Note: Descriptions are shown in the official language in which they were submitted.
---` 1(1 !37~86
--2--
q'he present ;nv~n~ion re~ates to novel cyclo-
alkanecarboxanilide derivatives which possess useful
herbicidal activity. The invention relates also to
herbicidal compositions comprising as active ingredient
at least one of the cycloalkanecarboxanilide derivatives
according to the present invention. The present invention
also relates to a method of controlling plant growth by
applying a cycloalkanecarboxanilide derivative according ~
to the present invention or a ~omp~ition comprising at ;
least one cycloalkanecarboxanilide derivative according
to the present invention to a locus containing plants to
be controlled.
The novel cycloalkanecar~xanilide derivatives
according to the present invention can be represented by
the general formula:
R1-X- ~ N- ~ C~2)n (I)
wherein X represents an 0, S, S0, S02 or -NR3 moiety;
Y represents a ~luorine, chlorine or bromine atom, a cyano,
nitro, C(R3)=NoR3 or C(o)R3 group, or the group -Zp-alkyl
in which the alkyl portion contains from 1 to 6 carbon atoms
and can be substituted by one or more fluorine, chlorine
or bromine atoms and Z represents an 0, S, S0 or S02 group;
R1 represents an alkyl group of from 1 to 6 carbon atoms,
an alkenyl group of from 2 to 6 carbon atoms or an aryl
group of from 6 to 10 carbon atoms, each optionally
substituted by one or more fluorine, chlorine or bromine
, , ~ .: . , ~ :
atoms or represents an alkynyl group of from 3 to 4
carbon atoms, an alkoxyalkyl group in which each alkyl
group contains from 1 to 6 carbon atoms, a cycloalkyl
group having from 3 to 7 carbon atoms in the ring, an
aralkyl group of from 7 to 9 carbon atoms optionally ring-
substituted by one or two fluorine, chlorine or bromine
atoms or by an alkyl group of from 1 to 4 carbon atoms,
a group of the formula:
R30 R30
' " 4 ' " 4 ~
-CHCR or -CHCNR RJ, or, when X represents the group
NR3- then R1 can represent the group -CR6, -S02R6, or,
when X represents the group S02 then R1 can also represent
the group -NR4R5, -NR4-CR6, or -NR4So2R6; R2 represents
an alkyl group of from 1 to 6 carbon atoms, a fluorine,
chlorine or bromine atom, an alkoxy or alkylthio group, in
which the alkyl portion contains from 1 to 6 carbon atoms;
with the proviso that when Y represents a N02 group, and
X represents an 0-moiety, then R1 does not represent a
methyl group; R3, R4 and R5 each independently represents
a hydrogen atom or an alkyl or cycloalkyl group of up to
6 carbon atoms and R5 can also represent an alkoxy group
of up to 6 carbon atoms; when X represents the group -NR3-
then R1 and R3 together can form a part of a heterocyclic
ring, such as -CH2-(CH2)mCH2-, -CH3(CH ) CH3 ' or
-CH2CH20CH2CH2-; when R1 represents the group -NR4R5
then R4 and R5 together can form a part o~ a heterocyclic
:
~ ~087~86
ring as is shown above lor It1 arld I~S w~len taken together;
R6 represents an alkyl group of Irom 1 to 6 car-bon atoms
or an aryl or aralkyl group Or from 6 to lO carbon atoms
optionally substituted by one or more fluorine, chlorine
or bromine atoms; m is 2 or 3; n is l or 2; and p is 0
or l.
The compounds shown in formula I above are
derivatives of substituted cyclopropane or substituted
cyclobutane carboxylic acids, such that n in the
formula I is l or 2. Examples where R2 in the formula
represents an alkyl group include methyl, ethyl, propyl
and n-butyl; R2 can also represent a methoxy- or methyl-
thio group or their lower alkyl homologues.
As a general rule, the compounds preferred because
of their herbicidal properties are those compounds of
formula I, wherein n is l and R2 represents a methyl
group. The compounds wherein R2 represents a chlorine
atom are also very active. Compounds wherein R2 represents
a methoxy group are also desirable.
The group Y can represent a chlorine, bromine or
fluorine atom, a cyano, nitro, unsubstituted amino, methyl-
amino, carboxy, methoxycarbonyl, aminocarbonyl, methyl-
aminocarbonyl, formyl, hydrox,~minomethyl, trifluoromethyl,
trifluoromethoxy, methyl, ethyl, methylsulphonyl or tri-
fluoromethylsulphonyl group.
Preferred because of their herbicidal properties
are compounds of formula I, wherein Y represents a tri-
fluoromethyl group. Compounds wherein Y represents a
:
10~37186
chlorine atom or a methyl or nitro group, are also very
active.
R can represent a straight- or, preferably,
branched-chPin alkyl group, such as methyl, ethyl, iso-
propyl, isobutyl, secondary butyl, tertiary butyl, iso-
amyl, 2-chlorethyl, trifluoromethyl, allyl, phenyl,
p-chlorophenyl, naphthyl or propargyl group. Where R
represents a cycloalkyl group it can be alkylated or
linked to X by an alkylene group, for example, a cyclo-
propyl, cyclohexyl, methylcyclopropyl or cyclopropyl-
methyl group. Additionally, Rl can represent such groups
as methoxyethyl, benzyl, phenethyl, p-chlorobenzyl or
o-methylbenzyl, or, when X represents the group -NR3
then Rl can also represent an acetyl, propionyl, caproyl,
benzoyl, methylsulphonyl, trifluoroacetyl or dimethylamino
group or, when X represents the group S02 then Rl can also
represent an unsubstituted amino, monomethylamino, di-
methylamino, acetamido or methylsulphonylamino group.
Compounds wherein R represents an alkyl group
of 1 to 4 carbon atoms or a cycloalkyl group are generally
preferred. Especially active are those compounds wherein
Rl represents a branched-chain alkyl, such as an iso-
propyl- or tert.-butyl group. Ethyl, methyl and cyclopropyl-
methyl derivatives and ring alkylated forms appear also
to be highly active. Variations in activity, of course,
depend on the individual combinations of R , R , R3, X
and Y.
5--
` 1~87~t36
R3, R4 and R5 each represents independently a ~;
hydrogen atom, an alkyl group, such as a methyl or ethyl
group or a cycloalkyl group, such as a methylcyclopropyl
group, or R5 can also represent an alkoxy group, such
as a methoxy or ethoxy group. Although, when X represents
the group -NR3, then R3 represents preferably an iso-
propyl-, n-propy~ or tert.-butyl group.
R6 can represent an alkyl group, such as a methyl,
ethyl, isopropyl, isobutyl, secondary-butyl, tertiary-
butyl, isoamyl or hexyl group or an aryl or aralkyl group,such as a phenyl, p-chlorophenyl, 2-bromophenyl, naphthyl,
phenethyl or benzyl group.
Species contemplated within the scope of the
present invention include those compounds with reference
to formula I, wherein R1, X, Y and R2 have the following
meanings:
i-C3H7, 0, CF3, n-C4H9 - isoamyl, 0, N02, n-C4Hg -
CH3C0, 0, N02, C2H5 - t.butyl, NH, CF3, OCH3 - sulphamoyl,
(R1 ~ X~, Et, SCH3 - i-C3H7, 0, Me, F and i-C4Hg~ S02,
CF3, F.
