Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ `~ lZW539
The present invention relates to new fungicidal
compounds and more especially to new fun~icidal N-aryl-N-
acyl-3-amino-oxazolidin-2-ones.
Fungicidal compounds of the class of N-phenyl-1,3-
oxazolidin-2,4-diones are described in, for instance, Dutch
Patent Application No. 68/17249 (Sumitomo), in French Patent No.
2,172,295 (BASF), and in selgium Patent No. 874,406 to
Montedison, S.p.A.
Recently, there has also been described the bacteri-
cidal and fungicidal activity of some derivatives of aniline and
glycine which carry on the nitrogen atom a variously substituted
phenyl group and an acylic group of varying nature.
More particularly, this acylic group may consist of an
a- or ~-haloalkanoyl (German Patent Application DOS 2,513,789 -
Ciba Geigy = U.S.P. 4,025,848),or of an acetyl group substituted in c~-position
with a sulphur or oxygen atom in its turn bound to groups of
varying nature (French Patent Application No. 7,510,722 - Ciba~eigy
= British patent 1,500,581) or again of a 2-furoyl, 2-thienoyl or pyridyl-2-
carbonyl group (German Patent Applications DOS 2,513,732 and 3,513,788 - Ciba-
Geigy = U.S.P. 4,046,911). ~ethylalaninates are kno~,n which possess microbi-
cidal activity; these methylalaninates carry on the nitrogen
atom a 2,6-dialkyl-phenyl and one of the following groups:
cyclopropanoyl , acryloyl, crotonoyl
Other derivatives of fungicidal acyl-anilines have
recently been described in Belgian Patent No. 863.615 (Ciba-
Geigy) and in German Patent ~pplication DOS 2 ,745, 633 (Chevron).
The interest in the search for new derivatives from
acylanilines having fungicidal action originates from the
exigency of finding acylaniline derivatives that will have a
high fungicidal activity combined with a lack of phytotoxicity.
In fact, some of the already known products, although
12~3539
developing an excellent fungicidal activity, prove, however, to be also
toxic for the plants that one wishes to protect against infec-
tions by fungi.
The damages caused by the phytotoxicity to the plants
to be protected can hardly be avoided by using a dose of a
fungicidal compound that may be the best compromise between
the fungicidal activity of the compound and its phytotoxicity.
In fact, in the practical application in agricultural
cultivations, the quantity of product that actually remains
on the plant varies considerably depending on various factors
such as, for instance, the weather conditions, (particularly
the frequency of rainfalls?, and the correctness and frequency
of the applications carried out by the farmer.
It would be advant~geous to have oxazolidin-2-ones
which are highly active fungicides and safe for use in fighting
fungi infestations of useful plants without damage to the
plants, even when used in large quantities.
A divisional application of the present application
relates to compounds of the general formula ~I)
\ / \
CH
C = O
C ~ / (I)
R l 4
\ C / n
R2 ~ O l ll
'~Rl O
wherein R and Rl equal to or different from each other, are
halogen, Cl-C4 alkyl or Cl-C4 alkoxy;
R is H, halogen or Cl-C4 alkyl,
ICH3
A is -CH2- or -CH-
- 2 -
1203539
n is 0 or 1,
R is -OR or -SR (R is Cl-C5 alkyl or a heterocyclic
group of 5 or 6 atoms containing from 1 to 3 hetero-
atoms) when n is 1 or
R is a heterocyclic group of 5 to 6 atoms containing
from 1 to 3 hetero-atoms or Cl-C5 alkyl substituted
with one or more halogen atoms, when n is 1 or 0
and R is H or CH3
and which are endowed with very effective fungicide activity
while having a very low phytotoxicity.
The present invention on the other hand provides com-
pounds of the general formula (I)
/
CH C =~o
.. H2 - N\ B
wherein B is a group of the formula (IIa)
R'
Rl~ \f (~, ~4 ~IIa~
or a group of the formula (IIb)
Rl ~ N \ R7 (IIb)
R' is H;
R, R and R2, equal to or different from each other
are: H, halogen, Cl-C4 alkyl or C1-C4 alkoxy;
R3 is H or CH3;
- 3 -
1203539
A is -CH2- or -CH-
n is 0 ox 1~
R is H, Cl-C5 alkyl, Cl-C5 aLkyl substituted with one or m~re
halogen atoms; C3-C6 cycloalkyl; C2-C5 alkenyl or
ethinyl; halogen (when n=l); CN;SCN: phenyl;phenyl
substituted with one or more members of the class
consisting of Cl-C5 alkyl and halogen atoms; acetyl;
-C-O-(alkyl); -oR5; -SR ; -NR R ~with R and R
(equal to or different from each other) being H;
Cl-C5 alkyl; C2-C5 alkenyl; C2-C5 alkynyl; phenyl;
-S02-alkyl or acetyl~T
and R7 is selected from the class consisting of phenylacetyl,
acetoxyacetyl, hydroxyacetyl, methoxyoxalyl,acetyl, and
phenoxyacetyl,
provided that when -(A~n-R is -CH3, or R is acetyl, at least
one of R, Rl, R2 and R3 is different from hydrogen:
and which are endowed with very effective fungicide activity
while having a very low phytotoxicity.
