ISOXAZOLINK DERIVATIVES AND THEIR USE AS HERBICIDES
The present invention relates to novel, herbicidal isoxazoline compounds, to
processes for their preparation, to compositions comprising those compounds, and to
their use in controlling weeds, especially in crops of useful plants, or in inhibiting plant
growth.
Isoxazoline compounds which display a herbicidal action are described, for
example, in WO 01/012613, WO 02/062770, WO 03/000686, WO 04/010165 and JP
2005/035924. The preparation of these compounds is also described in WO 04/013106.
Novel isoxazoline compounds which display herbicidal and growth-inhibiting
properties have now been found.
The present invention accordingly relates to compounds of formula I
(Figure Removed)
wherein
R1 and R2 are each independently of the other hydrogen, Ci-Cioalkyl, Ci-Ciohaloalkyl,
C3-C8cycloalkyl or C3-C8cycloalkyl-C1-C3alkyl, or
R1 and R2 together with the carbon atom to which they are bonded form a C3-C7ring,
R3 and R4 are each independently of the other hydrogen, C1-C10alkyl, C1-C10haloallcyl,
C3-C8cycloalkyl-C1-C10oalkyl, C1-C6alkoxy-C1-C10alkyl or C3-C8cycloalkyl, or
R3 and R4 together with the carbon atom to which they are bonded form a C3-C7ring, or
R1 with R3 or R4 and together with the carbon atoms to which they are bonded form a
C5-C8ring, or
R2 with R3 or R4 and together with the carbon atoms to which they are bonded form a
C5-C8ring;
R5 and R6 are each independently of the other C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6-
hydroxyalkyl, pyrrolyl-CH2-, pyrazolyl-CH2-5 4,5-dihydropyrazolyl-CH2-, triazolyl-CHa-
, imidazolyl-CHa-, tetrazolyl-CH2-, indolyl-CH2-, indazolyl-CH2-, benzotriazolyl-CH2-,
C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkenyl, C1-C6alkylcarbonyloxy-Ca-Cealkenyl,
C2-C6alkenyloxy, C2-C6alkynyloxy, C1-C6alkylcarbonyl, C1-C6haloalkylcarbonyl,
C3-C6cycloalkylcarbonyl, C1-C6alkoxy-C1-C6alkylcarbonyl, phenylcarbonyl or
phenylcarbonyl substituted by one to three R9, or
R5 and R6 are each independently of the other phenoxycarbonyl or phenoxycarbonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other benzyloxycarbonyl or benzyloxycarbonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other nitro, forrayl, carboxyl, halogen, azido,
thiocyanato, tri(C1-C6alkyl)silyl, C1-C6ealkylcarbonyl-C1-C2alkyl, C1-C6alkoxycarbonyl-
C1-C2alkyl, cyano-C1-C2alkyl, C1-C6alkylaminocarbonyl-C1-C2alkyl, di-Ci-C6alkylaminocarbonyl-
C1-C2alkyl, C1-C6alkoxy-C1-C2alkyl, C1-C2alkyl-P(O)(OC1-C6alkyl)2, Cr
C2alkyl-NO2, mercapto, phenylthio or phenylthio substituted by one to three R9, or
Rs and Re are each independently of the other pyridylthio, C1-C6alkylthio, C1-C6haloalkylthio,
C1-C6alkylthio-C1-C6alkyl, C1-C6alkylsulfmyl, C1-C6haloalkylsulfmyl, Cp
C6alkylsulfmyl-C1-C6alkyls CrC6alkylsulfonyl, CrC6haloalkylsulfonyl, C1-C6alkylsulfonyl-
C1-Cealkyl, C1-C6alkylsulfonyloxy-C1-C6alkyl, benzylsulfonyl orbenzylsulfonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other phenylsulfinyl or phenylsulfinyl
substituted by one to three R9, or
R5 and R are each independently of the other phenylsulfonyl or phenylsulfonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other hydroxyl, Q-Cealkoxy, C1-C6haloalkoxy,
C1-C6alkylsulfonyloxy, C1-C6haloalkylsulfonyloxy, phenoxy or phenoxy substituted by
one to three R9, or
R5 and R6 are each independently of the other benzyl or benzyl substituted by one to
three R9, or
R5 and R6 are each independently of the other benzyloxy or benzyloxy substituted by one
to three R9, or
R5 and R6 are each independently of the other -CONH-SO2-Ci-C6alkyl, -CONH-SO2-
Ci-C6haloalkyl, -NHCHO, -NHCO-C1-C6alkyl, -NHCO-CrC6haloalkyl, -NHCOO-QC6alkyl,
-NHCONH-C1-C6alkyl, -NHCONH-C1-C6haloalkyl, -NHSO2-Ci-C6alkyl,
-NHSOrC1-C6haloalkyl, -NHSO2-phenyl or -NHSOrphenyl substituted by one to three
R9,or
R5 and R6 are each independently of the other -OCO-C1-C6alkyl, -OCO-Ci-C6halbalkyl,
-OCO-phenyl or -OCO-phenyl substituted by one to three R9, or
R5 and R6 are each independently of the other -OCONH-Ci-C6alkyl, -OCONHCi-
C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by one to three R9, or
R5 and R6 are each independently of the other -CONR7R8 wherein R7 and R8 are each
independently of the other hydrogen, Ci-Cealkyl, Ca-Cscycloalkyl, Ci-Cehaloalkyl,
phenyl or phenyl substituted by Ci-Cehaloalkyl, nitro, cyano or by halogen, or R7 and R8
together form a Cs-Cgalkylene group which optionally contains one oxygen or sulfur
atom or one to two amino or Ci-Cealkylamino groups, or
R5 and R6 are each independently of the other phenyl or naphthyl, which is optionally
substituted by one to three substituents independently selected from C
C3-C6cycloalkyl, CrC6haloalkyl, CrC6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl,
Ci-Cehaloalkenyl, Ci-Cealkylcarbonyl, Ci-Cealkoxycarbonyl, benzyloxycarbonyl or
benzyloxycarbonyl substituted by one to three R9, nitro, cyano, formyl, carboxyl,
halogen, azido, thiocyanato, tri(Ci-C6alkyl)silyl, mercapto, phenylthio or phenylthio
substituted by one to three R9, phenylsulfinyl or phenylsulfinyl substituted by one to
three R9, -SF5, Ci-C6alkylthio, Q-Cealkylsulfinyl, Ci-C6alkylsulfonyl, CrC6alkyl-
SO(NH)-5 Q-Cealkyl-SOCNCHa), C,-C6haloalkylthio, Ci-C6haloalkylsulfinyl, Ci-C6haloalkylsulfonyl,
benzylsulfonyl or benzylsulfonyl substituted by one to three R9, phenylsulfonyl
or phenylsulfonyl substituted by one to three R9, hydroxyl, Ci-Cealkoxy, QCehaloalkoxy,
Ci-Cealkylsulfonyloxy, Ci-Cehaloalkylsulfonyloxy, phenoxy or phenoxy
substituted by one to three R9, benzyloxy or benzyloxy substituted by one to three R9,
-CONH-S02-CrC6alkyl, -CONH-SO2-Ci-C6haloalkyl, -NHCO-Ci-C6alkyl, -NHCOCi-
C6haloalkyl, -NHCO2-Ci-C6alkyl, -NHCO2-C1-C6haloalkyl, -OCO-CrC6alkyl,
-OCO-Ci-Cghaloalkyl, -OCO-phenyl or -OCO-phenyl substituted by one to three R9,
-OCONH-CrC6alkyl, -OCONH-C,-C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl
substituted by one to three R9, or by -CONR7R8 wherein R7 and R8 are each independently
of the other hydrogen, Ci-C6alkyl, Cj-Cehaloalkyl, C3-C6cycloalkyl, phenyl or
phenyl substituted by Ci-Cehaloalkyl, nitro, cyano or by halogen, or R and R together
form a Cs-Cgalkylene group which optionally contains one oxygen or sulfur atom or one
to two amino or Ci-Csalkylarm'no groups, or
R5 and R6 are each independently of the other a 5- to 10-membered heterocycle
containing one to three nitrogen, oxygen or sulfur atoms, which is optionally benzofused,
and which is optionally substituted by one to three substituents independently
selected from Ci-C6alkyl, Cs-Cecycloalkyl, Ci-C6haloalkyl, Ci-C6-hydroxyalkyl,
C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkenyl, Ci-C6alkylcarbonyl, d-C6alkoxycarbonyl,
benzyloxycarbonyl or benzyloxycarbonyl substituted by one to three R9,
phenylthio or phenylthio substituted by one to three R9, phenylsulfinyl or phenylsulfinyl
substituted by one to three R9, nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato,
tri(Ci-C6alkyl)silyl, mercapto, -SF5, CrC6alkylthio, Ci-C6alkylsulfmyl,
CrC6alkylsulfonyl, Ci-C6haloalkylthio, Ci-C6haloalkylsulfinyl, d-C6haloalkylsulfonyl,
benzylsulfonyl or benzylsulfonyl substituted by one to three R9, phenylsulfonyl or
phenylsulfonyl substituted by one to three R9, hydroxyl, d-Cealkoxy, d-Cehaloalkoxy,
d-Cealkylsulfonyloxy, d-Cbhaloalkylsulfonyloxy, phenoxy or phenoxy substituted by
one to three R9, benzyloxy or benzyloxy substituted by one to three R9, -CONH-SO2-
Ci-Qalkyl, -CONH-SO2-Ci-C6haloalkyl, -NHCO-CrC6alkyl, -NHCO-d-C6haloalkyl,
-NHCO2-Ci-C6alkyl, -NHCO2-Ci-C6haloalkyl, -OCO-C!-C6alkyl, -OCO-d-C6haloalkyl,
-OCO-phenyl or -OCO-phenyl substituted by one to three R9, -OCONH-Ci-C6alkyl,
-OCONH-C]-C6halOalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by one to
three R9, or by -CONR7R8 wherein R7 and R8 are each independently of the other
hydrogen, Cj-Cgalkyl, d-Cahaloalkyl, d-Cecycloalkyl, phenyl or phenyl substituted by
d-Qhaloalkyl, nitro, cyano or by halogen, or R7 and R8 together form a Cs-Qalkylene
group which optionally contains one oxygen or sulfur atom or one to two amino or d-
[
Cealkylamino groups, and
R6 may additionally be hydrogen, cyano, Ci-Cgalkyl or Ci-Cealkoxycarbonyl, or
R5 and R6 together with the carbon atom to which they are bonded form a 3- to 10-
membered ring, which optionally contains one to three nitrogen, oxygen or sulfur atoms,
and which is optionally substituted by one to four substituents independently selected
from d-Cealkyl, Ci-C6haloalkyl, d-Qalkoxy, Ci-C6alkoxycarbonyl, Ci-Cealkylcarbonyl,
Ci-Cgalkylsulfonyl, Ci-Cehaloalkylsulfonyl, Ci-Cehaloalkylcarbonyl, d-
Cealkenyl, halogen, cyano, nitro, phenyl or phenyl substituted by d-Cehaloalkyl, nitro,
cyano or by halogen, phenylcarbonyl or phenylcarbonyl substituted by Q-Cehaloalkyl,
nitro, cyano or by halogen, or
R5 and R6 together with the carbon atom to which they are bonded form a group of the
formula C=CR10Rn wherein R10 and R11 are independently selected from hydrogen, Ci-
C6alkyl, Ci-C6alkoxy, -NH(d-C6alkyl), -N(d-C6alkyl)2, d-C6alkoxy-d-C2alkyl, Cj-
C6alkylcarbonyloxy, Ci-C6alkylcarbonyloxy-Ci-C2alkyl, C]-C6alkoxy-Ci-C2alkylcarbonyloxy
or d-C6alkylcarbonyloxy-d-C2alkylcarbonyloxy;
m is 0,1 or 2;
n is 1,2 or 3;
Y is hydrogen, CrC6alkyl, C3-C6cycloalkyl, C]-C6haloalkyl, C2-C6alkenyl,
C2-C6alkynyl, C2-C6haloalkenyl, Ci-Cealkylcarbonyl, Ci-Cealkoxycarbonyl, nitro, cyano,
formyl, hydroxyl, carboxyl, halogen, azido, thiocyanato, tri(Ci-C6alkyl)silyl, Ci-Cealkylthio,
Ci-Cealkylsulfinyl, Ci-Cealkylsulfonyl, benzylsulfonyl or benzylsulfonyl substituted
by one to three R9, or
Y is phenylsulfonyl or phenylsulfonyl substituted by one to three R9, or
Y is Ci-Cealkoxy, Ci-Cghaloalkoxy, Ci-Cgalkylsulfonyloxy, Ci-Cdhaloalkylsulfonyloxy,
phenoxy or phenoxy substituted by one to three R9, or
Y is benzyloxy or benzyloxy substituted by one to three R9, or
Y is -CONH-SO2-C,-C6alkyl or -CONH-SO2-CrC6haloalkyl, or
Y is phenyl, naphthyl or tetrahydronaphthyl, which is optionally substituted by one to
three substituents independently selected from Ci-Cealkyl, Cs-Cgcycloalkyl, Ci-Cehaloalkyl,
CrCehydroxyalkyl, Ci-C6alkoxy-Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl,
C2-C6haloalkenyl, Ci-Cealkylcarbonyl, Ci-Cbhaloalkylcarbonyl, Ci-Cealkoxycarbonyl,
benzyloxycarbonyl, nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato, tri(Ci-
C6alkyl)silyl, mercapto, phenylthio, phenylsulfmyl, -SFs, Ci-Cealkylthio, Ci-Cshaloalkylthio,
C1-C6haloalkylsulfinyl, Ci-Cshaloalkylsulfonyl, Ci-C6alkylsulfinyl, CrCealkylsulfonyl,
benzylsulfonyl or benzylsulfonyl substituted by one to three R9, phenylsulfonyl
or phenylsulfonyl substituted by one to three R9, hydroxyl, CpCealkoxy, Cs-Cecycloalkyloxy
wherein one of the CHz groups is optionally replaced by an oxygen atom,
C1-Cehaloalkoxy, C2-Cealkenyloxy, C2-C6alkynyloxy, Ci-Cealkylsulfonyloxy, Ci-Cehaloalkylsulfonyloxy,
phenoxy or phenoxy substituted by one to three R9, benzyloxy or
benzyloxy substituted by one to three R9, -CONH-SO2-Ci-C6alkyl, -CONH-SO2-
C-C6haloalkyl, -NH-S02-Ci-C6alkyl, -NH-SO2-Ci-C6haloalkyl, -NHCO-Ci-C6alkyl,
-NHCO-Ci-Cehaloalkyl, -NHCO2-Ci-C6alkyl, -NHCO2-Ci-C6haloalkyl, -OCOCi-
Cealkyl, -OCO-Ci-C6haloalkyl, -OCO-phenyl or -OCO-phenyl substituted by one to
three R9, -OCONH-Ci-C6alkyl, -OCONH-CrC6haloalkyl, -OCONH-phenyl or
-OCONH-phenyl substituted by one to three R9, or by -CONR7R8 wherein R7 and R8 are
each independently of the other hydrogen, Cj-Cealkyl, Ci-C6haloalkyl, Cs-Cecycloalkyl,
phenyl or phenyl substituted by Ci-C6haloalkyl, nitro, cyano or by halogen, or R7 and R8
form a Cs-Cgalkylene group which optionally contains one oxygen or sulfur atom or one
to two amino or Ci-Cgalkylamino groups, or
Y is a 5- to 10-membered heterocycle containing one to three nitrogen, oxygen or sulfur
atoms, which is optionally benzo-fused, and which is optionally substituted by one to
three substituents independently selected from Cf-Cgalkyl, Cs-Cscycloalkyl, Ci-Cehaloalkyl,
Ci-C6hydroxyalkyl, Ci-C6alkoxy-Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl,
C2-C6haloalkenyl, Ci-C6alkylcarbonyl, Ci-C6haloalkylcarbonyl, C]-C6alkoxycarbonyl,
nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato, tri(Ci-C6alkyl)silyl,
mercapto, -SFs, Ci-Cealkylthio, Ci-Csalkylsulfinyl, Ci-Cgalkylsulfonyl, Ci-Cehaloalkylthio,
Ci-Cehaloalkylsulfinyl, Ci-Cehaloalkylsulfonyl, benzylsulfonyl or benzylsulfonyl
substituted by one to three R9, phenylsulfonyl or phenylsulfonyl substituted by one to
three R9, hydroxyl, Ci-Cealkoxy, Cs-C^cycloalkyloxy wherein one of the CH2 groups is
optionally replaced by an oxygen atom, Ci-Cehaloalkoxy, C2-C6alkenyloxy,
C2-Cealkynyloxy, Cj-Csalkylsulfonyloxy, Q-Cehaloalkylsulfonyloxy, phenoxy or
phenoxy substituted by one to three R9, benzyloxy or benzyloxy substituted by one to
three R9, -CONH-SO2-C,-C6alkyl, -CONH-SO2-Ci-C6haloalkyl, -NH-SO2-Ci-C6alkyl,
-NH-SO2-Ci-C6haloalkyl, -NHCO-CrC6alkyl, -NHCO-C,-C6haloalkyl, -NHCO2-
Ci-C6alkyl, -NHCO2-Ci-C6haloalkyl, -OCO-Ci-C6alkyl, -OCO-CrC6haloalkyl, -OCOphenyl
or -OCO-phenyl substituted by one to three R9, -OCONH-Ci-C6alkyl, -OCONHCi-
C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by one to three R9, or
by -CONR7R8 wherein R7 and R8 are each independently of the other hydrogen,
Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cscycloalkyl, phenyl or phenyl substituted by Ci-C6haloalkyl,
nitro, cyano or by halogen, or R7 and R8 together form a Cs-Csalkylene group
which optionally contains one oxygen or sulfur atom or one to two amino or Ci-Cealkylamino
groups;
R9 are independently from each other Ci-Cghaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano,
formyl, carboxyl or halogen;
and to N-oxides, salts and optical isomers of compounds of formula I.
The compounds of the invention may contain one or more asymmetric carbon
atoms, for example, in the -CR5R6- group and may exist as enantiomers (or as pairs of
diastereoisomers) or as mixtures of such. Further, when m is 1, the compounds of the
invention are sulfoxides, which can exists in two enantiomeric forms, and the adjacent
carbon can also exists in two enantiomeric forms. Compounds of general formula I can
therefore exist as racemates, diastereoisomers, or single enantiomers, and the invention
includes all possible isomers or isomer mixtures in all proportions. It is to be expected
that for any given compound, one isomer may be more herbicidal than another.
Except where otherwise stated, alkyl groups and alkyl moieties of alkoxy,
alkylthio, etc., suitably contain from 1 to 10, typically from 1 to 6, carbon atoms in the
form of straight or branched chains. Examples are methyl, ethyl, n-and zso-propyl and «-,
sec-, iso- and tert-butyl.
Except where otherwise stated, cycloalkyl groups and cycloalkyl moieties of
cycloalkoxy, cycloalkyl-alkoxy, etc., suitably contain from 3 to 8, typically from 3 to 6,
carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The
cycloalkyl radicals may be in bi- or tri-cyclic form.
Except where otherwise stated, haloalkyl groups and haloalkyl moieties of
haloalkoxy, haloalkylthio, etc., also suitably contain from 1 to 6, typically from 1 to 4,
carbon atoms in the form of straight or branched chains. Examples are difluoromethyl
and 2,2,2-trifluoroethyl.
Except where otherwise stated, hydroxyalkyl groups also suitably contain from 1
to 6, typically from 1 to 4, carbon atoms in the form of straight or branched chains.
Examples are 1,2-dihydroxyethyl and 3-hydroxypropyl.
Except where otherwise stated, alkenyl and alkynyl moieties also suitably contain
from 2 to 6, typically from 2 to 4, carbon atoms in the form of straight or branched
chains. Examples are allyl, but-2-enyl, 3-methylbut-2-enyl, ethynyl, propargyl and but-2-
ynyl.
Except where otherwise stated, haloalkenyl groups and haloalkynyl groups also
suitably contain from 2 to 6, typically from 2 to 4, carbon atoms in the form of straight or
branched chains. Examples are trifluoroallyl and l-chloroprop-l-yn-3-yl.
Halo includes fluoro, chloro, bromo and iodo. Most commonly it is fluoro, chloro
or bromo and usually fluoro or chloro.
Except where otherwise stated, alkylene groups suitably contain from 1 to 10,
typically from 1 to 6, carbon atoms in the form of straight or branched chains. Examples
are methylene, ethylene, /z-and iso-propylene and n-, sec-, iso- and tert-butylene.
Except where otherwise stated, heterocyclic groups suitably are 5- to 10-
membered rings containing one to three nitrogen, oxygen or sulfur atoms, which may be
optionally benzo-fused. Examples are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-
thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
1,2,3,4-tetrazinyl, 1,2,3,5-tetrazinyl, 1,2,4,5-tetrazinyl, benzofuryl, isobenzofuryl,
benzothiophenyl, isobenzothiophenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-benzisothiazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl,
1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl,
pteridinyl, indolizinyl, benzo-l,3-dioxolyl, 4H-benzo-l,3-dioxinyl, and 4H-benzo-l,4-
dioxinyl groups and, where appropriate, N-oxides and salts thereof.
The 3- to 10-membered rings which may be present as substituents in the
compounds according to the invention include both carbocyclic and heterocyclic,
aromatic and non-aromatic rings. Such rings may be in the form of single rings or in the
form of polycyclic rings. They may carry further substituents and/or be benzo-fused.
There may be mentioned by way of example phenyl, naphthyl, anthryl, indenyl and
phenanthrenyl, the above-mentioned cycloalkyl radicals, and also rings containing
oxygen, sulfur or nitrogen atoms, such as tetrahydrofuranyl, tetrahydropyranyl, 1,3-
dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, and morpholinyl, also furyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-
oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
triazinyl, 1,2,3,4-tetrazinyl, 1,2,3,5-tetrazinyl, 1,2,4,5-tetrazinyl, benzofuryl,
isobenzofuryl, benzothiophenyl, isobenzothiophenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl,
benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-
benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, quinolyl, isoquinolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl,
purinyl, pteridinyl, indolizinyl, benzo-l,3-dioxolyl, 4H-benzo-l,3-dioxinyl, and 4Hbenzo-
1,4-dioxinyl.
Where R5 or R6 is independently a heterocycle-methyl group, for example
imidazolyl-CHa-, the heterocycle is connected to the methyl group by a nitrogen.
The invention also includes N-oxides of the compounds of formula I.
The invention relates likewise to the salts which the compounds of formula I are
able to form with amines, alkali metal and alkaline earth metal bases and quaternary
ammonium bases.
Among the alkali metal and alkaline earth metal hydroxides as salt formers,
special mention should be made of the hydroxides of lithium, sodium, potassium,
magnesium and calcium, but especially the hydroxides of sodium and potassium. The
compounds of formula I according to the invention also include hydrates which may be
formed during the salt formation.
Examples of amines suitable for ammonium salt formation include ammonia as
well as primary, secondary and tertiary Ci-Cigalkylamines, Cj-C^ydroxyalkylamines
and C2-C4alkoxyalkylamines, for example methylamine, ethylamine, n-propylarnine,
isopropylamine, the four butylamine isomers, n-amylamine, isoamylamine, hexylamine,
heptylamine, octylamine, nonylamine, decylamine, pentadecylamine, hexadecylamine,
heptadecylamine, octadecylamine, methylethylamine, methylisopropylamine,
methylhexylamine, methylnonylamine, methylpentadecylamine, methyloctadecylamine,
ethylbutylamine, ethylheptylamine, ethyloctylamine, hexylheptylamine,
hexyloctylamine, dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, ditt-
butylamine, di-«-amylamine, diisoamylamine, dihexylamine, diheptylamine,
dioctylamine, ethanolamine, «-propanolamine, isopropanolamine, N,N-diethanolamine,
N-ethylpropanolamine, N-butylethanolamine, allylamine, ;j-butenyl-2-amine, n-pentenyl-
2-amine, 2,3-dimethylbutenyl-2-amine, dibutenyl-2-amine, n-hexenyl-2-amine,
propylenediamine, trimethylamine, triethylamine, tri-«-propylamine, triisopropylamine,
tri-H-butylamine, triisobutylamine, tri-jec-butylamine, tri-n-amylamine,
methoxyethylamine and ethoxyethylamine; heterocyclic amines such as, for example,
pyridine, quinoline, isoquinoline, morpholine, piperidine, pyrrolidine, indoline,
quinuclidine and azepine; primary arylamines such as, for example, anilines,
methoxyanilines, ethoxyanilines, o-, m- and p-toluidines, phenylenediamines, benzidines,
naphthylamines and o-, m- and p-chloroanilines; but especially triethylamine,
isopropylamine and diisopropylamine.
Preferred quaternary ammonium bases suitable for salt formation correspond, for
example, to the formula [N(RaRbRcRd )]OH wherein Ra, Rb, RC and Rd are each
independently of the others C)-C4alkyl. Other suitable tetraalkylammonium bases with
other anions can be obtained, for example, by anion exchange reactions.
Furthermore this invention relates to compounds of formula I wherein
R1 and R2 are each independently of the other hydrogen, Ci-Cioalkyl, Q-Ciohaloalkyl,
Cs-Cgcycloalkyl or Cs-Cgcycloalkyl-Ci-Csalkyl, or
R1 and R2 together with the carbon atom to which they are bonded form a Ca-Cvring,
R3 and R4 are each independently of the other hydrogen, Ci-Cioalkyl, Cj-Ciohaloalkyl,
C3-Cgcycloalkyl-Ci-Cioalkyl, CrC6alkoxy-Ci-Ci0alkyl or C3-C8cycloalkyl, or
R3 and R4 together with the carbon atom to which they are bonded form a Cs-Cvring, or
R1 with R3 or R4 and together with the carbon atoms to which they are bonded form a
Cs-Cgring, or
R2 with R3 or R4 and together with the carbon atoms to which they are bonded form a
Cs-Cgring,
R5 and R6 are each independently of the other Cs-Cecycloalkyl, Ci-Cghaloalkyl, Cj-Cehydroxyalkyl,
pyrrolyl-CEb-, pyrazolyl-CH2-, triazolyl-Ctb-, imidazolyl-CH2-,
tetrazolyl-CH2-, indolyl-CH2-, indazolyl-CH2-, benzotriazolyl-CH2-, C2-C6alkenyl,
Ci-Cealkynyl, CrCehaloalkenyl, C2-C6alkenyloxy, C^Cealkynyloxy, QCealkylcarbonyl,
Cj-Cehaloalkylcarbonyl, phenylcarbonyl or phenylcarbonyl substituted
by Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen,
or
R5 and R6 are each independently of the other phenoxycarbonyl or phenoxycarbonyl
substituted by Ci-Cehaloalkyl, CrQalkoxycarbonyl, nitro, cyano, formyl, carboxyl or by
halogen, or
R5 and R6 are each independently of the other benzyloxycarbonyl or benzyloxycarbonyl
substituted by Q-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by
halogen, or
R5 and R6 are each independently of the other nitro, formyl, carboxyl, halogen, azido,
thiocyanato, tri(Ci-C6alkyl)silyl, Ci-C6alkylcarbonyl-Ci-C2alkyl, Ci-Cealkoxycarbonyl-
Ci-C2alkyl, cyano-Ci-C2alkyl, Ci-C6alkylaminocarbonyl-Ci-C2alkyl, di-Ci-
C6alkylaminocarbonyl-Ci-C2alkyl, Ci-C6alkoxy-Ci-C2alkyl, Ci-C2alkyl-
P(O)(OCi-C6alkyl)2, Ci-C2alkyl-NO2, mercapto, phenylthio or phenylthio substituted by
d-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, or
RS and Re are each independently of the other pyridylthio, d-Cealkylthio, Cj-
C6haloalkylthio, CrC6alkylthio-Ci-C6alkyl, Ci-C6alkylsulfinyl, Ci-C6haloalkylsulfinyl,
CrC6alkylsulfinyl-Ci-C6alkyl, CrC6alkylsulfonyl, Ci-C6haloalkylsulfonyl, d-
Cealkylsulfonyl-Ci-Cealkyl, benzylsulfonyl or benzylsulfonyl substituted by
d-Cehaloalkyl, Ci-Cgalkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, or
R5 and R6 are each independently of the other phenylsulfinyl or phenylsulfinyl
substituted by Ci-Cehaloalkyl, Cj-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by
halogen, or
R5 and R6 are each independently of the other phenylsulfonyl or phenylsulfonyl
substituted by CpCehaloalkyl, Ci-C6alkoxycarbonyl, nitro, cyano, formyl, carboxyl or by
halogen, or
R5 and R6 are each independently of the other hydroxyl, Q-Cealkoxy, Ci-C6haloalkoxy,
Ci-Caalkylsulfohyloxy, Ci-Cghaloalkylsulfonyloxy, phenoxy or phenoxy substituted by
Ci-Cfihaloalkyl, Ci-Cgalkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, or
R5 and R6 are each independently of the other benzyl or benzyl substituted by
Ci-Cehaloalkyl, Q-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, or
R5 and R6 are each independently of the other benzyloxy or benzyloxy substituted by
Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, or
R5 and R6 are each independently of the other -CONH-SO2-Ci-C6alkyl, -CONH-SO2-
Ci-C6haloalkyl, -NHCHO, -NHCO-Ci-C6alkyl, -NHCO-CrC6haloalkyl, -NHCOO-d-
C6alkyl, -NHCONH-Ci-C6alkyl, -NHCONH-C1-C6haloalkyl, -NHSO2-Ci-C6alkyl, -
NHSO2-Ci-C6haloalkyl, -NHSO2-phenyl, -OCO-Ci-C6alkyl, -OCO-d-C6haloalkyl,
-OCO-phenyl or -OCO-phenyl substituted by Ci-Cehaloalkyl, C]-C6alkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, or
R5 and R6 are each independently of the other -OCONH-Ci-C6alkyl, -OCONHCi-
C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by Ci-C6haloalkyl, d-
Cealkoxycarbonyl, carboxyl, nitro, cyano or by halogen, or
R5 and R6 are each independently of the other -CONR7R8 wherein R7 and R8 are each
independently of the other hydrogen, Ci-Cealkyl, Cs-Cecycloalkyl, Ci-Cehaloalkyl,
phenyl or phenyl substituted by Ci-Cehaloalkyl, nitro, cyano or by halogen, or R7 and R8
together form a d-Cgalkylene group which may contain one or more oxygen or sulfur
atoms or one or more amino or alkylamino groups, or
R5 and R6 are each independently of the other phenyl or naphthyl, which rings may be
substituted by CrC6alkyl, C3-C6cycloalkyl, Ci-C6haloalkyl, C)-C6hydroxyalkyl,
C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkenyl, CrC6alkylcarbonyl, d-
Cealkoxycarbonyl, benzyloxycarbonyl or benzyloxycarbonyl substituted by
d-Cehaloalkyl, CpCealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen,
nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato, tri(d-C6alkyl)silyl,
mercapto, phenylthio or phenylthio substituted by Ci-Cghaloalkyl, Q-Csalkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, phenylsulfinyl or phenylsulfinyl substituted
by d-Cahaloalkyl, d-Csalkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, -
SF5, C,-C6alkylthio, C,-C6alkylsulfinyl, Ci-C6alkylsulfonyl, CrC6alkyl-SO(NH)-,
Ci-C6alkyl-SO(NCH3), d-C6haloalkylthio, d-C6haloalkylsulfinyl, C,-
Cehaloalkylsulfonyl, benzylsulfonyl or benzylsulfonyl substituted by Ci-Cghaloalkyl, Ci-
Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, phenylsulfonyl or
phehylsulfonyl substituted by d-Cehaloalkyl, d-Cealkoxycarbonyl, nitro, cyano,
formyl, carboxyl or by halogen, hydroxyl, Q-Cealkoxy, Ci-Cehaloalkoxy, d-
Cealkylsulfonyloxy, d-Cehaloalkylsulfonyloxy, phenoxy or phenoxy substituted by
Ci-Cghaloalkyl, d-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen,
benzyloxy or benzyloxy substituted by Cj-Cehaloalkyl, d-Q.alkoxycarbonyl, nitro,
cyano, formyl, carboxyl or by halogen, -CONH-SO2-Ci-C6alkyl, -CONH-SO2-
Ci-C6haloalkyl, -NHCO-CrC6alkyl, -NHCO-Ci-C6haloalkyl, -NHCO2-Ci-C6alkyl,
-NHCO2-Ci-C6haloalkyl, -OCO-d-C6alkyl, -OCO-d-C6haloalkyl, -OCO-phenyl or
-OCO-phenyl substituted by d-Cehaloalkyl, d-Cealkoxycarbonyl, nitro, cyano, formyl,
carboxyl or by halogen, -OCONH-d-C6alkyl, -OCONH-d-C6haloaIlcyl, -OCONHphenyl
or -OCONH-phenyl substituted by d-Qshaloalkyl, Ci-Cgalkoxycarbonyl,
carboxyl, nitro, cyano or by halogen, or by -CONR7R8 wherein R7 and R8 are each
independently of the other hydrogen, d-Cealkyl, d-Cehaloalkyl, Cs-Cgcycloalkyl,
phenyl or phenyl substituted by d-Cehaloalkyl, nitro, cyano or by halogen, or R7 and R8
together form a Q-Csalkylene group which may contain one or more oxygen or sulfur
atoms or one or more amino or alkylamino groups, or
R5 and R6 are each independently of the other a 5- to 10-membered heterocycle
containing one or more nitrogen, oxygen or sulfur atoms, which heterocycle may be
benzo-fused, and which heterocycle may be substituted by d-Cgalkyl, d-Cscycloalkyl,
l, d-C6-hydroxyalkyl, C2-Cealkenyl, C2-C6alkynyl, C2-C6haloalkenyl, d-
Cealkylcarbonyl, Ci-Cealkoxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl
substituted by Q-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by
halogen, phenylthio, phenylthio substituted by Ci-C6haloalkyl, Q-Cealkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, phenylsulfmyl, phenylsulfinyl substituted
by Cj-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen,
nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato, tri(C]-C6alkyl)silyl,
mercapto, -SFs, CpCealkylthio, Ci-Cealkylsulfmyl, Ci-Cealkylsulfonyl, C\-
Cehaloalkylthio, Ci-Cghaloalkylsulfinyl, Cj-Cghaloalkylsulfonyl, benzylsulfonyl or
benzylsulfonyl substituted by Q-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl,
carboxyl or by halogen, phenylsulfonyl or phenylsulfonyl substituted by Cj-Cehaloalkyl,
Ci-C6alkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, hydroxyl, Ci-
C6alkoxy, Ci-C6haloalkoxy, Ci-Caalkylsulfonyloxy, Ci-Cehaloalkylsulfonyloxy, phenoxy
or phenoxy substituted by Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl,
carboxyl or by halogen, benzyloxy or benzyloxy substituted by Ci-Cehaloalkyl, QCealkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, -CONH-SCh-
Ci-C6alkyl, -CONH-SO2-Ci-C6haloalkyl, -NHCO-CrC6alkyl, -NHCO-C]-C6haloalkyl,
-NHCO2-Ci-C6alkyl, -NHCO2-CrC6haloalkyl, -OCO-Ci-C6alkyl, -OCO-CrC6haloalkyl,
-OCO-phenyl or -OCO-phenyl substituted by Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, -OCONH-Ci-Cealkyl, -OCONHCi-
C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by Ci-C6haloalkyl, Cr
Cealkoxycarbonyl, carboxyl, nitro, cyano or by halogen, or by -CONR7R8 wherein R7
and R8 are each independently of the other hydrogen, CpCealkyl, Ci-Cehaloalkyl,
Cs-Cecycloalkyl, phenyl or phenyl substituted by Ci-Cghaloalkyl, nitro, cyano or by
halogen, or R7 and R8 together form a Ca-Cgalkylene group which may contain one or .