Species contemplated wherein X represents the
0 moiety and Y the trifluoromethyl group are those wherein
R1 and R2 have the following meanings:
isobutyl, methyl - isoamyl, propyl - 2-fluorobenzyl, methyl -
2-chlorobenzyl, n-butyl - 4-chlorobenzyl, methyl - 2,6-
dichlorobenzyl, ethyl - propargyl, methyl and sec.-butyl, propyl.
Preferred because of their herbicidal properties
are those compounds according to formula I, wherein X
. ' '
108~ 36
represents the 0 moiety, R2 represents a methyl group and
R represents an alkyl group of f`rom 1 to 4 carbon atoms,
a cyclopropylmethyl or a 1-methylcyclopropyl group. The
alkyl group is preferably a sec.-butyl or isopropyl group.
Haloalkyl groups, such as 2-chloroethyl groups, are also
desirable.
Species contemplated wherein X represents the
S, S0 or S02 moiety and Y the trifluoromethyl group are
those wherein R1, X and R2 have the following meanings:
CH30C2H4, S, methyl - allyl, S, pentyl - isoamyl, S0, ethyl -
i-C4Hg, S02, n-C4H9 - cyclopropyl, S0, methyl - 2-fluorobenzyl,
S02, n-C3H7 - 2-chlorobenzyl, S, methyl - sec.-C4Hg, S02,
methyl - 4-chlorobenzyl, S0, n-C4H9 - 2,6-dichlorobenzyl, S02,
methyl - propargyl, S, ethyl and sec.-C4Hg, S02, n-C3H7.
Preferred because of their herbicidal properties
are those compounds wherein X represents the S, S0 or S02
moiety, R2 represents a methyl group and R1 represents an
alkyl group of 1 to 4 carbon atoms, such as a methyl,
isopropyl or isobutyl group. Especially useful compounds
appear to be those wherein R1 represents an isopropyl
or an ethyl group.
Species contemplated wherein X represents the
group NR3 and Y the trifluoromethyl group are those
wherein R1, R3 and R2 have the following meanings:
t.-butyl, H, methyl - phenyl, H, methoxy - propargyl, H,
methylthio - benzyl, H, F - methoxy, methyl, methyl -
methylsulphonyl, H, methyl - trifluoromethylsulphonyl, H,
methyl - acetyl, H, methyl and trifluoroacetyl, H, methyl.
108~186
_~
--8--
A preferred subclass because of their herbicidal
properties are those compounds of formula I, wherein X
represents the group NR3, wherein R3 represents a hydrogen
atom or an alkyl group of from 1 to 4 carbon atoms, such
as a methyl, ethyl or propyl group, and R represents an
alkyl group of from 1 to 4 carbon atoms, especially an
isopropyl, t.-butyl or n-propyl group.
Species contemplated wherein R1 represents a
group -NR4R5, -NR4so2R6 or -NR4C(o~R6, X represents the
S02 moiety and Y a trifluoromethyl group are those
wherein R4, R5 (or R4 and R6) and R2 have the following
meanings:
H, H, methyl - methoxy, methyl, methyl - t.-butyl, H, methyl -
1-methylcyclopropyl, H, methyl - acetyl, H, methyl - trifluoro- -
acetyl, H, methyl - (H, methyl), methyl and (H, trifluoro-
methyl), methyl.
Similarly, compounds of the above subclasses, wherei n
Y represents a halogen atom, especially a bromine or chlorine
atom, or a methyl group in place of a trifluoromethyl group
are also highly useful subclasses of herbicides.
Compounds according to formula I, wherein Y
represents a nitro group are a useful subclass due to their
relatively easy and low cost of preparation as well as to
their herbicidal properties.
Species contemplated wherein Y represents a
nitro group are those wherein R1X and R2 have the fol-
lowing meanings:
:, ~
, 1~87186
propyloxyethylsulphonyl, ethyl - isobutylthio, n-C4H9 -
ethylsulphinyl, propyl - allyloxy, ethyl and 2,6-dichloro-
benzylsulphonyl, propyl.
Preferred because of their herbicidal properties
are those compounds wherein Y represents a nitro group and
R represents an alkyl group of 2 to 4 carbon atoms.
Especially useful compounds appear to be those wherein
R represents an isopropyl group and X represents an
0, S, S0 or S02 moiety as these compounds show useful
crop selectivities. The compounds wherein-X represents
a NR3 group are also highly active.
Species contemplated wherein Y represents an
alkyl group are those wherein R1X, Y and R2 have the
following meanings:
ethoxy, methyl, methyl - cyclopropylmethoxy, methyl, methyl -
1-cyclopropylethoxy, methyl, methyl - 1-methylpropoxy, methyl,
methyl - isopropoxy, ethyl, methyl - ethylthio, methyl,
methyl - ethylsulphonyl, methyl, methyl - methylthio, methyl,
methyl - methylsulphonyl, methyl, methyl - isopropylthio,
methyl, methyl - isopropylsulphonyl, methyl, methyl - methyl-
thio, isopropyl, methyl - isopropylamino, methyl, methyl -
t.-butylamino, methyl, methyl - (1-methylcyclopropyl)amino,
methyl, methyl - sulphamoy~,methyl, methyl - methoxy, sec.-
butyl, methyl - (N-methoxy-N-methyl)amino, methyl, methyl -
N-(methylsulphonyl)amino, methyl~ methyl - N-(trifluoro-
methylsulphonyl)amino, methyl, methyl - acetamido, methyl,
methyl and trifluoroacetamido, methyl, methyl.
--` 10871 !36
--10--
Species contemplated wherein Y represents a
bromine atom are those wherein R1X and R2 have the
following meanings:
ethoxy, methyl - methoxy, methyl - 2-methylpropoxy, methyl -
1-cyclopropylethoxy, methyl - ethylthio, methyl - methyl-
thio, methyl - isopropylthio, methyl - ethylsulphonyl,
methyl - dimethylamino, methyl - diethylamino, methyl -
isopropylamino, methyl and t.-butylamino, methyl. ` :
The corresponding chloro derivatives are also
contemplated:
sulphamoyl, methyl - dimethylsulphamoyl, methyl - t.butyl- .
sulphamoyl, methyl - N-(acetyl)sulphamoyl, methyl -
N-(methylsulphonyl)sulphamoyl, methyl - (N-methoxy-N-
methyl)amino, methyl - N-(methylsulphonyl)amino, methyl -
N-(tri~luoromethylsulphonyl)amino, methyl - acetamide,
methyl and trifluoroacetamido, methyl, as are the following
fluoro derivatives:
isopropoxy, methyl - isopropylamino, methyl - ethylthio,
methyl - isobutylsulphonyl, methyl and sec.-butoxy, methyl.
Of course,the corresponding bromo derivatives
can ~so be used.
The cycloalkane carboxanilides according to
formula I can be prepared according to the ~ollowing
æquenceo~ reactions:
` r~ 36
Rl-XNa + Cl ~ N02 ~ R -X ~ No2 (la)
Y Y
R -X- ~ N02 redUctio~ Rl X ~ ~H2 (2a)
10Rl-X- ~ NH2 + C18 ~ (CH2)n ~ Rl-X ~ l ~ 2)n
Y R2 Y R2
(3a)
The appropriate sodium alkoxide or mercaptide
compound (or the appropriate amine) is allowed to react
with a 3- substituted - 4 - chloronitrobenzene in step (la) to
give a 3, 4 - disubstituted nitrobenzene, which is reduced in
step (2a) to give the corresponding aniline. In step (3a)
the aniline and a cycloalkane carboxylic chloride are
allowed to react to give the desired cycloalkanecarboxanilide
according to formula I.
