CA2078065A1 - Heterocyclic derivatives of alkoxyacrylates with a fungicidal activity - Google Patents

Abstract

HETEROCYCLIC DERIVATIVES OF ALKOXYACRYLATES WITH A
FUNGICIDAL ACTIVITY.
Abstract A description follows of heterocyclic derivatives with a fungicidal activity, for agricultural use, having the formula (I):
(I) wherein:
- A, B, D, are N, or =C-G;
- G is H, halogen, NO2, CN, -COOR5, C1-C6 (halo)alkyl - R1, R2 and R5, are C1-C6 (halo)alkyl;
- R3 and R4 are H, C1-C2 alkyl, -COOR6, CN or bond;
- R6 is C1-C6 alkyl;
- Y, W, are H, halogen, C1-C6 alkyls, phenyls, heterocycles.

Description

2~7~

HETEROCYCLIC DERIVATIYES OF ALKOXYACRYLATES WITH A
FUNGICIDAL ACTIVITY.
The present invention relates to heterocyclic derivatives of alkoxy acrylates having a high fungicidal activity, the procesæ for their preparation and their use in agriculture.
Subject of the present invention are heterocyclic compounds having the general formula (I) ' A N

D \ ~ ~ t W

~O-CN = C - COOR1 -wherein:
- A, B, D, either the same or dif~erent, rspresent a nitrogen atom, or a =C-G group;

- G represents a hydrogen atom, a halogen atom, the nitro group, cyano group, a -COOR5 yroup, a Cl-C6 alkyl or C1-C6 haloalkyl group;
R1, R2 and F~, the same or different, represent .
, - 2 - 2~

C1-C6 alkyl or Cl-C6 haloalkyl groups;
- R3 and R4, the same or different, each represents a hydrogen atom, a Cl-C2 alkyl group, a -COOR6 group, a cyano group, or jointly form a bond;
- R6 represents a Cl-C6 alkyl group;
- - Y, W, the same or different, represent hydrogen, halogen, Cl-C6 alkyls, phenyl, heterocycle with 5-6 atoms wherein the heteroatoms are O, N, S, said phenyl, heterocycle, or C1-C6 alkyls also being optionally substituted with halogens, C1~C4 alkyls or C1-C4 haloal~yls, Cl-C4 alkoxyls or C1-C4 haloalkoxyls, phenyl groups, phenoxylic groups, heterocycloxylic groups or heterocycloxylic-benzocondensates optionally substituted.
Suitable substituents are, for exampl~, halogens, trifluoromethyl, methoxyl, phenoxyl and pyridoxyl.
The structure of general ~ormula ~I) may have at least one E/Z isomerism.
The compounds having general ~ormula (I) can be obtained by the addition of an aldoxymic compound :~ having the formula ~
OH
~: A B

~; N ;:

; ~ .

, - . , . : : . . . ~

- 2~7~

with an unsaturated compound having formula (III):

- F~ ~ / R4 C .~
~ y \ N (III) in the presence o~ a halogenating agent~ such as sodium hypochlorite, chlorine, bromine, to obtain a compound having formula tIV) ~ IVJ

CH2--COORl which is subsequently reacted wit~ an alkyl formiate having formula tv):
HCOOR
7 (V) wherein R7 represents a C1-~ alkyl group, in a dipolar protic or aprotic solvent, in the presence -..... of a base, at a temperature ranging ~rom -10C to 80C, to obtain the salt of the compound having formula (VI):
,.-, .;
:.;.-:.: ~ O~ R3 A~ R N ~ Y
D~ w (Vl) ; ~ from which, by reaction with an R2-X ~lkylating agent, '' :,.
. -..
. .
., . - . .
~ . . :' .
: . ..
.....

:
~. . : . . .

.

_ 4 _ 2~

wherein X represents a halogen atom (Cl, Br, I) or an activated ether, such as p-toluansulphonate, at a temperature ranging from -10C to 80OC, the desired compound having formula (I) i5 obtained.
S The compounds having formula (II) can be prepared by the reaction of (VII) with hydroxylamine hydrochlo-ride in the presence of a base:
A B ~

1 ~ / C ~ (VII) \

CHz -COOR1 The compounds having formula (VII) can be prepared by treatment of the heterocyclic compounds having formula (VIII) with a suitable base:
A B ~ o ~ 11 !1~ ~ (VIII) - D \ / H