more oxygen or sulfur atoms or one or more amino or alkylamino groups, and
R6 may additionally be hydrogen, cyano, Ci-Cgalkyl or Ci-Csalkoxycafbonyl, or
R5 and R6 together with the carbon atom to which they are bonded form a 3- to 10-
membered ring which may contain one or more nitrogen, oxygen or sulfur atoms and
which may be substituted by Ci-Cealkyl, Ci-Cehaloalkyl, Q-Cealkoxy, Ci-Csalkoxycarbonyl,
Ci-C6alkylcarbonyl, Ci-C6alkylsulfonyl, Ci-C6haloalkylsulfonyl, C\-
Cehaloalkylcarbonyl, Ci-Cealkenyl, halogen, cyano, nitro, phenyl or phenyl substituted
by Ci-Cshaloalkyl, nitro, cyano or by halogen, phenylcarbonyl or phenylcarbonyl
substituted by Ci-Cehaloalkyl, nitro, cyano or by halogen, or
R5 and R6 together with the carbon atom to which they are bonded form a group of the
formula C=CH2, C=CH-Ci-C6alkyl, C=CH-N(d-C6alkyl)2, C=CH-NH(C,-C6alkyl) or
C=CH-C]-C6alkoxy,
m is 0,1 or 2,
nis 1,2 or 3,
Y is hydrogen, Ci-C6alkyl, Cj-Cecycloalkyl, Ci-C6haloalkyl, C2-C6alkenyl,
C2-C6alkynyl, C2-C6haloalkenyl, Q-Cealkylcarbonyl, Q-Cealkoxycarbonyl, nitro, cyano,
formyl, hydroxyl, carboxyl, halogen, azido, thiocyanato, tri(C]-C6alkyl)silyl, Cp
Csalkylthio, Ci-Cgalkylsulfinyl, Ci-Cealkylsulfonyl, benzylsulfonyl or benzylsulfonyl
substituted by Ct-Cfihaloalkyl, d-Cealkoxycarbonyl, carboxyl, nitro, cyano or by
halogen, or
Y is phenylsulfonyl or phenylsulfonyl substituted by Q-Cehaloalkyl, Ci-
C6alkoxycarbonyl, carboxyl, nitro, cyano or by halogen, or
Yis Cj-Cealkoxy, Ci-Cshaloalkoxy, Ci-Cgalkylsulfonyloxy, Ci-Cghaloalkylsulfonyloxy,
phenoxy or phenoxy substituted by CpCehaloalkyl, CpCealkoxycarbonyl, carboxyl,
nitro, cyano or by halogen, or
Y is benzyloxy or benzyloxy substituted by Ci-Cghaloalkyl, CpCealkoxycarbonyl,
carboxyl, nitro, cyano or by halogen, or
Y is -CONH-SO2-Ci-C6alkyl or -CONH-SO2-Ci-C6haloalkyl, or
Y is phenyl, naphthyl or tetrahydronaphthyl, which rings may be substituted by
Ci-C6alkyl, C3-C6cycloalkyl, CrC6haloalkyl, Ci-C6hydroxyalkyl, C2-C6alkenyl,
C2-C6alkynyl, CrCshaloalkenyl, Ci-Cealkylcarbonyl, Ci-Cehaloalkylcarbonyl, Ci-
Cealkoxycarbonyl, benzyloxycarbonyl, nitro, cyano, formyl, carboxyl, halogen, azido,
thiocyanato, tri(C]-C6alkyl)silyl, mercapto, phenylthio, phenylsulfinyl, -SFs, Ci-
C6alkylthio, Q-Cehaloalkylthio, Ci-C6haloalkylsulflnyl, Ci-C6haloalkylsulfonyl, GICealkylsulfinyl,
Ci-Cealkylsulfonyl, benzylsulfonyl or benzylsulfonyl substituted by
Ci-Cghaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen,
phenylsulfonyl or phenylsulfonyl substituted by Ci-Cehaloalkyl, Ci-Cgalkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, hydroxyl, Q-Cealkoxy, Ci-Cehaloalkoxy,
Ci-Cgalkylsulfonyloxy, Ci-Cehaloalkylsulfonyloxy, phenoxy or phenoxy substituted by
Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen,
benzyloxy or benzyloxy substituted by Ci-Qhaloalkyl, Ci-Cealkoxycarbonyl, nitro,
cyano, formyl, carboxyl or by halogen, -CONH-SO2-Ci-C6alkyl, -CONH-SO2-
Ci-C6haloalkyl, -NHCO-C,-C6alkyl, -NHCO-CrC6haloalkyl, -NHCO2-C,-C6alkyl,
-NHCO2-Ci-C6haloalkyl, -OCO-Ci-C6alkyl, -OCO-Ci-C6haloalkyl, -OCO-phenyl or
-OCO-phenyl substituted by Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl,
carboxyl or by halogen, -OCONH-Q-Cealkyl, -OCONH-Ci-C6haloalkyl, -OCONHphenyl
or -OCONH-phenyl substituted by Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl,
1-1 n n Q
carboxyl, nitro, cyano or by halogen, or by -CONR R wherein R and R are each
independently of the other hydrogen, Q-Cealkyl, Cj-Cehaloalkyl, Ca-Cecycloalkyl,
phenyl or phenyl substituted by CpCshaloalkyl, nitro, cyano or by halogen, or R7 and R8
form a Cs-Cgalkylene group which may contain one or more oxygen or sulfur atoms or
one or more amino or alkylamino groups, or
Y is a 5- to 10-membered heterocycle containing one or more nitrogen, oxygen or sulfur
atoms, which heterocycle may be benzo-fused, and which heterocycle may be substituted
by Ci-C6alkyl, C3-C6cycloalkyl, d-C6haloalkyl, Ci-C6hydroxyalkyl, C2-C6alkenyl,
C2-C6alkynyl, CrQhaloalkenyl, Ci-Cealkylcarbonyl, Ci-Cghaloalkylcarbonyl, Ci-
Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato, tri(Ci-
C6alkyl)silyl, mercapto, -SFs, Ci-Cealkylthio, Ci-Cealkylsulfinyl, Ci-Cealkylsulfonyl,
Ci-Cehaloalkylthio, Ci-Cehaloalkylsulfmyl, Ci-Cehaloalkylsulfonyl, benzylsulfonyl or
benzylsulfonyl substituted by Ci-Cghaloalkyl, Ci-Cgalkoxycarbonyl, nitro, cyano, formyl,
carboxyl or by halogen, phenylsulfonyl or phenylsulfonyl substituted by Ci-Cghaloalkyl,
Ci-Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, hydroxyl, C\-
Cgalkoxy, Ci-Cehaloalkoxy, Ci-Cealkylsulfonyloxy, Ci-Cshaloalkylsulfonyloxy, phenoxy
or phenoxy substituted by Ci-C6haloalkyl, Ci-Cealkoxycarbonyl, nitro, cyano, formyl,
carboxyl or by halogen, benzyloxy or benzyloxy substituted by Ci-Cehaloalkyl, Ci-
Cealkoxycarbonyl, nitro, cyano, formyl, carboxyl or by halogen, -CONH-SCV
Ci-C6alkyl, -CONH-SO2-Ci-C6haloalkyl, -NHCO-Ci-C6alkyl, -NHCO-Ci-C6haloalkyl,
-NHCO2-Ci-C6alkyl, -NHCO2-Ci-C6haloalkyl, -OCO-CrC6alkyl, -OCO-Ci-C6haloalkyl,
-OCO-phenyl or -OCO-phenyl substituted by Ci-Cehaloalkyl, Ci-Cealkoxycarbonyl,
nitro, cyano, formyl, carboxyl or by halogen, -OCONH-Ci-C6alkyl, -OCONHCi-
C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by Ci-C6haloalkyl, Ci-
Csalkoxycarbonyl, carboxyl, nitro, cyano or by halogen, or by -CONR7R8 wherein R7
and R8 are each independently of the other hydrogen, Q-Cealkyl, Ci-Cehaloalkyl,
l, phenyl or phenyl substituted by Ci-Cehaloalkyl, nitro, cyano or by
7 R halogen, or R and R together form a C3-Cgalkylene group which may contain one or
more oxygen or sulfur atoms or one or more amino or alkylamino groups,
and to N-oxides, salts and optical isomers of compounds of formula I.
Alkyl and alkoxy radicals appearing in the substituent definitions are, for
example, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl, butoxy, hexyl,
hexyloxy, nonyl, nonyloxy and decyl and decyloxy and also branched isomers thereof.
Suitable alkenyl and alkynyl radicals are derived from the mentioned alkyl radicals.
Cycloalkyl radicals are generally cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl. The cycloalkyl radicals may be in bi- or tri-cyclic form.
Phenyl radicals may be in substituted form. For example, Y may be a phenyl radical
which can be substituted, for example, by alkoxy or by alkoxy substituted by halogen
etc.. The 3- to 10-membered rings which may be present as substituents in the
compounds according to the invention include both carbocyclic and heterocyclic,
aromatic and non-aromatic rings. Such rings may be in the form of single rings or in the
form of polycyclic rings. They may carry further substituents and/or be benzo-fused.
There may be mentioned by way of example phenyl, naphthyl, anthryl, indenyl and
phenanthrenyl, the above-mentioned cycloalkyl radicals, and also rings containing
oxygen, sulfur or nitrogen atoms, such as 1,3-dioxalanyl, dihydro-l,3-dioxolyl,
tetrahydrofuranyl and morpholinyl, also furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, dihydroisoxazolyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl,
pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl,
tetrazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl, benzimidazolyl,
2,1,3-benzoxadiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl and
indolizinyl.
The invention also includes N-oxides of the compounds of formula I.
The invention also includes the optical isomers of the compounds of formula I,
especially those which have a chiral carbon atom in the -CR5R6- group.
Tablel:
(Table Removed)
Table 8:
Table 8 consists of 240 compounds of the general formula 1.2, where R5 is chloro, and
R1, R2, R3, R4, m, R6, R17, R18 and R19 have the values listed in Table 7. Thus compound
1 of Table 8 is the same as compound 1 of Table 7 except that in compound 1 of Table 8
R5 is chloro instead of bromo. Similarly, compounds 2 to 240 of Table 8 are the same as
compounds 2 to 240 of Table 7, respectively, except that in the compounds of Table 8 R5
is chloro instead of bromo.
Table 9:
Table 9 consists of 240 compounds of the general formula 1.2, where R5 is fluoro, and R1,
R2, R3, R4, m, R6, R17, R18 and R19 have the values listed in Table 7. Thus compound 1 of
Table 9 is the same as compound 1 of Table 7 except that in compound 1 of Table 9 R5 is
fluoro instead of bromo. Similarly, compounds 2 to 240 of Table 9 are the same as
compounds 2 to 240 of Table 7, respectively, except that in the compounds of Table 9 R5
is fluoro instead of bromo.
Table 10:
Table 10 consists of 240 compounds of the general formula 1.2, where Rs is iodo, and R1,
R2, R3, R4, m, R6, R17, R18 and R19 have the values listed in Table 7. Thus compound 1 of
Table 10 is the same as compound 1 of Table 7 except that in compound 1 of Table 10 R5
is iodo instead of bromo. Similarly, compounds 2 to 240 of Table 10 are the same as
compounds 2 to 240 of Table 7, respectively, except that in the compounds of Table 10
R5 is iodo instead of bromo.
Table 11:
Table 11 consists of 240 compounds of the general formula 1.2, where Rs is
trifluoromethyl, and R1, R2, R3, R4, m, R6, R17, R18 and R19 have the values listed in
Table 7. Thus compound 1 of Table 11 is the same as compound 1 of Table 7 except that
in compound 1 of Table 11 R5 is trifluoromethyl instead of bromo. Similarly, compounds
2 to 240 of Table 11 are the same as compounds 2 to 240 of Table 7, respectively, except
that in the compounds of Table 11 R5 is trifluoromethyl instead of bromo.
Table 12:
Table 12 consists of 240 compounds of the general formula 1.2, where R6 is fluoro, and
R1, R2, R3, R4, m, R5, R17, R18 and R19 have the values listed in Table 7. Thus compound
1 of Table 12 is the same as compound 1 of Table 7 except that in compound 1 of Table
12 R6 is fluoro instead of hydrogen. Similarly, compounds 2 to 240 of Table 12 are the
same as compounds 2 to 240 of Table 7, respectively, except that in the compounds of
Table 12 R6 is fluoro instead of hydrogen.
Table 13:
Table 13 consists of 240 compounds of the general formula 1.2, where R5 is chloro and
R6 is fluoro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7.
Thus compound 1 of Table 13 is the same as compound 1 of Table 12 except that in
compound 1 of Table 13 R5 is chloro instead of bromo. Similarly, compounds 2 to 240 of
Table 13 are the same as compounds 2 to 240 of Table 12, respectively, except that in the
compounds of Table 13 R5 is chloro instead of bromo.
Table 14:
Table 14 consists of 240 compounds of the general formula 1.2, where R5 and R6 are
fluoro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7. Thus
compound 1 of Table 14 is the same as compound 1 of Table 12 except that in compound
1 of Table 14 R5 is fluoro instead of bromo. Similarly, compounds 2 to 240 of Table 14
are the same as compounds 2 to 240 of Table 12, respectively, except that in the
compounds of Table 14 R5 is fluoro instead of bromo.
Table 15:
Table 15 consists of 240 compounds of the general formula 1.2, where R5 is iodo and R6
is fluoro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7. Thus
compound 1 of Table 15 is the same as compound 1 of Table 12 except that in compound
1 of Table 15 R5 is iodo instead of bromo. Similarly, compounds 2 to 240 of Table 15 are
the same as compounds 2 to 240 of Table 12, respectively, except that in the compounds
of Table 15 R5 is iodo instead of bromo.
Table 16:
Table 16 consists of 240 compounds of the general formula 1.2, where R5 is
trifluoromethyl and R6 is fluoro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values
listed in Table 7. Thus compound 1 of Table 16 is the same as compound 1 of Table 12
except that in compound 1 of Table 16 R5 is trifluoromethyl instead of bromo. Similarly,
compounds 2 to 240 of Table 16 are the same as compounds 2 to 240 of Table 12,
respectively, except that in the compounds of Table 16 R5 is trifluoromethyl instead of
bromo.
Table 17:
Table 17 consists of 240 compounds of the general formula 1.2, where R6 is bromo, and
R1, R2, R3, R4, m, R5, R17, R18 and R19 have the values listed in Table 7. Thus compound
1 of Table 17 is the same as compound 1 of Table 7 except that in compound 1 of Table
17 R6 is bromo instead of hydrogen. Similarly, compounds 2 to 240 of Table 17 are the
same as compounds 2 to 240 of Table 7, respectively, except that in the compounds of
Table 17 R6 is bromo instead of hydrogen.
Table 18:
Table 18 consists of 240 compounds of the general formula 1.2, where R5 is chloro and
R6 is bromo, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7.
Thus compound 1 of Table 18 is the same as compound 1 of Table 17 except that in
compound 1 of Table 18 R5 is chloro instead of bromo. Similarly, compounds 2 to 240 of
Table 18 are the same as compounds 2 to 240 of Table 17, respectively, except that in the
compounds of Table 18 R5 is chloro instead of bromo.
Table 19:
Table 19 consists of 240 compounds of the general formula 1.2, where R5 is iodo and R6
is bromo, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7. Thus
compound 1 of Table 19 is the same as compound 1 of Table 17 except that in compound
1 of Table 19 R5 is iodo instead of bromo. Similarly, compounds 2 to 240 of Table 19 are
the same as compounds 2 to 240 of Table 17, respectively, except that in the compounds
of Table 19 R5 is iodo instead of bromo.
Table 20:
Table 20 consists of 240 compounds of the general formula 1.2, where R5 is
trifiuoromethyl and R6 is bromo., and R1, R2, R3, R4, m, R17, R18 and R19 have the values
listed in Table 7. Thus compound 1 of Table 20 is the same as compound 1 of Table 17
except that in compound 1 of Table 20 R5 is trifiuoromethyl instead of bromo. Similarly,
compounds 2 to 240 of Table 20 are the same as compounds 2 to 240 of Table 17,
respectively, except that in the compounds of Table 20 R5 is trifiuoromethyl instead of
bromo.
Table 21:
Table 21 consists of 240 compounds of the general formula 1.2, where R5 and R6 are
chloro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7. Thus
compound 1 of Table 21 is the same as compound 1 of Table 7 except that in compound
1 of Table 21 R5 is chloro instead of bromo and R6 is chloro instead of hydrogen.
Similarly, compounds 2 to 240 of Table 21 are the same as compounds 2 to 240 of Table
7, respectively, except that in the compounds of Table 21 R5 is chloro instead of bromo
and R6 is chloro instead of hydrogen.
Table 22:
Table 22 consists of 240 compounds of the general formula 1.2, where R5 is iodo and R6
is chloro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7. Thus
compound 1 of Table 22 is the same as compound 1 of Table 21 except that in compound
1 of Table 22 R5 is iodo instead of chloro. Similarly, compounds 2 to 240 of Table 22 are
the same as compounds 2 to 240 of Table 21, respectively, except that in the compounds
of Table 22 R5 is iodo instead of chloro.
Table 23:
Table 23 consists of 240 compounds of the general formula 1.2, where R5 is
trifluoromethyl and R6 is chloro, and R1, R2, R3, R4, m, R17, R18 and R19 have the values
listed in Table 7. Thus compound 1 of Table 23 is the same as compound 1 of Table 21
except that in compound 1 of Table 23 R5 is trifluoromethyl instead of chloro. Similarly,
compounds 2 to 240 of Table 23 are the same as compounds 2 to 240 of Table 21,
respectively, except that in the compounds of Table 23 R5 is trifluoromethyl instead of
chloro.
Table 24:
Table 24 consists of 240 compounds of the general formula 1.2, where R5 and R6 are
iodo, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7. Thus
compound 1 of Table 24 is the same as compound 1 of Table 7 except that in compound
1 of Table 24 R5 is iodo instead of bromo and R6 is iodo instead of hydrogen. Similarly,
compounds 2 to 240 of Table 24 are the same as compounds 2 to 240 of Table 7,
respectively, except that in the compounds of Table 24 R5 is iodo instead of bromo and
R6 is iodo instead of hydrogen.
Table 25:
Table 25 consists of 240 compounds of the general formula 1.2, where R5 is
trifluoromethyl and R6 is iodo, and R1, R2, R3, R4, m, R17, R18 and R19 have the values
listed in Table 7. Thus compound 1 of Table 25 is the same as compound 1 of Table 24
except that in compound 1 of Table 25 R5 is trifluoromethyl instead of iodo. Similarly,
compounds 2 to 240 of Table 25 are the same as compounds 2 to 240 of Table 24,
respectively, except that in the compounds of Table 25 R5 is trifluoromethyl instead of
iodo.
Table 26:
Table 26 consists of 240 compounds of the general formula 1.2, where R5 and R6 are
trifluoromethyl, and R1, R2, R3, R4, m, R17, R18 and R19 have the values listed in Table 7.
Thus compound 1 of Table 26 is the same as compound 1 of Table 7 except that in
compound 1 of Table 26 R5 is trifluoromethyl instead of bromo and R6 is trifluoromethyl
instead of hydrogen. Similarly, compounds 2 to 240 of Table 26 are the same as
compounds 2 to 240 of Table 7, respectively, except that in the compounds of Table 26
Rs is trifluoromethyl instead of bromo and R6 is trifluoromethyl instead of hydrogen.
A group of preferred compounds of formula I comprises those wherein
R1 and R2 are both C1-Ci0alkyl;
R3 and R4 are both hydrogen;
R5 and R6 are each independently of the other Ci-Cehaloalkyl, Ci-Cehydroxyalkyl,
pyrazolyl-CHi-, 4,5-dihydropyrazolyl-CH2-, triazolyl-CHa-, imidazolyl-CH2-, indazolyl-
CH2-, C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkenyl, Ci-C6alkylcarbonyloxy-
C2-C6alkenyl, d-Cealkylcarbonyl, C]-C6haloalkylcarbonyl, C3-C6cycloalkylcarbonyl, or
Ci-CealkoxyCi-Cealkylcarbonyl, or
R5 and R6 are each independently of the other halogen, Ci-C6alkylcarbonyl-Ci-C2alkyl,
Ci-C6alkoxycarbonyl-Ci-C2alkyl, Ci-C6alkylaminocarbonyl-Ci-C2alkyl, di-Ci-Cealkylaminocarbonyl-
Ci-C2alkyl, Ci-C6alkoxy-Ci-C2alkyl, Ci-C2alkyl-P(O)(OCi-C6alkyl)2, or
RS and Re are each independently of the other Ci-Cealkylthio, Ci-Cghaloalkylthio,
Ci-C6alkylsulfonyl, Ci-C6haloalkylsulfonyl, Ci-C6alkylsulfonyl-Ci-C6alkyl, Ci-C6alkylsulfonyloxy-
Ci-Cgalkyl, benzylsulfonyl or benzylsulfonyl substituted by one to three
halogen, or
R5 and R6 are each independently of the other benzyl or benzyl substituted by one to
three halogen, or
R5 and R6 are each independently of the other -CONR7R8 wherein R7 and R8 are each
independently of the other hydrogen, Ci-Cealkyl, Ca-Cecycloalkyl, Ci-Cehaloalkyl,
phenyl or phenyl substituted by Ci-Cehaloalkyl, nitro, cyano or by halogen, and
R6 may additionally be hydrogen, cyano, Ci-Cealkyl or Ci-Cealkoxycarbonyl, or
R5 and R5 together with the carbon atom to which they are bonded form a 3- to 10-
membered ring which is optionally substituted by one to four substituents independently
selected from Ci-C6alkyl, Ca-Cealkenyl, d-Cealkoxycarbonyl, halogen, nitro, or
phenylcarbonyl, or
R5 and R6 together with the carbon atom to which they are bonded form a group of the
formula C=CR10RU wherein R10 and R11 are independently selected from hydrogen, Cj-
C6alkyl, -NH(Ci-C6alkyl), -N(d-C6alkyl)2, Ci-C6alkoxy-Ci-C2alkyl, Ci-C6alkylcarbonyloxy,
Ci-C6alkylcarbonyloxy-Ci-C2alkyl, Ci-Cgalkoxy-Ci-Caalkylcarbonyloxy or
C i -Cealkylcarbonyloxy-C i -Caalkylcarbonyloxy;
m is 1 or 2;
nis 1;
Y is phenyl, which is optionally substituted by one to three substituents independently
selected from Q-Cealkyl, Ci-Cehaloalkyl, Q-Cealkoxycarbonyl, nitro, cyano, halogen,
Ci-C6alkylthio, CrC6haloalkylthio, CrC6alkylsulfinyl, Ci-C6haloalkylsulfmyl, Cr
Cealkylsulfonyl, Ci-Cehaloalkylsulfonyl, Ci-C6alkoxy, Ci-Cehaloalkoxy, C2-C6alkenyloxy,
C2-C6alkynyloxy, Ci-Cgalkylsulfonyloxy, Ci-C6haloalkylsulfonyloxy, phenyl or
phenyl substituted by Ci-C6haloalkyl, nitro, cyano or by halogen, or
Y is a 5- to 10-membered heterocycle containing one to three nitrogen, oxygen or sulfur
atoms, which is optionally substituted by one to three substituents independently selected
from Ci-Csalkyl, Cs-Cecycloalkyl, Ci-Cehaloalkyl, Ci-C6alkoxy-Ci-C6alkyl, cyano,
halogen, Ci-C6alkylsulfonyl, Ci-C6haloalkylsulfonyl, Ci-C6alkoxy, C3-C6cycloalkyloxy
wherein one of the CH2 groups is optionally replaced by an oxygen atom, or Ci-Cehaloalkoxy;
and to N-oxides, salts and optical isomers of compounds of formula I.
A group of especially preferred compounds of formula I comprises those wherein
R1 and R2 are both Ci-C]0alkyl;
R3 and R4 are both hydrogen;
R5 and R6 are each independently of the other Cj-Cehaloalkyl, triazolyl-CHa-, imidazolyl-
CH2-, C2-Cealkenyl, C2-Cealkynyl, C2-C6haloalkenyl, Ci-Cealkylcarbonyloxy-
C2-C6alkenyl, Ci-Cgalkylcarbonyl, Ci-Cehaloalkylcarbonyl, Cs-Cecycloalkylcarbonyl, or
Ci-Cealkoxy-Ci-Cealkylcarbonyl, or
R5 and R6 are each independently of the other halogen, Ci-Csalkoxycarbonyl-Ci^alkyl,
or CpCealkoxy-Cj^alkyl, or
RS and Re are each independently of the other benzylsulfonyl, or
R5 and R6 are each independently of the other-CONHa, and
R6 may additionally be hydrogen, Ci-Cealkyl or Ci-Cealkoxycarbonyl, or
R5 and R6 together with the carbon atom to which they are bonded form a 3- to 10-
membered ring which is optionally substituted by one to four substituents independently
selected from CpCsalkyl, C2-C6alkenyl, halogen, ornitro, or
R5 and R6 together with the carbon atom to which they are bonded form a group of the
formula C=CR10RU wherein R10 and R11 are independently selected from hydrogen, Ci-
Cealkyl, or Q-Cealkylcarbonyloxy;
mis 1 or 2;
nisi;
Y is phenyl, which is optionally substituted by one to three substituents independently
selected from Ci-Cgalkyl, Ci-Cehaloalkyl, Ci-Cgalkoxycarbonyl, cyano, halogen, Ci-
C6alkylthio, Ci-C6haloalkylthio, Ci-C6alkylsulfinyl, Ci-C6haloalkylsulfmyl, Ci-
Cgalkoxy, Ci-C6haloalkoxy, Q-Caalkylsulfonyloxy, or phenyl, or
Y is a 5- to 10-membered heterocycle containing one to three nitrogen, oxygen or sulfur
atoms, which is optionally substituted by one to three substituents independently selected
from Ci-Cealkyl, Cs-Cecycloalkyl, Ci-Cehaloalkyl, cyano, halogen, Q-Cealkoxy, or QCghaloalkoxy;
and to N-oxides, salts and optical isomers of compounds of formula I.
A group of preferred compounds of formula I comprises those wherein
R1 and R2 are each independently of the other hydrogen, methyl, ethyl, cyclopropyl,
cyclobutyl, fluoromethyl, chloromethyl, difluoromethyl or trifluoromethyl, or
I fR and R together with the carbon atom to which they are bonded form a €3- or Coring,
R3 and R4 are each independently of the other hydrogen, methyl, ethyl, cyclopropyl,
«
cyclobutyl, fluoromethyl, chloromethyl, difluoromethyl or trifluoromethyl, or
R3 and R4 together with the carbon atom to which they are bonded form a €3- or Coring,
or
R1 with R3 or R4 and together with the carbon atoms to which they are bonded form a €5-
or Ce-ring, or
R2 with R3 or R4 and together with the carbon atoms to which they are bonded form a GSor
Ce-ring.
A group of especially preferred compounds of formula I comprises those wherein
R1, R2, R3 and R4 are each independently of the others hydrogen, methyl, fluoromethyl,
chloromethyl, difluoromethyl or trifluoromethyl.
A further group of especially preferred compounds of formula I comprises those
wherein R1 and R2 are both Ci-Cioalkyl.
A further group of especially preferred compounds of formula I comprises those
wherein R1 and R2 are both methyl.
Another group of especially preferred compounds of formula I comprises those
wherein R3 and R4 are both hydrogen.
A further group of especially preferred compounds of formula I comprises those
wherein m is 1 or 2.
A further group of very especially preferred compounds of formula I comprises
those wherein m is 2.
A group of preferred compounds of formula I comprises those wherein R5 and R6
are each independently of the other fluoro, chloro, bromo, iodo, acetyl, 1-acetyloxyethen-
1-yl, benzylsulfonyl, carbamoyl, chloroacetyl, N-cyclopropyl-carbamoyl,
cyclopropylcarbonyl, N,N-diethyl-carbamoyl, 2-diethylphosphonato-eth-l-yl,
difluoroacetyl, N-(2,2-difluoroethyl)-carbamoyl, l,l-difluoroprop-l-en-3-yl, 4,5-
dihydropyrazol-1 -ylmethyl, 2-(N,N-dimethyl-carbamoyl)-eth-1 -yl, 2-ethoxycarbonyl-eth-
1-yl, 4-fluoroanilinocarbonyl, 4-fluorobenzyl, 1-hydroxy-but-l-yl, 1-hydroxy-prop-l-yl,
imidazol-1 -ylmethyl, indazol-1-ylmethyl, methoxyacetyl, 2-methoxy-eth-l-yl,
methoxymethyl, methylsulfonyl, 2-methylsulfonyl-eth-l-yl, methylsulfonylmethyl, 1-
methylsulfonyloxy-but-1-yl, propargyl, 2-propionoyl-eth-l-yl, pyrazol-1-ylmethyl, 1,2,4-
triazol-1-ylmethyl, trifluoromethyl, or trifluoromethylthio, and
R6 is additionally hydrogen, ethoxycarbonyl, ethyl, methoxycarbonyl or methyl,
or
R5 and R6 together with the carbon they are bonded to form 1-chloro-1-
methoxycarbonyl-cyclopropyl, cyclopropyl, 1,1-dichlorocyclopropyl, nitro-cyclopropyl,
phenylcarbonyl-cyclopropyl, propen-2-yl-cyclopropyl, or vinyl-cyclopropyl, or
Rs and R6 together with the carbon they are bonded to form 3-acetyloxy-2-
acetyloxyacetyloxy-propylidene, 2-acetyloxy-propylidene, butylidene, N,Ndimethylaminoethylidene,
or3-methoxy-2-methoxyacetyloxy-propylidene.
A group of especially preferred compounds of formula I comprises those wherein
R5 and R6 are each independently of the other fluoro, chloro, bromo, iodo, acetyl, 1-
acetyloxy-ethen-1-yl, benzylsulfonyl, carbamoyl, chloroacetyl, cyclopropylcarbonyl,
difluoroacetyl, l,l-difluoroprop-l-en-3-yl, imidazol-1-ylmethyl, methoxymethyl, 2-
methoxy-eth-1-yl, methoxymethyl, propargyl, 1,2,4-triazol-l-ylmethyl, or
trifluoromethyl, and
R6 is additionally hydrogen, ethyl, methoxycarbonyl or methyl, or
R5 and R6 together with the carbon they are bonded to form cyclopropyl, 1,1-
dichlorocyclopropyl, nitro-cyclopropyl, or vinyl-cyclopropyl, or
R5 and R6 together with the carbon they are bonded to form 2-acetyloxypropylidene.