Reaction (la) is readily conducted by mixing the
reactants in a solvent such an an alcohol, dimethyl sulphoxide
or dimethylformamide at room temperature or at a moderately
elevated temperature, for example up to 150 C.
--11--
10~7186
-~2-
The reduction ol` the 3,~l-disubstituted nitro-
benzenes, step (2a) is readily carried out in boiling water
containing iron filings and up to 5% of acetic or hydro-
chloric acid. However, any of numerous reduction techniques ;
that reduce an aromatic nitro group to the corresponding
amino group are applicable here (see, for instance,
R. Schr8ter and F. M811er in 1'Methoden der Organischen
Chemie", (Houben-Weyl), Vol. 11, 1, part IV, pages 341-731,
Georg Thieme Verlag, Stuttgart (1957)).
The corresponding 4'-hydrocarbylsulphinyl- or
sulphonyl derivatives are prepared by treating the
appropriate 4'-hydrocarbylthio derivative with 85% meta-
chloroperoxybenzoic acid.
The acylation reaction ~a) is conducted by treating
the 3,4-disubstituted aniline with a cycloalkanecarboxylic
acid chloride in a suitable solvent, such as ether, tetra-
hydrofuran, benzene, toluene or hexane in the presence of
one molar equivalent of an organic or inorganic base that
can serve as acceptor for the hydrogen chloride formed in
the reaction. Organic bases, such as tertiary amines
(pyridine, triethylamine, collidine, N,N-dimethylaniline,
diethylisopropylamine) or inorganic bases (Na2C03, NaHC03,
K2C03, CaC03) may be used to trap the hydrogen chloride
formed during the acylation reaction.
The cycloalkanecarboxylic acid chlorides used
in the reaction or simple esters from which they can be
generated are generally known in the art (e.g., U.S.
patents 3,277,171, 3S211,544 and South African patent
1~7186
application 64~1283). The l-fluorocycloalkanecarboxylic
acid chlorides can be readily prepared by treating
l-chlorocycloalkanecarboxylic acid ethyl ester with
potassium fluoride at elevated temperatures option~lly
in the presence of solvents and /or phase transfer
catalysts and converting the ester to acid chloride in
a known manner. The l-bromocycloalkanecarboxylic acid
chlorides can be prepared by bromination of cycloalkane-
carboxylic acid chlorides under refluxing conditions in
a nitrogen atmosphere.
~he l-ethoxycyclobutanecarboxylic acid chloride
used in the preparation of the above anilides can be
prepared by alkali treatment of ethyl l-bromocyclobutane
carboxylate, a known compound, to liberate a mixture of
l-bromocyclobutanecarboxylic acid and l-ethoxycyclobutane-
carboxylic acid and conversion to the corresponding acid
chlorides in a known manner, e.g., by treatment with
thionyl chloride.
~he compounds according to the present invention,
for example, 4'-(isopropylamino)-3`-(trifluoromethyl)-l-
methylcyclopropanecarboxanilide, 4 -(isopropoxy)-3~-
(trifluoromethyl)-l-methylcyclopropanecarboxanilide and
4 -(isopropylthio)-3'-(trifluoromethyl)-l-methylcyclo-
propanecarboxanilide have been found to be useful for
controlling undesirable plant growth. ~hat is, certain
members of the class have been found to be herbicidally
effective against a wide range of plant species. Others
of the class are effective only against a limited
-13-
.
10871~6
number of plant species and are considered to be selective
herbicides. Some of the compounds exhibit a high degree ~ - --
of herbicidal activity in the control of a variety of
economically important species of grasses and broad-
leaved weeds. Some of the compounds are particularly
useful as selective herbicides for use in certain im-
portant crops.
The invention therefore also includes plant
growth regulating compositions comprising a carrier or
a surface-active agent, or both a carrier and a surface-
active agent, and, as active ingredient, at least one
cycloalkane carboxanilide derivative according to
formula I. Likewise the invention also includes a method
of controlling plant growth which comprises applying to
the locus an effective amount of a cycloalkane carboxanilide
according to formula I.
The term "carrier" as used herein means a solid
or fluid material, which may be inorganic or organic and
of synthetic or natural origin, with which the active
compound is mixed or formulated to facilitate its
application to the plant, seed, soil or other object
to be treated, or its storage, transport or handling.
Suitable solid carriers are natural and syn-
thetic clays and silicates, for example, natural silicas,
such as diatomaceous earths; magnesium silicates, for
example, talcs; magnesium aluminium silicates, for
example, attapulgites and vermiculites; aluminium
silicates, for example, kaolinites, montmorillinites
10~37186
and micas; calcium carbonates, calcium sulphate;
synthetic hydrated silicon oxides and synthetic calcium
or aluminium silicates, elements, such as carbon and
sulphurj natural and synthetic resins, for example,
coumarone resins, polyvinyl chloride and styrene
polymers and copolymers, solid polychlorophenols;
bitumen, waxes, such as beeswax, paraffin wax, and
chlorinated mineral waxes; and solid fertilizers, for
example superphosphates.
Examples of suitable fluid carriers are water,
alcohols, for example, isopropanol, glycols; ketones,
such as acetone, methyl ethyl ketone, methyl isobutyl
ketone and cyclohexanone; ethers; aromatic hydrocarbons,
such as benzene, toluene and xylene, petroleum fractions,
for example, kerosene, light mineral oils; chlorinated
hydrocarbons, such as carbon tetrachloride; perchloro-
ethylene, trichloroethane, including liquefied normally
vaporous gaseous compounds. Mixtures of different liquids
are often suitable.
~he surface-active agent may be an emulsifying
agent or a dispersing agent or a wetting agent; it may be
non-ionic or ionic. Any of the surface-active agents
usually applied in formulating herbicides or insecticides
may be used. Examples of suitable surface-active agents
are the sodium or calcium salts of polyacrylic acids
and lignin sulphonic acids; the condensation products of
fatty acids or aliphatic amines or amides containing at
least 12 carbon atoms in the molecule with ethylene oxide
- ,. : , .
.
1()87186
and/or propylene oxide; fatty acid esters of glycerol, - -
sorbitan, sucrose or pentaerythritol; condensates of
these with ethylene oxide and/or propylene oxide;
condensation products of fatty alcohols or alkyl
phenols, for example, p-octylphenol or p-octylcresol,
with ethylene oxide and/or propylene oxide; sulphates
or sulphonates of these condensation products, alkali
or alkaline earth metal salts, preferably sodium salts ~ ,
of sulphuric or sulphonic acid esters containing at
least 10 carbon atoms in the molecule, for example,
sodium lauryl sulphate, sodium secondary alkyl sulphates,
sodium salts of sulphonated castor oil, and sodium alkyl~
aryl sulphonates, such as sodium dodecylbenzene sulphonate;
and polymers of ethylene oxide and copolymers of ethylene
oxide and propylene oxide.
The compositions of the invention may be formulated ~: :
as wettable powders, dusts, granules, solutions, emulsifiable
concentrates, emulsions, suspension concentrates and
aerosols. Wettable powders are usually compounded to ~.
contain 25, 50 or 75% by weight of toxicant and usually
contain in addition to solid carrier, 3-10% by weight of
a dispersing agent, 1-5~ by weight of a surface-active
agent and where necessary, 0-10% by weight of stabilizer(s)
and/or other additives, such as penetrants or stickers.
Dusts are usually formulated as a dust concentrate having
a similar composition to that of a wettable powder but
without a dispersant or surface-active agent, and are
diluted in the field with further solid carrier to give
-16-
.