The heterocyclic groups may for example be : furyl,
tetrahydrofuryl, thienyl, pyrimidyl, pyridyl, imidazolyl,
pyrazolyl or triazolyl.
N-phenyl-N-acetyl-3-amino-oxazolidin-2-one of formula
(II) : O
N
~ N-C-CH3 (II)
has been described in the Journal of Organis Chemistry, 31,
p. 968 (1966) but has not ~ re~nized , however, as possessing
fungicidal activity.
-- 4 --
1;~3~39
In accordance with another:aspect of the present inven-
tion, there is provided a method for fighting fungi infections
of plants consisting in distributing on the plants or on the soil
in which the plants live, an effective amount of at least one
of the compounds of the formula (I)
\ / \ (I)
CH2 N \ B
wherein s is a group of the formula (IIa)
~ ~' C ~ (A~n ~ R ~IIa~
or a group of the formula (IIb)
Rl ~ N \ R7 (IIb)
R' is H;
R, R and R2, equal to or different from each other
are: H, halogen, Cl-C4 alkyl or Cl-C4 alkoxy;
R is H or CH3;
A is -CH2- or -CH-
n is 0 or 1;
R is H; Cl-C5 alkyl; Cl-C5 alkyl substituted with one or more
halogen atoms; C3-C6 cycloalkyl; C2-C5 alkenyl or
ethinyl; halogen (when n = l); CN; SCN; phenyl;
phenyl substituted with one or more members of the
- 4 a -
1203539
class consisting of Cl-C5 alkyl and halogen atoms,
acetyl; ~-O-(àlkyl); -oR5; -SR5; -NR5R6 L~with R5
and R6 (equal to or different from each other)
being H; Cl-C5 alkyl; C2-C5 alkenyl; C2-C5 alkynyl;
phenyl; -SO2-alkyl or acetyi7
and R7 is selected from the class consisting of phenylacetyl,
acetoxyacetyl, hydroxyacetyl, methoxyoxalyl, acetyl,and
phenoxyacetyl,
provided that when -(A)n-R is -CH3, or R is acetyl, at least
one of R, Rl, R2 and R3 is different from hydrogen.
The preparation of the compounds of general formula (I)
is carried out by means of processes known in the normal practice
of organic chemistry.
For instance, an arylhydrazine (3) may be prepared by
reacting the corresponding aniline (1) with sodium nitrite (NaNO2)
in hydrochloric acid, and by then reducing the diazonium salt (2)
thus obtained (scheme 1, equation 1 below), as described for
instance in Journal of American Chemical Society, 81 , p.4673
(1959)
The aryl-hydrazine is then caused to react with 2-halo-
ethyl or l-methyl-2-haloethyl-chloroformate (4) (in its turn
prepared by the action of phosgene on a halohydrin) in the
presence of a base, and the intermediate (5) thus obtained is
then cyclized in the presence of bases, thereby obtaining
intermediate (6) (scheme 1, equation 2). This process has been
described in the jour. of Am. Chem. Soc. 48. 1951 (1926).
Intermediate (6) is then condensed by means of the
proper acylic halide (7?, according to known techniques (scheme
l,-equation 3). The condensation reaction between intermediate (6)
- 4 b -
1~03539
and acylic halide (7) may be substituted or replaced by analogous
reactions known in the literature, which allow the introduction
of particular acylic groups. For instance, the compounds of general
formula (I), in which the acylic part
R4 = -oR5 , -SR5 or -N \ R6 may be prepared by
reacting intermediate (6) with phosgene or with haloacetyl or
halopropion~l hal1des (such as, for i~stance, C1 C_CK 1 ~c
,/
,/
,
/
/
/'
/
i
_ 4 c ~
` ` 12~3S39
Cl-C-CH-CH3 respectively) and by then substituting the halogen
O Cl
atom according to known techniques.
The compounds of formula (I), in which the acylic part
is _Il_R , and where R4 is NHR5, may be prepared by reacting
intermediate (6) with an isocyanate of the formula: R5-N -. C = O.