A group of preferred compounds of formula I comprises those wherein R5 and R6
are each independently of the other fluoro, chloro, bromo, iodo, acetyl, 1-acetyloxyethen-
1-yl, benzylsulfonyl, carbamoyl, chloroacetyl, N-cyclopropyl-carbamoyl,
cyclopropylcarbonyl, N jN-diethyl-carbamoyl, 2-diethylphosphonato-eth-1 -yl,
difluoroacetyl, N-(2,2-difluoroethyl)-carbamoyl, l,l-difluoroprop-l-en-3-yl, 4,5-
dihydropyrazol-1 -ylmethyl, 2-(N,N-dimethyl-carbamoyl)-eth-1 -yl, 2-ethoxycarbonyl-eth-
1-yl, 4-fluoroanilinocarbonyl, 4-fluorobenzyl, 1-hydroxy-but-l-yl, 1-hydroxy-prop-l-yl,
imidazol-1-ylmethyl, indazol-1-ylmethyl, methoxyacetyl, 2-methoxy-eth-l-yl,
methoxymethyl, methylsulfonyl, 2-methylsulfonyl-eth-l-yl, methylsulfonylmethyl, 1-
methylsulfonyloxy-but-1-yl, propargyl, 2-propionoyl-eth-l-yl, pyrazol-1-ylmethyl, 1,2,4-
triazol-l-ylmethyl, trifluoromethyl, or trifluoromethylthio, and R6 is additionally
hydrogen, ethoxycarbonyl, ethyl, methoxycarbonyl or methyl.
A group of especially preferred compounds of formula I comprises those wherein
R5 and R6 are each independently of the other fluoro, chloro, bromo, iodo, acetyl, 1-
acetyloxy-ethen-1-yl, benzylsulfonyl, carbamoyl, chloroacetyl, cyclopropylcarbonyl,
difluoroacetyl, l,l-difluoroprop-l-en-3-yl, imidazol-1-ylmethyl, methoxymethyl, 2-
methoxy-eth-1-yl, methoxymethyl, propargyl, 1,2,4-triazol-l-ylmethyl, or
trifluoromethyl, and R6 is additionally hydrogen, ethyl, methoxycarbonyl or methyl.
A group of preferred compounds of formula I comprises those wherein R5 and R6
together with the carbon they are bonded to form 1-chloro-1-methoxycarbonylcyclopropyl,
cyclopropyl, 1,1-dichlorocyclopropyl, nitro-cyclopropyl, phenylcarbonylcyclopropyl,
propen-2-yl-cyclopropyl, or vinyl-cyclopropyl.
A group of especially preferred compounds of formula I comprises those wherein
R5 and R6 together with the carbon they are bonded to form cyclopropyl, 1,1-
dichlorocyclopropyl, nitro-cyclopropyl, or vinyl-cyclopropyl.
A group of preferred compounds of formula I comprises those wherein R5 and R6
together with the carbon they are bonded to form 3-acetyloxy-2-acetyloxyacetyloxypropylidene,
2-acetyloxy-propylidene, butylidene, N,N-dimethylaminoethylidene, or 3-
methoxy-2-methoxyacetyloxy-propylidene.
A group of especially preferred compounds of formula I comprises those wherein
R5 and R6 together with the carbon they are bonded to form 2-acetyloxy-propylidene.
A group of especially preferred compounds of formula I comprises those wherein
R5 and R6 are each independently of the other cyclopropyl, difluoromethyl,
trifluoromethyl, trifluoroethyl, hydroxymethyl, methoxymethyl, methylthiomethyl,
methylsulfmylmethyl, methylsulfonylmethyl, vinyl, difluorovinyl, dichlorovinyl,
ethynyl, propargyl, acetyl, trifluoroacetyl, methoxycarbonylethyl, nitro, formyl, bromine,
chlorine, fluorine, iodine, azido, trimethylsilyl, methoxycarbonylmethyl,
ethoxycarbonylmethyl, cyanomethyl, cyanoethyl, -CH2CH2CON(CH3)2, -
CH2CH2P(O)(OCH3)2, -CH2CH2P(O)(OC2H5)2, -CH2CH2COCH3, -CH2CH2COCH2CH3,
-CH2CH2C02CH3, -CH2CH2CO2CH2H3, -CH2CH2SO2CH3, -CH2CH2NO2, mercapto,
phenylthio, methylthio, methylsulfinyl, methylsulfonyl, benzylsulfonyl, phenylsulfinyl,
phenylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl,
hydroxyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methanesulfonyloxy,
trifluoromethanesulfonyloxy, phenoxy, benzyloxy, -CONH-SO2-CH3, -CONH-SO2-CF3,
-NHCO-CH3, -NHCO-CF3, -OCO-CH3, -OCO-CF3, -OCO-phenyl, -OCONH-CH3,
-OCONH-CH2CF3, -OCONH-phenyl, -CONH2, -CONHCH3 or-CON(CH3)2, and R6
may additionally be hydrogen, cyano, methyl, ethyl, isopropyl, methoxycarbonyl,
ethoxycarbonyl or benzyloxycarbonyl.
A further group of especially preferred compounds of formula I comprises those
wherein R5 and R6 are each independently of the other phenyl or naphthyl, which rings
may be substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, cyclopropyl,
methyl, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethylthio,
trifluoromethylsulfinyl, trifluoromethylsulfonyl, methoxy, ethoxy, trifluoromethoxy,
difluoromethoxy, cyano, nitro, methoxycarbonyl, -CONH2 or by carboxyl, and R6 may
additionally be hydrogen, cyano, methyl, ethyl, isopropyl, methoxycarbonyl,
ethoxycarbonyl or benzyloxycarbonyl or halogen or trifluoromethyl.
A further group of especially preferred compounds of formula I comprises those
wherein R5 and R6 are each independently of the other 1,3-dioxalanyl, tetrahydrofuranyl,
morpholinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazoIyI, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyi, pyridazinyl, pyrazinyl, 1,2,3-
triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, tetrazinyl, benzoruryl, benzisofuryl,
benzothienyl, benzisothienyl, indolyl, benzimidazolyl, 2,1,3-benzoxadiazolyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
benzotriazinyl, purinyl, pteridinyl and indolizinyl, which heterocycles may be substituted
by fluorine, chlorine, bromine, iodine, trifluoromethyl, cyclopropyl, methyl, methylthio,
methylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl,
trifluoromethylsulfonyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, cyano,
nitro, methoxycarbonyl, -CONH2 or by carboxyl, and R6 may additionally be hydrogen,
cyano, methyl, ethyl, isopropyl, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl
or halogen or trifluoromethyl.
A further group of especially preferred compounds of formula I comprises those
wherein R5 and R6 are each independently of the other 1,3-dioxalanyl, tetrahydrofuranyl,
morpholinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, oxazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, pyridyl, pyrimidinyi, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-triazinyl, tetrazolyl, tetrazinyl, benzofuryl, benzisofuryl, benzothienyl,
benzisothienyl, indolyl, benzimidazolyl, 2,1,3-benzoxadiazolyl, quinolyl, isoquinolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl,
purinyl, pteridinyl and indolizinyl, which heterocycles may be substituted by fluorine,
chlorine, bromine, iodine, trifluoromethyl, cyclopropyl, methyl, methylthio,
methylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl,
trifluoromethylsulfonyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, cyano,
nitro, methoxycarbonyl, -CONHz or by carboxyl, and R6 may additionally be hydrogen,
cyano, methyl, ethyl, isopropyl, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl
or halogen or trifluoromethyl.
A further group of especially preferred compounds of formula I comprises those
wherein R5 and R6 together with the carbon atom to which they are bonded form a
cyclopropyl ring which may be substituted by methyl, trifluoromethyl, methoxycarbonyl,
ethoxycarbonyl, nitro, vinyl, 2-propenyl, acetyl, phenylcarbonyl, phenyl, trifluoroacetyl,
methylsulfonyl, cyano, chlorine, fluorine, bromine or by methoxy.
A further group of especially preferred compounds of formula I comprises those
wherein R5 and R5 together with the carbon atom to which they are bonded form a 3- to
6-membered heterocycle containing a nitrogen, oxygen or sulfur atom, which heterocycle
may be substituted by methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl,
trifluoroacetyl, trifluoromethylsulfonyl, methylsulfonyl, acetyl, phenyl, cyano, chlorine,
fluorine, bromine or by methoxy.
A further group of especially preferred compounds of formula I comprises those
wherein R5 and R6 together with the carbon atom to which they are bonded form a radical
of formula C=CH2, C=CH-CH3, C=CH-N(CH3)2, OCH-NH(CH3), C=CH-OCH3 or
C=CH-OC2H5.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, m, n and Y are as defined above and R5 and R6 together with the
carbon atom to which they are bonded form a 3- to 10-membered ring which may contain
one or more nitrogen, oxygen or sulfur atoms, especially a 3- to 6-membered carbocyclic
ring, more especially cyclopropyl, and which may be substituted by alkyl, haloalkyl,
alkoxy, alkoxycarbonyl, halogen, nitro or by cyano.
A further group of very especially preferred compounds of formula I comprises
those wherein R5 and R6 are each independently of the other cyclopropyl, difluoromethyl,
trifluoromethyl, trifluoroethyl, vinyl, difluorovinyl, dichlorovinyl, ethynyl, propargyl,
acetyl, trifluoroacetyl, benzyloxycarbonyl, nitro, formyl, bromine, chlorine, fluorine,
iodine, azido, trimethylsilyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,
cyanomethyl, mercapto, phenylthio, methylthio, methylsulfinyl, methylsulfonyl,
benzylsulfonyl, phenylsulfinyl, phenylsulfonyl, trifluoromethylthio,
trifluoromethylsulfinyl, trifluoromethylsulfonyl, hydroxyl, methoxy, ethoxy,
trifluoromethoxy, trifluoroethoxy, methylthiomethyl, methylsulfinylmethyl,
methylsulfonylmethyl, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenoxy,
benzyloxy, -CONH-S02-CH3, -CONH-SO2-CF3, -NHCO-CH3, -NHCO-CF3, -OCO-CH3,
-OCO-CF3, -OCO-phenyl, -OCONH-CH3, -OCONH-CH2CF3 or -OCONH-phenyl, and
R6 may additionally be hydrogen, cyano, methyl, ethyl, methoxycarbonyl or
ethoxycarbonyl or halogen or trifluoromethyl.
A further group of very especially preferred compounds of formula I comprises
those wherein R5 and R6 are each independently of the other phenyl or naphthyl, which
rings may be substituted by fluorine, chlorine, trifluoromethyl, methylsulfonyl, methoxy,
trifluoromethoxy, cyano, nitro or by methoxycarbonyl and Rg may additionally be
hydrogen, cyano, methyl, ethyl, methoxycarbonyl or ethoxycarbonyl or halogen or
trifluoromethyl.
A further group of very especially preferred compounds of formula I comprises
those wherein R5 and R6 are each independently of the other isothiazolyl, isoxazolyl,
pyrazolyl, thiadiazolyl, oxadiazolyl, dihydroisoxazolyl or a radical of formula
n , which rings may be substituted by methyl or methoxy and R6 may
(Figure Removed)
additionally be hydrogen, cyano, methyl, ethyl, methoxycarbonyl or ethoxycarbonyl or
halogen or trifluoromethyl.
A further group of very especially preferred compounds of formula I comprises
those wherein R5 and R6 together with the carbon atom to which they are bonded form a
cyclopropyl ring which may be substituted by methoxycarbonyl, ethoxycarbonyl, cyano,
trifluoromethyl, methoxy, nitro, vinyl, bromine, fluorine or by chlorine.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, R6, m, n and Y are as defined above and R5 is halogen.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, m, n and Y are as defined above and R5 and R6 are both halogen.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, R6, m, n and Y are as defined above and R5 is fluorine.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, m, n and Y are as defined above and R5 and R6 are both fluorine.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, R6, m, n and Y are as defined above and R5 is chlorine.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, m, n and Y are as defined above and R5 and R6 are both chlorine.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, m, n and Y are as defined above and R5 is fluorine and R6 is
chlorine.
A further group of especially preferred compounds of formula I comprises those
wherein R1, R2, R3, R4, R6, m, n and Y are as defined above and R5 is Ci-Cshaloalkyl,
especially trifluoromethyl.
A further group of especially preferred compounds of formula I comprises those
wherein n is 1 or 2.
A further group of very especially preferred compounds of formula I comprises
those wherein nisi.
A further group of especially preferred compounds of formula I comprises those
wherein Y is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, trifluoromethyl,
trifluoroethyl, vinyl, ethynyl, difluorovinyl, propargyl, acetyl, methoxycarbonyl,
ethoxycarbonyl, nitro, cyano, formyl, hydroxyl, carboxyl, halogen, azido, thiocyanato,
trimethylsilyl, methylthio, methylsulfonyl, ethylsulfonyl, benzylsulfonyl, phenylsulfonyl,
methoxy, ethoxy, propoxy, butoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,
methylsulfonyloxy, trifluoromethylsulfonyloxy, phenoxy, benzyloxy, -CONH-SC^-CHs
or-CONH-S02-CF3.
A group of preferred compounds of formula I comprises those wherein Y is
phenyl which is optionally substituted by one to three substituents independently selected
from fluoro, chloro, cyano, difluoromethoxy, ethoxycarbonyl, methoxy, methoxycarbonyl,
methyl, methylsulfonyloxy, nitro, phenyl, propargyloxy, trifluoromethoxy,
trifluoromethyl, trifluoromethylthio or trifluoromethylsulfinyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is phenyl which is optionally substituted by one to three substituents independently
selected from fluoro, chloro, cyano, difluoromethoxy, ethoxycarbonyl, methoxy,
methoxycarbonyl, methyl, methylsulfonyloxy, phenyl, trifluoromethoxy, trifluoromethyl,
trifluoromethylthio or trifluoromethylsulfinyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is phenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-biphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 6-chloro-2-fluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-cyanophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-difiuoromethoxyphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2,3-difluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2,4-difluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2,5-difluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2,6-difluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 3,5-difluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2,6-difluoro-3-tolyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 3,5-dimethoxyphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-fluorophenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-fluoro-4-ethoxycarbonylphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-fluoro-4-methoxycarbonylphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-fluoro-6-trifluoromethylphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-methoxyphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-methylsulfonyloxyphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-tolyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 3-tolyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-trifluoromethoxyphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-trifluoromethylphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-trifluoromethylsulfinylphenyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 2-trifluoromethylthiophenyl.
A group of preferred compounds of formula I comprises those wherein Y is
pyrazolyl which is optionally substituted by one to three substituents independently
selected from chloro, 2,2-difluoroethoxy, difluoromethoxy, ethoxy, methoxy, methyl,
oxetan-3-yloxy, /so-propylsulfonyl, 2,2,2-trifluoroethoxy or trifluoromethyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is pyrazol-3-yl, most preferably l-methyl-4-trifluoromethyl-pyrazol-3-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is pyrazol-4-yl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 5-chloro-l-methyl-3-trifluoromethyl-pyrazol-4-yl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 3-difluoromethoxy-l-methyl-5-trifluoromethyl-pyrazol-4-yl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 5-difluoromethoxy-l-methyl-3-trifluoromethyl-pyrazol-4-yl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is l,3-dimethyl-5-(2,2,2-rrifluoroethoxy)-pyrazol-4-yl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is 5-ethoxy-l-methyl-3-trifluoromethyl-pyrazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is pyrazol-5-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is l-methyl-5-(2,2-difluoroethoxy)-3-trifluoromethyl-pyrazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is l-methyl-5-methoxy-3-trifluoromethyl-pyrazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is l-methyl-5-(oxetan-3-yloxy)-3-trifluoromethyl-pyrazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is l-methyl-5-wo-propylsulfonyl-3-trifluoromethyl-pyrazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Yis l-methyl-5-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-pyrazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Yis l-methyl-3-trifluoromethyl-pyrazol-4-yl.
A group of preferred compounds of formula I comprises those wherein Y is
imidazolyl which is optionally substituted by one to three substituents independently
selected from methyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is imidazol-2-yl, most preferably l-methylimidazol-2-yI.
A group of preferred compounds of formula I comprises those wherein Y is
isoxazolyl which is optionally substituted by one or two substituents independently
selected from bromo, cyclopropyl, methoxy or methyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is isoxazol-3-yl, most preferably 5-methylisoxazol-3-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is isoxazol-4-yl, most preferably 3,5-dimethylisoxazol-4-yl, 3-cycloproyl-5-
methylisoxazol-4-yl or 5-cyclopropyl-3-methylisoxazol-4-yl.
A group of especially preferred compounds of formula I comprises those wherein
Y is isoxazol-5-yl, most preferably 3-methoxyisoxazol-5-yl or 3-bromo-4-methylisoxazol-
5-yl.
A group of preferred compounds of formula I comprises those wherein Y is
isothiazolyl which is optionally substituted by one or two substituents independently
selected from cyano or methyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is isothiazol-4-yl, most preferably 5-cyano-3-methylisothiazol-4-yl.
A group of preferred compounds of formula I comprises those wherein Y is
thiazolyl which is optionally substituted by one or two substituents independently
selected from ethoxy, ethyl, methoxymethyl and trifluoromethyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is thiazol-5-yl, most preferably 4-ethoxy-2-trifluoromethylthiazol-5-yl or 2-ethyl-4-
methoxymethylthiazol-5-yl.
A group of preferred compounds of formula I comprises those wherein Y is
pyridyl which is optionally substituted by one to three substituents independently
selected from chloro, methyl, or trifluoromethyl.
A group of especially preferred compounds of formula I comprises those wherein
Y is pyrid-3-yl, most preferably 2-chloropyrid-3-yl or 2-methyl-6-trifiuoromethyl-pyrid-
3-yl.
A group of preferred compounds of formula I comprises those wherein Y is 4Hbenzo-
1,3-dioxinyl which is optionally substituted by one or two fluorine atoms.
A group of especially preferred compounds of formula I comprises those wherein
Y is 4H-benzo-l,3-dioxin-8-yl, most preferably 6-fluoro-4H-benzo-l,3-dioxin-8-yl.
A group of preferred compounds of formula I comprises those wherein Y is
benzo-l,3-dioxolyl which is optionally substituted by one or two fluorine atoms.
A group of especially preferred compounds of formula I comprises those wherein
Y is benzo-l,3-dioxol-5-yl, most preferably 2,2-difluoro-benzo-l,3-dioxol-5-yl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is phenyl, naphthyl, tetrahydronaphthyl, 1,3-dioxalanyl, tetrahydrofuranyl,
morpholinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-
triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, tetrazinyl, 4H-benzo-l,3-dioxinyl,
benzo-l,3-dioxolyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl,
benzimidazolyl, 2,1,3-benzoxadiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl or
indolizinyl, which rings may be substituted by fluorine, chlorine, bromine, iodine,
trifhioromethyl, cyclopropyl, methyl, methylthio, methylsulfinyl, methylsulfonyl,
trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, methoxy, ethoxy,
trifluoromethoxy, difluoromethoxy, cyano, nitro, methoxycarbonyl, -CONH2 or by
carboxyl.
A further group of especially preferred compounds of formula I comprises those
wherein Y is phenyl, naphthyl, tetrahydronaphthyl, 1,3-dioxalanyl, tetrahydrofuranyl,
morpholinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, oxazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3>4-
oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-triazinyl, tetrazolyl, tetrazinyl, benzofuryl, benzisofuryl, benzothienyl,
benzisothienyl, indolyl, benzimidazolyl, 2,1,3-benzoxadiazolyl, quinolyl, isoquinolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl,
purinyl, pteridinyl or indolizinyl, which rings may be substituted by fluorine, chlorine,
bromine, iodine, trifluoromethyl, cyclopropyl, methyl, methylthio, methylsulfinyl,
methylsulfonyl, trifluoromethylthio, trifluoromethylsulfmyl, trifluoromethylsulfonyl,
methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, cyano, nitro, methoxycarbonyl, -
CONH2 or by carboxyl.
A further group of veiy especially preferred compounds of formula I comprises
those wherein Y is phenyl, pyrimidin-5-yl, pyridin-3-yl, thiazol-2-yl, thiazol-5-yl,
isothiazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, imidazol-2-yl, pyrazol-4-yl,
pyrazol-5-yl, thiophen-3-yl, 4H-benzo-l,3-dioxin-8-yl or benzo-l,3-dioxol-5-yl, where
all of these heterocycles can be further substituted, preferably by the substituents shown
in Tables 1 to 26.
A further group of very especially preferred compounds of formula I comprises
those wherein Y is phenyl, pyrimidin-5-yl, pyridin-3-yl, isothiazol-4-yl, isoxazol-4-yl,
pyrazol-4-yl, pyrazol-5-yl or thiophen-3-yl, where all of these heterocycles can be further
substituted, preferably by the substituents shown in Tables 1 to 26.
The compounds of formula I wherein R1, R2, R3, R4, R5, R6and Y are as defined
above, m is 2, and n is 1, can be prepared by processes known per se, by reacting e.g. the
compounds of formula la
(Figure Removed)
wherein R1, R2, R3, R4 and Y are as defined above, and m is 2, a) in a single step or
stepwise in succession with compounds of the formula R5-X and/or R6-X, wherein Rs
and R6 are as defined above and X is a suitable leaving group such as e.g. halogen, such
as bromide, a carboxylate, such as acetate, an alkyl- or aryl-sulfonate, such as p-toluenesulfonate,
an imide, such as succinimide, a sulfonimide, such as bis(phenylsulfonyl)-
imide, or a haloalkylsulfonate, such as trifluoromethylsulfonate, in the presence of a
base, optionally in the presence of a diluent, preferably an inert solvent, and optionally in
the presence of a complexing agent in a temperature range of from -120°C to 100°C,
preferably from -80°C to 50°C. Such processes are known in the literature and are
described, for example, in J. Med. Chem., 2003 (46) 3021-3032; J. Org. Chem., 2003
(68) 1443-1446; J. Org. Chem., 2002 (67) 5216-5225 and J. Org. Chem., 2002 (67) 3065-
3071.
The compounds of formula la, wherein R1, R2, R3, R4 and Y are as defined above,
and m is 2, can also be reacted b) with compounds of formula
or
wherein G is an electron-withdrawing group, such as cyano, nitro, P(O)(O-Ci-Cealkyl)2,
CON(Ci-C6alkyl)2, CONH(d-C6aIkyl), Ci-C6alkoxycarbonyl, C1-C4alkylsulfonyl or
Ci-C4alkylcarbonyl, optionally in the presence of a base, optionally in the presence of a
diluent and optionally in the presence of a complexing agent in a temperature range of
from -120°C to 100°C, preferably from -80°C to 50°C. Such processes are known in the
literature and are described, for example, in J. Org. Chem., 2002 (67) 5216-5225 and
Heterocycles, 2002 (57) 2267-2278.
The compounds of formula la, wherein R1, R2, R3, R4 and Y are as defined above,
and m is 2, can also be reacted c) with compounds of formula
wherein A may be O or S and Rc is Ci-Cealkyl, Ci-Cehaloalkyl, phenyl (unsubstiruted or
substituted on the phenyl ring by Cj-Cehaloalkyl, nitro, cyano, halogen), benzyl
(unsubstiruted or substituted by Ci-Cehaloalkyl, nitro, cyano, halogen), tri-Ci-C4alkylsilyl,
Ci-Cealkylcarbonyl, Cj-Cehaloalkylcarbonyl, benzylcarbonyl (unsubstiruted or
substituted by Ci-CehaloalkyI, nitro, cyano, halogen), phenylcarbonyl (unsubstituted or
substituted by Ci-C6haloalkyl, nitro, cyano, halogen), Ci-Cealkylsulfonyl, Ci-Cehaloalkylsulfonyl,
Ci-Cebenzylsulfonyl (unsubstituted or substituted by Ci-Cehaloalkyl, nitro,
cyano, halogen), Ci-Cephenylsulfonyl (unsubstituted or substituted by Ci-Cehaloalkyl,
nitro, cyano, halogen), optionally in the presence of a base, optionally in the presence of
a diluent and optionally in the presence of a complexing agent in a temperature range of
from -120°C to 100°C, preferably from -80°C to 50°C. Such processes are known in the
literature and are described, for example, in Eur. J. Org. Chem., 2000 (16) 2851-2860; J.
Org. Chem., 1996 (61) 5004-5012 and Tetrahedron, 1995 (51) 2763-2776.
The compounds of formula la, wherein R1, R2, R3, R4 and Y are as defined above,
and m is 2, can also be reacted d) with compounds of formula
(Formula Removed)
wherein RDl and RD2 are hydrogen or Ci-Cealkyl and Z is a suitable counter-ion, e.g.
halogen, optionally in the presence of a base, optionally in the presence of a diluent,
optionally in the presence of a complexing agent and optionally in the presence of a
Lewis acid in a temperature range of from -120°C to 100°C, preferably from -80°C to
I
50°C. Some of those processes are known in the literature and are described, for example,
in J. Org. Chem., 2002 (67) 5216-5225; Chem. Europ. J., 1999 (5) 1355-1363; J. Amer.
Chem. Soc., 1974 (96) 2275-2276 and Synthesis, 1984 (12) 1045-1047. Reagent ii) can
be generated in situ from N,N,N',N'-tetramethyldiaminomethane in the presence of acetic
anhydride as described in Tetrahedron Lett., 2004 (45) 3345-3348.
The compounds of formula la, wherein R1, R2, R3, R4 and Y are as defined above,
and m is 2, can also be reacted e) with compounds of formula
in which XA and XB .are each independently of the other a suitable leaving group, such as
Cl, OCCU or 1-imidazolyl, and compounds of formula
(Formula Removed)
wherein R7 and R8 are as defined above, in the presence of a base, optionally in the
presence of a diluent and optionally in the presence of a co'mplexing agent in a
temperature range of from -120°C to 100°C, preferably from -80°C to 50°C.
As diluents in the said processes there may be used inert solvents such as e.g.
hydrocarbons, ethers, such as THF or 1,2-dimethoxyethane, N,N-dimethylformamide or
halogenated hydrocarbons, such as dichloromethane, or optionally mixtures thereof. The
base can be, for example, an alkyl-lithium compound, such as methyl-lithium, n-butyllithium
and tert-butyl-lithium, a lithium dialkylamide, such as lithium diisopropylamide,
a metal hydride, preferably an alkali metal hydride, such as sodium hydride, or an alkali
metal amide, such as sodium amide, a metal bis(tri(Ci-C6alkyl)silyl)amide, such as
lithium bis(trimethylsilyl)amide, a metal alkoxide, such as potassium terf-butoxide, or a
phosphazene base, such as N'-/e^-buryl-N,N,N',N',N",N"-hexamethylphosphorimidic
triamide (Pi-'Bu), 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-
catenadi(phosphazene) (P2-Et), 1 -ter^-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-
lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-'Bu), 2-terf-butylimino-2-
diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (BEMP) or 2,8,9-
triisobutyl-2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane (Verkade's base). The
complexing agent can be, for example, l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
(DMPU), hexamethylphosphoramide (HMPA) and tetramethylethylenediamine
(TMEDA). The Lewis acid can be, for example, SnCl4, A1C13 and ZnCl2.
Process steps a), b), c) and e) can be carried out independently, repeatedly or in
combination with each other.
Compounds of formula la are known e.g. from WO 01/012613, WO 02/062770,
WO 03/000686, WO 04/010165 and WO 04/013106.
In particular, process a) is useful for the preparation of a compound of formula I
wherein R1, R2, R3, R4 and Y are as defined above, R5 is halogen, R6 is hydrogen or
halogen, m is 2, and n is 1, by halogenation of a compound of formula la (see above),
wherein R1, R2, R3, R4 and Y are defined as above, and m is 2, in a single step or
stepwise in succession with compounds of formula R5-X and/or R6-X, wherein R5 and/or
R6 are halogen, e.g. fluorine, chlorine, bromine and iodine, and X is a suitable leaving
group as described above. Preferred reagents are N-fluorobenzenesulfonimide (NFSI) or
1 -(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
(SELECTFLUOR) for the fluorination, N-chlorosuccinimide (NCS) or hexachloroethane
for the chlorination, N-bromosuccinimide (NBS) or phenyl trimethylamino tribromide
(PTT) for the bromination, and N-iodosuccinimide (NIS) for the iodination. The
halogenations are conveniently carried out in an inert solvent, preferably an ether, e.g.
THF, and in the presence of a base, preferably phosphazene bases, e.g. 1 -ter/-butyl-
2,2J4,4,4-pentakis(dimethylamino)-2-lambdas-5,4-lambda5-5-catenadi(phosphazene)
(P2-'Bu) or l-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4 lambdas-5-catenadi(
phosphazene) (Pz-Et), or 2,8,9-triisobutyl-2,5,8,9-tetraaza-l-phosphabicycIo[3.3.3]undecane
(Verkade's base), in a temperature range from 0°C to 50°C, preferably from 0°C
to 30°C. Alternatively, the halogenations are carried out in the presence of alkoxide
bases, e.g. potassium tert-butoxide, in the presence of a diluent, preferably an ether, e.g.
THF, in a temperature range from -100°C to 50°C, preferably from -80°C to 0°C.
Alternatively, the halogenations are carried out iri the presence of an alkyl-lithium
compound, e.g. n-butyl lithium, in the presence of a complexing agent, e.g. 1,3-dimethyl-
3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), in the presence of a diluent, preferably
an ether, e.g. THF, in a temperature range from -100°C to 50°C, preferably from -80°C to
0°C. Alternatively, the halogenations are carried out in the presence of a metal bis(tri(Ci-
C6alkyl)silyl)amide, e.g. sodium bis(trimethylsilyl)amide, in the presence of a diluent,
preferably an ether, e.g. THF, in a temperature range from -100°C to 50°C, preferably
from -80°C to 0°C.
Furthermore, process a) is useful for the preparation of a compound of formula I
wherein R1, R2, R3, R4, R5 and Y are as defined above, R6 is Ci-Cioalkyl or halogen, m is
2, and n is 1, by reaction of a compound of formula Ib,
wherein R1, R2, R3, R4 and Y are defined as above, m is 2, and R6 is Ci-Cioalkyl, e.g.
methyl, or halogen, e.g. chlorine or fluorine, with a compound of formula R5-X, wherein
R5 is as defined above, and X is a suitable leaving group as described above, in the
presence of abase, optionally in the presence of a diluent, preferably an inert solvent, and
optionally in the presence of a complexing agent in a temperature range of from -120°C
to 100°C, preferably from -80°C to 50°C.
In particular, process a) is useful for the preparation of a compound of formula I
wherein R1, R2, R3, R4 and Y are as defined above, R5 is halogen, R6 is Ci-Cioalkyl or
halogen, m is 2, and n is 1, by halogenation of a compound of formula Ib,
(Figure Removed)
wherein R1, R2, R3, R4 and Y are defined as above, m is 2, and R6 is Ci-Cioalkyl, e.g.
methyl, or halogen, e.g. chlorine or fluorine, with a compound of formula R5-X, wherein
R5 is halogen, e.g. fluorine, chlorine, bromine and iodine, and X is a suitable leaving
group as described above. Preferred reagents are N-fluorobenzenesulfonimide (NFSI) or
1 -(chloromethyl)-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate)
(SELECTFLUOR) for the fluonnation, N-chlorosuccinimide (NCS) or hexachloroethane
for the chlorination, N-bromosuccinimide (NBS) or phenyl trimethylamino tribromide
(PTT) for the bromination and N-iodosuccinimide (NIS) for the iodihation. The
halogenations are conveniently carried out in an inert solvent, preferably an ether, e.g.
THF, and in the presence of a base, preferably phosphazene bases, e.g. l-?err-butyl-
2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene)
(P2-lBu) or 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(
phosphazene) (P2-Et), or 2,8,9-triisobutyl-2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane
(Verkade's base), in a temperature range from 0°C to 50°C, preferably from 0°C
to 30°C. Alternatively, the halogenations are carried out in the presence of alkoxide
bases, e.g. potassium tert-butoxide, in the presence of a diluent, preferably an ether, e.g.
THF, in a temperature range from -100°C to 50°C, preferably from -80°C to 0°C.
Alternatively, the halogenations are carried out in the presence of an alkyl-lithium
compound, e.g. n-butyl lithium, in the presence of a complexing agent, e.g. 1,3-dimethyl-
3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), in the presence of a diluent, preferably
an ether, e.g. THF, in a temperature range from -100°C to 50°C, preferably from -80°C to
0°C. Alternatively, the halogenations are carried out in the presence of a metal bis(tri(Ci-
C6alkyl)silyl)amide, e.g. sodium bis(trimethylsilyl)amide, in the presence of a diluent,
preferably an ether, e.g. THF, in a temperature range from -100°C to 50°C, preferably
from -80°C to 0°C.