~ 7186
1 ~/
a composition usually containing 0.5-10% by weight of
toxicant. Granules are usually prepared to have a size
between 10 and 100 BS mesh (1.676 - 0.152 mm), and may
be manufactured by agglomeration or impregnation techniques.
Generally,granules will contain 0.5-25% by weight of
toxicant and 0-10% by weight of additives, such as
stabilizers, slow-release modifiers and binding agents.
Emulsifiable concentrates usually contain, in addition
to the solvent and, when necessary, co-solvent, 10-50%
by weight per volume of toxicant, 2-20% by weight per volume
of emulsifiers and 0-20% by weight per volume of appropriate
additives, such as stabilizers, penetrants and corrosion
inhibitors. Suspension concentrates are compounded so as
to obtain a stable, non-sedimenting, flowable product and
usually contain 10-75% by weight of toxicant, 0.5-5% by
weight of dispersing agents, 1-5% by weight of surface-
active agent, 0.1-10% by weight of suspending agents,
such as protective colloids and thixotropic agents,
0-10% by weight of appropriate additives, such as de-
foamers, corrosion inhibitors, stabilizers, penetrantsand stickers, and as carrier, water or an organic liquid
in which the toxicant is substantially insoluble; certain
organic solids or inorganic salts may be dissolved in
the carrier to assist in preventing sedimentation or as
anti-freeze agents for water.
Aqueous dispersions and emulsions, for example,
compositions obtained by diluting a wettable powder or a
concentrate according to the invention with water, also
.:
.
1()~7186
lie within the scope of the present invention. The said
emulsions may be of the water-in-oil or Or the oil-in-water
type, and may have a thick mayonnaise-like consistency.
The compositions of the invention may also contain
other ingredients, for example,other compounds possessing
pesticidal, especially insecticidal, acaricidal, herbicidal
or fungicidal properties.
The method of applying the compounds according to
the present invention comprises applying a compound according
to formula I, ordinarily in a composition of one of the afore-
mentioned types, to a locus or area to be protected from un-
desirable plant growth. The active compound, of course, is
applied in amounts sufficient to exert the desired action. ~-
The amount of compound to be used in controlling un-
desirable vegetation will naturally depend on the condition
of the vegetation, the degree of activity desired, the form-
ulation used, the mode of application, the climate, the
season of the year, and other variables. Recommendations as
to precise amounts are, therefore, not possible. In general,
however, application to the locus to be protected of from
0.1 to 10.0 pounds per acre of the compound used in this
invention will be satisfactory.
EXAMPLES
The manner in which the compounds according to the
present invention can be prepared is illustrated in the fol-
lowing examples, which demonstrate the preparation of typical
species of the invention. In these examples, the identities of
all compounds, intermediates and final, were confirmed by
elemental analysis, and infrared and nuclear magnetic spectral
analyses. The examples are for the purpose of illustration only
and should not be regarded as limiting the invention in any way.
1~8~186
-1'3-
Example 1
4'-Isopropoxy-3'-(trifluor~methyl)-1-methyl-
cyclopropanecarboxanilide
a) Preparation of 3-(tr~fluoromethyl) -4-isopropoxy-
nitrobenzen~
To a chilled (5C) solution of 118g (0.5 mole) of
3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of dimethyl
sulfoxidetDMSO) was added dropwise a solution containing 41g
(0.5 mole) of sodium isopropoxide in 300 ml of dimethyl sulpn-
oxide. The dark reaction mixture was stirred at ambienttemperature for one hour, poured into water and extracted with
ether. The ether extracts were washed with water, dried and
concentrated. Recrystallization of the residual liquid from
hexane gave 115.5g (92.7~)of~ white cry~talline solid;
m.p. 34-36C (la).
~j Preparation of 3-(*rifluoromethyl)-4-
-isopropoxyaniline
To a refluxing mixture containing 113.3g (0.455 mole)
of (la) in 1200 ml of 5% aqueous acetic acid and 50 ml of
methanol was added portionwise with stirring 137.5g of iron
filings. Th.e reaction mixture was refluxed for one hour,
filtered while hot, cooled and extracted with ether. The
ether extracts were dried and concentrated to give 72.3g
(72.6~) of product as an amber oil (lb).
c) Preparation of 4'-isopropoxy-3'-(trifluoro-
methyl)-l-methylcyclo~opanecarboxanilide
To a stirred solution containing lO.9g (0.05 mole)
of (lb) and 5.0g (0.05 mole) of triethylamine in 100 ml of
tetrahydrofuran was added dropwise 5.9g (0.05 mole) of
l-methylcyclopropanecarboxylic acid chloride. This addition was
. .
7186
-20-
exothermic to 55C. The reaction mixture was stirred and
refluxed for 30 minutes, and concentrated under reduced
pressure. ~he resulting solid was washed with water, dried and
recrystallized from ether to give 14.5g (97%) of a white
crystalline solid; m.p. 106-109C. -~
Example 2
4'-(Benzyloxy)-3~-trifluoromethyl-l-meth
propanec-arboxanilide
a) Preparation of 3-(trifluoromethyl)-4-
-(benzyloxy)nitrobenzene
To a solution containing 45.1g (0.2 mole) of
3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO was
added dropwise at ambient temperature a solution containing
26g tO.2 mole) of sodium benzyloxide in 75 ml of benzyl
alcohol causing the temperature to rise ~o 40`~.After 48 hours
at ambient temperature, the reaction mixture was poured into
ice water and extracted with ether, and the extract was dried
and concentrated to about 200 ml. To the concentrated
solution was added 200ml of hexane and the resulting
solution was cooled. Filtration gave 51.5g (87%) of
colourlesscrystalline solid; m.p. 112-114C (2a).
b) Preparation of 3-(trifluoromethy1)-4- -
-~benzylox~ aniline
~o a refluxing mixture containing 64.5g (0.217 mole)
of ~2a) in 700 ml of 5% aqueous acetic acid and 30 ml of
methanol was added portionwise within 15 minutes 65.5g of iron
filings. The mixture was stirred and refluxed for an additional
30 minutes, filtered while hot, cooled and extracted with
ether. ~he ether extract was washed with water, dried and
concentrated to give 56.0g (97%) of product as a light-amber
oil that crystallized on standins (2b)~
'.
--` 1087~86
-,'1 -
c) Pre~aration of 4'-(benzyloxy)-3'-(trifluoro-
methyl?-l-methylcyclopro~anecarboxanilide
To a solution of 2.7g (O.Ol~mole) of (2b) and
2.7 g,(0.01 mole) of triethylamine in 50 ml of tetra-
hydrofuran was added with stirring at ambient temperature
1.2g (0.01 mole) of l-methylcyclopropanecarboxylic acid chloride.
After one hour, the reaction mixture was poured into ice
water and extracted with 200 ml of ether. The ether
extract was dried and concentrated. Recrystallization of the
residual solid from ether gave 3.6 g of product, m.p. 120-122C.
Example 3
4'-(Cyclopropylmethoxy)-3'-(trifluoromethyl)-
-l-methylcyclopropanecarboxanilide
a) Preparation of 3-(trifluoromethy1)-4-
-(cyclopropylmethoxy)nitrobenzene
To a cooled (10C) solution containing 22.5g (0.1 mole)
of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO
was added with stirring at ambient temperature a solution
containing 0.11 mole of sodium cyclopropylmethoxide (prepared
by dissolving 4.9g of 57~ sodium hydride in 7.9g of cyclo-
propylmethanol and 50 ml of tetrahydrofuran) in 100 ml of DMSO.