The compounds of formula (I), in which the acylic part
is -Cl-CH2-lCI-CH3 (A = CH2; R4 = acetyl), may be prepared by
O O
reacting the intermediate (6) with diketene.
Scheme 1: B being the group of formula (IIa)
ffl e
N1~2 N=N Cl NH`-NH2
1) ~ NaN02 ~ R ~ Reducer ~ R
(1) (2) (3)
R3 .-
IR3 ~-NH-C-O-CH-CH2X
2)(3) + Cl-~-O-CH-CH2X ~R ~
O R R2 r
(4) (5)
r
~/0
IN
NH
R' I .
-HX ~ (6) t
R~R<2
-- 5 --
.~
1203S39
3) ~) + X C-(A)n-R P (I)
- /X=halogen; R,R ,R ,R , R , A and n have the same meanings as in general fon~a(I)_/ . Reaction 3 is carried out in an inert solvent, in the presence of a
halogenhydric acid-accepting base, at reflux t~ærature.
The above scheme may be used for the case wherein B is the group
of fon~a (IIb).
The compounds of general formula (I) are endowed with an excellent
fungicide activity against phytopathogenous fungi and their action has both a
lD preventive character(i.e.,they hinder the inception of the disease,as well as a
- curative character (when,that is, the infection is already in progress).
The most important class of phytopathogenous fungi
which can be fought by using the compounds of the invention, is
that of Phycomicetes which comprises Plasmopara ~E~ ~
Phytophtora spp., Peronospora æ, Pseudoperonospora spp. and
Phvthium sPP .
- The fungicidal compounds of the invention are effective
for fighting-fungi infections of useful plants such as vine, I
tomato, tobacco, potato and other cultivations.
They possess good systemic characteristics(i.e., they
are carried into the various parts of the plant) wherefore it
is ~ossible to apply these products both on the leaves as well
as on the soil.
Moreover, the compounds of general formula (I) proved
to be compatible with the plants that are to be protected ?
against fungi attacks.
The majority of the compounds of general formula (I)
do not show any sign of phytotoxicity at the amounts tried
out, while the remainder showed only a low phytotoxicity,lo~er,
at any rate, than that of the previously known fungicides.
In practical agricultural applications, the compounds
of formula (I) can be used as such or in form of suitable com-
-- 6 --
Gl
1203539
positions, consistmg of the compounds of formula (I) as active principle, agri-
culturalIy acceptable carriers (e.g.solid or liquid inert carriers)and,optionally,
surfactants and other additives. If desired, active compounds,
such as other fungicides, insecticides, plant-growth regulators
and so on, may be present in the compositions.
The compounds may be formulated according to the normal
agricultural practice, as dusts, powders, wettable powders,
emulsifiable liquids, granular formulates and so on.
The amounts of compounds of formula (I) to be dis-
tributed for fighting infections by fungi depends on various
factors, such as the active compound used, the type of com-
position or formulation, the kind of infection and its degree,
the kind of agricultural cultivation to be protected from fungi
attack, the climatic and weather conditions, and so on.
Generally, amounts of compounds of formula (I) com-
prised between 10 and 500 g/ha are sufficient, the preferred
amount being from 100 to 250 g/ha. The following examples are
given to illustrate the invention in more detail, and are not
intended to be limiting.
EXAMPLE 1
Preparation of N-~methoxYacetYl)-N-(2,6-dimethvl-phenyl)-3-
amino-oxazolidin-2-one.
(A) PreParation of 2,6-dimethYlphenylhydrazine :
107 g of 2,6-xylidine were dripped into a solution of
220 ml of concentrated HCl in 150 ml of water. After cooling
down to -5C, this mixture was thereupon additioned with a
solution of 66 ml of NaNO2 in 150 ml of H2O, over a period of
time of about 1 hour and under vigorous stirring.
To the yellow-orange colored suspension thus obtained
were added, at 0C and in about 4 hours, 450 g of SnC12.2H2O in
600 ml of a 5N aqueous solution of HCl.
The mixture was then maintained under stirring for 24
- 7 -
~`
1203~39
hours, allowing the temperature to rise up to +20C. The solid
thus formed was filtered, dissolved in 700 ml of H20 and then
treated with a solution of 230 g of NaOH in 300 ml of H2O, at a
temperature of between 10 and 15 & , after which the product was
extrac-ted with diethylether (3 x 250 ml).
The etheric extract, after washing with H2O and anhy-
drification on Na2SO4, was brought up to a volume of 1500 ml
with diethylether and then was treated with anhydrous gaseous
HCl, until attaining the complete precipitation of the chloro-
hydrate of 2,6-dimethylhydrazine.