The compounds of fonnula I wherein R1, R2, R3, R4, R5 and Y are as defined
above, R6 is hydrogen, m is 2, and n is 1, can, furthermore, be prepared starting from
compounds of formula II
(Figure Removed)
wherein R1, R2, R3, R4, R5 and Y are as defined above, RN is Ci-Cealkyl or allyl, and m is
2, by decarboxylating those compounds. Such reactions are known in the literature and
can be carried out optionally in the presence of a base, e.g. an alkali metal hydroxide,
such as NaOH or LiOH (J. Org. Chem., 1998 (63) 220-221), optionally in the presence of
a mineral acid or organic acid such as e.g. HC1, HiSO4 or acetic acid (Synthesis, 1997 (6)
691-695), or optionally under neutral conditions (Tetrahedron 1995 (51) 8573-8584; J.
Chem. Soc. Perkin Trans. 1,1985,1541-1546). As diluents there are usually used ethers,
such as THF or dioxane, alcohols, such as methanol or ethanol, DMSO or water, or
mixtures thereof, and the reaction is usually carried out in a temperature range of from
-20°C to 200°C, preferably from 25°C to 160°C.
The compounds of formula II wherein R1, R2, R3, R4, R5 and Y are as defined
above, RN is Ci-Qalkyl or allyl, and m is 2, can be prepared, for example, starting from
compounds of formula II wherein R1, R2, R3, R4 and Y are as defined above, R5 is
hydrogen, RN is Ci-Qalkyl or allyl, and m is 2, by processes described under a) to c), or
e), as the case may be.
The compounds of formula II wherein R1, R2, R3, R4 and Y are as defined above,
R5 is hydrogen, RN is Ci-Cgalkyl or allyl, and m is 2, can be prepared, for example,
starting from compounds-of formula la (see above) wherein R1, R2, R3, R4 and Y are as
defined above, and m is 2, by processes described under a) using the reagent RN-OaCXA
wherein RN is Ci-Cealkyl or allyl and XA is a suitable leaving group as described above.
Alternatively, compounds of formula II wherein R1, R2, R3, R4 and Y are as
defined above, R5 is hydrogen, RN is Ci-Cealkyl or allyl, and m is 2, are obtainable from
compounds of formula III
(Figure Removed)
wherein R1, R2, R3 and R4 are as defined above, RN is Ci-C6alkyl or allyl, and m is 2, by
reacting with compounds of formula Y-XC wherein Y is an activated, electron-poor
aromatic or heteroaromatic group and Xc is a suitable leaving group such as e.g. halogen,
nitro, alkyl- or aryl-sulfonate, such as methylsulfonate or phenylsulfonate, haloalkylsulfonate,
such as trifluoromethylsulfonate, optionally in the presence of a base, e.g. a
lithium dialkylamide, such as lithium diisopropylamide, a metal hydride, preferably an
alkali metal hydride, such as sodium hydride, a metal bis(tri(Ci-C6alkyl)silyl)amide, such
as lithium bis(trimethylsilyl)amide, a metal alkoxide, such as potassium terf-butoxide, or
phosphazene base, such as N'-?erf-butyl-N,N,N',N',N",N"-hexamethylphosphorimidic
triamide (Pj-'Bu), l-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-
catenadi(phosphazene) (Pa-Et), 1 -te^butyl-2,2,4,4,4-pentakis(dimethylamino)-2-
lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-'Bu), 2-ter/-butylimino-2-
diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (BEMP) or 2,8,9-
triisobutyl-2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane(Verkade'sbase),
optionally in the presence of a diluent such as e.g. THF, DMF or dioxane in a
temperature range of from -120°C to 150°C, preferably from -20°C to 120°C. Such
processes are known in the literature and are described e.g. in Synthesis 1997 (6)
691-695 and Chem. Heterocycl. Compd. (Engl. Trans) 1984 (20) 676-680.
Compounds of formula III wherein R1, R2, R3 and R4 are as defined above, RN is
Ci-Cealkyl or allyl, and m is 1 or 2, can be obtained, e.g. by oxidation of compounds of
formula III wherein R1, R2, R3 and R4 are as defined above, RN is Ci-Cealkyl or allyl, and
m is 0, by reaction with suitable organic or inorganic oxidising agents, e.g. a peroxy acid,
such as 3-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, an
alkoxyperoxide or a periodate, such as sodium periodate, optionally in the presence of a
diluent, such as a halogenated hydrocarbon, e.g. dichloromethane, 1,2-dichloroethane, an
alcohol, e.g. methanol, N,N-dimethylformamide, water or acetic acid or a mixture
thereof. The reactions are usually carried out in a temperature range of from -80°C to
120°C, preferably from -20°C to 50°C. Such processes are known in the literature and are
described e.g. in J. Org. Chem., 2003 (68) 3849-3859; J. Med. Chem., 2003 (46) 3021-
3032; J. Org. Chem., 2003 (68) 500-511 and Bioorg. Med. Chem., 1999 (9) 1837-1844.
One equivalent of oxidizing agent is required to convert a sulfide, were m is 0, to the
corresponding sulfoxide, where m is 1, or to convert a sulfoxide, where m is 1, to the
corresponding sulfone, where m is 2. Two equivalents of oxidizing agent are required to
convert a sulfide, where m is 0, to the corresponding sulfone, where m is 2.
Compounds of formula III wherein the substituents R1, R2, R3 and R4 are as
defined above, RN is Ci-Cgalkyl or allyl, and m is 0, can be prepared, for example,
starting from compounds of formula IV
(Figure Removed)
wherein R1, R2, R3 and R4 are as defined above and XD is a suitable leaving group such
as halogen, e.g. chloride, an alkyl- or aryl-sulfonyl group, e.g. methylsulfonyl or
phenylsulfonyl, a haloalkylsulfonyl group, e.g. trifluoromethylsulfonyl, or nitro, by
reaction with compounds of formula V
(Figure Removed)
wherein RN is Ci-Cealkyl or allyl, optionally in the presence of a base, an alkali metal
hydride, e.g. sodium hydride, an alkali metal carbonate, such as potassium or sodium
carbonate, a basic amine, e.g. triethylamine or pyridine, optionally in the presence of a
diluent, e.g. DMF, acetone or an ether, such as THF, in a temperature range of from
-20°C to 120°C, preferably from -0°C to 80°C.
Compounds of formula IV are known e.g. from WO 01/12613, WO 02/062770
and WO 03/000686; compounds of formula V are commercially available.
The compounds of formula VI are examples of compounds of formula I wherein
R5 and R6 together with the carbon atom to which they are bonded form a cyclopropyl
ring which is optionally substituted by one to four substituents independently selected
from Ci-Cealkyl, CpCealkoxycarbonyl, Ci-Cgalkylcarbonyl, nitro or phenylcarbonyl, m
is 2, and n is 1. The compounds of formula VI
(Figure Removed)
wherein R1, R2, R3, R4 and Y are as defined above, m is 2, RD3 and Rw are hydrogen or
l, and RCY1 and RCY2 are hydrogen, halogen, Cj-Cealkoxycarbonyl, d-
Cealkylcarbonyl, phenylcarbonyl or nitro, can be prepared by processes known per se,
starting from compounds of formula VII
(Figure Removed)
wherein R1, R2, R3, R4 and Y are as defined above, m is 2, and RD3 and R04 are hydrogen
or Ci-Cgalkyl, which can in turn be prepared as described under process d), for example,
by reaction with a tri(C]-C6alkyl)sulfonium halide, such as trimethylsulfonium iodide, or
a tri(Ci-C6)alkylsulfoxonium halide, such as trimethylsulfoxonium iodide, in the
presence of a base, e.g. an alkali metal hydride, such as NaH or an alkali metal
hydroxide, such as NaOH, KOH, in the presence of a diluent, such as DMSO, DMF,
water, dichloromethane or a mixture thereof, usually in a temperature range of from 0°C
to 50°C (Indian. J. Chem. Sect. B; 1982 (21) 1092-1094; J. Chem. Soc., Perkin Trans. 1,
1997 (20) 3035-3042), or by reaction with diazomethane, in the presence of a diluent,
e.g. an ether, such as diethyl ether, usually in a temperature range of from -25°C to 0°C
(Heterocycles, 1995 (40) 191-204) or by reaction with a compound of formula,
(Figure Removed)
wherein RCY1 and RCY2 are halogen, Ci-Cealkoxycarbonyl, Q-Cealkylcarbonyl,
phenylcarbonyl or nitro, RCY1 can additionally be hydrogen, and XL is a suitable leaving
group, such as halogen, in the presence of a base, such as an alkali metal hydroxide, e.g.
NaOH, or an alkyl-lithium compound, e.g. rc-butyl-lithium, or a lithium dialkylamide,
such as lithium diisopropylamide, or a metal hydride, preferably an alkali metal hydride,
such as sodium hydride, or a metal bis(tri(Ci-C6alkyl)silyl)amide, such as lithium
bis(trimethylsilyl)amide, or a alkali metal carbonate, such as potassium carbonate, in the
presence of a diluent, e.g. tetrahydrofuran (THF), acetonitrile, water or a halogenated
'hydrocarbon, such as chloroform, or a mixture of these solvents, for example water and
chloroform, optionally in the presence of a phase transfer catalyst, e.g.
triethylbenzylammonium chloride, usually in a temperature range of from -80°C to 20°C
(Indian. J. Chem. Sect. B; 1997 (36) 608-611; Synth. Commun., 1986 (16) 1255-1259,
Tetrahedron, 2001 (57) 9423-9427).
The compounds of formula I wherein R1, R2, R3, R4, R5 and Y are as defined
above, R6 is hydrogen, m is 2, and n is 1, can also be prepared by processes known per
se, by reacting e.g. the compound of formula VII (see above) wherein R1, R2, R3, R4 and
Y are as defined above, RD3 and R04 are hydrogen or Ci-C6alkyl, m is 1 or 2, as a
Michael acceptor with nucleophiles of the formula RD5-M or RD5-H, wherein RD5-M is a
suitable salt or an organometal compound in which M is e.g. Li, MgBr, Na, K or
tetraalkylammonium and R05 is a nucleophile, such as Ci-Cealkyl, Q-Cealkoxy, Ci-
Cealkylthio, Ci-Cealkylsulfinyl, Q-Cealkylsulfonyl, cyano, nitro-Ci-Cg-alkyl-,
r\c imidazolyl, triazolyl, indazolyl, or pyrazolyl. The compounds R -M can either be
preformed or generated in situ. The reactions can also be carried out by using RD5-H
wherein RD5 is, for example, imidazolyl, triazolyl, indazolyl, or pyrazolyl under neutral
conditions. As solvents can be used ethers such as THF, halogenated solvent, such as
dichloromethane, alcohols such as methanol, acetonitrile or acetone in a temperature
range of from -120°C to 100°C, preferably from -80°C to 50°C. Such processes are
known in the literature and are described, for example, in Tetrahedron Letters (2002),
43(17), 3175-3179; Tetrahedron Letters (1992), 33(1), 131-4; Journal of Organic
Chemistry (1991), 56(13), 4098-112; Tetrahedron (1989), 45(18), 5805-5814.
The compounds of formula I wherein R1, R2, R3, R4, R5, R6, Y and n are as
defined above, and m is 1 or 2, can, furthermore, be prepared by processes known per se
by starting from compounds of formula I wherein R1, R2, R3, R4, R5, R6, Y and n are as
defined above, and m is 0 or 1, respectively, and reacting those compounds with suitable
organic or inorganic oxidising agents, e.g. a peroxy acid, such as 3-chloroperoxybenzoic
acid, peracetic acid, hydrogen peroxide, an alkoxyperoxide or a periodate, such as
sodium periodate, optionally in the presence of a diluent, such as a halogenated hydrocarbon,
e.g. dichloromethane, 1,2-dichloroethane, an alcohol, e.g. methanol, N,Ndimethylformamide,
water or acetic acid or a mixture thereof. The reactions are usually
carried out in a temperature range of from -80°C to 150°C, preferably from -20°C to
120°C. Such processes are known in the literature and are described e.g. in J. Org. Chem.,
2003 (68) 3849-3859; J. Med. Chem., 2003 (46) 3021-3032; J. Org. Chem., 2003 (68)
500-511; Bioorg. Med. Chem., 1999 (9) 1837-1844. One equivalent of oxidizing agent is
required to convert a sulfide, were m is 0, to the corresponding sulfoxide, where m is 1,
or to convert a sulfoxide, where m is 1, to the corresponding sulfone, where m is 2. Two
equivalents of oxidizing agent are required to convert a sulfide, where m is 0, to the
corresponding sulfone, where m is 2.
The compounds of formula I wherein R1, R2, R3, R4, R5, R6 and Y are as defined
above, m is 0, and n is 1, can be prepared, for example, by starting from compounds of
formula I, wherein R1, R2, R3, R4 and Y are as defined above, R5, R6 are hydrogen, m is
0, and n is 1, or compounds of formula I, wherein R1, R2, R3, R4, R5 and Y are as defined
above, R is hydrogen, m is 0, and n is 1,
(Figure Removed)
by reacting those compounds with a halogenating agent, e.g. bromine or an N-halosuccinimide,
such as N-chlorosuccinimide or N-bromosuccinimide, to form compounds
of formula I wherein R1, R2, R3, R4 and Y are as defined above, R5 is XE, and XE in turn
is halogen, R6 is hydrogen, m is 0, and n is 1, or compounds of formula I wherein R1, R2,
R3, R4, R5 and Y are as defined above, R6 is XE, and XE in turn is halogen, m is 0, and n
is 1, respectively, optionally in the presence of a diluent, e.g. acetic acid or a halogenated
hydrocarbon, such as CCU or dichloromethane, in a temperature range of from -80°C to
120°C, preferably from -20°C to 60°C.
The compounds of formula I wherein R1, R2, R3, R4 and Y are as defined above,
R5 is XE, and XE in turn is halogen, R6 is hydrogen, m is 0, and n is 1, or the compounds
of formula I wherein R1, R2, R3, R4, Rs and Y are as defined above, R6 is XE, and XE in
turn is halogen, m is 0, and n is 1, can then be oxidised directly as described above, or
optionally in a second or third step reacted with compounds of formula
M-R5 and/or M-R6,
wherein R5 and R6 are as defined and M-R5 and M-R6 is a suitable salt or an organometal
compound in which M is e.g. Li, MgBr, Na, K or tetraalkylammonium, optionally in the
presence of a Lewis acid, e.g. SnCU, optionally in the presence of a complexing agent,
e.g. hexamethylphosphoramide (HMPA) or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-
pyrimidinone (DMPU), and optionally in the presence of a diluent, e.g. acetonitrile,
dichloromethane, ether or THF, in a temperature range of from -120°C to 100°C,
preferably from -80°C to 80°C. Such processes are known in the literature and are
described, for example, in J. Org. Chem., 1998 (63) 3706-3716; J. Chem. Soc. Perkin
Trans., 1995 (22) 2845-2848; Synthesis 1982 (2), 131-132; Liebigs Annalen, 1993, 49-54
and Synth. Commun., 1990 (20) 1943-1948.
Compounds of formula 1 wherein R1, R2, R3, R , R6 and Y are as defined above,
R5 is chlorine, bromine or iodine, m is 1 or 2, and n i s i , can be prepared by reaction of a
compound of formula Ic
(Figure Removed)
wherein R1, R2, R3, R4, R6 and Y are as defined above, in an inert solvent first with an Nhalosuccinimide
and then with one of the above-mentioned oxidising agents.
Alternatively, compounds of formula I wherein R1, R2, R3, R4, R5, R6 and Y are as
defined above, m is 0, and n i s i , can be prepared by reacting a compound of formula
VIII wherein R5, R6 and Y are defined as above, and XF is a leaving group such as
halogen e.g. bromide or chloride, or alkylsulfonate, e.g. methylsulfonate, or
arylsulfonate, e.g. tosylate, with thiourea, optionally in the presence of a diluent e.g. an
alcohol, e.g. ethanol, optionally in the presence of an alkali iodide, e.g. sodium iodide,
potassium iodide, in a temperature range of from -30°C to 100°C, preferably from 0°C to
80°C, to give an isothiourea intermediate of formula XI, which is reacted with a
compound of formula IV
(Figure Removed)
wherein R1, R2, R3 and R4 are defined as above, and XD is a suitable leaving group such
as halogen, e.g. chloride, an alkyl- or aryl-sulfonyl group, e.g. methylsulfonyl or
phenylsulfonyl, a haloalkylsulfonyl group, e.g. trifluoromethylsulfonyl, or nitro, in the
presence of abase, such as a carbonate, e.g. potassium carbonate, sodium carbonate or
potassium bicarbonate, or a hydroxide, e.g. potassium hydroxide, or an alkoxide, e.g.
sodium alkoxide, optionally in the presence of a diluent, such as an alcohol, e.g. ethanol,
an ether, e.g. 1,4-dioxane, THF, a polar solvent, e.g. water, DMF, or a mixture of
solvents, e.g. a mixture of 1,4-dioxane and water, in a temperature range of from 20°C to
200°C, preferably from 50°C to 150°C, optionally in the presence of an inert gas e.g.
nitrogen, and optionally under microwave irradiation. Such processes are known in the
literature and are described, for example, in WO 04/0131106.
A further method of preparing intermediates of formula XI, wherein R5, R6 and Y
are as defined above, is to react a compound of the formula IX, wherein R5, R6 and Y are
defined as above, with thiourea in the presence of an acid, for example a mineral acid
such as hydrochloric acid or hydrobromic acid, or sulfuric acid, or an organic acid such
as trifluoroacetic acid, and optionally in the presence of a diluent, such as an ether, e.g.
1,4-dioxane, THF, a polar solvent, e.g. water, DMF, or a mixture of solvents, e.g. a
mixture of 1,4-dioxane and water, in a temperature range of from 20°C to 270°C,
preferably from 20°C to 150°C, optionally under microwave irradiation. Such processes
are known in the literature and are described, for example, in Buchwald and Neilsen,
JACS, 110(10), 3171-3175 (1988); Frank and Smith, JACS, 68, 2103-2104 (1946);
Vetter, Syn. Comm., 28, 3219-3233 (1998).
A further method of preparing compounds of formula I wherein R1, R2, R3, R4,
R5, R6 and Y are as defined above, m is 0, and n is 1, is to react compound of the formula
XII wherein R5, R6 and Y are as defined above,
(Figure Removed)
with a compound of formula IV wherein R1, R2, R3 and R4 are defined as above, and XD
is a suitable leaving group such as halogen, e.g. chloride, an alkyl- or aryl-sulfonyl group,
e.g. methylsulfonyl or phenylsulfonyl, a haloalkylsulfonyl group, e.g. trifluoromethylsulfonyl,
or nitro, in the presence of a base, e.g. potassium carbonate, optionally in the
presence of a diluent e.g. DMF in a temperature range of from 0°C to 100°C, preferably
from 20°C to SOT and optionally under an inert atmosphere, e.g. nitrogen. Such
processes are known in the literature and are described, for example in WO 01/012613,
WO 02/062770 and WO 04/010165.
In the particular case that R5 is Ci-C6haloalkyl, in particular perfluoroalkyl, for
example trifluoromethyl, compounds of the formula I wherein R1, R2, R3, R4 and Y are as
defined above, R6 is hydrogen, Q-Cealkyl or Ci-Cehaloalkyl, m is 0, and n is 1, can be
conveniently prepared by reacting carbonyl compounds of the formula XIII
(Figure Removed)
wherein Y is as defined above, and R6 is hydrogen, Ci-C6alkyl or Ci-Cghaloalkyl, with a
reagent R5-XG, wherein XG is a trialkylsilyl group, e.g. trimethylsilyl, in the presence of
an initiator, such as a fluoride salt, e.g. caesium fluoride, tetrabutylammonium fluoride,
potassium fluoride, or an alkoxide salt, and an optional diluent, such as an ether, e.g.
THF, 1,4-dioxane, in a temperature range of from 0°C to 100°C, preferably from 20°C to
30°C, to form the silylated intermediate of the formula XIV. Typically the silylated
intermediate of formula XIV is desilylated without isolation or purification in the
presence of an acid, e.g. hydrochloric acid, hydrobromic acid, or acetic acid, and
optionally in the presence of an additional diluent, such as an ether, e.g. THF, 1,4-
dioxane, a polar solvent, e.g. water, DMF, or a mixture of solvents, in a temperature
range of from 0°C to 100°C, preferably from 20°C to 30°C, to form the alcohol of formula
X. Such processes are known in the literature and are described, for example, in Chem.
Rev., 1997, 97, 757-786; J. Am. Chem. Soc. 1989, 111, 393; J. Med. Chem. 1992, 35,
641; J. Org. Chem. 1992, 57,1124.
The alcohols obtained in such fashion can be derivatised as described in e.g. WO
01/012613 and WO 02/062770, e.g. first by replacing the alcohol with a more suitable
leaving group, such as a halogen, for example bromide, or alkylsulfonate, for example
methylsulfonate, or arylsulfonate, for example tosylate, and then by reacting with
compounds of the formula IV (see above) wherein R1, R2, R3 and R4 are as defined above
and XD is a suitable leaving group e.g. halogen, such as chloride, an alkylsulfonyl group,
such as methylsulfonyl, or an aryl-sulfonyl group, such as phenylsulfonyl, in the presence
of a base, e.g. potassium carbonate, sodium hydrosulfide hydrate or Rongalit salt
(hydroxy methanesulfinic acid sodium salt and hydrate), optionally in the presence of a
diluent, e.g. DMF, in a temperature range of from -20°C to 150°C, preferably from 0°C to
40°C, optionally in the presence of an inert gas, for example nitrogen. Such processes are
known in the literature and are described, for example, in WO 01/012613, WO
02/062770 and WO 04/010165.
Additionally, compounds of formula IX wherein R5 and R6 are hydrogen can be
prepared from compounds of formula XV by reacting with reagent XVI
(Figure Removed)
wherein XH is a halogen atom such as bromine or chlorine in the presence of a diluent
such as a halogenated hydrocarbon such as dichloromethane, a hydrocarbon such as
hexane, an alcohol such as ethanol, N-N-dimethylformamide, tetrahydrofuran (THF) or a
mixture thereof. The preparation of aromatic benzyl halides is described in Tetrahedron
Letts. 2000 (41) 5161-5164. The preparation of the reagent XVI is described in J. Org.
Chem. 1980 (45) 384-389.
The compounds of formula I according to the invention can be used as herbicides
in unmodified form, as obtained in the synthesis, but they are generally formulated into
herbicidal compositions in various ways using formulation adjuvants, such as carriers,
solvents and surface-active substances. The formulations can be in various physical
forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible
granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable
concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions,
oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble
liquids, water-soluble concentrates (with water or a water-miscible organic solvent as
carrier), impregnated polymer films or in other forms known e.g. from the Manual on
Development and Use of FAO Specifications for Plant Protection Products, 5th Edition,
1999. Such formulations can either be used directly or they are diluted prior to use. The
dilutions can be made, for example, with water, liquid fertilisers, micronutrients,
biological organisms, oil or solvents.
The formulations can be prepared e.g. by mixing the active ingredient with the
formulation adjuvants in order to obtain compositions in the form of finely divided
solids, granules, solutions, dispersions or emulsions. The active ingredients can also be
formulated with other adjuvants, such as finely divided solids, mineral oils, oils of
vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents,
water, surface-active substances or combinations thereof. The active ingredients can also
be contained in very fine microcapsules consisting of a polymer. Microcapsules contain
the active ingredients in a porous carrier. This enables the active ingredients to be
released into the environment in controlled amounts (e.g. slow-release). Microcapsules
usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an
amount of about from 25 to 95 % by weight of the capsule weight. The active ingredients
can be in the form of a monolithic solid, in the form of fine particles in solid or liquid
dispersion or in the form of a suitable solution. The encapsulating membranes comprise,
for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers,
polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or
chemically modified polymers and starch xanthates or other polymers that are known to
the person skilled in the art in this connection. Alternatively, very fine microcapsules can
be formed in which the active ingredient is contained in the form of finely divided
particles in a solid matrix of base substance, but the microcapsules are not themselves
encapsulated.
The formulation adjuvants that are suitable for the preparation of the
compositions according to the invention are known per se. As liquid carriers there may
be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl
ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-
butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of
acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene,
diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene
glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl
sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene
glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene
carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate,
ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gammabutyrolactone,
glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate,
hexadecane, hexylene glycol, isoamyl acetate, isobomyl acetate, isooctane, isophorone,
isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol,
methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl
octanoate, methyl oleate, methylene chloride, m-xylehe, «-hexane, ;i-octylamine, octadecanoic
acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene
glycol (PEG400), propionic acid, propyl lactate, propylene carbonate, propylene glycol,
propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol,
xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl
acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol
methyl ether, methanol, ethanol, isopropanol, and alcohols of higher molecular weight,
such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol,
propylene glycol, glycerol, N-methyl-2-pyrrolidone and the like. Water is generally the
carrier of choice for diluting the concentrates. Suitable solid carriers are, for example,
talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone,
calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour,
soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances,
as described, for example, in CFR 180.1001. (c) & (d).
A large number of surface-active substances can advantageously be used in both
solid and liquid formulations, especially in those formulations which can be diluted with
a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or
polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for
other purposes. Typical surface-active substances include, for example, salts of alkyl
sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as
calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as
nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol
ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as
sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as
sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary
amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty
acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and
propylene oxide; and salts of mono- and di-alkylphosphate esters; and also further
substances described e.g. in "McCutcheon's Detergents and Emulsifiers Annual" MC
Publishing Corp., Ridgewood New Jersey, 1981.
Further adjuvants that can usually be used in pesticidal formulations include
crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants,
foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents,
neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances,
wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants,
dispersants, thickeners, antifreezes, microbicides, and also liquid and solid fertilisers.
The compositions according to the invention can additionally include an additive
comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or
mixtures of such oils and oil derivatives. The amount of oil additive in the composition
according to the invention is generally from 0.01 to 10 %, based on the spray mixture.
For example, the oil additive can be added to the spray tank in the desired concentration
after the spray mixture has been prepared. Preferred oil additives comprise mineral oils
or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil,
emulsified vegetable oil, such as AMIGO® (Rhone-Poulenc Canada Inc.), alkyl esters of
oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin,
such as fish oil or beef tallow. A preferred additive contains, for example, as active
components essentially 80 % by weight alkyl esters offish oils and 15 % by weight
methylated rapeseed oil, and also 5 % by weight of customary emulsifiers and pH
modifiers. Especially preferred oil additives comprise alkyl esters of Cg-C22 fatty acids,
especially the methyl derivatives of Ci2-Cig fatty acids, for example the methyl esters of
lauric acid, palmitic acid and oleic acid, being of importance. Those esters are known as
methyl laurate (CAS-111-82-0), methyl palmitate (CAS-112-39-0) and methyl oleate
(CAS-112-62-9). A preferred fatty acid methyl ester derivative is Emery® 2230 and
2231 (Cognis GmbH). Those and other oil derivatives are also known from the
Compendium of Herbicide Adjuvants, 5th Edition, Southern Illinois University, 2000.
The application and action of the oil additives can be further improved by
combination with surface-active substances, such as non-ionic, anionic or cationic
surfactants. Examples of suitable anionic, non-ionic and cationic surfactants are listed on
pages 7 and 8 of WO 97/34485. Preferred surface-active substances are anionic
surfactants of the dodecylbenzylsulfonate type, especially the calcium salts thereof, and
also non-ionic surfactants of the fatty alcohol ethoxylate type. Special preference is given
to ethoxylated Ci2-Cz2 fatty alcohols having a degree of ethoxylation of from 5 to 40.
Examples of commercially available surfactants are the Genapol types (Clariant AG).
Also preferred are silicone surfactants, especially polyalkyl-oxide-modified
heptamethyltriloxanes which are commercially available e.g. as Silwet L-77®, and also
perfluorinated surfactants. The concentration of the surface-active substances in relation
to the total additive is generally from 1 to 30 % by weight. Examples of oil additives
consisting of mixtures of oil or mineral oils or derivatives thereof with surfactants are
Edenor ME SU®, Turbocharge® (Syngenta AG, CH) or ActipronC (BP Oil UK Limited,
GB).
If desired, it is also possible for the mentioned surface-active substances to be
used in the formulations on their own, that is to say without oil additives.
Furthermore, the addition of an organic solvent to the oil additive/surfactant
mixture may contribute to an additional enhancement of action. Suitable solvents are, for
example, Solvesso® (ESSO) or Aromatic Solvent® (Exxon Corporation). The
concentration of such solvents can be from 10 to 80 % by weight of the total weight. Oil
additives that are present in admixture with solvents are described, for example, in US-A-
4,834,908. A commercially available oil additive disclosed therein is known by the name
MERGE® (BASF Corporation). A further oil additive that is preferred according to the
invention is SCORE® (Syngenta Crop Protection Canada).
In addition to the oil additives listed above, for the purpose of enhancing the
action of the compositions according to the invention it is also possible for formulations
of alkylpyrrolidones (e.g. Agrimax®) to be added to the spray mixture. Formulations of
synthetic lattices, e.g. polyacrylamide, polyvinyl compounds or poly-1-p-menthene (e.g.
Bond®, Courier® or Emerald®) may also be used. It is also possible for solutions that
contain propionic acid, for example Eurogkem Pen-e-trate®, to be added to the spray
mixture as action-enhancing agent.
The herbicidal compositions generally comprise from 0.1 to 99 % by weight,
especially from 0.1 to 95 % by weight, compounds of formula I and from 1 to 99.9 % by
weight of a formulation adjuvant which preferably includes from 0 to 25 % by weight of
a surface-active substance. Whereas commercial products will preferably be formulated
as concentrates, the end user will normally employ dilute formulations.
The rates of application of compounds of formula I may vary within wide limits
and depend on the nature of the soil, the method of application (pre- or post-emergence;
seed dressing; application to the seed furrow; no tillage application etc.), the crop plant,
the grass or weed to be controlled, the prevailing climatic conditions, and other factors
governed by the method of application, the time of application and the target crop. The
compounds of formula I according to the invention are generally applied at a rate of from
10 to 2000 g/ha, especially from 50 to 1000 g/ha.
Preferred formulations have especially the following compositions (% = percent
by weight):
Emulsifiable concentrates:
active ingredient: 1 to 95 %, preferably 60 to 90 %
surface-active agent: 1 to 30 %, preferably 5 to 20 %
liquid carrier: 1 to 80 %, preferably 1 to 35 %
Dusts:
active ingredient: 0.1 to 10 %, preferably 0.1 to 5 %
solid carrier: 99.9 to 90 %, preferably 99.9 to 99 %
Suspension concentrates:
active ingredient: 5 to 75 %, preferably 1 0 to 50 %
water: 94 to 24 %, preferably 88 to 30 %
surface-active agent: 1 to 40 %, preferably 2 to 30 %
Wettable powders:
active ingredient: 0.5 to 90 %, preferably 1 to 80 %
surface-active agent: 0.5 to 20 %, preferably 1 to 15 %
solid carrier: 5 to 95 %, preferably 1 5 to 90 %
Granules:
active ingredient: 0. 1 to 30 %, preferably 0. 1 to 1 5 %
solid carrier: 99.5 to 70 %, preferably 97 to 85 %
The following Examples further illustrate, but do not limit, the invention.
Formulation Examples for herbicides of formula I (% = % by weight)
Fl . Emulsifiable concentrates a) b) c) d)
active ingredient 5% 10% 25% 50%
calcium dodecylbenzenesulfonate 6 % 8 % 6 % 8 %
castor oil polyglycol ether 4 % - 4 % 4 %
(36 mol of ethylene oxide)
octylphenol polyglycol ether - 4 % - 2 %
(7-8 mol of ethylene oxide)
NMP - - 10% 20%
arom. hydrocarbon mixture 85% 78% 55% 16%
Emulsions of any desired concentration can be obtained from such concentrates by
dilution with water.
F2. Solutions a) b) c) d)
active ingredient 5% 10% 50% 90%
1 -methoxy-3 -(3 -methoxypropoxy)-
propane - 20% 20%
polyethylene glycol MW 400 20% 10%
NMP - - 30% 10%
arom. hydrocarbon mixture 75 % 60 % -
The solutions are suitable for use in the form of microdrops.
F3. Wettable powders a) b) c) d)
active ingredient 5 % 25 % 50 % 80 %
sodium lignosulfonate 4 % - 3 %
sodium lauryl sulfate 2% 3% - 4%
sodium diisobutylnaphthalenesulfonate
- 6% 5% 6%
octylphenol polyglycol ether - 1 % 2 %
(7-8 mol of ethylene oxide)
highly dispersed silicic acid 1% 3% 5% 10%
kaolin 88% 62% 35%
The active ingredient is mixed thoroughly with the adjuvants and the mixture is
thoroughly ground in a suitable mill, affording wettable powders which can be diluted
with water to give suspensions of any desired concentration.