The reaction mixture was heated at 50C for one hour, poured
into ice water and filtered. Recrystallization of the
filtrate from hexane gave ll.Og (42~) of product as a white
crystalline solid, m.p. 41-44C (3a).
~) Preparation of 3-(trifluoromethyl)-4-(cyclo-
propylmethoxy)aniline
To a stirring and refluxing mixture containing
; ll.Og (0.042 mole) of (3a) in 150 ml of 5% aqueous acetic acid
was added 28g of iron filings and 10 ml of methanol. The
.
`" 10~3~186
mixture was refluxed and stirred vieorously for one hour, then
extracted with ether after cooling. The ether extract was ~ :
washed with aqueous sodium bicarbonate, dried, and concentrated
to give 9.5g (98%) of product as an amber oil (3b).
c) Preparation of 4!i-(cyclopropylmethoxy)-3'-
-(trifluoromethyl)-l-methylcyclopropane-
carboxanilide
To a solution of 4.6 g (0.02 mole) of (3b) and
2.0g (0.02 mole) of triethylamine in 30 ml of tetrahydrofuran
was added 2.4g (0.02 mole) of l-methylcyclopropanecarboxylic
acid chloride. The mixture was refluxed for one hour, poured
into ice water, and extracted with ether. The extract was dried
and concentrated, and the residue was recrystalli~ed from hexane
to give 5.0g (79%) of white crystalline solid;m.p. 84-85 C.
Example 4
4'-(Methylthio)-3'-(trifluoromethyl)-1-
-methylcyclopropanecarboxanilide
a) Preparation of 3-(trifluoromethyl)-4-(methyl-
thio)-nitrobenzene
To a stirred solution containing 45.1g (0.20 mole)
of 3-(trifluoromethyl)-4-chloronitrobenzene and 15 g (0.30 mole)
of methyl mercaptan in 150 ml of DMS0 was added dropwise
at ambient a solution containing ô.Og (0.20 mole)
of sodium hydroxide in 20 ml of water. This addition was
exothermic to 60C. After one hour, the reaction mixture was
poured into ice water. The product was filtered and dried
to give 45.0g (95%) of yellow solid; m.p. 50C (4a).
b) Preparation of 3-(trifluoromethyl
-(methylthio) aniline
To a mixture containing 45.0g (0.19 mole) of (4a)
in refluxing 5% aqueous acetic acid was added 61g
-22-
.
1~87186
-23-
of iron powder. The reaction mixture was reflu~:ed for 3 hoursand filtered through Celite (filter aid) t~Jhile hot. The
cooled filtrate was extracted with ether. The ether extract
was washed with 10~ aqueous sodium bicarbonate, and then
with water, dried over anhydrous MgSO~, and concentrated
under reduced pressure to give 31.8g (81~) of product as a light
yellow oil (4b).
c) Preparation of 4'-(methylthio)-3'-(trifluoro-
methyl)-l-methylcyclopropanecarboxanilide
To a stirred solution containing 31.8g ~0.154 mole)
of (4~) and 15.6g (0.154 mole) of triethylamine in 200 ml of
tetrahydrofuran was added dropwise over 10 minutes 18.2g
(0.154 mole) of l-methylcyclopropanecarboxylic acid chloride. This
addition was exothermic to 65C. The mixture was stirred and
refluxed for one hour, poured into ice water and filtered.
The filter cake was washed with water and dried to give
43.5g (98~) of product as a yellow solid; m.p. 97-98C.
Example 5
4'-(Methylsu~hiny1)-3'-(trifluoro~ethyl)~
-methylcyclopropanecarboxanilide
To a chilled (5C) solution containing 14.5g (0.05 mole)
of 4'-(methylthio)-3'-(trifluoromethyl)-1-methylcyclopropane-
carboxanilide (prepared in Example 4 above) in 150 ml of
chloroform was added dropwise over 20 minutes with stirring
a solution of 10.2g (0.05 mole) of 85% meta-chloroperoxy-
benzoic acid in 150 ml of chloroform. The reaction solution
was allowed to equilibrate gradually to 25C, and after
16 hours, washed well with lO~ sodium carbonate and
~ 1087186
- -2~!-
water, dried, and concentrated. The residual solid was
crystallized from methanol to give 13.0g (86%) of product
as a light-cream colored solid; m.p. 181-184 C.
ExampIe 6
4'-(Methylsu~nyl)-3'-trifluoromethyl-1-methyl-
cyclopropanecarboxanilide
To a stirred solution containing 7.0g (0.024 mole)
of 4'-(methylthio)-3'-(trifluoromethyl)-1-methylcyclopropane-
carboxanilide (prepared in Example 4 above) in 200 ml of
chloroform was added dropwise over a period of 10 minutes
at ambient temperature 10.2g (0.05 mole) of 85% meta-
-chloroperoxybenzoic acid. The reaction was exothermic to
50C. The reaction mixture was stirred for 16 hours, washed
with 10%-a~ueous sodium carbonate and then with water. The
- chloroform layer was dried and concentrated to dryness. The
- residue was crystallized from methanol to give 7.5g (97~) of
product as a light-cream solid; m.p. 135-138C.
Example 7 -
4'- lorophenoxy)-3'-(trifluoromethyl)-1-methyl-
cyclopropanecarboxanilide
a) Preparation of 4-(4-chlorophenoxy?-3-
ttrifluoromethyl~nltrobenzene
To a solution containing 64.2g (0.5 mole) of
4-chlorophenol and 112.7g tO.5 mole) of 2-chloro-5-nitro-
benzotrifluoride in 400 ml of DMSO was added dropwise
with stirring at 30-35C a solution containing 20g
(0.5 mole) of sodium hydroxide in 20 ml of water. After ~- -
1.5 hours, the reaction mixture was poured into cold water
: ,.... . ~
.
--- 1087186 ~:
-25-
and extracted with 800 ml of ether. The ether solution was
dried and concentrated under reduced pressure to give 158 g
(99~) of product that crystallized on standing; melting
point, 46-48C tfrom hexane) (7a).
b) Preparation of 4-(4-chlorophenoxy)-3-
(trifluoromethyl)aniline
To a refluxing mixture containing 156 g (0.492 mole) -~-~
of the nitro compound (7a) in 1180 ml
of 5~ aqueous acetic acid was added portionwise 140g
of powdered iron. After 2 hours, the reaction mixture
was filtered through filter aid and the residue was
washed with methanol. The combined filtrates were extracted
with 7 X 300 ml of ether. The combined ether extracts were
washed with aqueous sodium bic3rbonate, dried and concentrated
to give 141.5g of product; melting point, 43-45C (from hexane) (7b)
c) Preparation of 4'-(4-chlorophenoxy)-3'-
(trifluorometh~l)-1-methylcyclopropane-
.
carboxanilide
To a stirred solution of 5.75g (0.02 mole) --
of the aminQ ~7b) in 40 ml of tetrahydrofuran was
added dropwise 2.4g (0.02 mole) of l-methylcyclopropylcarboxy]ic acid
chloride. The mixture was stirred and heated at 60C for 0.5
hour, poured into ice water and filtered. The filter cake
was recrystallized from ether-hexane (1:3) to give 6.5g (88~)
of product, m.p. 115-117C.
. : ,
.
~ 1~87186
-26-
Example 8
4'-(4-Chlorophenoxy)-3'-(trifluoromethyl)
-l-butylcyclopropanecarboxanilide
To a solution containing 2.9g (0.01 mole) of the amine
prepared according to Example 7b),an~1.0g(0.01 mole) of
triethylamine in 50 ml of tetrahydrofuran was added dropwise
1.7g (0.01 mole) of l-butylcyclopropanecarboxylic acid chloride.