The salt was then filtered and dried, thereby obtaining
40 g of a white solid having a melting point (m.p.) equal to
205-207 & with decomposition.
By treatment with NaOH, from the chlorohydrate was
obtained 2,6-dimethyl-phenylhydrazine.
(B) PreParation of 3-(2,6-dimethylaniline) oxazolidin-2-one:
To 41.4 g of 2-bromoethyl-chloroformate, prepared from
phosgene and ethylenic bromohydrine, in 200 ml of benzene,
there were additioned, at 10 & , the following reactants: 36.5 g
of 2,6-dimethyl-phenylhydrazine (see point A), and 18 g of
pyridine in 100 ml of benzene. This addition once completed,
the temperature was allowed to rise up to 20& under constant
vigorous stirring.
The pyridine chlorohydrate was removed by washing with
water. The benzenic solution was further washed with HCl and
with water to a neutral pH, and was then dried on Na2SO4 and
evaporated to yield 61 g of an oily product which, crystallized
from ligroin, gave 43 g of a light colored solid having a m.p.
of 58C-63C, and which consisted of 1-(2,6-dimethylphenyl-2-
(~-bromoethyl)-oxycarbonyl hydrazine. ~The IR spectroscopy gave:
v(C=O) = 1710 cm ; v~NH-CO) = 3180 cm ; v(NH-Ar) = 3340 cm 1~7
40 g ofi this intermediate were dissolved in 500 ml of
1~203539
toluene and the solution was treated with 1~ g of tetramethyl-
guanidine. This mixture was reflux-heated for 3 hours under
stirring. After cooling down, the mixture was washed with 200
ml of H2O and then with 100 ml of diluted HCl and finally again
with 200 ml o H2O.
The aqueous phases, reunited, were extracted with
CH2C12 (2 x 200 ml)-
The combined organic phases were anhydrified on Na2SO4and then the solvent was evaporated, thereby obtaining a solid
residue which was crystallized from ligroin-ethylacetate (2:1).
There were thus obtained 22.5 g of 3-(2,6-dimethyl-
aniline)-oxazolidin-2-one having a m.p. of 107-110C. ~The IR
spectrum showed: v(C=O) = 1770 cm ; v(NH) = 3340 cm .~
The cyclization reaction was repeated, dissolving the
intermediate with m.p. of 58-62C in ethanol containing sodium
ethylate, and by then reflux-heating the solution. After an
analogous treatment of the reaction mixture, the same inter-
- mediate was isolated; it had a m.p. of 107-110C.
(C) To 2 g of the intermediate, prepared as described in
(B), in 70 ml of toluene and 0.2 ml of dimethylformamide, there
were added 1.1 g of methoxyacetyl chloride. The reaction
mixture was then reflux-heated for 8 hours. After cooling down,
the reaction mixture was subjected to complete evaporation of
the solvents. The residue, consisting of 2,9 g of a thick oily
product, was purified on a silica gel column, using as eluent a
mixture of benzene/ethylacetate, in a 1/1 ratio.
Thereby were obtained, after removal of the solvents,
1.1 g of a syrupy product which crystallized spontaneously and
which, after re-crystallization from ligroin/ethylacetate (1:1)
mixture, yields 1 g of the desired compound whose characteristics
have been recorded in Table 1 (compound No. 6).
C The IR spectrum gave : v(N-CO-CH2) = 1680 cm ; v(N-CO-O) =
1203S39
-1 1
EXAMP~E 2
Operating analogously to Example 1, and in
accordance with the reactions at pages 5 and 6, there were
prepared, in addition to Compound N 6, the other compounds
reported in the following Table I:
- TABLE I(a)
Table Ia - B being a group of the formula (IIa)
Compound R Rl R2 R3 4 m.p.( ) IR(c)
10 N ` (C) -1
1 H H H H 1 CH2 Cl 71-4 1690-1760
2 H H H H 1 CH2 C6H5 112-4 1680-1760
3 H H H H 1 CH2 i.C3H7 oil 1680-1770
42 CH3 3 H H 0 - CH2C1 88-92 1635-1770
62 C 3 3 H H 1 CH2 OCH3 103-6 1680-1780
7 H H H H 1 CH2 OCH3 86-91 1690-1760
Table Ib - B being a group of the formula (IIb)
Compound R Rl R2 R3 R7 m.p.(b) IR(c)
N (0C) (cm_l)
.