F4. Coated granules a) b) c)
active ingredient 0.1% 5% 15%
highly dispersed silicic acid 0.9 % 2 % 2 %
inorganic carrier 99.0% 93% 83%
(diameter 0.1-1 mm)
e.g. CaCO3 or SiO2
The active ingredient is dissolved in methylene chloride and applied to the carrier by
spraying, and the solvent is then evaporated off in vacua.
-91-
F5. Coated granules a) b) c)
active ingredient 0.1% 5% 15%
polyethylene glycol MW 200 1.0% 2% 3%
highly dispersed silicic acid 0.9 % 1 % 2 %
inorganic carrier 98.0% 92% 80%
(diameter 0.1 - 1 mm)
e.g. CaCO3 or SiO2
The finely ground active ingredient is uniformly applied, in a mixer, to the carrier
moistened with polyethylene glycol. Non-dusty coated granules are obtained in this
manner.
F6. Extruder granules a) b) c) d)
active ingredient 0.1% 3% 5% 15%
sodium lignosulfonate 1.5% 2% 3% 4%
carboxymethylcellulose 1.4% 2% 2% 2%
kaolin 97.0% 93% 90% 79%
The active ingredient is mixed and ground with the adjuvants, and the mixture is
moistened with water. The mixture is extruded and then dried in a stream of air.
F7. Dusts a) b) c)
active ingredient 0.1% 1% 5%
talcum 39.9% 49% 35%
kaolin 60.0% 50% 60%
Ready-to-use dusts are obtained by mixing the active ingredient with the carriers and
grinding the mixture in a suitable mill.
F8. Suspension concentrates a) b) c) d)
active ingredient 3% 10% 25% 50%
ethylene glycol 5% 5% 5% 5%
nonylphenol polyglycol ether - 1 % 2 %
(15 mol of ethylene oxide)
sodium lignosulfonate 3 % 3 % 4 % 5 %
carboxymethylcellulose 1 % 1 % 1 % 1 %
37 % aqueous formaldehyde 0.2% 0.2% 0.2% 0.2%
solution
silicone oil emulsion 0.8% 0.8% 0.8% 0.8%
water 87% 79% 62% 38%
The finely ground active ingredient is intimately mixed with the adjuvants, giving a
suspension concentrate from which suspensions of any desired concentration can be
obtained by dilution with water.
The invention relates also to a method for the selective control of grasses and
weeds in crops of useful plants, wherein the useful plants or the area of cultivation or
locus thereof is treated with the compounds of formula I.
Useful plant crops in which the composition according to the invention can be
used include especially maize, soybeans, cotton, cereals, e.g. wheat and barley, rice,
sugar cane, sugar beet, sunflowers and rape. Crops are to be understood as also including
those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g.
ALS-, GS-, EPSPS-, PPO- and HPPD-inhibitors) by conventional methods of breeding or
by genetic engineering. An example of a crop that has been rendered tolerant to
imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield®
summer rape (canola). Examples of crops that have been rendered tolerant to herbicides
by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize
varieties commercially available under the trade names RoundupReady® and
LibertyLink®. The weeds to be controlled may be both monocotyledonous and
dicotyledonous weeds, for example Stellaria, Nasturtium, Agrostis, Digitaria, Avena,
Setaria, Sinapis, Lolium, Solanum, Echinochloa, Scirpus, Monochoria, Sagittaria,
Bromus, Alopecurus, Sorghum, Rottboellia, Cyperus, Abutilon, Sida, Xanthium,
Amaranthus, Chenopodium, Ipomoea, Chrysanthemum, Galiurn, Viola and Veronica.
Crops are also to be understood as being those which have been rendered resistant
to harmful insects by genetic engineering methods, for example Bt maize (resistant to
European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes
(resistant to Colorado beetle). Examples of Bt maize are the Bt 176 maize hybrids of
NK® (Syngenta Seeds). The Bt toxin is a protein that is formed naturally by Bacillus
thuringiensis soil bacteria. Examples of toxins, or transgenic plants able to synthesise
such toxins, are described in EP-A-451 878, EP-A-374 753, WO 93/07278, WO
95/34656, WO 03/052073 and EP-A-427 529. Examples of transgenic plants comprising
one or more genes that code for an insecticidal resistance and express one or more toxins
are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard®
(cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®. Plant crops or seed
material thereof can be both resistant to herbicides and, at the same time, resistant to
insect feeding ("stacked" transgenic events). For example, seed can have the ability to
express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
Crops are also to be understood as being those which are obtained by conventional
methods of breeding or genetic engineering and contain so-called output traits (e.g.
improved storage stability, higher nutritional value and improved flavour).
Areas under cultivation include land on which the crop plants are already growing
and land intended for cultivation with those crop plants.
The compounds of formula I according to the invention can also be used in
combination with one or more other herbicides. In particular, the following mixtures of
the compound of formula I are important:
compound of formula I + acetochlor, compound of formula I + acifluorfen, compound of
formula I + acifluorfen-sodium, compound of formula I + aclonifen, compound of
formula I + acrolein, compound of formula I + alachlor, compound of formula I +
alloxydim, compound of formula I + allyl alcohol, compound of formula I + ametryn,
compound of formula I + amicarbazone, compound of formula I + amidosulfuron,
compound of formula I -f- aminopyralid, compound of formula I + amitrole, compound of
formula I + ammonium sulfamate, compound of formula I + anilofos, compound of
formula I + asulam, compound of formula I + atraton, compound of formula I + atrazine,
compound of formula I + azimsulfuron, compound of formula I + BCPC, compound of
formula I + beflubutamid, compound of formula I + benazolin, compound of formula I +
benfluralin, compound of formula I + benfuresate, compound of formula I + bensulfuron,
compound of formula I + bensulfuron-methyl, compound of formula I + bensulide,
compound of formula I + bentazone, compound of formula I + benzfendizone, compound
of formula I + benzobicyclon, compound of formula I + benzofenap, compound of
formula I + bifenox, compound of formula I + bilanafos, compound of formula I +
bispyribac, compound of formula I + bispyribac-sodium, compound of formula I + borax,
compound of formula I + bromacil, compound of formula I + bromobutide, compound of
formula I + bromoxynil, compound of formula I + butachlor, compound of formula I +
butafenacil, compound of formula I + butamifos, compound of formula I + butralin,
compound of formula I + butroxydim, compound of formula I + butylate, compound of
formula I + cacodylic acid, compound of formula I + calcium chlorate, compound of
formula I + cafenstrole, compound of formula I + carbetamide, compound of formula I +
carfentrazone, compound of formula I + carfentrazone-ethyl, compound of formula I +
CDEA, compound of formula I + CEPC, compound of formula I + chlorfiurenol,
compound of formula I + chlorflurenol-methyl, compound of formula I + chloridazon,
compound of formula I + chlorimuron, compound of formula I + chlorimuron-ethyl,
compound of formula I + chloroacetic acid, compound of formula I + chlorotoluron,
compound of formula I + chlorpropham, compound of formula I + chlorsulfuron,
compound of formula I + chlorthal, compound of formula I + chlorthal-dimethyl,
compound of formula I + cinidon-emyl, compound of formula I + cinmethylin,
compound of formula I + cinosulfuron, compound of formula I + cisanilide, compound
of formula I + clethodim, compound of formula I + clodinafop, compound of formula I +
clodinafop-propargyl, compound of formula I + clomazone, compound of formula I +
clomeprop, compound of formula I + clopyralid, compound of formula I + cloransulam,
compound of formula I + cloransulam-methyl, compound of formula I + CMA,
compound of formula I + 4-CPB, compound of formula 14- CPMF, compound of formula
I + 4-CPP, compound of formula I + CPPC, compound of formula I + cresol, compound
of formula I + cumyluron, compound of formula I + cyanamide, compound of formula I
+ cyanazine, compound of formula I + cycloate, compound of formula I +
cyclosulfamuron, compound of formula I + cycloxydim, compound of formula I +
cyhalofop, compound of formula I + cyhalofop-butyl, compound of formula I + 2,4-D,
compound of formula I + 3,4-DA, compound of formula I + daimuron, compound of
formula I + dalapon, compound of formula I + dazomet, compound of formula I + 2,4-
DB, compound of formula I + 3,4-DB, compound of formula I + 2,4-DEB, compound of
formula I + desmedipham, compound of formula I + dicamba, compound of formula I +
dichlobenil, compound of formula I + ortho-dichlorobenzene, compound of formula I +
para-dichlorobenzene, compound of formula I + dichlorprop, compound of formula I +
dichlorprop-P, compound of formula I + diclofop, compound of formula I + diclofopmethyl,
compound of formula I + diclosulam, compound of formula I + difenzoquat,
compound of formula I + difenzoquat metilsulfate, compound of formula I +
diflufenican, compound of formula I + diflufenzopyr, compound of formula I +
dimefuron, compound of formula I + dimepiperate, compound of formula I +
dimethachlor, compound of formula I + dimethametryn, compound of formula I +
dimethenamid, compound of formula I + dimethenamid-P, compound of formula I +
dimethipin, compound of formula I + dimethylarsinic acid, compound of formula I •+
dinitramine, compound of formula I + dinoterb, compound of formula I + diphenamid,
compound of formula I + diquat, compound of formula I + diquat dibromide, compound
of formula I + dithiopyr, compound of formula I + diuron, compound of formula I +
DNOC, compound of formula 1 + 3,4-DP, compound of formula I + DSMA, compound
of formula I + EBEP, compound of formula I + endothal, compound of formula I +
EPTC, compound of formula I + esprocarb, compound of formula I + ethalfluralin,
compound of formula I + ethametsulfuron, compound of formula I + ethametsulfuronmethyl,
compound of formula I + ethofumesate, compound of formula I + ethoxyfen,
compound of formula I + ethoxysulfuron, compound of formula I + etobenzanid,
compound of formula I + fenoxaprop-P, compound of formula I + fenoxaprop-P-ethyl,
compound of formula I + fentrazamide, compound of formula I + ferrous sulfate,
compound of formula I + flamprop-M, compound of formula I + flazasulfuron,
compound of formula I + florasulam, compound of formula I + fluazifop, compound of
formula I + fluazifop-butyl, compound of formula I + fluazifop-P, compound of formula
I + fluazifop-P-butyl, compound of formula I + flucarbazone, compound of formula I +
flucarbazone-sodium, compound of formula I + flucetosulfuron, compound of formula I
+ fluchloralin, compound of formula I + flufenacet, compound of formula I + flufenpyr,
compound of formula I + flufenpyr-ethyl, compound of formula I + flumetsulam,
compound of formula I + flumiclorac, compound of formula I + flumiclorac-pentyl,
compound of formula I + flumioxazin, compound of formula IH- fluometuron, compound
of formula I + fluoroglycofen, compound of formula I + fluoroglycofen-ethyl, compound
of formula I + flupropanate, compound of formula I + flupyrsulfuron, compound of
formula I + flupyrsulfuron-methyl-sodium, compound of formula I + flurenol, compound
of formula I + fluridone, compound of formula I + flurochloridone, compound of formula
I + fluroxypyr, compound of formula I + flurtamone, compound of formula I + fluthiacet,
compound of formula I + fluthiacet-methyl, compound of formula I + fomesafen,
compound of formula I + foramsulfuron, compound of formula I + fosamine, compound
of formula I + glufosinate, compound of formula I + glufosinate-ammonium, compound
of formula I + glyphosate, compound of formula I + halosulfuron, compound of formula
I + halosulfuron-methyl, compound of formula I + haloxyfop, compound of formula I +
haloxyfop-P, compound of formula 1 + HC-252, compound of formula I + hexazinone,
compound of formula I + imazamethabenz, compound of formula I + imazamethabenzmethyl,
compound of formula I + imazamox, compound of formula I + imazapic,
compound of formula I + imazapyr, compound of formula I + imazaquin, compound of
formula I + imazemapyr, compound of formula I + imazosulfuron, compound of formula
I + indanofan, compound of formula I + iodomethane, compound of formula I +
iodosulfuron, compound of formula I + iodosulfuron-methyl-sodium, compound of
formula I + ioxynil, compound of formula I + isoproturon, compound of formula I +
isouron, compound of formula I + isoxaben, compound of formula I + isoxachlortole,
compound of formula I + isoxaflutole, compound of formula I + karbutilate, compound
of formula I + lactofen, compound of formula I + lenacil, compound of formula I +
linuron, compound of formula I + MAA, compound of formula I + MAMA, compound
of formula I + MCPA, compound of formula I + MCPA-thioethyl, compound of formula
I + MCPB, compound of formula I + mecoprop, compound of formula I + mecoprop-P,
compound of formula I + mefenacet, compound of formula I + mefluidide, compound of
formula I + mesosulfuron, compound of formula I + mesosulfuron-methyl, compound of
formula I + mesotrione, compound of formula I + metam, compound of formula I +
metamifop, compound of formula I + metamitron, compound of formula I + metazachlor,
compound of formula I + methabenzthiazuron, compound of formula I + methylarsonic
acid, compound of formula I + methyldymron, compound of formula I + methyl
isothiocyanate, compound of formula I + metobenzuron, compound of formula I +
metolachlor, compound of formula I + S-metolachlor, compound of formula I +
metosulam, compound of formula I + metoxuron, compound of formula I + metribuzin,
compound of formula I + metsulfuron, compound of formula I + metsulfuron-methyl,
compound of formula I + MK-616, compound of formula I + molinate, compound of
formula I + monolinuron, compound of formula I + MS MA, compound of formula I +
naproanilide, compound of formula I + napropamide, compound of formula I + naptalam,
compound of formula I + neburon, compound of formula I + nicosulfuron, compound of
formula I + nonanoic acid, compound of formula I + norflurazon, compound of formula I
+ oleic acid (fatty acids), compound of formula I + orbencarb, compound of formula I +
orthosulfamuron, compound of formula I + oryzalin, compound of formula I +
oxadiargyl, compound of formula I + oxadiazon, compound of formula I + oxasulfuron,
compound of formula I + oxaziclomefone, compound of formula I + oxyfluorfen,
compound of formula I + paraquat, compound of formula I + paraquat dichloride,
compound of formula I + pebulate, compound of formula I + pendimethalin, compound
of formula I + penoxsulam, compound of formula 1 + pentachlorophenol, compound of
formula I + pentanochlor, compound of formula I + pentoxazone, compound of formula I
+ pethoxamid, compound of formula I + petrolium oils, compound of formula I +
phenmedipham, compound of formula 14- phenmedipham-ethyl, compound of formula I
+ picloram, compound of formula I + picolinafen, compound of formula I + pinoxaden,
compound of formula I + piperophos, compound of formula I + potassium arsenite,
compound of formula I + potassium azide, compound of formula I + pretilachlor,
compound of formula I + primisulfuron, compound of formula I + primisulfuron-methyl,
compound of formula I + prodiamine, compound of formula I + profluazol, compound of
formula I + profoxydim, compound of formula I + prometon, compound of formula I +
prometryn, compound of formula I + propachlor, compound of formula I + propanil,
compound of formula I •+ propaquizafop, compound of formula I + propazine, compound
of formula I + propham, compound of formula I + propisochlor, compound of formula I
+ propoxycarbazone, compound of formula 14- propoxycarbazone-sodium, compound of
formula I + propyzamide, compound of formula I + prosulfocarb, compound of formula I
+ prosulfuron, compound of formula I + pyraclonil, compound of formula I + pyraflufen,
compound of formula I + pyraflufen-ethyl, compound of formula I + pyrazolynate,
compound of formula I + pyrazosulfuron, compound of formula I + pyrazosulfuronethyl,
compound of formula I + pyrazoxyfen, compound of formula I + pyribenzoxim,
compound of formula I + pyributicarb, compound of formula I + pyridafol, compound of
formula I + pyridate, compound of formula I + pyriftalid, compound of formula I +
pyriminobac, compound of formula I + pyriminobac-methyl, compound of formula I +
pyrimisulfan, compound of formula I + pyrithiobac, compound of formula I +
pyrithiobac-sodium, compound of formula I + quinclorac, compound of formula I +
quinmerac, compound of formula I + quinoclamine, compound of formula I +
quizalofop, compound of formula I + quizalofop-P, compound of formula I +
rimsulfuron, compound of formula I + sethoxydim, compound of formula I + siduron,
compound of formula I + simazine, compound of formula I + simetryn, compound of
formula I + SMA, compound of formula I + sodium arsenite, compound of formula I +
sodium azide, compound of formula I + sodium chlorate, compound of formula I +
sulcotrione, compound of formula I + sulfentrazone, compound of formula I +
sulfometuron, compound of formula I + sulfometuron-methyl, compound of formula I + '
sulfosulfuron, compound of formula I + sulfuric acid, compound of formula I + tar oils,
compound of formula I + 2,3,6-TBA, compound of formula I + TCA, compound of
formula I + TCA-sodium, compound of formula I + tebuthiuron, compound of formula I
+ tepraloxydim, compound of formula I + terbacil, compound of formula I + terbumeton,
compound of formula I + terbuthylazine, compound of formula I + terbutryn, compound
of formula I + thenylchlor, compound of formula I + thiazopyr, compound of formula I +
thifensulfuron, compound of formula I + thifensulfuron-methyl, compound of formula I
+ thiobencarb, compound of formula I + tiocarbazil, compound of formula I +
topramezone, compound of formula I + tralkoxydim, compound of formula I + tri-allate,
compound of formula I + triasulfuron, compound of formula I + triaziflam, compound of
formula I + tribenuron, compound of formula I + tribenuron-methyl, compound of
formula I + tricamba, compound of formula I + triclopyr, compound of formula I +
trietazine, compound of formula I + trifloxysulfuron, compound of formula I +
trifloxysulfuron-sodium, compound of formula I + trifluralin, compound of formula I +
triflusulfuron, compound of formula I + triflusulfuron-methyl, compound of formula I +
trihydroxytriazine, compound of formula I + tritosulfuron, compound of formula I + [3-
[2-cUoro-4-fluoro-5-(l-methyl-6-trifluoromethyl-2,4-dioxo-l,2}3,4-tetrahydropyrimidin-
3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl ester.
The mixing partners of the compound of formula I may also be in the form of
esters or salts, as mentioned e.g. in The Pesticide Manual, 12th Edition (BCPC), 2000.
The mixing ratio of the compound of formula I to the mixing partner is preferably
from 1:100 to 1000:1.
The mixtures can advantageously be used in the above-mentioned formulations
(in which case "active ingredient" relates to the respective mixture of compound of
formula I with the mixing partner).
Preferred mixtures of a compound of formula I with one or more further
herbicides include:
Mixtures of a compound of the formula I with a triazine (e.g. compound of
formula I + ametryn, compound of formula I + atrazine, compound of formula I +
cyanazine, compound of formula I + dimethametryn, compound of formula I +
metribuzin, compound of formula I + prometon, compound of formula I + prometryn,
compound of formula I + propazine, compound of formula I + simazine, compound of
formula I + simetryn, compound of formula I + terbumeton, compound of formula I +
terbuthylazine, compound of formula I + terbutryn, compound of formula I + trietazine).
Particularly preferred are mixtures of a compound of formula I with atrazine, metribuzin,
prometryn or with terbuthylazine (i.e. compound of formula I + atrazine, compound of
formula I + metribuzin, compound of formula I + prometryn, and compound of formula I
+ terbuthylazine).
Mixtures of a compound of formula I with isoxaflutole (e.g. compound of
formula I + isoxaflutole).
Mixtures of a compound of formula I with isoxaflutole and a triazine.
Mixtures of a compound of formula I with isoxaflutole and glyphosate (e.g.
compound of formula I + isoxaflutole + glyphosate).
Mixtures of a compound of formula I with isoxaflutole and glufosinate (e.g.
compound of formula I + isoxaflutole + glufosinate).
Mixtures of a compound of formula I with mesotrione (e.g. compound of formula
iI + mesotrione).
Mixtures of a compound of formula I with mesotrione and a triazine.
Mixtures of a compound of formula I with mesotrione and glyphosate (e.g.
compound of formula I + mesotrione + glyphosate).
Mixtures of a compound of formula I with mesotrione and glufosinate (e.g.
compound of formula I + mesotrione + glufosinate).
Mixtures of a compound of formula I with sulcotrione (e.g. compound of formula
I + sulcotrione).
Mixtures of a compound of formula I with sulcotrione and a triazine.
Mixtures of a compound of formula I with sulcotrione and glyphosate (e.g.
compound of formula I + sulcotrione + glyphosate).
Mixtures of a compound of formula I with sulcotrione and glufosinate (e.g.
compound of formula I + sulcotrione + glufosinate).
Mixtures of a compound of formula I with a triazolinone (e.g. compound of
formula I + amicarbazone).
Mixtures of a compound of formula I with an ALS inhibitor (e.g. compound of
formula I + chlorsulfuron, compound of formula I + cinosulfuron, compound of formula
I + cloransulam, compound of formula I + ethametsulfuron, compound of formula I +
flazasulfuron, compound of formula I + foramsulruron, compound of formula I +
flumetsulam, compound of formula I + imazamethabenz, compound of formula I +
imazamox, compound of formula I + imazapic, compound of formula I + imazapyr,
compound of formula I + imazethapyr, compound of formula I + iodosulfuron,
compound of formula I + metsulfuron, compound of formula I + nicosulfuron, compound
of formula I + oxasulfuron, compound of formula I + primisulfuron, compound of
formula I + prosulfuron, compound of formula I + pyrithiobac, compound of formula I +
rimsulfuron, compound of formula I + sulfosulfuron, compound of formula I +
thifensulfuron, compound of formula I + triasulfuron, compound of formula I +
tribenuron, compound of formula I + trifloxysulfuron, compound of formula I + 4-[(4,5-
dihydro-3-methoxy-4-methyl-5-oxo)-lH-l,2,4-triazol-l-ylcarbpnylsulfamoyl]-5-
methylthiophene-3-carboxylic acid (BAY636)). Particularly preferred are mixtures of a
compound of formula I with flazasulfuron, foramsulruron, flumetsulam, imazapyr,
imazethapyr, iodosulfuron, nicosulfuron, rimsulfuron, trifloxysulfuron or with 4-[(4,5-
dihydro-3-methoxy-4-methyl-5-oxo)- 1H-1,2,4-triazol-l -ylcarbonylsulfamoyl]-5-
methylthiophene-3-carboxylic acid (BAY636) (i.e. compound of formula I + .
flazasulfuron, compound of formula I + foramsulruron, compound of formula I +
flumetsulam, compound of formula I + imazapyr, compound of formula I + imazethapyr,
compound of formula I + iodosulfuron, compound of formula I + nicosulfuron,
compound of formula I + rimsulfuron, compound of formula I + trifloxysulfuron, and
compound of formula I + 4-[(4,5-dihydro-3-methoxy-4-methyl-5-oxo)-lH-l,2,4-triazol-
1 -ylcarbonylsulfamoyl]-5-methylthiophene-3-carbo'xylic acid (BAY636)).
Mixtures of a compound of formula I with a PPO inhibitor (e.g. compound of
formula I + fomesafen, compound of formula I + fiumioxazin, compound of formula I +
sulfentrazone, compound of formula I + [3-[2-chloro-4-fluoro-5-(l-methyl-6-trifluoromethyl-
2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid
ethyl ester). Particularly preferred are mixtures of a compound of formula I with
flumioxazin, sulfentrazone or [3-[2-chloro-4-fluoro-5-(l-methyl-6-trifluoromethyl-2,4-
dioxo-l,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl ester
(i.e. compound of formula I + flumioxazin, compound of formula I + sulfentrazone, and
compound of formula I + [3-[2-chloro-4-fluoro-5-(l-methyl-6-trifluoromethyl-2,4-dioxol,
2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl ester).
Mixtures of a compound of formula I with glyphosate (i.e. compound of formula I
+ glyphosate).
Mixtures of a compound of formula I with glufosinate (i.e. compound of formula
I + glufosinate).
Mixtures of a compound of formula I with paraquat (i.e. compound of formula I +
paraquat).
Mixtures of a compound of formula I with pendimethalin or trifluralin (i.e.
compound of formula I + pendimethalin, compound of formula I + trifluralin).
Particularly preferred are mixtures of a compound of formula I with pendimethalin (i.e.
compound of formula I + pendimethalin).
Mixtures of a compound of formula I with metamitron (i.e. compound of formula
I + metamitron).
Mixtures of a compound of formula I with clomazone (i.e. compound of formula I
+ clomazone).
Mixtures of a compound of formula I with metazachlor (i.e. compound of formula
I + metazachlor).
Mixtures of a compound of formula I with clodinafop or with pinoxaden (i.e.
compound of formula I + clodinafop, and compound of formula I + pinoxaden).
The compounds of formula I according to the invention can also be used in
combination with safeners. Likewise, mixtures of a compound of formula I according to
the invention with one or more further herbicides can also be used in combination with
one or more safeners. The safeners can be cloquintocet-mexyl (CAS RN 99607-70-2) or
a lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium,
quaternary ammonium, sulfonium or phosphonium salt thereof such as those disclosed in
WO 02/34048, fenchlorazol-ethyl (CAS RN 103112-35-2) and the corresponding acid
(CAS RN 103112-36-3), mefenpyr-diethyl (CAS RN 135590-91-9) and the
corresponding di-acid (CAS RN 135591-00-3), isoxadifen-ethyl (CAS RN 163520-33-0)
and the corresponding acid (CAS RN 209866-92-2), furilazole (CAS RN 121776-33-8)
and the corresponding R isomer (CAS RN 121776-57-6), benoxacor (CAS RN 98730-
04-2), dichlormid (CAS RN 37764-25-3), MON4660 (CAS RN 71526-07-3), oxabetrinil
(CAS RN 74782-23-3), cyometrinil (CAS RN 78370-21-5) and the corresponding (Z)
isomer (CAS RN 63278-33-1), fenclorim (CAS RN 3740-92-9), N-cyclopropyl-4-(2-
methoxy-benzoylsulfamoyl)-benzamide(CAS RN 221667-31-8), N-isopropyl-4-(2-
methoxy-benzoylsulfamoyl)-benzamide (CAS RN 221668-34-4), naphthalic anhydride
(CAS RN 81-84-5) and flurazole (CAS RN 72850-64-7).
Preferably the mixing ratio of compound of formula I to safener is from 100:1 to
1:10, especially from 20:1 to 1:1.
The mixtures can advantageously be used in the above-mentioned formulations
(in which case "active ingredient" relates to the respective mixture of compound of
formula I with the safener).
Preferred mixtures of a compound of formula I with further herbicides and
safeners include:
Mixtures of a compound of formula I with a triazine and a safener.
Mixtures of a compound of formula I with glyphosate and a safener.
Mixtures of a compound of formula I with glufosinate and a safener.
Mixtures of a compound of formula I with isoxaflutole and a safener.
Mixtures of a compound of formula I with isoxaflutole and a triazine and a
safener.
Mixtures of a compound of formula I with isoxaflutole and glyphosate and a
safener.
Mixtures of a compound of formula I with isoxaflutole and glufosinate and a
safener.
Mixtures of a compound of formula I with mesotrione and a safener.
Mixtures of a compound of formula I with mesotrione and a triazine and a
safener.
Mixtures of a compound of formula I with mesotrione and glyphosate and a
safener.
Mixtures of a compound of formula I with mesotrione and glufosinate and a
safener.
Mixtures of a compound of formula I with sulcotrione and a safener.
Mixtures of a compound of formula I with sulcotrione and a triazine and a
safener.
Mixtures of a compound of formula I with sulcotrione and glyphosate and a
safener.
Mixtures of a compound of formula I with sulcotrione and glufosinate and a
safener.
The following Examples further illustrate, but do not limit, the invention.
Preparation Examples:
Example PI: Preparation of 3-[l-(2.6-difluoro-phenyl)-2-(4-fluoro-phenvl)-
ethanesulfonvl]-5.5 -dirnethyl.-4,5-dihydroispxazole
P2-Et
Phosphazene base 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-
lambda5-5-catenadi(phosphazene) (Pa-Et) (0.61 ml, 1.6 mmol) was added dropwise to a
solution of 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole
(0.3 g, 1.04 mmol) in THF (2 ml) at room temperature. After 10 minutes 4-fluorobenzyl
bromide (0.16 ml, 1.3 mmol) was added dropwise at room temperature and the mixture
was stirred for 1 hour. The reaction was quenched by addition of aqueous hydrochloric
acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated.
The organic phase was washed several times with brine, dried over magnesium sulfate
and concentrated. The crude product was purified by chromatography on silica gel
(eluent: ethyl acetate / hexane) to give the product (Compound No. 1.05 of Table 27) as a
white solid (405 mg, 98% yield).
The same method was used with l-bromo-prop-2-yn-3-yl and 2-bromoethyl
methyl ether, as the starting material to give Compound No. 1.02 of Table 27 and
Compound No. 1.03 of Table 27, respectively.
Example P2: Preparation of 3-[(2.6-difluoro-phenylViodo-methanesulfonyl]-S,5-
dimethvl-4.5-dihydroisoxazole
•^ / MIS,
n-BuLi,
DMPU
l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidone (DMPU) (0.10ml,
0.83 mmol) and 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole
(0.20 g, 0.69 mmol) were dissolved under nitrogen in THF (7 ml) and cooled to
-78°C. n-Butyl lithium (2.5M in hexane) (0.33 ml, 0.83 mmol) was added dropwise.
After 30 min at -78°C, N-iodosuccinimide (MS) (187 mg, 0.83 mmol) was added. The
mixture was stirred for 1 hour and allowed to warm slowly to room temperature. The
reaction was quenched by addition of aqueous ammonium chloride solution. Extraction
was carried out several times with ethyl acetate. The combined organic phases were dried
over magnesium sulfate and concentrated. The crude product was purified by
chromatography on silica gel (eluent: ethyl acetate / hexane) and recrystallised from
isopropyl alcohol to give the product (Compound No. 1.25 of Table 27) as a white solid
(HOmg, 38% yield).
Example P3: Preparation of 3-[chloro-(2.6-difluoro-phenyl)-methanesulfonvl]-5.5-
dimethyl-4.5-dihvdroisoxazole
F
mCPBA
F
N-Chlorosuccinimide (NCS) (0.39 g, 2.93 mmol) was added to a solution of 3-
(2,6-difluoro-phenylmethanesulfanyl)-5,5-dimethyl-4,5-dihydroisoxazole(0.5g,
1.95 mmol) in dichloromethane (25 ml) at 45°C and the mixture was stirred for 2.5 hours
at 45°C. The solution was cooled to 0°C and 3-chloroperoxybenzoic acid (mCPBA) (50-
60% weight content) (1.68 g, 4.90 mmol) was added in portions. After stirring for 30
minutes at 0°C and for 12 hours at room temperature, the reaction was quenched by
addition of saturated aqueous sodium metabisulfite solution. The organic phase was
washed several times with aqueous sodium hydroxide solution (2M), dried over
magnesium sulfate and concentrated. Chromatographic purification on silica gel (eluent:
ethyl acetate / hexane) gave the product (Compound No. 1.07 of Table 27) (158 mg) and
a 1:2 mixture of 3-[chloro-(2,6-difluoro-phenyl)-methanesulfonyl]-5,5-dimethyl-4,5-
dihydroisoxazoleand3-[chloro-(2,6-difluoro-phenyl)-methanesulfinyl]-5,5-dimethyl-4,5-
dihydroisoxazole (364 mg). The mixture was oxidised again with mCPBA (1.0 g,
0.28 mmol) as described above. Aqueous workup and chromatographic purification on
silica gel (eluent: ethyl acetate / hexane) gave more product (Compound No. 1..07 of
Table 27) as a white solid (210 mg, i.e. in total 368 mg, 58% yield).
Example P4: Preparation of 4-(2.6-difluoro-phenvl)-4-(5.5-dimethvl-4.5-dihydroisoxazole-
3-sulfonvl)-butvric acid ethyl ester
(Figure Removed)
One drop of phosphazene base l-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-
lambda5-5,4 lambdas-5-catenadi(phosphazene) (?2-Et) (catalytic amount, 0.1 mmol) was
added to 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole
(300 mg, 1.04 mmol) in THF (8 ml) at -78°C. After 10 minutes ethyl acrylate (130 mg,
1.3 mmol) was added. The mixture was stirred for 3.5 hours at -78°C and quenched by
addition of aqueous hydrochloric acid (2M). Extraction was carried out several times
with ethyl acetate and the organic phases were washed with brine, dried over magnesium
sulfate and concentrated. The crude product was purified by chromatography on silica gel
(eluent: ethyl acetate / hexane) which gave the product (Compound No. 1.08 of Table 27)
as a colourless oil (375 mg, 93% yield).
The same method was used with ethyl vinyl ketone, diethyl vinyl phosphonate,
N,N-dimethylacrylamide and methyl vinyl sulfone as the starting material to give
Compound No. 1.09 of Table 27, Compound No. 1.10 of Table 27, Compound No. 1.11
of Table 27 and Compound No. 1.12 of Table 27, respectively.