The mixture was stirred and heated at 60C for 0.5 hour, poured
into ice water and extracted with ether. The ether
extract was dried and concentrated under reduced pressure.
The residual yellow syrup was crystallized from hexane to
give 3.3g (80~) of product as a tan solid, m.p. 104-106C.
Example 9
4'-(Isopropylthio)-3'-ltrifluoromethy~
-l-methylcyclopropanecarboxanilide
a) Preparation of 4-(Isopropylthio)-3-
(trifluoromethyl)nitrobenzene
To a solution containing 112.8g tO.5 mole) of
2-chloro-5-nitrobenzotrifluoride and 46g (0.6 mole) of
isopropyl mercaptan in 400 ml of DMS0 was added dropwise
over 0.5 hour 40g of 50% aqueous sodium hydroxide.
This addition was exothermic to 50C. After 24 hours,
the reaction mixture was poured into ice water and
extracted with 3 X 200 ml of methylene chloride. The
combined extracts were washed with water, dried and concentrated
to give 132g (99%) of product as an orange liquid (9a).
~) Preparation of 4-(isopropylthio)-3-
-~trifluoromethyl)aniline
A mixture containing 132.5g ~0.5 mole)
of the nitro compound (~a) - in 800 ml of 5% aqueous
1~871~36
-27-
acetic acid was heated to reflux with stirring. The heat
mantle was removed and 150g o~ powdered iron
was added at such a rate as to maintain reflux. After com-
. .
pletion of the addition, the mixture was stirred and refluxedfor one hour, and filtered while hot. The filtrate was
extracted with ether (3 X 300 ml). The combined extracts
were washed with 10% sodium carbonate, and then with water.
The dried solution was concentrated to dryness under reduced
pressure to give 70.5~g (60~) of product as a yellow oil (9b).
c) Preparation of 4'-(isopropylthio)-3'-
(trifluorometh~ l-methylcyclopropane-
carboxanil de
To a stirred solution containing 23.5g
(O.1 mole).of the amine (9b) and lO.lg (0.1 mole)
of triethylamine in lS0 ml of tetrahydrofuran was added
dropwise over 5 minutes ll.9g (0.1 mole) of l-methylcyclopropyl- -
carboxylic acid chloride. This addition was exothermic to 55C.
The mixture was refluxed for 1 hour, poured into ice water
and filtered. The filter cake was recrystallized from
hexane to give 25g (79~) of product as acoIourless crystalline
solid, m.p. 103-105C.
Examples 10-41
In the manner described above, and illustrated in
foregoing Examples, additional cyclopropanecarboxanilides
listed in Table 1 were prepared.
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--29--
- 1~87186
-3o-
Example 43
4'-(Isopropylthio)-3~-nitro-l-methylcyclopr
panecarboxanilide
a) Preparation of 4-(isoE~ropylthio)-3-nitroaniline
To a stirred solution containing 34.5g (0.20 mole)
of 4-chloro-3-nitroaniline and 24g (0.30 mole) of isopropyl
mercaptan in 200 ml of DMSO was added dropwise at
ambient temperature a solution of 8.0g (0.20 mole) of
sodium hydroxide in 10 ml of water. The addition was
10 exothennic to 60Cand the mixture became deep red in colour.
After three day~, the reaction mixture was poured into
water and extracted with methylene chloride.~ The combined
- extracts were washed with water, dried with anhydrous MgSO4,
filtered and concentrated to give 41.1g (976)- of product
as a red-brown syrup.(43a).
b) Preparation of 4'-(isopropy-lthio)-3l-nitr
-methylcyclopropanecarboxanilide
To a solution containing 16.0g (0.75 mole) of
(4~) and 7.6g (0.75 mole) of triethylamine in 150 ml of
20 tetrahydrofuran was added dropwise with stirring 8.9g
(0.075 mole) of l-methylcyclopropanecarboxylic aCi~t chloride.
This addition was exothermic to 60. The mixture was refluxed
for one hour~ poured over ice water and extracted with ether.
The ether extract was dried and concentrated to give 20.7g
of a dark red-brown oil. Purification by silica chromatography
gave 10.5g (48~) of product as a light-yellow solid,
melting point, 92-94C.
Examples 44-46
In the manner described in Example 43, additional
30 cyclopropanecarboxanilides listed in Table 2 were prepared.
.
, :., .
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~-' 1087186
-31-
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10~7~86
-32-
Example 47
4'-(Cyclopropylmethoxy)-3'-chloro-1-methyl_
cyclopropanecarboxanilide
a) Preparation of 3-chloro-4-(cyclopropylmethoxy)- -
nitrobenzene
To a solution containing 38.4 g of 3,4-dichloronitro- ~ -
benzene in 150 ml of DMS0 was added 17.3 g of cyclopropylmethanol.
This solution was stirred during the dropwise addition of 92 g -~
of sodium hydroxide dissolved in 10 ml of water. This addition
was exothermic to 45C. The mixture was stirred and heated to
75-80C for 18 hours, then poured over ice water and filtered.
The filter cake was recrystallized from methanol to yield 27 g ~ ~-
(59%) of light tan solid, melting point, 42-44C (47a).
b) PreParation of 3-chloro-4-(cyclopropylmethoxy)aniline
To a heated mixture containing 26.7 g of (47a) in ~ -
300 ml of 5% aqueous acetic acid was added 56 g of iron filings
and 15 ml of methanol. The mixture was refluxed and stirred
vigorously for one hour. The mixture was filtered while hot
and the cooled filtrate was extracted with ether. The ether
extract was washed with aqueous sodium bicarbonate, dried, and
concentrated to give 22.8 g (99%) of product, melting point,
54-55C (47b).
c) Preparation of 4'-(cyclopropylmethoxy)-3'-chloro-
1-methylcyclopropanecarboxanilide
To a solution of 4.9 g of (47b) and 2.5 g of triethyl- -
amine in 50 ml of tetrahydrofuran was added dropwise 3.0 g of
1-methylcyclopropanecarboxylic acid chloride. The mixture was
refluxed for 30 minutes, poured into ice water, and filtered, and
the filtrate was recrystallized from methanol/water (4:1) to
give 6.5 g (93%) of white crystalline solid; m.p. 111-113C.
: - .
: - . ~ . :
1~7186
~33-
Examples 48-54
In the manner described in Example 47 :
additional cyclopropanecarboxanilides listed in Table 3
were prepared.
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10~37~86
-35-
Example 5
4'-Piperidinyl-3'-(trifluoromethyl)-1-methyl-
cyclopro~anecarboxanilide
.. a) Preparation of 4-nitro-1-piperidinyl-2-
-(trifluoromethyl)benzene
-
To a solution of 4-nitro-2-(trifluoromethyl)-
chlorobenzene in 150 ml DMSO was added dropwise 17g
of piperidine. The mixture was stirred at ambient ..
temperature, while protected from air and moisture, for ~
several days, then poured over ice water and extracted with ~ -
methylene chloride. The extract was washed with cold water,
dried and concentrated to give 27.4g tlOO~) of yellow-brown oil(56a:
~) Preparation of 4-piperidinyL-3-(trifluor
methyl)benzenamine
To about 500 ml of 5% acetic acid heated to 95C
was added.26g of 56 a). 17g of iron powder
was added portionwise at a rate to maintain reflux without
an external source of heat. After the addition, the mixture
was stirred and heated at reflux for 1.5 hours, then
filtered while hot, and the cooled filtrate was extracted with
ether. The ether extract was washed with 10% aqueous
sodium bicarbonate and then with water, dried, and concentrated
to 22g (96~) of yellow-brown oil (56b).
c) Preparation of 4'-piperidinyl-3'-(trifluoro-
methyl?-l-methylcyclopropanecarboxanilide
To llg of(56 b) in 75 ml of tetrahydrofuran
; and 4.6g of triethylamine was added dropwise 5.3g of l-methyl-
cyclopropanecarboxylic acid chloride, the reaction temperature
~0!37186
-36-
going to 55C. The mixture was thel stlrred and heated at
64C for 1.5 hours, poured over ice water and extracted with
ether. The ether extrac~ was washed with water, dried and
concentrated to give 13g (88~) of a yellow syrup, which ~-
was crystallized from hexane to give 12g (82~) of off-white
solid; m.p. 109-11C.