~ N
:~. Z0 H ~:
and an acetic ester having formula (IX):
R1-OOC-CH2-X . (IX) The compounds having the general ~ormula (VIII~
can be obtained with different processes, depending on `~ 25 the nature of A, B and D.
When A, B and D, represent a =C-G group, the compounds having formula (VIII) can be prepared , . . . :
, - ` _ 5 _ 2~

according to the synthesis methods of pyrroles mentioned for example in "THE CHEMISTRY OF HETEROCYCLIC
COMPOUNDS" vol. ~, part 1, R.A. JONES (Ed.), WILEY, 1990 .
When A and D are both =N- and B represents a =C-G
group, the compounds having formula lVIII) can be prepared according to the methods for the synthesis of 1,2,3-triazoles mentioned for example in "THE
CHEMISTRY OF HETEROCYCLIC COMPOUNDS", Vol.39, ~.A.
MONTGOMERY (Ed.), WILEY, 1980.
When A and B are both =N- and D represents a =C~G
group, the compounds having formula (VIII) can be prepared according to the methods for the synthesi~ of 1,2,4-triazoles mentioned for example in "THE CHEMISTR~
OF HETEROCYCLIC COMPOUNDS" Vol 37, J.A. MONTGOMERY
(Ed.), WILEY, 1981.
When A and D both represent =C-G groups and B is =N-, the compounds having formula (VIII) can be prepared according to the methods for the synthesis of imidazoles mentioned for example in "COMPREHENSIVE
HETEROCYCLIC CHEMISTRY", Vol. 5, page 373, K.T. POTTS
(Ed.~, PERGAMON, 1984.
When A, B and D are =N , the compounds having formula tVIII) can be prepared according to the methods for the synthesis of tetrazoles: D. MODERHACK, CHEM.
BER. 1975, 108, 887; Do MODER~CK, CHEM. ZTG., 1977, 101f 403 (C~A. 1978, 88, 37706).

:

$~

The compounds having formula (III) can be obtained with the methods known in the art.
When R3 and R4 jointly represent a carbon-carbon bond, these compounds can be prepared according to the methods for the synthesis of alkynes described, for example, in HOUBEN-WEYL "METHODEN DER ORGANISCHEN
CHEMIE", Vol 5/2a, 1977; and L. aRANDsMA "PREPARATIVE
ACETYLENIC CHEMISTRY", ELSEVIER PUBLISHING Co., 1971.
The compounds having formula (III) where R3 and R4 have one of the other meaninys taken into considera-tion, they can be prepared according to the methods for the synthesis of alkenes described, for example, in HOUBEN-WEYL "METHODEN DER ORGANISCHEN CHEMIE", Vol 5/lb, 1972.
The compounds having general formula (I) have a particularly high fungicidal activity against phytopa-thogen fungi which attack cultivations of vines, ~` cereals, Cocurbitacee and fruit trees.
~,i Plant diseases which can be fought with the compounds of the present invention are, for example, - the following:

Helminthosporium of cereals -Plasmopara viticola of vines Phytium of vegetables -Sphaerothec~ uli~inea of cucurbitacee (e.g.

` cucumbers) -Se~toria of cereals - :

.
.

. ~

- 7 ~ 2 -Erysiphe qraminis of cereals -Rhynchos~orium of cereals -Podosphaera leucotricha on apple trees -Uncinula necator on vines -Venturia inequalis on apple trees -Piricularia oryzae on rice -Botrytis cinerea -Fusarium on cereals The compounds having formula (I) are capable of carrying out a fungicidal activity which is both curative and preventive with limited or no phytoto-XlCity .
For practical use in agriculture it is oftenuseful to have fungicidal compositions containing one or more compounds having formula (I), possibly also in isomeric form, as an active substance.
These compositions oan be applied to all parts of the plant, for example, leaves, stems, branches and roots, or on the seeds, before planting, or also on the soil where the plant grows.
Compositions can be used in the form of dry powders, wettable powders, emulsionable concentrates, microemulsions, pastes, flakes*, solutions, suspensions etc.: the choice of the type of composition depends on the specific use.
The compositions are prepared with the known methods, for example by diluting or dissolving the ' . ' ' ~

:

- 8 - ~ a 7~

active substance with a ~olvent and/or solid diluent, possibly in the presence of sur~ace-active agents.
The following can be used as solid diluents, or supports: silica, kaolin, b~ntonite, talc, infusorial earth, dolomite, calcium carbonate, magnesia, chalk, clays, synthetic silicates, attapulgite, sepiolite.
As liquid diluents, apart from wat~r, naturally, it is possible to use various types of solvents, for example aromatics ~xylenes or mixtures of alkylben-zols), chloro aromatics (chlorobenzol), paraffins(fractions of petxoleum), alcohols (methanol, propanol, butanol, octanol), amines, amides (N,N'-dimethylfor-mamide, N-methylpyrrolidone), ketones ~cyclohexane, acetophenone, isophorone, ethylamylketone), esters ; 15 (isobutyl acetate).
Surface-active agents which can be used are: salts of sodium, calcium or triethanolamine of alkylsulpha-tes, alkylsulphonates, alkyl-arylsulphonates; polyetho-xylated alkylphenols, fatty alcohols condensed with ethylene oxide, polyoxyethylated fatty acids, polyoxy-ethylated esters of sorbitol, ligninsulphonates.
The compositions may also contain special addi-~`~ tives for specific purposes, for example tacking agents such as arabic rubber, polyvinylic alcohol, polyvinyl-pyrrolidone.
If desired, it is also possible to add other compatible active substances to the compositions of the . ~ , -' ~' - , ' '' .-- ~
~ ~ r3 ~

present invention, such as fungicides, phytoregulators, antibiotics, weed-killers, insecticides, fertilizers.
The concentration of active substance in the above compositions can vary within a wide range, depending on the active compound, cultivation, pathogen, environmen~
tal conditions and type of formulation adopted.
The concentration of active substance generally varies from 0.1 to 95%l preferably from 0.5 to 90%.
The following examples illustrate the invention.
EXAMPL~E 1 Preparation of (Z)-3-methoxy-2-~2-[5-(4-chlorophenyl) isooxazol-3-yl]pyrrol-1-yl} methyl acrylate (compound N.l).
0.32 g of 80% (w/w~ sodium hydride in paraffin are dispersed in 10 cm3 of anhydrous D~F.
:~ 1.7 g of 2-{2-t5-(4-chlorophenyl)isooxazol-3-yl]
~. pyrrol-}-yl)methyl acetate in 6.5 cm3 of ethyl formiate -~ and 10 cm3 of anhydrous DMF are then added to the ~: solution dropwise in 30'.
The mixture thus obtained is heated to 50C for 4 hrs.
It is cooled to 5 D C and 3.3 cm3 of CH3I are added.
The mixture is kept at room temperature for 4 hrs, and is then diluted with water and extracted with ethyl acetate.
: The organic phase is washed with brine, anhydri-fied on sodium sulphate and concentrated at reduced . .

.~ .
- - -: : . . :

- lo - ~ ~7~

pressure.
The oil obtaine~ is purified by silica gel chroma-tography, and eluated with hexane/ethyl acetate = 8/2.
1.07 g of compound No.l are obtained having m.p.
= 170.172-C the structure being shown in Table l and NMR spectroscopic data in Table 2.
EXAMPLES 2~18 Using the same procedure described in Example 1, compounds 2-,8were prepared; the structure is shown in Table 1 and the respecti~e NME spectroscopic data in Table 2.
` EXAMPLE T9 Preparation o~ 2-~2-~5-(4-chlorophenyl)isooxazol-l-yl]pyrrol-l-yl}methyl acetate.
Sl cm3 of an aqueous solution of 7% HClO with 0.45 g o~ NaOH are added dropwise at 5-10C into a solution of 5 g of 2-~(2-hydroxyiminomethyl)pyrrol-l-yl]methyl . .
'~ acetate and 7.5 g of 4-chlorophenylacetylene in 60 cm3 `'` 0~ C}~2C12.

~ 20 The biphasic solution is left under vigorous -`~ stirring overnight at room temperature.
The organic phase is separated, and, after washing with brine, is anhydrified with Na2SO4 and concentrated at reduced pressure.
The crude product obtained is purified by silica gel chromatography, eluating with hexane/ethyl acetate ;; = 8/2.
..
~`' ;:

,~.......... .

: .:

- 11 2~J,~

1.7 g of the desire compound are obtained.

Preparation of 2-[(2-hydroxyiminomethyl)pyrrol-1-yl]-methyl acetate.
A suspension of 30 g of 2-carboxyaldehyde-1-methoxy-carbonylmethy~pyrrol, 18.1 g of hydroxylamine hydrochloride and 20.1 g of sodium acetate in 200 cm3 of ethanol is stirred vigorously for 20 h at room tempera-ture.
It is dîluted with 500 cm3 of water and the ethanol is distilled at reduced pressure.
The aqueous solution obtained is extracted with ethyl ether, which is subsequently washed with water, dried on Na2SO4 and concentrated at reduced pressure.
The oily crude product obtained (41 g) is purified by silica gel chromatography, eluating with the mixture hexane/ethyl ac~tate =85/15.
16.4 g of the desired compound are obtained as a light yellow solid.
EXAMPLE ~l ~
Deternination of the preventive ~ungicidal activity against powdery mildew of cucumbers (Sphaerotheca_fuli~inea "Schlech"~Salmon).
Cuoumber plants cv. Marketer, grown in a vase in a conditioned environment, were sprayed on the lower faces of the leaves with the products under examination in a 2Q% hydroacetonic solution of acetone (v/v).