Example P5: Preparation of N-cvclopropvl-2-(2.6-difluoro-phenyl)-2-(5.5-dimethyl-4.5-
dihvdroisoxazole-3-sulfonvlVacetamide
1.P2-Et
2. phosgene
3. cyclopropylamine
Phosphazene base 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-
lambda5-5-catenadi(phosphazene) (P2-Et) (0.68 ml, 1.37 mmol) was added at 0°C to a
solution of 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole
(180 mg, 0.62 mmol) in THF (5 ml). Phosgene (20% by weight in toluene) (0.33 ml,
0.62 mmol) and cyclopropylamine (0.043 ml, 0.69 mmol) were added. The solution was
allowed to warm slowly to room temperature and after stirring at room temperature for
2 hours was quenched by addition of aqueous hydrochloric acid (2M). The mixture was
extracted with ethyl acetate, dried over magnesium sulfate and concentrated. Purification
of the crude product was effected by chromatography on silica gel (eluent: ethyl acetate /
hexane) which gave the product (Compound No. 1.3 5 of Table 27) as a white solid (460
mg, 20% yield).
The same method was used with diethylamine and 2,2-difluoroethylamine as the
reagent to give Compound No. 1.36 of Table 27 and Compound No. 1.56 of Table 27,
respectively.
Example P6: Preparation of 3-[l-(2.6-difluoro-phenvlVcvclopropanesulfonvl1-5.5-
dimethvl-4.5-dihvdroisoxazole
(Figure Removed)
Trimethylsulfoxonium iodide (0.28 g, 1.25 mmol) was added to a suspension of
sodium hydride (60% by weight in paraffin oil) (0.052 g, 1.3 mmol) in DMSO (4 ml).
The mixture was stirred for 30 minutes at room temperature. A solution of 3-[l-(2,6-
difluoro-phenyl)-ethenesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (prepared according
to Example P12) (80% purity) (0.3 g, 0.8 mmol) in DMSO (2 ml) was added dropwise.
The mixture was stirred at room temperature for 1 hour, The reaction was quenched by
addition of saturated aqueous ammonium chloride solution and the mixture was extracted
several times with diethyl ether. The combined organic phases were dried over
magnesium sulfate and concentrated. Purification by chromatography on silica gel
(eluent: ethyl acetate / hexane) gave the product (Compound No.l .01 in Table 27) (70
mg, 28% yield).
Example P7: Preparation of 3-Il-chloro-l-(2.6-difluoro-phenvlV4.4-difluoro-but-3-enel-
sulfonyl]-5.5-dimethyl-4.5-dihydroisoxazole
R
Br P2-'Bu
Phosphazene base 1 -tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-larnbda5-5,4-
lambda5-5-catenadi(phosphazene) (P2-'Bu) (2M in THF) (0.34 ml, 0.68 mmol) was added
dropwise to a solution of 3-[chloro-(2,6-difluoro-phenyl)methanesulfonyl]-5,5-dimethyI-
4,5-dihydroisoxazole (prepared according to Example P3) (0.1 g, 0.31 mmol) in THF
(5 ml). The solution was stirred for 10 minutes at room temperature. l,3-Dibromo-l.,ldifluoropropane
(0.09 ml, 0.37 mmol) was added dropwise and the mixture was stirred
for 2 hours. The reaction was quenched by addition of aqueous hydrochloric acid (2M).
The mixture was diluted with ethyl acetate and the two phases were separated. The
organic phase was washed several times with saturated aqueous sodium chloride
solution, dried over magnesium sulfate and concentrated. The crude product was purified
by chromatography on silica gel (eluent: ethyl acetate / hexane) to give the product
(Compound No. 1.17 of Table 27) as a white solid (58 mg, 47% yield).
The same method was used with 3-(2,6-difluoro-phenylmethanesulfonyl)-555-
dimethyl-4,5-dihydroisoxazole as the starting material to give Compound No. 1.04 of
Table 27.
Example P8: Preparation of 3-[chlQro-m-tolyl-methanesulfonyl]-5.5-dimethyl-4.5-
dihvdroisoxazoleand3-[dichloro-m-tolvl-methanesulfonyl]-5.5-dimethvl-4.5-dihydroisoxazole
(Figure Removed)
Phosphazene base 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-
lambda5-5-catenadi(phosphazene) (Pz-Et) (0.34 ml, 0.68 mmol) was added dropwise at
0°C to a solution of 3-(3-memyl-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole
(0.2 g, 0.79 mmol) in THF (4 ml). The solution was stirred for 10 minutes at
room temperature. N-chlorosuccinimide (NCS) (0.13 g, 0.95 mmol) was added and the
mixture was stirred for 2 hours at room temperature. The reaction was quenched by
addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate
and the two phases were separated. The organic phase was washed several times with
brine, dried over magnesium sulfate and concentrated. The crude product was purified by
chromatography on silica gel (eluent: ethyl acetate / hexane) which gave the mono-chloro
product (Compound No. 1.30 of Table 27) as a white solid (76 mg, 32% yield) and the
di-chloro product (Compound No. 1.31 of Table 27) as a white solid (53 mg, 20% yield).
Example P9: Preparation of 3-rdichloro-(2.6-difluoro-phenvlVmethanesulfonvl1-5.5-
dimethyl-4.5-dihvdroisoxa2ole
F Cl NCS,
Pjr'Bu
Phosphazene base 1 -ter^butyl-2,2,4,4,4-pentakis(dimethylamino)-2 lambda5-5,4-
lambda5-5-catenadi(phosphazene) (P2-lBu) (2M in THF) (0.38 ml, 0.77 mmol) was added
dropwise at 0°C to a solution of 3-[chloro-(2,6-difiuoro-phenyl)methanesuIfonyl]-5,5-
dimethyl-4,5-dihydroisoxazole (prepared according to Example P3) (0.2 g, 0.64 mmol) in
THF (5 ml). The solution was stirred for 10 minutes at room temperature. Nchlorosuccinimide
(NCS) (0.10 g, 0.77 mmol) was added and the mixture was stirred for
1 hour at room temperature. The reaction was quenched by addition of aqueous
hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases
were separated. The organic phase was washed several times with brine, dried over
magnesium sulfate and concentrated. The crude product was recrystallised from ethanol
to give the product (Compound No. 1.26 of Table 27) as a white solid (110 mg, 48%
yield).
Example P10: Preparation of 3-[2,2-dichloro-l-(2.6-difluQro-phenyl)-cycIopropanesulfonvl1-
5.S-dimethvl-4.5-dihvdroisoxazole
CHCI3, NaOH,
cat. Et3PhCH2N+C|-
3-[l-(2,6-Difluoro-phenyl)-ethenesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole
(prepared according to Example PI 2) (purity 80%) (0.2 g, 0.53 mmol) and a catalytic
amount of triethylbenzylammonium chloride were dissolved in chloroform (1 ml). A
solution of sodium hydroxide (0.64 g, 16 mmol) in water (1 ml) was added dropwise.
After stirring for 1 .5 hours at room temperature the mixture was diluted with water and
extracted several times with chloroform. The combined organic phases were washed with
water, dried over magnesium sulfate and concentrated. The crude product was purified
by chromatography on silica gel (eluent: ethyl acetate / hexane) to give the product
(Compound No. 1 .45 of Table 27) as a light brown gum that slowly solidified (74 mg,
36% yield).
Example II: Preparation of l-methyl-5-(oxetan-3-yloxv)-3-trifluoromethyl-lH-pyrazole-
4-carbaldehyde
(Figure Removed)
Oxetane-3-ol (6.12 g, 82.7 mmol) was added dropwise to potassium tert-butoxide
(1M in THF) (69.6 ml, 69.6 mmol) at room temperature. 5-Chloro-l-methyl-3-
trifluoromethyl-lH-pyrazole-4-carbaldehyde (9.86 g, 46.4 mmol) was dissolved in THF
(40 ml) and added slowly to the solution. After 25 minutes the mixture was concentrated
and the residue partitioned between ethyl acetate and water. The two phases were
separated and the aqueous phase was extracted several times with ethyl acetate. The
combined organic phases were washed with brine,, dried over magnesium sulfate and
concentrated to yield the product as brown oil (11.6 g) which was used in the next step
without further purification.
Example 12: Preparation of [l-methyl-5-(oxetan-3-yloxyV3-trifluoromethvl-lH-pvrazol-
4-yl]-methanol
(Figure Removed)
l-Methyl-5-(oxetan-3-yloxy)-3-trifluoromethyMH-pyrazole-4-carbaldehyde
(11.6 g, 46.4 mmol) was dissolved in methanol (100 ml) and sodium borohydride (0.87
g, 23.0 mmol) was added in portions at 0°C. After stirring at 0°C for 2 hours the mixture
was concentrated and the oil was dissolved in dichloromethane (100 ml). The solution
was washed with water and brine, dried over magnesium sulfate and concentrated to give
the product as yellow solid (8.14 g) which was used in the next step without further
purification.
Example 13: Preparation of 4-bromomethyl-l-methyl-5-(oxetan-3-yloxy)-3-
trifluoromethyl- 1 H-pvrazole
(Figure Removed)
[l-Methyl-5-(oxetan-3-yloxy)-3-trifluoromethyl-lH-pyrazol-4-yl]-methanol (8.14
g, 32.3 mmol) was dissolved in dichloromethane (100 ml) and triphenyl phosphine (8.96
g, 34.2 mmol) and carbon tetrabromide (10.31 g, 31.05 mmol) were added. The solution
was stirred for 2 hours and concentrated to give an orange oil. Purification by
chromatography on silica gel (eluent: ethyl acetate / hexane) yielded the product as an
orange oil (10.1 g) which was used in the next step without further purification.
Example 14: Preparation of 5.5-dimethyl-3-[l -methvl-5-foxetan-3-yloxyV3-trifluoromethvl-
lH-pvrazol-4-vlmethvlsulfanvl1-4.5-dihvdroisoxazole
(Figure Removed)
4-Bromomethyl-1 -methyl-5-(oxetan-3 -yloxy)-3 -trifluoromethyl-1 H-pyrazole
(10.1 g, 32.2 mmol) and thiourea (2.7 g, 35.5 mmol) were stirred in ethanol (100 ml) at
5,5-Dimethyl-3-[l-methyl-5-(oxetan-3-yloxy)-3-trifluoromethyl-lH-pyrazol-4-
ylmethanesulfonyl]-4,5-dihydroisoxazole (390 mg, 1 mmol) was stirred in dry THF (8
ml) under nitrogen and sodium hexamethyldisilazide (NaHMDS) (1M in THF) (0.9 ml,
0.9 mmol) was added dropwise at -78°C. After 15 minutes N-fluorobenzenesulfonimide
(NFSI) (310 mg, 1 rnmol) was added. After 15 minutes more sodium hexamethyldisilazide
(NaHMDS) (1M in THF) (0.9 ml, 0.9 mmol) was added dropwise at -78°C,
followed by more N-fluorobenzenesulfonimide (NFSI) (310 mg, 1 mmol). After stirring
at -78°C for 1 hour the reaction was quenched by addition of saturated aqueous
ammonium chloride (0.5 ml) and the mixture was allowed to warm to room temperature.
Water (2 ml) and dichloromethane (2 ml) were added, the two phases were separated and
the aqueous phase was extracted three times with dichloromethane. The combined
organic phases were washed with brine, dried over magnesium sulfate and concentrated.
The crude product was purified by chromatography on silica gel (eluent: ethyl acetate /
hexane) to give the mono-fluoro product (Compound No. 2.27 of Table 28) as a white
solid (203 mg, 50% yield) and the di-fluoro product (Compound No. 2.28 of Table 28) as
a colourless oil (28 mg, 7% yield).
Example P12: Preparation of 3-[l-(2.6-difluoro-phenyl)-2-methoxy-ethanesulfonyl]-5.5-
dimethvl-4.5-dihvdroisoxazole
(Figure Removed)
3-(2,6-Difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole(1.0
g, 3.46 mmol) and NjNjN'jN'-tetramethyldiaminomethane (1 ml, 7.34 mmol) were
dissolved in DMF (7 ml) at room temperature and acetic anhydride (0.7 ml, 3.8 mmol)
was added at 60°C. After stirring for 3 hours at 80°C acetic anhydride (0.7 ml, 3.8 mmol)
in DMF (2 ml) was added via syringe pump over 2.5 hours. After stirring for 3 hours at
60°C the mixture was allowed to cool and was stirred for 10 hours at room temperature.
The mixture was diluted with ethyl acetate (30 ml), washed with water (3x 10 ml), dried
over magnesium sulfate and concentrated. The crude product (1.02 g, 88% yield) was
used without further purification. 3-[l-(2,6-Difiuoro-phenyl)-ethenesulfonyl]-5)5-
dimethyl-4,5-dihydroisoxazole (100 mg, 0.3 mmol) was dissolved in methanol (4 ml)
under nitrogen and sodium methoxide (0.5M in methanol) (0.7 ml, 0.35 mmol) was
added. After 1 hour the mixture was concentrated and the residue was purified by
chromatography (eluent: ethyl acetate / hexane) to give the product (Compound No. 1.51
of Table 27) (48 mg, 48% yield).
The same method was used with pyrazole, imidazole, indazole, 4,5-dihydropyrazole
and 1,2,4-triazole under neutral conditions (i.e. replacing the sodium methoxide
as the starting material) to give Compound No. 1.86 of Table 27, Compound No. 1.87 of
Table 27, Compound No. 1.88 of Table 27, Compound No. 1.89 of Table 27 and
Compound No. 1.90 of Table 27, respectively.
Example PI3: Preparation of 3-[chloro-(2.6-difluoro-phenyl)-fluoro-methanesulfonyl]-
5.5-dimethvl-4,5-dihydroisoxazole
(Figure Removed)
Phosphazene base 1 -te^butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambdas-5,4-
lambda5-5-catenadi(phosphazene) (P2-lBu) (2M in THF) (0.38 ml, 0.77 mmol) was added
dropwise to a solution of 3-[chloro-(2,6-difluoro-phenyl)-methanesulfonyl]-5,5-dimethyl-
4,5-dihydroisoxazole (0.2 g, 0.64 mmol) in THF (2 ml), and the solution was stirred for
10 minutes at room temperature. N-Fluorobenzenesulfonimide (NFSI) (0.15 g, 0.77
mmol) was added and the mixture was stirred for 1 hour. The reaction was quenched by
addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate
and the two phases were separated. The organic phase was washed several times with
brine, dried over magnesium sulfate and concentrated. The crude product was purified by
chromatography on silica gel (eluent: ethyl acetate / hexane) to give the product
(Compound No. 1.21 of Table 27) as a white solid (44 mg, 98% yield).
Example P14: Preparation of 3-[fluoro-(2-trifluoromethoxy-phenylVmethanesulfonvl]-
5.5-dimethvl-4t5-dihvdroisoxazole
NFSI
5,5-Dimethyl-3-(2-trifluoromethoxy-phenylmethanesulfonyl)-4,5-dihydroisoxazole
(0.2 g, 0.59 mmol) was dissolved in acetonitrile (5 ml) and 2,8,9-triisobutyl-
2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane (Verkade's base) (0.44 ml, 1.24
mmol) was added dropwise at room temperature. After 5 minutes N-fluorobenzenesulfonimide
(NFSI) (393 mg, 1.24 mmol) was added in one portion. After 10 minutes the
reaction was quenched by addition of water (10 ml). The mixture was acidified by
addition of aqueous hydrochloric acid (2M) and extracted several times with ethyl acetate
(3x 10 ml). The combined organic phases were washed with saturated aqueous sodium
hydrogencarbonate solution and with water, dried over magnesium sulfate and
concentrated. The crude product was purified by chromatography on silica gel (eluent:
ethyl acetate / hexane) to give the product (Compound No.l .68 of Table 27) as colourless
oil (145 mg, 69% yield).
Example P15: Preparation of 3-[difluorp-(5-methoxy-l-methyl-3-trifluoromethyl-lHpwazol-
4-vlVmethanesulfonvl1-5.5-dimethyl-4.5-dihydroisoxazole
(Figure Removed)
3-(5-Methoxy-l-methyl-3-trifluoromethyl-lH-pyrazol-4-ylmethanesulfonyl)-5,5-
dimethyl-4,5-dihydroisoxazole (0.209 mg, 0.59 mmol) was dissolved in dry THF (4 ml)
under nitrogen and sodium hexamethyldisilazide (1M in THF) (1.07 ml, 1.07 mmol) was
added dropwise at -78°C. After 10 minutes N-fluorobenzenesulfonimide (NFSI) (0.185
mg, 0.59 mmol) was added. After 15 minutes more sodium hexamethyldisilazide (1M in
THF) (1.07 ml, 1.07 mmol) was added, followed by more N-fluorobenzenesulfonimide
(NFSI) (0.185 mg, 0.59 mmol). After stirring for 1 hour at -78°C the reaction was
quenched by addition of saturated aqueous ammonium chloride solution (0.5 ml) and the
mixture was allowed to warm to room temperature. Water (2 ml) and dichloromethane (2
ml) were added, the two phases were separated and the aqueous phase was extracted
three times with dichloromethane. The combined organic extracts were washed with
aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and
concentrated. The mixture was purified by chromatography on silica gel (eluent: ethyl
acetate / hexane) and reverse phase HPLC (eluent: water / acetonitrile) to give the
product (Compound No. 2.23 of Table 28) as a colourless oil (55 mg, 24% yield).
Example 16: Preparation of 3-cvclopropyl-S-methyl-isoxazole and 5-cyclopropyl-3-
methvl-isoxazole
0-N
l-Cyclopropyl-butane-l,3-dione (prepared according to DE 4404059, EP 569760)
(3.5 g, 25.4 mmol), hydroxylamine hydrochloride (2.12 g, 30.5 mmol) and ethanol (1 ml)
were mixed and the mixture heated in a sealed vessel in the microwave at 130°C twice
for 3 minutes. The mixture was diluted with water (50 ml) and extracted with diethyl
ether (3x 25 ml). The combined organic phases were dried over magnesium sulfate and
concentrated. The brown oil was filtered through a plug of silica gel. The silica gel was
washed with diethyl ether and the filtrate was concentrated. The mixture of crude
products (5.6 g) was used without further purification.
Example 17: Preparation of 4-bromo-3-cyclopropyl-5-methyl-isoxazole and 4-bromo-5-
cvclopropvl-3 -methyl-isoxazole
(Figure Removed)
A mixture of 3-cyclopropyl-5-methyl-isoxazole and 5-cyclopropyl-3-methylisoxazole
(5.6 g) was dissolved in DMF (20 ml) and N-bromosuccinimide (NBS) (8.66 g,
48.6 mmol) was added. The mixture was stirred at room temperature for 18 hours, diluted
with water (50 ml) and extracted with diethyl ether (3x 30 ml). The combined organic
phases were dried over magnesium sulfate and concentrated. The crude mixture was
purified by chromatography on silica gel (eluent: ethyl acetate / hexane) to give the
mixture of products as an orange oil (3.0 g) which was used without further purification.
Example 18: Preparation of 3-cyclopropyl-4-formyl-5-methyl-isoxazole and 5-
cvclopropvl-4-formvl-3-methyl-isoxazole
(Figure Removed)
A mixture of 4-bromo-3-cyclopropyl-5-methyl-isoxazole and 4-bromo-5-cyclopropyl-
3-methyl-isoxazole (3.0 g) was dissolved in diethyl ether (70 ml) under nitrogen.
rc-Butyl lithium (1.6M inhexane) (12.5 ml, 20 mmol) was added dropwise at -78°C,
followed by the addition of DMF (1.39 ml, 18 mmol) at -78°C. The mixture was stirred at
-78°C for two hours and was allowed to warm to room temperature. The reaction was
quenched by addition of water (20 ml), the two phases were separated and the aqueous
phase was extracted with diethyl ether (3x 50 ml). The combined organic phases were
dried over magnesium sulfate and concentrated. The crude mixture was purified by
chromatography on silica gel (eluent: ethyl acetate / hexane) to give the mixture of
products as an orange oil (2.4 g) which was used without further purification.
Example 19: Preparation of 3-cyclopropyl-4-hydroxymethyl-5-methyl-isoxazole and 5-
cyclopropyl-4-hydroxymethyl-3-methyl-isoxa2ole
(Figure Removed)
A mixture of 3-cyclopropyl-4-formyl-5-methyl-isoxazole and 5-cyclopropyl-4-
formyl-3-methyl-isoxazole (2.4 g) was dissolved in methanol (20 ml) and sodium
borohydride (312 mg, 8.2 mmol) was added in portions at 0°C. The mixture was allowed
to warm to room temperature and was stirred at room temperature for two hours. The
reaction was quenched by addition of water (20 ml) and the mixture was extracted with
ethyl acetate (3x 30 ml). The combined organic phases were dried over magnesium
sulfate and concentrated to give the mixture of products as a colourless oil (1.95 g, 51%
yield over 4 steps).
Example IIP: Preparation of 4-bromomethvl-3-cyclopropyl-5-methyl-isoxazole and 4-
bromomethyl-5-cyclopropyl-3-methyl-isoxazole
(Figure Removed)
A mixture of 3-cyclopropyl-4-hydroxymethyl-5-methyl-isoxazole and 5-cyclopropyl-
4-hydroxymethyl-3-methyl-isoxazole (1.95 g, 12.7 mmol) was dissolved in
dichloromethane (20 ml) and triphenyl phosphine (4.47 g, 17 mmol) and carbon tetrabromide
(4.89 g, 15 mmol) were added at 0°C. The mixture was stirred at 0°C for 2 hours
and was concentrated. The crude product was purified by chromatography on silica gel
(eluent: ethyl acetate / hexane) to yield the mixture of products (706 mg, 26% yield).
Example 111: Preparation of 3-cyclopropyl-4-(5.5-dimethyl-4.5-dihydroisoxazol-3-vlsulfanvlmethyl)-
5-methyl-isoxazoleand5-cyclopropvl-4-(5,5-dimethvl-4.5-dihydroisoxazol-
3-ylsulfanvlmethvlV3-niethyl-isoxazole
(Figure Removed)
A mixture of 4-bromomethyl-3-cyclopropyl-5-methyl-isoxazole and 4-bromomethyl-
5-cyclopropyl-3-methyl-isoxazole (706 mg, 3.3 mmol) were dissolved in ethanol
(20 ml) and thiourea (275 mg, 3.6 mmol) was added in portions. After stirring for 1 hour
at room temperature 3-methylsulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (586 mg, 3.3
mmol) and potassium carbonate (454 mg, 3.3 mmol) were added and the mixture heated
under reflux for 2 hours. The mixture was filtered, the crude product absorbed onto silica
gel and purified by chromatography on silica gel (eluent: ethyl acetate / hexane) to give
the mixture of products (930 mg, 100% yield).
Example 112: Preparation of 3-cyclopropyl-4-(5.5-dimethyl-4.5-dihydroisoxazol-3-
ylsulfonylmethyl)-5-methvl-isoxazoleand5-cyclopropyl-4-(5.5-dimethyl-4.5-dihydroisoxa2ol-
3-vlsulfbnvlmethvl)-3-methvl-isoxazole
mCPBA
A mixture of 3-cyclopropyl-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfanylmethyl)-
5-methyl-isoxazoleand5-cyclopropyl-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-
ylsulfanylmethyl)-3-methyl-isoxazole (930 mg, 3.5 mmol) was dissolved in dichloro-
methane (20 ml) and 3-chloroperoxybenzoic acid (mCPBA) (60% by weight) (2.21 g, 7.7
mmol) was added in portions. The solution was stored at room temperature for 10 hours
before it was quenched by addition of 10% aqueous sodium metabisulfite solution (10
ml). The suspension was diluted with aqueous sodium hydroxide solution (1M) and
extracted with dichloromethane (2x 100 ml). The combined organic phases were washed
with aqueous sodium hydroxide solution (1M), dried over magnesium sulfate and
concentrated. The crude products were purified and separated by preparative HPLC on
silica gel (eluent: hexane / dichloromethane) to give product A as a white solid (536 mg,
51% yield) and product B as a white solid (198 mg, 19% yield).
Example P16: Preparation of 4-[chloro-(5.5-dimethyl-4.5-dihydroisoxazol-3-ylsulfonylV
methvll-S-cyclopropyl-3-methyl-isoxazQle and 5-cyclopropyl-4-[dichloro-(5.5-dimethyl-
4.5-dihydroisoxazole-3-sulfonvl)methyl]-3-methyl-isoxazole
(Figure Removed)
5-Cyclopropyl-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfonylmethyl)-3-
methyl-isoxazole (420 mg, 1.4 mmol) was dissolved in THF (10 ml) under nitrogen. The
solution was cooled to -78°C and potassium tert-butoxide (2.2 ml, 2.2 mmol) added,
followed by hexachloroethane (491 mg, 2.2 mmol). The solution was allowed to warm to
room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x 30 ml).
The combined organic phases were dried over magnesium sulfate and concentrated. The
crude products were purified and separated by chromatography on silica gel (eluent:
ethyl acetate / hexane) to give the mono-chloro product (Compound No. 3.05 of Table
29) as a white solid (273 mg, 58% yield) and the di-chloro product (Compound No. 3.06
of Table 29) as a white solid (185 mg, 36% yield).
Example P17: Preparation of 4-rchloro-(5.5-dimethvl-4.5-dihydroisoxazole-3-sulfonyl)-
methvl1-3-cvclooropvl-5-methvl-isoxazole
(Figure Removed)
3 -Cyclopropyl-4-(5 ,5 -dimethyl-4, 5-dihydroisoxazol-3 -ylsulfonylmethyl)- 5-
methyl-isoxazole (108 mg, 0.36 mmol) was dissolved in THF (5 ml) under nitrogen. The
solution was cooled to -78°C and potassium tert-butoxide (0.4 ml, 0.4 mmol) added,
followed by hexachloroethane (90 mg, 0.4 mmol). The solution was allowed to warm to
room temperature, diluted with water (20 ml) and extracted with ethyl acetate (3x 15 ml).
The combined organic phases were dried over magnesium sulfate and concentrated. The
crude product was purified by chromatography on silica gel (eluent: ethyl acetate /
hexane) to give the product (Compound No. 3.07 of Table 29) as a white solid (53 mg,
44% yield).
Example 113: Preparation of 5-cyano-4-methoxvcarbonyl-3-methvl-isothiazole
(Figure Removed)
4,5-Dichloro-[l,2,3]-dithiazol-l-ylium chloride (prepared according to Chem.
Ber. (1985) 118, 1632) (8.34 g, 40 mmol) was dissolved in dichloromethane (30 ml) and
methyl-3-aminocrotonate (4.6 g, 40 mmol) was added dropwise at room temperature.
After stirring the solution for 1 hour at room temperature pyridine (6.47 ml, 80 mmol)
was added slowly. The mixture was concentrated and purified by chromatography on
silica gel (eluent: ethyl acetate / hexane) to give the product as an orange solid (1.14 g,
15.6% yield). JH-NMR (400 MHz, CDC13): 2.88 (3H, s, Me), 4.0 (3H, s, Me).
Example 114: Preparation of S-cvano-4-hydroxymethl-3-methyl-isothiazole
LiBH4
5-Cyano-4-methoxycarbonyl-3-methyl-isothiazole (1.14 g, 6.3 mmol) was
dissolved in diethyl ether (20 ml) and methanol (0.38 ml, 9.4 mmol). Lithium borohydride
(204 mg, 9.4 mmol) was added and the mixture was stirred at 40°C for 2 hours.
The reaction was quenched by addition of aqueous hydrochloric acid (1M) (20 ml). The
two phases were separated and the aqueous phase was extracted with diethyl ether (2x 20
ml). The combined organic phases were dried over magnesium sulfate and concentrated
to give a crude product (1 .2 g), which consisted of a 1 : 1 mixture of methyl ester and
product. The mixture was used without further purification.
ExampleI15: Preparation of 4-bromomethyl-5-cyano-3-methvl-isothiazole
CBr44, \ Br
5-Cyano-4-hydroxymethyl-3-methyl-isothiazole (50% purity) (1.14 g, 3.7 mmol)
was dissolved in dichloromethane (10 ml) and triphenyl phosphine (1.07 g, 4.0 mmol)
and carbon tetrabromide (1.18 g, 3.6 mmol) were added at 0°C. The mixture was stirred
at 0°C for 2 hours, concentrated and the crude product was purified by chromatography
on silica gel (eluent: ethyl acetate / hexane). The colourless oil (0.65 g) consisted of a 1:1
mixture of methyl ester (see Example 114) and product. The mixture was used without
further purification.
Example 116: Preparation of 4-(5,5-dimethyl-4.5-dihydroisoxazol-3-ylsulfanylmethyl)-3-
methyl-isothiazole-5-carbonitrile
"I. thiourea
(Figure Removed)
4-Bromomethyl-5-cyano-3-methyl-isothiazole (50% purity) (0.65 g, 1.5 mmol)
was dissolved in ethanol (30 ml) and thiourea (242 mg, 3.2 mmol) was added. The
mixture was stirred at room temperature until the solids were dissolved. 3-Methanesulfonyl-
5,5-dimethyl-4,5-dihydroisoxazole (540 mg, 3.2 mmol) and potassium
carbonate (440 mg, 3.2 mmol) were added and the mixture was heated under reflux for 1
hour. The solids were removed by filtration and the filtrate was concentrated. The crude
product was purified by chromatography on silica gel (eluent: ethyl acetate / hexane) to
give the product (0.25 g, 62% yield). ^-NMR (400 MHz, CDC13): 1.44 (6H, s, Me), 2.6
(3H, s, Me), 2.8 (2H, s, CH2), 4.4 (2H, s, CH2).
Example 117: Preparation of 4-(5.5-dimethyl-4.5-dihydroisoxazole-3-sulfonylmethylV3-
methvl-isothiazole-5-carbonitrile
mCPBA
4-(5,5-Dimethyl-4,5-dihydroisoxazol-3-ylsulfanylmethyl)-3-methyl-isothiazole-
5-carbonitrile (0.25 g, 1 mmol) was dissolved in dichloromethane (25 ml) and 3-chloro-
I l l -
room temperature until the solids were dissolved. 3-Methanesulfonyl-5,5-dimethyl-4,5-
dihydroisoxazole (6.28 g, 35.5 mmol) and potassium carbonate (4.91g, 35.5 mmol) were
added and the mixture was heated under reflux for 2 hours. The mixture was concentrated
and purified by chromatography (eluent: ethyl acetate / hexane) to give the product
as a white solid (4 g, 34 % yield over two steps).
Example 15: Preparation of 5.5-dimethvl-3-[l-methyl-5-(oxetan-3-vloxyV3-trifluoromethvl-
lH-vrazol-4-vlmethanesulfonyl]-4.5-dihydroisoxazole
mCPBA >• f O
5,5-Dimethyl-3 -[ 1 -methyl-5 -(oxetan-3-yloxy)-3 -trifiuoromethyl-1 H-pyrazol-4-
ylmethylsulfanyl]-4,5-dihydroisoxazole (2.71 g, 7.4 mmol) was dissolved in dichloromethane
(100 ml) and 3-chloroperbenzoic acid (mCPBA) (60% by weight) (5.33 g, 18.5
mmol) was added. The solution was stored at room temperature for 18 hours and was
quenched by addition of 40% aqueous sodium metabisulfite solution (20 ml). The
mixture was diluted with aqueous sodium hydroxide solution (2M), the two phases were
separated and the aqueous phase extracted with dichloromethane. The combined organic
phases were washed with aqueous sodium hydroxide solution (1M) and brine, dried over
magnesium sulfate and concentrated to yield a green oil. Purification by chromatography
on silica gel (eluent: ethyl acetate / hexane) gave the product as white solid (2 g, 67%
yield).
Example PI 1: Preparation of 3-(fluoro-ri-methyl-5-(oxetan-3-vloxv)-3-trifluoromethyllH-
pvrazol-4-vll-methanesulfonyl}-5.5-dimethyl-4.5-dihvdroisoxazoleand3-{difluoro-
[l-methyl-5-(oxetan-3-yloxyV3-trifluoromethyl-lH-pyrazol-4-yl]-methanesulfonvll-5.5-
dimethyl-4.5-dihvdroisoxazole
(Figure Removed)
peroxybenzoic acid (mCPBA) (60% by weight) (0.68 g, 2.4 mmol) was added in
portions. The solution was stored at room temperature for 1 6 hours before it was
quenched by addition of 10% aqueous sodium metabisulfite solution (20 ml). The
suspension was diluted with aqueous sodium hydroxide solution (1M) and extracted with
dichloromethane (2x 30 ml). The combined organic phases were washed with aqueous
sodium hydroxide solution (1M), dried over magnesium sulfate and concentrated. The
crude product was purified by chromatography on silica (eluent: ethyl acetate / hexane)
to give the product as a white solid (0.15 g, 50.1% yield).