Example 57
4~-(Isopropylamino)-3~-(trifluorom~th
-methylcyclopropanecarboxanilide
a) Preparation of N-isopropyl-4-nitro-2-(tri- -
fluoromethyl)benzenamine
To a solution of 45g of 3-(trifluoromethy1)-4-
-chloronitrobenzene in 150 ml of DMS0 was added 13g of
isopropylamine. The mixture was heated at 80-90C for '
two hours, poured over ice water, acidified and filtered.
The filtra~e was dried to yield 49.6g of product; m.p.35~36Qc (57a)-
~) Prepar'ation of 4-'(isopropYlamino')-3-(trifluoro- - '
methyl)_enzenamine
About 565 ml of 5~ acetic acid was heated to 90C
and 49.6 g of 57 a) - was added. 123g of iron powder was ' -
added portionwise. The resulting mixture was refluxed for
1 hour, then filtered while hot. The filtrate was cooled
and extracted with ether. The ether extract was washed
with 10% aqueous sodium bicarbonate and then with water,
dried and concentrated to give 38.7g (89~) of product
as a light amber oil (57b).
.
.
,
. . ~
86
-37-
c) Pre~aration of 4'-(isopropylamino)-3'-
-~trifluoromethyl)-l-methylcyclopropane-
carboxanilide
To a solution of about l9g of 57 b) in ~-
150 ml of tetrahydrofuran and 8.8g of triethylamine was
added 118.5g of l-methylcyclopropanecarboxylic acid chloride
dropwise over 5 minutes at 25-64C. The reaction mixture
was stirred, refluxed for 30 minutes, poured over ice
water, and extracted with ether. The ether extract was
dried and concentrated, and the residue was crystallized
from ether/petroleum ether to give 22g (84~) of grey solid;
m.p. 100-102C.
Example 58-73
In the manner described in the E~amples 56 and 57
additional cyclopropanecarboxanilides listed in Table 4
were prepared.
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--39--
-- 10~71~6
-40-
Example 72
4'-(I opropoxy~-3'-(trifluoromethyl)-1-chlorocyclo-
.
propanecarboxanilide
To a solution of 10.95g(1 b) in 100 ml of
tetrahydrofuran and 5.05 g of triethylamine was added dropwise
at ambient temperature 6.95g of l-chlorocyclopropanecarboxylicacid
chloride. The reaction mixture was allowed to stand for two
days, then concentrated to dryness. The r~sulting solid was
washed with water and recrystallized from 80~ aqueous methanol
to give lOg (62~) of white solid; m.p. 106-108C.
ExamPle 73 -
4'-Isopropoxy-3~-(trifluoromethy~ ethoxycyclobutane
carboxanilide and 4'-isopropoxy-3'-(trifluoro-
methyl)-l-bromoc~clobutanecarboxanilide
- a) Preparation of l-ethoxycyclobutanecarboxylic acid
chloride and l-bromocyclobutanecarboxylic acid
.
chloride
A solution containing 82.8 g of ethyl l-bromo-
cyclobutanecarboxylate and 28 g of potassium hydroxide in -
250 ml of 85% aqueous ethanol was refluxed for 15 minutes.
The reaction mixture was concentrated to dryness under
reduced pressure, treated with cold hydrochloric acid, and
extracted with ether. The ether extract was dried and
concentrated to give 53 g of a viscous mixture of acids.
Treatment of this mixture with an excess of thionyl chloride
under reflux conditions followed by distillation gave 18 g
of a colourlessliquid, boiling at 70-75C ~16 mm). Gas-
-liquid chromatography indicated the presence, in the
approximate ratio of 4:1, of l-bromocyclobutanecarboxylic acid
chloride and l-ethoxycyclobutanecarboxylic acid chloride.
.
1C)87186
~) Preparation_of 4'-isoproxy-3-(trifluoro-
methyl)-l-ethoxycyclobutanecarboxanilide and 4'-
-isopropoxy-3'-(trifluoromethyl)-l-bromo-
cyclobutanecarboxanilide
To a solution containing 10.9 g of(l~) and 5.1 g
of triethylamine in 175 ml of tetrahydrofuran was added
dropwise at 10-20C 12.1 g of(73 a). After standing overnight,
the reaction mixture was concentrated to dryness, washed with
water, and extracted with ether. The ether extract was concen-
trated and the product was purified by silica chromatography.The first fraction comprised 3.0 g (16~) of the l-ethoxycyclo-
butane ester as a tan solid, m.p. 48-50C. The second fraction
comprised 2.4 g (13~) of the l-bromocyclobutane ester as a
white solid, m.p. 82-84C.
Example 74
4'-(IsopropoxY)-3l-methyl-l-methylcyclopropane
carboxanilide
a) Preparation of isopropyl ortho-tolyl ether
To a solution of 54.1 g (0.5 mole) of ortho-cresol
in 150 ml of DMSO was added portionwise and with
stirring 12 g of 57% sodium hydroxide. This addition was
exothermic to 45C. After 2 hours at ambient temperature,
61.5 g (0.5 mole) of isopropyl bromide in 50 ml of DMSO
was added dropwise with stirring. After another 2 hours,
the reaction mixture was poured into 1000 ml of ice
water and extracted with ether. Distillation of the dried
extract gave 53.9 g of product as a colorless liquid;
b.p. 94-96C (30 mm)~ (74a).
~) Preparation of 2-isopropoxy-5-nitrotoluene
To a chilled (6C) solution containing 31.8 g (0.2 mole)
of the ether ~74a) and 28.7 g of acetic
anhydride in 200 ml of glacial acetic acid was added dropwise
. . .. . , ~ . : '~, .,
~087186
-42-
a solution of 13.9 g (0.22 mole) of 90% nitric acid in 100 ml
of glacial acetic acid. The reaction mixture was allowed to
stand at ambient temperature for 12 hours, poured into water
and extracted with methylene chloride. The extract
was washed with 5% sodium carbonate, water, dried,
and concentrated to give 21.8 g of product as an amber oil (74b).
c) Preparation of 4'-(isopropoxy)i-3'-methyl-
-l-methylcyclopropanecarboxanilide
A Parr shaker was charged with 21.8 g tO.ll mole) -- -
of (74b) and 2 g of 10% palladium-charcoal catalyst in 150 ml
of tetrahydrofuran. The glass cylinder was pressurized with
hydrogen (40 pounds) and shaken until hydrogen uptake ceased.
The catalyst was removed by filtration. To the resulting
solution was added 11.2 g of triethylamine and 12.6 g of
l-methylcyclopropanecarboxylic acid Gh~oride. T~is-additi~ was
exotbermic to 35C. After 1 hour, the reaction mixture
was concentrated to dryness and washed with water.