' ::

, - ~ "
': , ~

', ', ' The plants were then kept in a conditivned environment for 1 day and were then sprayed on the upper fac~s of the leaves with an aqueous suspension of conidia of Sphaerotheca fuliainea (200000 conidia per cm3).
The plants were then returned to a conditioned environment at 20C and 70% o~ relative humidity.
At the end of the incubation period of the fungus (8 days), the gravity of the infection was evaluated with indexes o~ an evaluation scale from 100 (=healthy plant) to 0 (=completely infected plant).
Compound No.3 showed a control of over 90, at a concentration of 500 ppm.
EXAMPLE ?2 15Determination of the preventive fungicidal activity against Helminthosporium ~eres.
Barley leaves cv. Arna, grown in a vase in a conditioned environment, were sprayed on both ~aces with the products under examination in a Z0~ hydroa-cetonic solution in acetone (v/v).
After remaining 2 days in a conditioned ~-~ environment at 20C and 70% of relatiYe humidity, the plants were sprayed on both ~aces of the leaves with an ~ aqueous suspension o~ conidia o~ Helminthosporium teres `~ 25(250000 conidia per cm3~.
After remaining 24 h in an envixonment saturated with humidity, at 21C, the plants were kept in a ,~
''`'':
`

- 13 - ~07~.3 conditioned environment for ~he incubation of the fungus.
At the end of this period (12 days), the gravity of the inf~ction was evaluated with indexes of an evaluation scale from 100 (=healthy plant) to 0 (=completely infected plant).
Using compounds 2 and 3 in a concentration of 500 ppm an index of over 90 was obtained.

Determination of the curative ~ungicidal activity against vine mildew (Plasmopara viticola) (B.et C.) (Berl et de Toni).
The leaves of the vine cv. Dolcetto, grown in a vase in a conditioned environment, at 25C and 60% of relative humidity, were sprayed on the lower face with an aqueous suspension of conidia of Plasmopara viticola (200000 conidia per cm3).
After remaining 24 h in an environment saturated with humidity at 21C, the plants were sprayed on both faces of the leaves with the products under examination in a 20~ hydroacetonic solution of acetone (v/v).
At the end of the incubation period of ~he fungus (7 days), the gravity of the infection was evaluated with indexes of an evaluation scale from 100 (=healthy plant) to 0 (=completely infected).
Using compound No.3 in a concentration of 125 ppm an index =100 was obtained.

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1' , ' -16- ~8 TA~LE 2: NMR 200 MHz (CDCC13) sp~ctroscopic da~a ( second part ) Compound ._ 6 7.56 (lH, s), 6.68 (lH,dd), 6.61 (lH,dd3, 6.30 (lH,dd), 6.07 (lH, s), 3.83 (3H, s), 3.68 (3H, s), 2.36 (3H, s).
7 7,60 (5H, m), 7.61 (lH~ s), 6.72 (2H, m), 6.64 (lH, s), 6.36 (lH,dd), 3.87 (3H, s), 3.72 (3H, s).
8 6.86 ~lH, s), 6.69 (lH,dd), 6.38 (lH,dd), 6.21 (lH,dd), 4.23 (lH,dd), 3.92 (3H, s), 3.68 (3H, s), 3.08 (2H, m), 0.90 (9H, s).
9 7.60 (lH, s), 7.48 (lH,dd), 7.41 ~lH,dd), 7.10 (lH,dd), 6.72 (2H, m), 6.50 (lH, s), 6.35 (lH,dd), 3.86 (3H, s), 3.71 (3H, s).
7.62 (lOH,m), 6.75 (2H, m), 6.68 (lH, s), 6.38 ~lH,dd), 3.88 (3H, s), 3.73 (3H, s).
11 7.56 (lH, s), 7.37 (lH, d), 7.15 (lH,dd), 6.90 (lH, d), 6.71 (lH, d), 6.66 (lH,dd), 6.46 (lH, s), 6.31 (lH,dd), 5.14 (2H, s), 3.82 (3H, s), 3.68 (3H, s).
12 7.51 (lH, s), 7.22 (4H, m), 6.72 (lH,dd), 6.49 (lH,dd), 6.30 (lH,dd), 4.92 (lH, m), 4.05 (2H, m), 3.86 (3H, s), 3.72 (3H, s), 3.35 (2H, m).
13 7.60 ~2H, m), 7.40 (lH, s), 7.10 (2H, t), 6.70 (2H, m), 6.40 (lH, t), 3.90 (3H, s), 3.70 (3H, s).
14 7.70 (2H, d), 7.60 (lH, s), 7.50 (2H, d), 6.70 (2H, m), 6.60 (lH, s), 6.40 (lH, t), 3.90 (3H, s), 3.70 (3H, s), 1.40 ~9H, s).