Example P18: Preparation of 4-[(5.5-dimethyl-4.5-dihvdroisoxazole-3-sulfonvl)-fluoromethyl]-
3-methyl-isothiazole-5-carbonitrileand4-[f5.5-dimethyl-4.5-dihydroisoxazole-
3-sulfonvlVdifluoro-methvl]-3-methyl-isothiazole-5-carbonitrile
KO'Bu
CN
4-(5,5-Dimethyl-4,5-dihydroisoxazole-3-sulfonylmethyl)-3-methyl-isothiazole-5-
carbonitrile (0.15 g, 0.57 mmol) was dissolved in THF (10 ml) under nitrogen and
sodium hexamethyldisilazide (1M in THF) (1.3 ml, 1.29 mmol) was added slowly at
-78°C. After 5 minutes N-fluorobenzenesulfonimide (NFSI) (0.377 g, 1.2 mmol) was
added and the solution was allowed to warm to room temperature. The mixture was
concentrated and the crude product was purified by chromatography on silica (eluent:
ethyl acetate / hexane) to give the mono-fluoro product (Compound No. 3.01 of Table
29) as a white solid (49 mg, 25.6% yield) and the di-fluoro product (Compound No. 3.02
of Table 29) as a white solid (49 mg, 27.1% yield).
Example 118: Preparation of (3-methoxy-isoxazol-5-yn-methanol
3-Methoxy-isoxazole-5-carboxylic acid methyl ester (prepared according to Eur.
J. Org. Chem., 1998, 473) (1.0 g, 6.4 mmol) was dissolved in methanol (30 ml) and
sodium borohydride (300 mg, 8.0 mmol) was added in portions. The mixture was stirred
for 1 hour at room temperature, concentrated and the residue dissolved in dichloro-
122-
methane (30 ml). The solution was washed with water, dried over magnesium sulfate and
concentrated to give the product as a concentrated solution in dichloromethane. The
solution was used without further purification.
Example 119: Preparation of 5-bromomethyl-3-methoxv-isoxazole
OH CBr4 /—Br
(3-Methoxy-isoxazol-5-yI)-methanol (822 mg, 6.4 mmol) was dissolved in
dichloromethane (10 ml) and triphenyl phosphine (1.84 g, 7.0 mmol) and carbon tetrabromide
(2 g, 6.11 mmol) were added at 0°C. The mixture was stirred for 2 hours at 0°C
and concentrated. The crude product was purified by chromatography on silica gel
(eluent: ethyl acetate / hexane) to give the product as a colourless oil (1.22 g, 99% yield)
which was used in the next step without further purification.
Example 120: Preparation of S-(5.5-dimethyl-4.5-dihydroisoxazol-3-ylsulfanylmethyl)-3-
methoxy-isoxazole
Br 1. thiourea
2. K2CO3
N-0
5-Bromomethyl-3-methoxy-isoxazole (1.22 g, 6.35 mmol) was dissolved in
ethanol (30 ml) and thiourea (484 mg, 6.4 mmol) was added. The mixture was stirred at
room temperature until the solids were dissolved. 3-Methanesulfonyl-5,5-dimethyl-4,5-
dihydroisoxazole (1.08 g, 6.4 mmol) and potassium carbonate (880 mg, 6.4 mmol) were
added and the mixture was heated under reflux for 1 hour. The solids were removed by
filtration and the filtrate was concentrated. The crude product was purified by chromatography
on silica gel (eluent: ethyl acetate / hexane) to give the product as colourless oil
(0.69 g, 45% yield over 3 steps).
Example 121: Preparation of 5-(5.5-dimethyl-4.5-dihvdroisoxazole-3-sulfonylmethyl)-3-
methoxy-isoxazole
(Figure Removed)
5-(5,5-Dimethyl-4,5-dihydroisoxazol-3-ylsulfanylmethyl)-3-methoxy-isoxazole
(693 mg, 2.9 mmol) was dissolved in dichloromethane (10 ml) and 3-chloroperoxybenzoic
acid (mCPBA) (60% by weight) (1.81 g, 6.3 mmol) was added in portions. The
solution was stored at room temperature for 10 hours before it was quenched by addition
of 10% aqueous sodium metabisulfite solution (10 ml). The suspension was diluted with
aqueous sodium hydroxide solution (1M) and extracted with dichloromethane (2x 100
ml). The combined organic phases were washed with aqueous sodium hydroxide solution
(1M), dried over magnesium sulfate and concentrated. The crude product was purified by
chromatography on silica gel (eluent: ethyl acetate / hexane) to give the product as a
white solid (0.78 g, 99% yield).
Example P19: Preparation of 5-[(5,5-dimethyl-4.5-dihydroisoxazole-3-sulfonyl)-fluoromethyl]-
3-methoxy-isoxazole and S-[(5.5-dimethvl-4.5-dihydroisoxazole-3-sulfonyl)-
difluoro-methyl] -3 -methoxy-isoxazole
(Figure Removed)
5-(5,5-Dimethyl-4,5-dihydroisoxazole-3-sulfonylmethyl)-3-methoxy-isoxazole
(0.2 g, 0.73 mmol) was dissolved in THF (10 ml) under nitrogen and potassium tertbutoxide
(1M in THF) (1.13 ml, 1.13 mmol) was added slowly at -78°C. N-fluorobenzenesulfonimide
(NFSI) (0.356 g, 1.13 mmol) was added and the mixture was
allowed to warm to room temperature. The mixture was filtered and the filtrate was
concentrated. The residue was purified by chromatography on silica (eluent: ethyl acetate
/ hexane) to give the mono-fluoro product (Compound No. 5.03 of Table 31) as a white
solid (0.087 g, 40.8% yield) and the di-fluoro product (Compound No. 5.04 of table 31)
as a white solid (0.063 g, 27.7% yield).
Example P20: Preparation of 5-[chloro-(5.5-dimethyl-4.5-dihydroisoxazole-3-sulfonylV
methyl]-3-methoxv-isoxazole and 5-[dichloro-f 5.5 -dimethyl-4.5-dihydroisoxazole-3 -
sulfonvl)-methvl]-3-methoxy-isoxazole
(Figure Removed)
5-(5,5-Dimethyl-4,5-dihydroisoxazole-3-sulfonylmethyl)-3-methoxy-isoxazole
(0.269 g, 0.98 mmol) was dissolved in THF (10 ml) under nitrogen and potassium tertbutoxide
(1M in THF) (1.28 ml, 1.28 mmol) was added slowly at -78°C. N-Chlorosuccinimide
(NCS) (0.171 g, 1.28 mmol) was added and the mixture was allowed to
warm to room temperature. The mixture was concentrated and purified by chromatography
on silica (eluent: ethyl acetate / hexane) to give the mono-chloro product
(Compound No. 5.01 of Table 31) as a colourless oil (90 mg, 31.1% yield) and the dichloro
product (Compound No. 5.02 of Table 31) as a white solid (94 mg, 27.9% yield).
Example 122: Preparation of l-methyl-4-trifluoromethvl-lH-pyrazole-3-carboxvlic acid
ethyl ester and l-methyl-3-trifluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester
(Figure Removed)
5-Hydroxy-3-methyl-[l ,2,3]-oxadiazolium (3-methylsydnone) (prepared"
according to J. Heterocycl. Chem. (1996) 33, 719) (25.7 g, 256 mmol) was suspended in
xylene (120 g) and heated to 100°C. 4,4,4-Trifluoro-but-2-ynoic acid ethyl ester
(prepared according to Organic Syntheses (1992) 70, 246-255) (44.8 g, 270 mmol) was
slowly added dropwise. The mixture was stirred at 100°C for 4 hours and concentrated.
Ethyl acetate (10 ml) was added to the crude oil which caused the product to crystallise.
The crystalline product was washed with a 1 :1 mixture of ethyl acetate and hexane (50
ml), with hexane (50 ml) and dried to give product A as white crystals (20.9 g, 36.6%
yield). The mother liquor was concentrated and purified by chromatography over silica
gel (eluent: ethyl acetate / cyclohexane) which gave more product A (14.3 g, 25.1%
yield) and product B (1 0.0 g, 1 7.5% yield).
Examle 123: Prearation of l-methl-4-trifluQromethyMH-yrazole-3-carboxlic acid
(Figure Removed)

l-Methyl-4-trifluoromethyl-lH-pyrazole-3-carboxylic acid ethyl ester (20 g, 90
mmol) was dissolved in methanol (100 ml). Sodium hydroxide in methanol (1M) (95 ml,
95 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours,
stored at room temperature for 16 hours and concentrated. The residue was dissolved in
aqueous hydrochloric acid (2M) (55 ml) and isopropyl acetate (300 ml). The two phases
were separated and the aqueous phase was extracted with more isopropyl acetate (100
ml). The combined organic extracts were dried over magnesium sulfate and concentrated.
This gave the product as a white solid (17.5 g, 100% yield). M.p. 174-175°C.
Example 124: Preparation of 3-hydroxymethyl-l-memyl-4-trifluoromethvl-lH-pyrazole
F3C COOH F3C -OH
(Figure Removed)
Lithium aluminium hydride (1M in THF) (11 ml, 11 mmol) was added dropwise
to a solution of l-methyl-4-trifluoromethyl-lH-pyrazole-3-carboxylic acid (1.94 g, 10
mmol) in THF (20 ml) under nitrogen. More THF (20 ml) was added to facilitate the
stirring. After stirring for 5 hours at room temperature the reaction was quenched by
addition of water (0.5 ml), 15% aqueous sodium hydroxide (0.5 ml), and more water (0.5
ml). Ethyl acetate (50 ml) and magnesium sulfate (25 g) were added and the mixture
stored at room temperature for 18 hours. Kieselguhr (30 g) was added, the mixture
filtered and the solids washed with ethyl acetate. The combined filtrate and washings
were concentrated to give the product as a pale yellow oily solid (1.38 g, 77% yield). !HNMR
(400 MHz, CDC13): 2.3 (1H, bs, OH), 3.91 (3H, s, Me), 4.75 (2H, s, CH2), 7.62
(1H.S.CH).
Example 125: Preparation of 5.5-dimethyl-3-(l-methyl-4-trifluoromethyl-lH-pyrazol-3-
vlmethvlsulfanvl)-4.5-dihvdroisoxazole
(Figure Removed)
Concentrated hydrochloric acid (36% by weight) (3.0 ml, 36 mmol) was added to
a solution of 3-hydroxymethyl-l-methyl-4-trifluoromethyl-lH-pyrazole (1.34 g, 7.4
mmol) and thiourea (836 mg, 11 mmol) in 1,4-dioxane (5 ml) and water (2 ml). The
mixture was heated in a sealed vessel in the microwave at 130°C for 10 minutes, cooled
to room temperature and potassium carbonate (4.14 g, 30 mmol) dissolved in water (5
ml) was added. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (2.12 g, 12 mmol)
and 1,4-dioxane (5 ml) were added and the mixture was heated in a sealed vessel in the
microwave at 150°C for 30 minutes. More potassium carbonate (1.38 g, 10 mmol) was
added and the mixture was heated in a sealed vessel in the microwave at 150°C for 20
minutes. The mixture was cooled to room temperature, extracted with ethyl acetate (3x
50 ml), the extract dried over magnesium sulfate and concentrated. The residue was
purified using preparative HPLC on silica gel (eluent: dichloromethane / ethyl acetate) to
give the product as a white solid (220 mg, 10% yield). 'H-NMR (400 MHz, CDClj): 1.42
(6H, s, Me), 2.84 (2H, s, CH2), 3.89 (3H, s, Me), 4.36 (2H, s, CH2), 7.60 (1H, s, CH).
Example 126: Preparation of 5.5-dimethyl-3-(l-methyl-4-trifluoromethyl-lH-pyrazol-3-
vlmethanesulfonvl)-4.5-dihvdroisoxazole
A solution of peracetic acid (40% by weight in acetic acid) (0.3 ml, 1.6 mmol)
was added dropwise to a solution of 5,5-dimethyl-3-(l-methyl-4-trifluoromethyl-lHpyrazol-
3-ylmethylsulfanyl)-4,5-dihydroisoxazole (200 mg, 0.68 mmol) in dichloromethane
(3 ml) at room temperature. The solution was heated under reflux for 3 hours
and stored at room temperature for 17 hours. The reaction was quenched by addition of
10% aqueous sodium metabisulfite solution (1.5 ml). The two phases were separated and
the aqueous phase was extracted with dichloromethane (2x 3 ml). The combined organic
extracts were washed with aqueous potassium carbonate solution (2M) (2 ml) and the
wash extracted with dichloromethane (2x 3 ml). The combined organic extracts were
dried over magnesium sulfate and concentrated to give the product as a white solid (220
mg, 99% yield). M.p. 125-126°C. 'H-NMR (400 MHz, CDC13): 1.52 (6H, s, Me), 3.08
(2H, s, CH2), 3.94 (3H, s, Me), 4.72 (2H, s, CH2), 7.70 (1H, s, CH).
Example P21: Preparation of 3-[fluoro-n-methyl-4-trifluoromethyl-lH-pyrazol-3-yl)-
methanesulfonyl]-5.5-dimethvl-4.5-dihydroisoxazole and 3-[difluoro-(l -methyl-4-
trifluoromethl-lH-vrazol-S-D-methanesulfonvl-S.S-dimethvl^.S-dihdro-isoxazole
(Figure Removed)
Phosphazene base 1 -ter^-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-
lambda5-5-catenadi(phosphazene) (P2-lBu) (2M in THF) (0.65 ml, 1.3 mmol) was added
to a solution of 5,5-dimethyl-3-(l-methyl-4-trifluoromethyl-lH-pyrazol-3-ylmethanesulfonyl)-
4,5-dihydroisoxazole (200 mg, 0.61 mmol) in THF (6 ml) at room temperature.
After 10 minutes N-fluorobenzenesulfonimide (NFSI) (410 mg, 1.3 mmol) was added.
The mixture was stirred at room temperature for 3 hours and stored at room temperature
for 17 hours. The mixture was concentrated and the residue dissolved in ethyl acetate
(100 ml) and passed through silica gel. The filtrate was concentrated and the residue was
purified using preparative HPLC on silica gel (eluent: dichloromethane) which gave the
mono-fluoro product (Compound No. 4.04 of Table 30) as a white solid (87 mg, 41%
yield) and the di-fluoro product (Compound No. 4.05 of Table 30) as a white solid (72
mg, 33% yield).
Example 127: Preparation of (1-methyl-lH-imidazol-2-yl')-methanol
-CH° NaBH4
Sodium borohydride (380 mg, 10 mmol) was added to a solution of 1-methyl-1Himidazole-
2-carbaldehyde (1.1 g, 10 mmol) in ethanol (25 ml). The mixture was stirred at
room temperature for 2 hours. The reaction was quenched by addition of methanol (20
ml). The mixture was partitioned between water and dichloromethane. The combined
organic extracts were dried over magnesium sulfate and concentrated to give the product
as a white solid (480 mg, 42% yield). 'H-NMR (400 MHz, CDClj): 3.73 (3H, s, Me),
4.32 (1H, bs, OH), 4.67 (2H, s, CH2), 6.84 (1H, s, CH), 6.90 (1H, s, CH).
Example 128: Preparation of 5.5-dimethvl-3-(l-methyl-lH-imidazol-2-vlmethylsulfanyl)-
4.5-dihydroisoxazole
1. SOCIj,
2. thiourea
H 3. K2C03
Thionyl chloride (0.909 ml» 12.5 mmol) was added dropwise to a solution of (1-
methyl-lH-imidazol-2-yl)-methanol (467 mg, 4.16 mmol) in acetonitrile (30 ml). The
mixture was stirred at room temperature for 3 hours and concentrated to give a yellow
gum. The gum was dissolved in THF and concentrated to give a pale yellow solid. The
- 128-
solid was dissolved in ethanol (42 ml), thiourea (634 mg, 8.33 mmol) was added and the
mixture was heated under reflux for 1 hour. The mixture was cooled slightly and 3-
methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (740 mg, 4.18 mmol) and potassium
carbonate (1.63 g, 11.8 mmol) were added to the mixture. The mixture was heated under
reflux for 2 hours. The mixture was diluted with water and extracted with ethyl acetate.
The combined organic extracts were concentrated. The residue was triturated with
chloroform and the precipitate removed by filtration. The filtrate was concentrated to
give the product as a yellow gum (829 mg, 88% yield). *H-NMR (400 MHz, CDC13): 1.4
(6H, s, Me), 2.85 (2H, s, CH2), 3.7 (3H, s, Me), 4.45 (2H, s, CH2), 6.82 (IH, d, CH), 6.95
(lH,d,CH).
5,5-Dimethyl-3-(l-methyl-lH-imidazol-2-ylmethylsulfanyl)-4,5-dihydroisoxazole
was oxidised using the method described in Example 126 and then fluorinated using the
method described in Example P21 to give Compound No. 6.01 of Table 32.
Example 129: Preparation of 2-emoxy-4-trifluoromethyl-thiazole-5-carboxvlic acid ethyl
ester
2-Chloro-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (259 mg, 1.0
mmol), sodium ethoxide (23% by weight in ethanol) (0.33 ml, 1.1 mmol) and ethanol (2
ml) were heated under reflux for 2 hours. The mixture was partitioned between water and
ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated to
give the product as a yellow gum (187 mg, 70% yield). :H-NMR (400 MHz, CDCls):
1.36 (3H, t, Me), 1.45 (3H, t, Me), 4.35 (2H, q, CH2), 4.55 (2H, q, CH2).
2-Ethoxy-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester was reduced
using the method described in Example 124, derivatised using the method described in
Example 128, oxidised using the method described in Example 126 and then fluorinated
using the method described in Example P21 to give Compound No. 7.01 of Table 33.
Example 130: Preparation of 3-amino-4.4.4-trifluoro-2-methyl-but-2-enoic acid ethvl
ester
(Figure Removed)
Ethyl a-methyl-4,4,4-trifluoroacetoacetate (24.5 g, 124 mmol) and ammonium
acetate (28.6 g, 372 mmol) were dissolved in ethanol (50 ml) and water (2.5 ml). The
solution was heated under reflux for 16 hours, allowed to cool to room temperature,
diluted with water and extracted with ethyl acetate. The combined organic phases were
dried over sodium sulfate and concentrated to give the product as a pale brown liquid
(25.5 g, 100% yield) which was used without further purification.
Example 131: Preparation of 1.4-dimethvl-5-trifluoromethvl-lH-pvrazol-3-ol
(Figure Removed)
3-Amino-4,4,4-trifluoro-2-methyl-but-2-enoic acid ethyl ester (25.5 g, 124 mmol)
was cooled to 0°C and methyl hydrazine (7 ml, 132 mmol) was added dropwise. The
mixture was allowed to warm to room temperature and heated to 50°C for 20 hours. The
mixture was allowed to cool to room temperature and was stirred for 16 hours. The
mixture was cooled to 0°C and saturated aqueous sodium hydrogencarbonate solution (50
ml) was added. The solid was removed by filtration and washed with cold water (0°C) to
give the product as a white solid (8.46 g, 38% yield over two steps).
Example 132: Preparation of 3-difluoromethoxy-1,4-dimethvl-5-trifluoromethyl-1Hpyrazole
(Figure Removed)
Freon gas (50 ml) was condensed into a reaction flask cooled to -78°C and 1,4-
dimethyl-5-trifluoromethyI-lH-pyrazol-3-ol (4.5 g, 25 mmol) and tetrabutylphosphonium
bromide (2.8 g, 8.25 mmol) in dichloromethane (75 ml) were added. Aqueous sodium
hydroxide solution (50% by weight) (75 ml) was added dropwise at -78°C. The mixture
was allowed to warm to room temperature and was stirred for 3 hours. The reaction was
quenched by addition of water. The two phases were separated and the aqueous phase
extracted with dichloromethane. The combined organic phases were washed with water,
dried over magnesium sulfate and concentrated. The crude material was purified by
chromatography on silica gel (eluent: dichloromethane / hexane) to give the product as a
colourless liquid (2.9 g, 50% yield). 19F-NMR (400 MHz, CDC13): -84.1 (2F, d, J = 75
Hz, CF2), -58.92 (3F, s, CF3).
Example 133: Preparation of 4-bromomethyl-3-difluoromethoxv-l-methyl-5-trifluoromethvl-
1 H-pyrazole
NBS
3-Difluoromethoxy-l,4-dimethyl-5-trifluoromethyl-lH-pyrazole (2.9 g, 12.6
mmol) was dissolved in carbon tetrachloride (50 ml) and N-bromosuccinimide (NBS)
(2.49 g, 13.9 mmol) and AIBN (206 mg, 1.3 mmol) were added under nitrogen. The
mixture was heated under reflux and illuminated with a quartz halogen sunlamp. After 30
minutes the mixture was allowed to cool to room temperature, filtered and the solids
washed with dichloromethane. The combined filtrate and washings were concentrated.
The crude product was purified by chromatography on silica gel (eluent: ethyl acetate /
hexane) to give the product (3.3 g, 85% yield).
4-Bromomethyl-3-difluoromethoxy-1 -methyl-5-trifluoromethyl-1 H-pyrazole was
derivatised using the method described in Example 14, oxidised using the method
described in Example 121 and then fluorinated using the method described in Example
P21 to give Compound No. 2.34 of Table 28.
Example 134: Preparation of 3-but-2-vnvlsulfanvl-5.5-dimethvl-4.5-dihvdroisoxazole
1. thiourea
(Figure Removed)
Thiourea (2.15 g, 28.21 mmol) was added to a solution of l-bromo-2-butyne
(2.47 ml, 28.21 mmol) in ethanol (69 ml) and the solution was heated under reflux for 1
hour 40 minutes. The mixture was allowed to cool to room temperature and 3-methanesulfonyl-
5,5-dimethyl-4,5-dihydroisoxazole (5 g, 28.21 mmol) and potassium carbonate
(4.28 g, 31.03 mmol) were added. The mixture was heated under reflux for 2 hours 35
minutes and allowed to cool to room temperature. The mixture was partitioned between
water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The
combined organic phases were washed with brine, dried over magnesium sulfate and
concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl
acetate / hexane) to give the product (3.085 g, 60% yield) as a pale yellow oil. 'H-NMR
(400 MHz, CDC13): 1.42 (6H, s, Me), 1.83 (3H, t, Me), 2.81 (2H, s, CH2), 3.77 (2H, q,
CH2).
Example 135: Preparation of 3-bromo-5-(5.5-dimethvl-4.5-dihvdroisoxazol-3-vlsulfanylmethylV4-
methyl-isoxazole and 3-bromo-4-(5.5-dimethyl-4.S-dihydroisoxazoI-3-yIsulfanvlmethvl)-
5-methyl-isoxazole
Dibromoformaldoxime (prepared according to Synlett 2002, 3071) (944 mg, 4.68
mmol) and sodium hydrogencarbonate (872 mg, 10.37 mmol) were added to a solution of
3-but-2-ynylsulfanyi-5,5-dimethyl-4,5-dihydroisoxazole (428 mg, 2.34 mmol) in ethyl
acetate (4 ml) and the mixture was heated under reflux for 4 days. The mixture was
allowed to cool to room temperature and was partitioned between water and ethyl
acetate. The aqueous phase was extracted with ethyl acetate. The combined organic
phases were washed with brine, dried over magnesium sulfate and concentrated. The
residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane) to
give the mixture of products (347 mg, 49% yield) as a yellow oil. A: rH-NMR (400
MHz, CDC13): 1.41 (6H, s, Me), 2.51 (3H, s, Me), 2.77 (2H, s, CH2), 4.01 (2H, s, CH2);
B: 'H-NMR (400 MHz, CDC13): 1.42 (6H, s, Me), 2.03 (3H, s, Me), 2.79 (2H, s, CH2),
4.32 (2H, s, CH2).
-132-
Example 136: Preparation of 3-bromo-5-(5,5-dimethyl-4.5-dihydroisoxazoIe-3-sulfonylmethvl)-
4-methyl-isoxazoleand3-bromo-4-f5.5-dimethyl-4,5-dihydroisoxazole-3-
sulfonylmethvlVS-methyl-isoxazole
ON
(Figure Removed)
3-Chloroperoxybenzoic acid (mCPBA) (70% by weight) (774 mg, 2.24 mmol)
was added to a solution of 3-bromo-5-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfanylmethyl)-
4-methyl-isoxazoleand3-bromo-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfanylmethyl)-
5-methyl-isoxazole (310 mg, 1.02 mmol) in dichloromethane (5 ml) at
0°C. The mixture was allowed to warm to room temperature and was stirred at room
temperature for 24 hours. The reaction was quenched by addition of saturated aqueous
sodium hydrogencarbonate solution. The two phases were separated and the aqueous
phase was extracted with dichloromethane. The combined organic phases were washed
with 20% aqueous sodium metabisulfite solution, with saturated aqueous sodium
hydrogencarbonate solution, dried over magnesium sulfate and concentrated. The residue
was purified by chromatography on silica gel (eluent: ethyl acetate / hexane) to give the
mixture of products as a white solid. The solid was purified and separated by preparative
HPLC (eluent: ethyl acetate / hexane) to give product A as a white solid (124 mg, 34%
yield) and product B as a white solid (136 mg, 39% yield). A: M.p. 98.5-100.5°C. JHNMR
(400 MHz, CDC13): 1.51 (6H, s, Me), 2.10 (3H, s, Me), 2.99 (2H, s, CH2), 4.76
(2H, s, CH2); B: M.p. 167-168°C. 'H-NMR (400 MHz, CDC13): 1.51 (6H, s, Me), 2.58
(3H, s, Me), 3.06 (2H, s, CH2), 4.43 (2H, s, CH2).
Example P22: Preparation of 3-bromo-5-[(5.5-dimethyl-4.5-dihvdroisoxazole-3-
sulfonvl)-difluoro-methvl1-4-methvl-isoxazole
P2-Et
NFSI
Phosphazene base 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino-2-lambda5-5,4-
lambda5-5-catenadi(phosphazene) (Pa-Et) (0.216 ml, 0.65 mmol) was added dropwise to
a solution of 3-bromo-5-(5,5-dimethyl-4,5-dihydroisoxazole-3-sulfonylmethyl)-4-
methyl-isoxazole (106 mg, 0.31 mmol) in THF (3 ml) at 0°C. After 5 minutes Nfluorobenzenesulfonimide
(NFSI) (205 mg, 0.65 mmol) was added. The mixture was
stirred at 0°C for 20 minutes and then allowed to warm to room temperature. The mixture
was stirred at room temperature for 4 hours. The reaction was quenched by addition of
aqueous hydrochloric acid (2M) and extracted twice with ethyl acetate. The combined
organic phases were washed with brine, dried over magnesium sulfate and concentrated.
The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane)
to give the product (Compound No. 5.06 of Table 31) as a white solid (65 mg, 56%
yield).
Example 137: Preparation of l-(2>6-difluoro-phenylV2.2.2-trifluoroethanol
(Figure Removed)
Caesium fluoride (32 mg, 2.1 mmol) was added to a mixture of 2,6-difluorobenzaldehyde
(2 ml, 18.2 mmol) and trimethyl(trifluoromethyl)silane (2 ml, 19.6 mmol)
in THF (30 ml) at room temperature. The suspension was stirred at room temperature for
6 hours and stored at room temperature 18 hours. A mixture of concentrated hydrochloric
acid (3 ml) in water (7 ml) was added and the solution was stirred at room temperature
for 4 hours. The mixture was concentrated to give the product (3.4 g, 87% yield) which
was used without further purification.
Example 138: Preparation of 2-(l-bromo-2.2.2-trifluoroethvl)-1.3-difluorobenzene
NBS
(PhO)3P
N-Bromosuccinimide (NBS) (500 mg, 2.9 mmol) was added to a solution of 1-
(2,6-difluoro-phenyl)-2,2,2-trifluoroethanol (500 mg, 1.8 mmol) and triphenyl phosphite
(0.75 ml, 2.8 mmol) in dichloromethane (5 ml) at room temperature. The mixture was
stirred for 6 hours at room temperature and stored at room temperature for 48 hours. The
mixture was filtered, the filtrate concentrated and the residue absorbed on to silica gel.
The crude product was purified by chromatography on silica gel (eluent: ethyl acetate /
hexane) to give the product as a colourless oil (240 mg, 48% yield) which was used
without further purification.
Example 139: Preparation of 3-[l-(2.6-difluoro-phenyl)-2.2.2-trifluoro-ethvlsulfanvl1-
5.5-dimethvl-4.5-dihvdroisoxazole
Br CH2(OH)S02Na.2H2O,
NaSH.H20, K2C03
3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (87 mg, 0.49 mmol),
sodium hydrosulfide hydrate (73 mg, 0.99 mmol), sodium hydroxy methanesulfonate
dihydrate (151 mg, 0.99 mmol) and potassium carbonate (136 mg, 0.99 mmol) were
added to DMF (10 ml) at 0°C and the mixture was stirred at 0°C for 2 hours. 2-(l-Bromo-
2,2,2-trifluoroethyl)-l,3-difluorobenzene (135 mg, 0.49 mmol) was added and the
suspension was stirred at room temperature for 5 hours. The reaction was partitioned
between water and ethyl acetate. The organic phase was washed with water, dried over
magnesium sulfate and concentrated. The crude product was purified by chromatography
on silica gel (eluent: ethyl acetate / hexane) to give the product as a white solid (55 mg,
35% yield). !H-NMR (400 MHz, CDC13): 1.41 (3H, s, Me), 1.45 (3H, s, Me), 2.80 (1H,
d, GHz), 2.82 (1H, d, CH2), 5.98 (1H, m, CH), 6.97 (2H, m, CH), 7.37 (1H, m, CH).
Example P23: Preparation of 3-Fl-('2.6-difluoro-phenvl')-2.2.2-trifluoro-ethanesulfonvl1-
5.5-dimethyl-4.5-dihydroisoxazole
(Figure Removed)
A mixture of 3-[ 1 -(2,6-difluoro-phenyl)-232,2-trifluoro-ethylsulfanyl]-5,5-
dimethyl-4,5-dihydroisoxazole (110 mg, 0.33 mmol) and peracetic acid (40% by weight
in acetic acid) (0.2 ml, 1.05 mmol), 1,2-dichloroethane (5 ml) and dichloromethane (5
ml) was heated under reflux for 2 hours. More peracetic acid (40% by weight in acetic
acid) (0.2 ml, 1.05 mmol) was added and the mixture heated under reflux for 2 hours.
The mixture was allowed to cool to room temperature and was stored at room
temperature for 18 hours. The mixture was poured into saturated aqueous sodium
hydrogencarbonate solution and extracted with dichloromethane. The combined organic
phases were washed with saturated aqueous sodium hydrogencarbonate solution, dried
over magnesium sulfate and concentrated. The residue was purified by chromatography
on silica gel (eluent: ethyl acetate / hexane) to give a mixture of diastereomeric
sulfoxides (Compound No. 1.140 ofTable 27) as a white solid (21.1 mg, 17.8% yield)
and the sulfone (Compound No. 1.113 ofTable 27) as a white solid (66.1 mg, 56%
yield).
Example P24: Preparation of 5.5-dimethvl-3-l2.2.2-trifluoro-l-[l-methvl-5-(2.2.2-
trifluoro-ethoxyV3-trifluoromethvl-lH-pyrazol-4-vl1-ethanesulfinvll-4.S-dihvdroisoxazole
CF
3-Chloroperoxybenzoic acid (mCPBA) (70% by weight) (305 mg, 1.24 mmol)
was added in portions to a solution of 5,5-dimethyl-3-{2,2,2-trifluoro-l-[l-methyl-5-
(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-lH-pyrazol-4-yl]-ethylsulfanyl}-4,5-dihydroisoxazole
(190 mg, 0.41 mmol) in dichloromethane (5 ml) at room temperature. The
mixture was stirred at room temperature for 18 hours. The reaction was quenched by
addition of saturated aqueous sodium metabisulfite solution, followed by addition of
saturated aqueous sodium hydrogencarbonate solution. The two phases were separated
and the aqueous phase was extracted with dichloromethane. The combined organic
phases were washed with saturated aqueous sodium hydrogencarbonate solution, dried
over magnesium sulfate and concentrated. The crude product was purified by chromatography
on silica gel (eluent: hexane / dichloromethane) to give the product (Compound
No. 2.35 ofTable 28) as a colourless gum (105 mg, 51% yield).
Example 140: Preparation of 5.5-dimethyl-3-(l-phenvl-ethylsulfanyl)-4.5-dihvdroisoxazole
1. thiourea
2. K2C03
Thiourea (180 mg, 2.4 mmol) was added to a solution of 1-methyl benzyl
bromide (0.3 ml, 2.2 mmol) in ethanol (10 ml) at room temperature. The mixture was
heated under reflux for 5 hours. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole
(420 mg, 2.4 mmol) and potassium carbonate (330 mg, 2.4 mmol) were added and the
mixture was heated under reflux for 3 hours. The mixture was allowed to cool to room
temperature, poured into water and the mixture extracted with ethyl acetate. The
combined organic phases were washed with water, dried over magnesium sulfate and
concentrated. The crude product was purified by chromatography on silica gel (eluent:
ethyl acetate / hexane) to give the product as a white solid (210 mg, 43% yield) which
was used without further purification.