Purification by silica chromatography gave 0.8 g of a white
crystalline solid; m.p. 99-101C.
Example 75
4'~tDimethylsu hamoy~3'-(trifluoromethyl)-l-
-methylcyclopropanecarboxanilide
a) Preparation of 4-nitro-3-ttrifluoromethyl)-
benzenesulphonyl chloride
A mixture containing 57.5 g (0.28 mole) of
4-nitro-2-(trifluoromethyl)aniline in 200 ml of concentrated
hydrochloric acid was heated to 90Cfor 15 minutes and left
stirring at ambient temperature for 18 hours. The resulting
mixture was chilled to 4 and diazotized with 21.4 g (0.31 mole)
o~ sodium nitrite in 50 ml of water. After 1 hour, the
diazonium salt solution was added dropwise over 20 minutes and
.
.
,. . :
~ 1087186
-43-
with stirring to a cold (5-10C) solution containing 13 g of
copper(II) chloride and 64 g of sulphur dioxide in 250 ml of
glacial acetic acid. After 2 hours, the mixture was filtered.
The filter cake was washed well with water and dried to give
68 g (84%) of product as a light tan solid; m.p. 77-79C (75a).
b) Preparation of N,N-dimethyl-4-nitro-2-
(trifluoromethyl)benzenesulphonamide
To a stirred solution containing 14 g (0.05 mole) of
the sulphonyl chloride (75a) in 100 ml of tetrahydrofuran was
added through a gas-inlet tube an excess of anhydrous dimethyl-
amine causing the internal temperature to rise to 60C. The
mixture was stirred at ambient temperature for ~ hour, poured
into 500 ml of ice water and filtered. The filter cake was
washed with water and dried to give 14 g (94%) of product as
a light tan solid; m.p. 95-97C (75b).
c) Preparation of 4-(dimethylsulphamoyl-3-
(trifluoromethyl)aniline
To a heated mixture containing 13.5 g (0.045 mole)
of the amide (75b) in 250 ml of 5% acetic acid was added
portionwise and with stirring 12 g of iron powder. The
mixture was refluxed for ~ hour. The mixture was filtered
while hot and the cooled filtrate was extracted with ether.
The ether extract was washed with aqueous sodium bicarbonate,
dried, concentrated and recrystallized from ether-hexane (1:2)
to give 10.1 g (83%) of product as a colourless solid; m.p.
140-142C (75c).
d) Preparation of 4'-(dimethylsulphamoyl)-3'-(trifluoro-
.
methyl)-1-methylcyclopropanecarboxanilide
To a solution of 6.7 g (0.025 mole) of the aniline
(75c) and 2.5 g of triethylamine in 50 ml of tetra-
hydrofuran was added dropwise 3.0 g (0.025 mole) of
.. . . .
: . ,
71~ -
-44-
l-methylcyclopropanecarboxylic acid chloride. ~he mixture was
refluxed for one hour, poured into ice water, filtered and
recrystallized from methanol to give 7.5 g (86~) of product as
a whi~e crystalline solid; m.p. 153-156C.
Example 76
4~-(Isopropoxy)-3'-chloro-l-methoXycyc-lopropane
carboxanilide
A mixture consisting of 5.6 g of 3-chloro-4-isopropoxy-
aniline, 3.9 g of methyl l-methoxycyclopropanecarboxylate and
1.8 g of sodium methoxide in 50 ml of benzene was refluxed
for 3 hours. The reaction mixture was concentrated to a
volume of 25 ml, poured over ice water, acidified with - -
hydrochloric acid and extracted with ether. The extract was
dried, filtered and concentrated. Purification by silica ;~
chromatography gave 1.8 g of product as a white crystalline
solid; m.p. 86-87C.
Examples 77-94
In the manner described for the above examples,
additional cyclopropanecarboxanilides listed in Tables 5 and 6
were prepared.
10871~6
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~xample 95 - Demonstration of herbicidal activity
The pre-emergence herbicidal activity of the compounds
according to the invention was evaluated by planting seeds of
garden cress, downey brome, wild mustard, velvet leaf, soybean,
wheat, and cotton in test tubes, nominally measuring 25 x 200
millimeters, containing soil treated with the test compound at
the rates of 0.1 and 1 mg per tube designated in Table I at
Rates I and II, respectively. The planted soil was held under
controlled conditions of temperature, moisture, and light for
1~ to 14 days. The amount of germination and growth in each
tube were evaluated on a 0 to 9 scale, 0 rating indicating no
effect, 9 death of the seedlings or no germination.
The post-emergence activity of the compounds according
to this invention was evaluated by spraying 7-day old crabgrass
plants, 10-day old pigweed plants, 7-day old downey brome plants,
10-day old wild mustard, 10-day old velvet leaf, 14-day old
soybean plants, 7-day old wheat and 14-day old cotton plants
to run-off with a liquid formulation of the test compound at
the rates of 0.62 milliliter of an 0.05% solution designated Rate I :~
in Table I, and o.56 milliliter of an 0.5% solution designated :~
Rate II in Table I. The sprayed plants were held under con-
trolled conditions for 10 to 11 days and the effect of the test
compound was then evaluated visually, the results being rated
on the 0 to 9 scale described above.
The results of the pre- and post-emergence tests are
summarized in Table I.
The herbicidal activity of the compounds according to the
- present invention was further determined with respect to several
common species of weeds, by spraying a formulation of the test
compound on the soil in which the weed seeds had been planted
--` 1087186
--48--
(pre-emergence test) or onto the foliage of the plants
(post-emergence test). In each series of tests, the plants
were grown in narrow trays and sprayed with the appropriate
chemical. The solution of the test compound was sprayed over
the tray, from one end to the other, the concentration of the
test compound in the formulation varying logarithmically from
a higher value at one end of the band to a lower value at the
other end of the band. The effect of the test compound was
evaluated visually and reported as the nominal rate of
application, in pounds of test compound per acre (1.12 kg/ha)
of the soil band, at which 90% inhibition of the growth of
the weeds occurred, this being referred to as the 90% growth
inhibition dosage (GIDgo)~ Results of the pre-emergence and
post-emergence tests, as well as the weed species involved,
are set out in Tables II and III.
ql86
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-65-
In many instances the compounds according to the
invention possess a selective action against weeds in crop
plant cultures. For example, control of grasses and broadleaf
weeds in grain crops such as wheat can be achieved by post- :- -
emergence application of such compounds according to the in-
vention as:
4'-(sec-butoxy)-3'-(trifluoromethy~-1-methyl-
cyclopropanecarboxanilide,
4'-(isobutoxy)-3'-(trifluoromethyl)-1-methyl-
cyclopropanecarboxanilide,
4!-(isobutylsulphonyl)-3'-(trifluoromethyl)-1-
methylcyclopropanecarboxanilide, or
4'-(ethylthio)-3'-(trifluoromethyl)-1-methyl-
cyclopropanecarboxanilide.
Control of weeds in soybean crops is an example of
the selective herbicidal activity of 4'-(isopropylamino)-3'-
(trifluoromethyl)-l-methylcyclopropanecarboxanilide or
4'-(isopropylthio)-3'-(trifluoromethyl)-1-methylcyclopropane-
carboxanilide~
The above species and/or other species of the in-
vention have likewise shown post-emergence, and in some cases,
pre-emergence selective activity for peanuts, grain sorghum,
cotton, rice, corn, alfalfa or the like.