7.90 (2H, d), 7.70 (2H, d), 7.60 (lH, s), 6.70 (3H, m), 6.40 (lH, t), 3.90 (3H, s), 3.70 (3H, s).
16 7.90 (2H, d), 7.70 (2H, d), 7.60 (1~, s), 6.70 (3H, m), 6.30 (lH, t), 3.90 (3H, s), 3.70 (3H, s).
1~ 7.90 (lH, d), 7.60 (lH, s), 7.50 ~lH, d), 7.40 (lH, q), 7.10 (lH, s), 6.70 (2H, m), 6.40 (lH, t), 3.90 (3H, s), ~ 3.70 (3H, s).

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Claims (8)

1. Heterocyclic derivatives of alkoxyacrylates with a fungicidal activity having the general formula:

(I) wherein:
- A, B, D, the same or different, represent a nitrogen atom, or a =C=G group;
- G represents a hydrogen atom, a halogen atom, the nitro group, cyano group, a -COOR5 group, a C1-C6 alkyl group or C1-C6 haloalkyl group;
- R1, R2 and R5, the same or different, represent C1-C6 alkyl groups or C1-C6 halo-alkyl groups;
- R3 and R4, the same or different, each represent a hydrogen atom, a C1-C2 alkyl group, a -COOR6 group, a cyano group, or jointly form a bond;
- R6 represents a C1-C6 alkyl group;
- Y, W, the same or different, represent hydrogen, halogen, C1-C6 alkyls, phenyl, heterocycle with 5-6 atoms wherein the hetero-atoms are O, N, S, said phenyl, heterocycle or C1-C6 alkyls being optionally substituted with halogens, C1-C4 alkyls or C1-C4 haloalkyls, C1-C4 alkoxyls or C1-C4 haloalkoxyls, phenyl groups, phenoxylic groups, heterocycloxylic groups or hetero-cycloxylic-benzocondensates optionally substituted.

2. Heterocyclic derivatives of alkoxyacrylates according to Claim 1, wherein:
- A, B, D represent =C-G, where G is an H atom;
- R1 and R2 are CH3;
- R3, R4 are H or jointly form a bond;
- W is an H atom;
- Y is a C1-C4 haloalkyl-phenyl and/or halogen substituted, a C1-C6 alkyl, C1-C4 alkyl phenyl and/or alkoxy substituted.

3. Compound according to Claim 1 which is (Z)-3-methoxy-2-{2-[5-(4-chlorophenyl)isooxazol-3-yl]
pyrrol-1-yl}methyl acrylate.

4. Compound according to Claim 2 wherein: R3, R4 are H, Y is p-chlorophenyl.

5. Compound according to Claim 2 wherein: R3, R4 form a bond between them, Y is a tert-butyl group.

6. Compound according to Claim 2 wherein: R3, R4 are H, Y is p-methoxybenzyl.

7. Compound according to Claim 2 wherein: R3 and R4 form a bond between them, Y is a m-trifluorome-thylphenyl group.

8. Process for the preparation of the compounds according to Claim 1 consisting in the addition of an aldoximic compound having formula (II):

(II) with an unsaturated compound having formula (III):

(III) in the presence of a halogenating agent, such as sodium hypochlorite, chlorine, bromine, to obtain a compound having formula (IV):

(IV) which is subsequently reacted with an alkyl formiate having formula (V):

where R7 represents a C1-C3 alkyl, in a dipolar protic or aprotic solvent, in the presence of a base, at a temperature ranging from -10°C to 80°C, to obtain the salt of the compound having formula (VI):

(VI) which reacts with an alkylating agent R2-X, where X represents a halogen atom (C1, Br, I) or an activated ester, such as p-toluensulphonate, at a temperature ranging from -10°C to 80°C.
Fungicidal compositions containing one or more of the compounds according to Claim 1 either alone or together with solid supports, liquid diluents, surface-active agents, or other active principles.
Method for fighting fungal infections consisting in spraying the plants with one or more compounds according to Claim 1 either alone or in the presence of solid supports, liquid diluents, surface-active agents, or other active principles.