 2: yield,
1.96 g (33.3%, based on 1); bp 85 °C/15 Torr; 1H NMR (CDCl3)
4.0 (s, 4H), 2.4 (s, 3H) ppm.
5,6-Dih yd r o-3-m eth yl-1,4-d ioxin -2-ca r boxylic Acid (3).
To a solution of 2 (1.96 g, 10 mmol) in toluene (50 mL) was
added powdered potassium hydroxide (100 g, 18 mmol). The
mixture was refluxed for 7 h with stirring and then acidified
with dilute hydrochloric acid and extracted with dichlo-
romethane. After drying with sodium sulfate, the solvent was
removed under reduced pressure to give 3: yield, 1.00 g (69%,
based on 2); mp 120 °C; H NMR (CDCl3) 8.2 (bs, 1H), 4.0 (s,
4H), 2.4 (s, 3H) ppm.
Dioxin ca r boxa m id es 4a-g. A mixture of dioxincarboxylic
acid 3 (1.44 g, 10 mmol) and thionyl chloride (5 mL) was
LITERATURE CITED
Abbott, W. S. A method for computing the effectiveness of an
insecticide. J . Econ. Entomol. 1925, 18, 265-267.
Bottini, A. T.; Corson, F. P.; Bottner, E. F. Base-induced
cyclization reactions of propargyloxyethanol and 2-haloal-
lyoxyethanols. J . Org. Chem. 1965, 30, 2988-2994.
Davis, R. A.; Grahame, R. E.; Kulka, M. Control of virus
diseases of plants with 5,6-dihydro-2-methyl-1,4-oxathiin-
3-carboxamides. U.S. Patent 3657449, 1972.
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