C 3 3 H H CH2C6H5 oil 1670-1770
8 2 C 3 3 H H CH O CO CH oil 1690-1770
9 2 3 3 H H CH2H 135-8 1690-1770( )
3 3 H H CO-OCH3 116-9 1680-1730-
11 3 3 H H CH3 132-5 1670-1770
12 3 3 H H CH2OC6H5 109-12 1690-1780
1203539
~otes to Table I:
(a) The ele~ental analysis of all the compounds is consistent
~ith the assigned structure.
(b) Melting points have not been corrected.
(c) Only the bands corresponding to vC=O are reported.
( ~ vOH = 3300
`/
/
/
/
/
~ 10 a -
1203539
EXAMP~E 3
Curative activitY on vine~PeronosPora~ (PlasmoPara vitivola
~B et C) Berl et de Toni)
Vine leaves of Cv. Dolcetto, grown in pots in a con-
ditioned environment stabilized at 25C and 60~ of relative
humidity, were sprinkled on the lower faces thereof with an
aqueous suspension of PlasmoPara viticola conidia (200,000
conidia/cc). After 24 hours of dwelling in a humidity (moisture)
saturated environment, stabilized at 21C, the plants were
treated by sprinkling both faces of the leaves with the products
under examination in a hydroacetone solution at 20~ of acetone
(vol./vol.).
At the end of the incubation period (7 days), the
degree of infection was assessed by sight on the basis of a
value scale with indexes going from :
0 : no control, infection equal to that of witness
- plant (infected but non-treated plants)
1 : 1-20% reduction of the infection ;
2 : 20-60~ reduction of the infection ;
3 : 60~90~ reduction of the infection ;
4 : reduction of the infection greater than 90%.
The results obtained are-recorded in the following
Table 2:
TABLE 2
Curative activity against vine Peronospora
by foliar application at the dose of 0.5~.
Compound No. ActivityCompound No. Activity
1 3 7 4
2 . 3 8 4
3 4 9 4
4 4 10 4
4 11 4
6 4 12 4
-- 11 --
1203539
EXAMPLE 4
Curative activitY on PeronosPora of Tobacco (Peronospora
tabacina Adam).
The leaves of tobacco plants Cv. Burley, grown in pots
in a conditioned environment, were sprinkled, on the lower ~aces
of the leaves, with a Peronospora tabacina conidia-suspension
~200,000 conidia/cc). After 6 hours of dwelling in a humidity
saturated environment, the plants were transferred to a con-
ditioned environment stabilized at 20C and 70~ of relative
10- humidity, for the incubation of the fungus. 24 hours after the
infection, treatment was carried out by sprinkling both leaf
faces with the product under examination, in a hydroacetone
solution of 20% in acetone (vol./vol.).
At the end of the incubation period (6 days) the extent
of the infection was assessed by sight according to a value
scale with an index range equal to that of Example 3.
- The results of the test are recorded in the following
Table 3:
TABLE 3
Curative activity by foliar application at
doses of 0.5% on plants infected with
Peronospora of Tobacco.
Compound No. Activity
4 4
6 4
EXAMPLE 5
Determination of the phvtotoxicity deqree
Leaves of Cv. Dolcetto vine plants, grown in pots in a
conditioned environment stabilized at 25C and 60% relative
humidity, were treated by sprinkling both leaf faces with a
- 12 -
lZ03S39
hydroacetone solution at 204 of acetone (vol./vol.) of the
products under examination.
After 7 days, the extent or degree of phytotoxic
symptoms were evaluated by sight according to a value scale with
indexes ranging from 100 (for fully damaged plant) to 0 (for a
healthy plant).
The corresponding data are recorded in Table 4, in
comparison with the phytotoxicity indexes of the two compounds
known to be shortly marketed, i.e.: "Furalaxyl" (British
10` Patent No. 1,448.810 - Ciba-Geigy) and "Ridomil" (French Patent
Application No. 2,267,042 - Ciba-Geiqy).
TABLE 4
Phytotoxity index for doses at 0.6%.
Compound No.Phytotoxicity index
3 10
4 0
6 ~ 0
"Furalaxyl" (1) 100
"Ridomil" (2)60
(1) "Furalaxyl" = N-(2,6-dimethylphenyl)-N-(l'-carbomethoxy-
ethyl)-2-furoyl-amide :
CH3 O
H3CO-C-lH 1~3
H3C ~ ~CH3
'~
(2) "Ridomil" = N-(2,6-dimethylphenyl)-N -(l'-carbomethoxy-
ethyl)-methoxyacetamide :
- 13 -
1203539
IH3 R
H3C-O-CI-CH ~C-CH20CH3
o
3C~CH3
-- 14 --