Example 141: Preparation of 5.5-dimethyl-3-(l-phenvl-ethanesulfonylV4.5-dihydroisoxazole
(Figure Removed)
3-Chloroperoxybenzoic acid (mCPBA) (70% by weight) (615 mg, 2.5 mmol) was
added in portions to a solution of 5,5-dimethyl-3-(l-phenyl-ethylsulfanyl)-4,5-dihydroisoxazole
(195 mg, 0.83 mmol) in dichloromethane (15 ml) at room temperature. The
suspension was stirred at room temperature for 18 hours. The reaction was quenched by
addition of saturated aqueous sodium metabisulfite solution, followed by addition of
saturated aqueous sodium hydrogencarbonate solution. The two phases were separated
and the aqueous phase extracted with dichloromethane. The combined organic phases
were dried over magnesium sulfate and concentrated. The crude product was purified by
chromatography on silica gel (eluent: hexane / dichloromethane) to give the product (85-
90% purity) which was used without further purification.
Example P25: Preparation of 3-(l-fluoro-l-phenyl-ethanesulfonyl)-5.S-dimethyl-4.5-
dihydroisoxazole
NFSI
Phosphazene base 1 -te/^-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-
lambdas-5-catenadi(phosphazene) (P2-lBu) (2M in THF) (0.3 ml, 0.6 mmol) was added to
a solution of 5,5-dimethyl-3-(l-phenyl-ethanesulfonyl)-4,5-dihydroisoxazole (150 mg,
0.56 mmol) in THF (8 ml) at room temperature. After 10 minutes N-fluorobenzenesulfonimide
(NFSI) (190 mg, 0.6 mmol) was added. The mixture was stirred at room
temperature for 15 minutes. The mixture was absorbed onto silica gel and purified by
chromatography on silica gel (eluent: ethyl acetate / hexane) to give the product
(Compound No. 1.138 of Table 27) as a white solid (89 mg, yield 56%).
Example 142: Preparation of 3-(2.6-difluoro-benzylsulfanylV5.5-dimethyl-4.5-dihvdroisoxazole
/r-C] . fTV^SH K2C03
0-N
2,6-Difluorbenzylthiol (0.33 g, 2 mmol) and potassium carbonate (1.84 g, 13
mmol) were added to a solution of 3-chloro-5,5-dimethylisoxazoline (0.26 g, 2 mmol) in
dry DMF (7.5 ml) under nitrogen. The mixture was stirred for 5 hours at room
temperature and stored at room temperature for 1 week. The mixture was filtered and the
filtrate diluted with water. The aqueous phase was extracted with ethyl acetate twice. The
combined organic extracts were washed with water and brine, dried over magnesium
sulfate and concentrated. The crude product was purified by chromatography on silica gel
(eluent: ethyl acetate / hexane) to give the product as a white solid (0.23 g, 45% yield).
Example 143: Preparation of 3-(2<6-difluoro-benzylsulfanyl)-5,5-dimethyl-4.5-dihydroisoxazole
1. HCI, thiourea
2. K2C03
(Figure Removed)
2,6-Difluorobenzyl alcohol (0.2 ml, 1.8 mmol), thiourea (165 mg, 2.2 mmol),
aqueous hydrochloric acid (2M) (2.7 ml) and 1,4-dioxane (3 ml) were mixed and the
mixture heated in a sealed vessel in the microwave at 140°C for 10 minutes. Potassium
carbonate (1.1 g, 8 mmol) and 3-methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole
(380 mg, 2.1 mmol) were added and the mixture was stirred in an open vessel for 10
minutes. The mixture was heated in a sealed vessel in the microwave at 150°C for 10
minutes. The mixture was diluted with water and extracted with ethyl acetate. The
organic extract was washed with water, dried over magnesium sulfate and concentrated.
The crude material was purified by chromatography on silica gel (eluent: ethyl acetate /
hexane) to give the product as a white solid (120 mg, 26% yield). M.p. 85-87°C. JH-
138-
NMR (400 MHz, CDC13): 1.43 (6H, s, Me), 2.82 (2H, s, CH2), 4.36 (2H, s, CH2), 6.90
(2H,d,CH), 7.26(1 H,t,CH).
Example 144: Preparation of 3-(2-trifluoromethoxy-benzylsulfanyl)-5JS-dimethyl-4.5-
dihydroisoxazole
1.HCI, thiourea rinH N~~ v
2. K2C03
2-(Trifluoromethoxy)benzyl alcohol (200 mg, 1.04 mmol), thiourea (100 mg,
1.31 mmol), aqueous hydrochloric acid (2M) (1.6 ml) and 1,4-dioxane (3 ml) were mixed
and the mixture heated in a sealed vessel in the microwave at 140°C for 10 minutes.
Potassium carbonate (620 mg, 4.5 mmol) and 3-methanesulfonyl-5,5-dimethyl-4,5-
dihydroisoxazole (220 mg, 1.24 mmol) were added and the mixture was stirred in an
open vessel for 10 minutes. The mixture was heated in a sealed vessel in the microwave
at 150°C for 10 minutes. The mixture was diluted with water and extracted with ethyl
acetate. The organic extract was washed with water, dried over magnesium sulfate and
concentrated. The crude material was purified by chromatography on silica gel (eluent:
ethyl acetate / hexane) to give the product as a white solid (50 mg, 15% yield). 'H-NMR
(400 MHz, CDC13): 1.41 (6H, s, Me), 2.78 (2H, s, CH2), 4.32 (2H, s, CH2), 7.2-7.4 (2H,
m,CH),7.57(lH,m,CH).
Example 145: Preparation of 4-(S.5-dimethyl-4.5-dihydroisoxazol-3-ylsulfanylmethvl)-
3.5-dimethvl-isoxazole
r. 1. Nal, thiourea
u 2. K2C03
4-Chloromethyl-3,5-dimethyl-isoxazole (3.0 g, 20.6 mmol) was.dissolved in
ethanol (20 ml) and to it was added thiourea (1.725 g, 22.7 mmol) and sodium iodide
(3.087 g, 20.6 mmol). After heating to 80°C for 1 hour the mixture was cooled and 3-
methylsulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (3.676 g, 20.6 mmol), potassium
carbonate (3.132 g, 22.7 mmol), ethanol (10 ml) and water (2 ml) were added and the
mixture was again heated at 80°C for 2 hours. The mixture was filtered and concentrated.
The crude product was dissolved in ethyl acetate, washed with water, dried over
magnesium sulfate and concentrated. The crude product was purified by chromatography
over silica gel (eluent: hexane / ethyl acetate) to give the product (4.667 g, 94% yield).
'H NMR (400 MHz, CDC13): 1.425 (6H, s, Me), 2.3 (3H, s, Me), 2.4 (3H, s, Me), 2.8
(2H,s,CH2),4.0(2H,s,CH2).
4-(5,5-Dimethyl-4,5-dihydroisoxazol-3-ylsulfanylmethyl)-3,5-dimethyl-isoxazole
was oxidised using the method described in Example 121 and then chlorinated using the
method described in Example P20 to give Compound No. 3.03 of Table 29 and
Compound No. 3.04 of Table 29.
Example 146: Preparation of 5-isppropylsulfanyl-l-methyl-3-trifiuoromethyl-lHpyrazole-
4-carbaldehyde
(Figure Removed)
Potassium carbonate (1.68 g, 12 mmol) was suspended in DMF (50 ml) and isopropylthiol
(1 ml, 11 mmol) added. The suspension was stirred at room temperature for
15 minutes before a solution of 5-chloro-l-methyl-3-trifluoromethyl-lH-pyrazole-4-
carbaldehyde (2.12 g, lOmmol) in DMF (5 ml) was added. The reaction was stirred at
room temperature for 16 hours. The reaction was partitioned between aqueous
ammonium chloride solution and diethyl ether and the two phases were separated. The
organic phase was washed with water and brine, dried over sodium sulfate and
concentrated to give the product (2.584 g, 100% yield) which was used without further
purification. 'H NMR (400 MHz, CDC13): 1.29 (3H, s, Me), 1.31 (3H, s, Me), 3.52 (1H,
heptet, CH), 4.02 (3H, s, Me), 10.03 (1H, s, CH).
Example 147: Preparation of 4-bromomethyl-5-isopropvlsulfanvl-l-methvl-3-
trifluoromethvl-1 H-pyrazole
F3<\ xCHO /£/-— F3°-
5-Isopropylsulfanyl-1 -methyl-3 -trifluoromethyl-1 H-pyrazole-4-carbaldehyde (2.5
g, 10 mmol) was dissolved in dichloromethane (10 ml) and hexane (10 ml) and a solution
of isopinocampheyl-boron dibromide dimethylsulfide complex (prepared according to J.
Org. Chem. 1980 (45) 384-389) (4.49 g, 12 mmol) in dichloromethane (5ml) was added
slowly. The reaction was stirred at room temperature for 2 hours and stored at room
temperature for 18 hours. The reaction was heated to reflux for 2 hours and then
concentrated. The residue was partitioned between water and dichloromethane and the
two phases were separated. The organic phase was dried over magnesium sulfate and
concentrated. The crude product was absorbed onto silica and purified via chromatography
to give the product as a mobile oil (2.5 g, 79% yield). *H NMR (400 MHz,
CDC13): 1.29 (3H, s, Me), 1.31 (3H, s, Me), 3.42 (1H, heptet, CH), 4.00 (3H, s, Me), 4.54
(2H,s,CH).
4-Bromomethyl-5-isopropylsulfanyl-l -methyl-3-trifluoromethyl-1 H-pyrazole was
derivatised using the method described in Example 14, oxidised using the method
described in Example 126 and then fluorinated using the method described in Example
P21 to give Compound No. 2.36 of Table 28.
Example 148: Preparation of 1.3-dimethyl-5-f2.2.2-trifluoroethoxy)-lH-pyrazole-4-
carbaldehyde
(Figure Removed)
2,2,2-Trifluoroethanol (7.11 ml, 97.6 mmol) was added dropwise to potassium
tert-butoxide (1M in THF) (97.6 ml, 97.6 mmol) at 0°C. A solution of 5-chloro-l,3-
dimethyl-lH-pyrazole-4-carbaldehyde (10.3 g, 65.1 mmol) in THF (28 ml) was added
slowly to the solution at 0°C. The solution was allowed to warm to room temperature and
stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane,
washed with water and brine, dried over magnesium sulfate and concentrated to give the
product as a yellow oil (15.82 g, 109% yield) which was used without further
purification. >H NMR (400 MHz, CDC13): 2.42 (s, 3H, Me), 3.65 (s, 3H, Me), 4.93 (q,
2H, CH2), 9.72 (s, 1H, CH).
Example 149: Preparation of [L3-dimethvl-5-(2.2,2-trifluoro-ethoxy)-lH-pvrazol-4-yl]-
methanol
l,3-Dimethyl-5-(2,2,2-trifluoroethoxy)-lH-pyrazole-4-carbaldehyde (14.45 g, 65
mmol) was dissolved in methanol (130 ml). Sodium borohydride (1.23 g, 32.5 mmol)
was added in portions at 0°C. The mixture was allowed to warm to room temperature and
stirred at room temperature for 2 hours. The mixture was concentrated and the residue
dissolved in dichloromethane. The solution was washed with water and brine, dried over
magnesium sulfate and concentrated to give the product as a white solid (14.6 g, 100%
yield) which was used without further purification. !H NMR (400 MHz, CDC13): 2.20 (s,
3H, Me), 3.64 (s, 3H, Me), 4.49 (s, 2H, CH2), 4.64 (q, 2H, CH2).
[l,3-Dimethyl-5-(2,2,2-trifluoro-ethoxy)-lH-pyrazol-4-yl]-methanol was
derivatised using the method described in Example 125, oxidised using the method
described in Example 121 and then fluorinated using the method described in Example
P21 to give Compound No. 2.24 of Table 28 or chlorinated using the method described in
P20 to give Compound No. 2.31 of Table 28.
Example P26: Preparation of chloro-(2.6-difluorophenylVf5.S-diniethyl-4.5-dihydroisoxazole-
3-sulfonvlVacetic acid methyl ester
Under nitrogen 3-[chloro-(2,6-difluorophenyl)-methanesulfonyl]-5,5-dimethyl-
4,5-dihydroisoxazole (200 mg, 0.62 mmol) was dissolved in dry THF (5 ml). The
solution was cooled to 0°C before l-te^butyl-2,2,4,4,4-pentakis(dimethylamino-2-
lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-'Bu) (2M in THF) (0.37 ml, 0.74
mmol) was added followed by addition of methyl chloroformate (0.06 ml, 0.74 mmol) at
0°C. The mixture was allowed to warm to room temperature and stirred at room
temperature for 2 hours. The reaction was quenched by addition of aqueous hydrochloric
acid (2M) and the mixture was extracted with ethyl acetate. The combined organic
extracts were dried over magnesium sulfate and concentrated. The crude product was
purified by chromatography over silica gel (eluent: hexane / ethyl acetate) to give the
product (Compound No. 1.14 of Table 27).
Example P27: Preparation of 3-[bromo-(2.6-difluorophenyl)-methanesulfonyl]-5.5-
dimethvl-4.5-dihvdroisoxazole
Under nitrogen 3-(2,6-difluorophenyl-methanesulfonyl)-5,5-dimethyl-4,5-
dihydroisoxazole (75 mg, 0.26 mmol) was dissolved in dry THF (5 ml). The solution was
cooled to 0°C before l-ethyl-2,2,4,4,4-pentakis(dimethylamino-2-lambda5-5,4-lambda5-
5-catenadi(phosphazene) (Pa-Et) (0.1 ml, 0.3 mmol) was added followed by addition of
N-bromosuccinimide (NBS) (0.05 g, 0.286 mmol) at 0°C. The mixture was allowed to
warm to room temperature and stirred at room temperature for 2 hours. The reaction was
quenched by addition of aqueous hydrochloric acid (2M) and the reaction mixture was
extracted with ethyl acetate. The combined organic extracts were dried over magnesium
sulfate and concentrated. The crude product was purified by chromatography over silica
gel (eluent: hexane / ethyl acetate) to give the product (Compound No. 1.19 of Table 27)
as a white solid (30 mg, 31% yield).
Example P28: Preparation of 3-[bromo-chloro-(2.6-difluorophenyn-methanesulfonyl]-
5.5-dimethvl-4.5-dihydroisoxazole
F Cl 1 r~\ 11 \ s
KO'Bu
PhNMe3Br • Brz
Under nitrogen 3-[chloro-(2,6-difluorophenyl)-methanesulfonyl]-5,5-dimethyl-
4,5-dihydroisoxazole (6.387 g, 19.7 mmol) was dissolved in dry THF (200 ml) and the
solution cooled to -78°C. Potassium tert-butoxide (l.OM in THF) (20.7 ml, 20.7 mmol)
was added forming an orange solution. On addition of phenyl trimethylamino tribromide
(PIT) (7.785 g, 20.7 mmol) a much paler thick precipitate formed and the mixture was
allowed to warm to room temperature. The mixture was filtered through sand which was
subsequently washed with ethyl acetate, the combined organic fractions were
concentrated. The crude product was purified by chromatography over silica gel (eluent:
hexane / ethyl acetate) to give the product (Compound No. 1.53 of Table 27) as a pale
yellow solid (7.225 g, 91 % yield).
Example P29: Preparation of l-f2,6-difluorophenylM-(5,5-dimethyI-4.S-dihydroisoxazole-
3-sulfonvl)-propan-2-one
P2-'Bu,
Under nitrogen 3-(2,6-difluorophenyl-methanesulfonyl)-5,5-dimethyl-4,5-
dihydro-isoxazole (200 mg, 0.69 mmol) was dissolved in dry THF (5 ml). The solution
was cooled to 0°C before l-tert-butyl-2,2,4,4,4-pentalds(dimethylamino~2-lambda5-5,4-
lambdas-5-catenadi(phosphazene) (P2-'Bu) (2M in THF) (0.41 ml, 0.83 mmol) was added
followed by addition of acetic anhydride (0.08 ml, 0.83 mmol) at 0°C. The mixture
allowed to warm to room temperature and stirred at room temperature for 2 hours. The
reaction was quenched with aqueous hydrochloric acid (2M) and the mixture was
extracted with ethyl acetate. The combined organic extracts were dried over magnesium
sulfate and concentrated. The crude product was purified by chromatography over silica
gel (eluent: hexane / ethyl acetate) to give the product (Compound No. 1.27 of Table 27)
as a white solid (57 mg, 25% yield).
The same method was used with cyclopropanecarbonyl chloride, difluoroacetyl
chloride, methoxyacetyl chloride, chloroacetyl chloride as the reagent to give Compound
No. 1.54 of Table 27, Compound No. 1.57 of Table 27, Compound No. 1.59 of Table 27,
Compound No. 1.60 of Table 27, respectively.
Example P30: Preparation of acetic acid l-[chloro-2.6-difluoro-phenyl]-(5.5-dimethyl-
4.5-dihydroisoxazole-3-sulfonyl)-methyl]-vinyl ester
(Figure Removed)
Under nitrogen 3-[chloro-(2,6-difluorophenyl)-methanesulfonyl]-5,5-dimethyl-
4,5-dihydroisoxazole (250 mg, 0.77 mmol) was dissolved in dry THF (10 ml) and the
solution cooled to -78°C. Potassium tert-butoxide (l.OM in THF) (0.85 ml, 0.85 mmol)
was added forming a yellow solution, followed by acetyl chloride (0.06 ml, 0.85 mmol)
which caused the colour to fade. The mixture was allowed to warm to room temperature.
The reaction was quenched by addition of aqueous hydrochloric acid (2M) and extracted
-144-
with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and
concentrated. The crude product was purified by chromatography over silica gel (eluent:
hexane / ethyl acetate) to give the product (Compound No. 1.58 of Table 27) as a white
solid (72 mg, 23% yield).
The same method was used with 3-[fluoro-(2,6-difluorophenyl)-methanesulfonyl]-
5,5-dimethyl-4,5-dihydroisoxazole as the starting material to give Compound
No. 1.62 of Table 27.
Example P31: Preparation of acetic acid 2-(2.6-difluoro-phenyl)-2-(5.5-dimethyl-4.5-
dihvdroisoxazole-3-sulfonvl VI -methvl-vinvl ester
KO'Bu,
AcCI
Under nitrogen 3-(2,6-difluorophenyl-methanesulfonyl)-5,5-dimethyl-4,5-
dihydroisoxazole (250 mg, 0.865 mmol) was dissolved in dry THF (10 ml) and the
solution cooled to -78°C. Potassium tert-butoxide (l.OM in THF) (0.95 ml, 0.95 mmol)
was added forming a yellow solution, followed by acetyl chloride (0.7 ml, 0.95 mmol)
which caused the colour to fade. The mixture was allowed to warm to room temperature.
The reaction was quenched by addition of aqueous hydrochloric acid (2M) and extracted
with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and
concentrated. The crude product was purified by chromatography over silica gel (eluent:
hexane / ethyl acetate) to give the product (Compound No. 1.98 of Table 27) as a white
solid (HOmg, 34% yield).
Example P32: Preparation of 3-[bromo-(2.6-difluorophenvlVfluoro-methanesulfonyl]-
5.5-dimethvl-4.5-dihvdroisoxazole
KO'Bu,
NBS
Under nitrogen 3 -[fluoro-(2,6-difluorophenyl)-methanesulfonyl]-5,5-dimethyl-
4,5-dihydroisoxazole (200 mg, 0.65 mmol) was dissolved in dry THF (10 ml) and the
solution cooled to -78°C. Potassium tert-butoxide (l.OM in THF) (0.71 ml, 0.71 mmol)
was added forming a yellow solution, followed by N-bromosuccinimide (NBS) (127 mg,
0.71 mmol) which caused the colour to become brown. The mixture was allowed to
warm to room temperature. The reaction was quenched by addition of aqueous
hydrochloric acid (2M) and extracted with ethyl acetate. The combined organic extracts
were dried over magnesium sulfate and concentrated. The crude product was purified by
chromatography over silica gel (eluent: hexane / ethyl acetate) and then HPLC (eluent:
hexane / ethyl acetate) to give the product (Compound No. 1.63 of Table 27) as a pale
yellow solid (154 mg, 62% yield).
The same method was used with N-iodosuccinimide as reagent to give Compound
No. 1.61 of Table 27.
Example P33: Preparation of 3-[l-(2.6-difluoro-phenyl)-2-vinylcyclopropane-sulfonyl]-
5.5-dimethvl-4.5-dihydroisoxazole
P2-B
Under nitrogen, 1 -ethyl-2,2,4,4,4-pentakis(dimethylamino-2-lambda5-5,4-
lambda5-5-catenadi(phosphazene) (Pi-Et) (0.52 ml, 1.56 mmol) was added to a solution
of3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole(200mg,
0.7 mmol) in THF (5 ml) at 0°C. After 10 minutes l,4-dibromo-2-butene (166 mg, 0.78
mmol) was added and the mixture stirred at room temperature for Ihour. The mixture
was poured onto aqueous hydrochloric acid (2M) and extracted several times with ethyl
acetate. The combined organic phases were washed with water, dried over magnesium
sulfate and concentrated. The crude product was purified by chromatography over silica
gel (eluent: hexane / ethyl acetate) to give the product (Compound No. 1.46 of Table 27)
as a white solid (145 mg, 61% yield).
The same method was used with l,4-dibromo-2-methyl-2-butene as reagent to
give Compound No. 1.47 of Table 27.
Example P34: Preparation of 2-(2.6-difluoro-phenyl)-2-(5.5-dimethvl-4.5-dihvdroisoxazole-
3-sulfonyl)-acetamide
F
Under nitrogen 3-(2,6-difluorophenyl-methanesulfonyl)-5,5-dimethyl-4,5-
dihydro-isoxazole (200 mg, 0.69 mmol) was dissolved in dry THF (5 ml). The solution
was cooled to 0°C before phosphazene base l-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-
2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-lBu) (2M in THF) (0.41 ml,
0.82 mmol) was added, followed by addition of trimethylsilyl isocyanate (0.11 ml, 0.83
mmol) at 0°C. The mixture was allowed to warm to room.temperature and stirred at room
temperature for 2 hours. The reaction was quenched by addition of aqueous hydrochloric
acid (2M) and the mixture was extracted with ethyl acetate. The combined organic
extracts were dried over magnesium sulfate and concentrated. The crude product was
purified by chromatography over silica gel (eluent: hexane / ethyl acetate) to give the
product (Compound No. 1.23 of Table 27) as a pale yellow solid (64 mg, 28% yield).
The same method was used with 4-fluorophenylisocyanate as the reagent to give
Compound No. 1.22 of Table 27.
The following compounds are either commercially available or can be prepared
by known literature methods and were derivatised using the method described in e.g.
Example 14 or Example 145, oxidised using the method described in e.g. Example 121 or
Example 126, and then fluorinated using the method described in e.g. Example P21: 8-
chloromethyl-6-fluoro-4H-benzo-l ,3-dioxine, 3-chloromethyl-5-methyl-isoxazole, 5-
chloro-2-nitrobenzyl bromide (prepared according to J. Heterocycl. Chem. (1972), 9(1),
119-22), 2,3-difluorobenzyl bromide, 2,4-difluorobenzyl bromide, 2,5-difluorobenzyl
bromide, 3,5-difluorobenzyl bromide, 2-fluoro-4-(ethoxycarbonyl)benzyl bromide
(prepared according to J. Med. Chem. (1983), 26(9), 1282-93), 2-fluoro-4-(methoxycarbonyl)
benzyl bromide (prepared according to J. Med. Chem. (1990), 33(9), 2437-51),
2-fluoro-6-(trifluoromethyl)benzyl bromide, 2-phenylbenzyl bromide and 2-(trifluoromethylthio)
benzyl bromide.
The following compounds are either commercially available or can be prepared
by known literature methods and were reduced using the methods described in e.g.
Example 12, brominated using the method described in Example 13, derivatised using the
method described in e.g. Example 14, oxidised using the method described in e.g.
Example 121, and then fluorinated using the method described in e.g. Example P21:
2,2-difluoro-benzo-1,3-dioxole-4-carbaldehyde and 2-(methylsulfonyloxy)benzaldehyde
(prepared according to J. Am. Chem. Soc. (1957), 79, 741).
The following compound is either commercially available or can be prepared by
known literature methods and were reduced using the method described in e.g. Example
124, derivatised using the method described in e.g. Example 128, oxidised using the
method described in e.g. Example 126 and then fluorinated using the method described in
e.g. Example P21: 4-ethyl-2-methoxymethyl-thiazole-5-carboxylic acid (prepared
according to EP 434620).
The following compound is either commercially available or can be prepared by
known literature methods and were reduced using the method described in e.g. Example
124, derivatised using the method described in e.g. Example 125, oxidised using the
method described in e.g. Example 126 and then fluorinated using the method described in
e.g. Example P21: l-methyl-3-trifluoromethyl-lH-pyrazole-4-carboxylic acid.
The following compounds are either commercially available or can be prepared
by known literature methods and were reduced using the method described in e.g.
Example 124, derivatised using the method described in e.g. Example 125, oxidised using
the method described in e.g. Example 126 and then fluorinated using the method
described in e.g. Example P21: 2-chloro-nicotinic acid ethyl ester and 2-methyl-6r
trifluoromethyl-nicotinic acid ethyl ester (prepared according to WO 00/015615 and WO
01/094339).
The compounds mentioned in the following Tables can be prepared in analogous manner.
Table 27: Compounds of formula 1,3
(Table Removed)
Biological Examples
Example Bl: Herbicidal action
Monocotyledonous and dicotyledonous test plants were sown in seed trays in
standard soil. Immediately after sowing (pre-emergence) or after 8 to 9 days cultivation
(post-emergence), the test compounds were applied by spraying in the form of an
aqueous solution derived from the formulation of the technical active ingredient in 0.6 ml
acetone and 45 ml formulation solution containing 10.6% Emulsogen EL (CAS RN
61791-12-6), 42.2% N-methyl pyrrolidone, 42.2% dipropylene glycol monomethyl ether
(CAS RN 34590-94-8) and 0.2 % X-77 (CAS RN 11097-66-8). The test plants were then
grown in a greenhouse under optimum conditions. After a test duration of 3 weeks (postemergence)
or 4 weeks (pre-emergence), the test was evaluated (10 = total damage to
plant, 0 = no damage to plant).
Table Bla: Application post-emergence
(Table Removed)
Example El: Pre-emergent safening test on maize
The test plants were sown in seed trays under greenhouse conditions. A standard
earth was used as the culture substrate. In a pre-emergent stage, the herbicides were
applied both by themselves and in a mixture with safeners to the soil surface. The
application was carried out with an aqueous suspension of the test substances, prepared
from a 25% wettable powder (Example F3, b according to WO 97/34485) or from a
suspension concentrate (Example F8 according to WO 97/34485), to achieve a field
equivalent of 2001/ha. The tests were evaluated after 14 days (100% = plants completely
dead; 0% = no phytotoxic action on the plants).
Table El: Safener action on pre-emergent use on maize (Marista)
(Table Removed)
The test substances showed good results. The same results were obtained when
the compounds of the formula I were formulated in accordance with the other Examples
of WO 97/34485.
Example Fl: Post-emergent safening test on maize
The test plants were sown in containers under glasshouse conditions. A standard
earth was used as the culture substrate, hi a maize growth stage of one leaf (GS 11), the
herbicides were applied both by themselves and in a mixture with safeners to the soil and
leaf surface. The application was carried out with an aqueous suspension of the test
substances, prepared from a 25% wertable powder (Example F3,b according to WO
97/34485) or a suspension concentrate (Example F8 according to WO 97/34485), to
achieve a field equivalent of 2001/ha. The tests were evaluated after 28 days (100% =
plants completely dead; 0% = no phytotoxic action on the plants).
Table Fl: Safener action on post-emergent use on maize (Marista llf)
(Table Removed)

What is claimed is:
1. A compound of formula
(Figure Removed)
wherein
R1 and R2 are each independently of the other hydrogen, C-Calkyl, C-Chaloalkyl,
Ca-Cgcycloalkyl or Cs-Cgcycloalkyl-Ci-Csalkyl, or
R1 and R2 together with the carbon atom to which they are bonded form a
R3 and R4 are each independently of the other hydrogen, Ci-Cioalkyl, C-Ciohaloalkyl,
C3-C8cycloalkyl-C-Calkyl, C-Calkoxy-C-Calkyl or C-Ccycloalkyl, or
R3 and R4 together with the carbon atom to which they are bonded form a Cs-Cvring,
or
R1 with R3 or R4 and together with the carbon atoms to which they are bonded form
a Cs-Csring, or
R2 with R3 or R4 and together with the carbon atoms to which they are bonded form
a Cs-Cgring;
R5 and R6 are each independently of the other Cs-Cecycloalkyl, Ci-Cehaloalkyl,
Q-Cehydroxyalkyl, pyrrolyl-CH2-, pyrazolyl-CHi-, 4,5-dihydropyrazolyl-CH2-,
triazolyl-CH2-, imidazolyl-CH2-, tetrazolyl-CH2-, indolyl-CH2-, indazolyl-CH2-,
benzotriazolyl-CHz-, C2-C6alkenyl, C2-Cealkynyl, C2-C6haloal
carbonyloxy-C2-C6alkenyl, C2-C6alkenyloxy, C2-C6alkynyloxy,
Ci-CehaloalkylCarbonyl, Cs-Cecycloalkylcarbonyl, Ci-Cealkoxy-Ci-Csalkylcarbonyl,
phenylcarbonyl or phenylcarbonyl substituted by one to three R9, or
R5 and R are each independently of the other phenoxycarbonyl or phenoxycarbonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other benzyloxycarbonyl or benzyloxycarbonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other nitro, formyl, carboxyl, halogen,
azido, tbiocyanato, tri(Ci-C6alkyl)silyl, Ci-Cealkylcarbonyl-Ci^alkyl, Ci-
C6alkoxycarbonyl-Ci-C2alkyl, cyano-Ci-C2alkyl, Ci-Cealkylaminocarbonyl-
Ci-C2alkyl, di-Ci-C6alkylaminocarbonyl-Ci-C2alkyl, Ci-C6alkoxy-Ci-C2alkyl, Cr
C2alkyl-P(O)(OCi-C6alkyl)2, Ci-C2alkyl-NO2, mercapto, phenylthio or phenylthio
substituted by one to three R9, or
RS and Re are each independently of the other pyridylthio, Ci-Cealkylthio, Cj-
C6haloalkylthio, Ci-C6alkylthio-Ci-C6alkyl, C,-C6alkylsulfinyl, d-C6haloalkylsulfinyl,
Ci-Cealkylsulfmyl-Ci-Csalkyl, Ci-Cealkylsulfonyl, Ci-Cehaloalkylsulfonyl,
Q-Cealkylsulfonyl-Ci-Cealkyl, Cj-Cealkylsulfonyloxy-Ci-Cealkyl, benzylsulfonyl or
benzylsulfonyl substituted by one to three R9, or
R5 and R6 are each independently of the other phenylsulfinyl or phenylsulfinyl
substituted by one to three R9, or
R5 and R6 are each independently of the other phenylsulfonyl or phenylsulfonyl
substituted by one to three R9, or
R5 and R6 are each independently of the other hydroxyl, Q-Cealkoxy, Ci-Cehaloalkoxy,
Cj-Cealkylsulfonyloxy, Ci-Cghaloalkylsulfonyloxy, phenoxy or phenoxy
substituted by one to three R9, or
R5 and R are each independently of the other benzyl or benzyl substituted by one to
three R9, or
R5 and R6 are each independently of the other benzyloxy or benzyloxy substituted by
one to three R9, or
R5 and R6 are each independently of the other -CONH-SO2-Ci-C6alkyl, -CONHSOz-
Ci-Qshaloalkyl, -NHCHO, -NHCO-Cj-C6alkyl, -NHCO-Ci-C6haloalkyl,
-NHCOO-Ci-C6alkyl, -NHCONH-C,-C6alkyl, -NHCONH-Ci-C6haloalkyl, -NHSO2-
CrC6alkyl, -NHSO2-Ci-C6haloalkyl, -NHSO2-phenyl or -NHSO2-phenyl substituted
by one to three R9, or
R5 and R6 are each independently of the other -OCO-Ci-C6alkyl, -OCOCi-
Cehaloalkyl, -OCO-phenyl or -OCO-phenyl substituted by one to three R9, or
R5 and R6 are each independently of the other -OCONH-Ci-C6alkyl, -OCONHCi-
Cehaloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by one to three R9,
or
R5 and R6 are each independently of the other -CONR7R8 wherein R7 and R8 are
each independently of the other hydrogen, Ci-Cgalkyl, Cs-Cecycloalkyl, Cj-Cshaloalkyl,
phenyl or phenyl substituted by Q-Cehaloalkyl, nitro, cyano or by halogen, or
R7 and R8 together form a Cs-Cgalkylene group which optionally contains one
oxygen or sulfur atom or one to two amino or Ci-Cealkylamino groups, or
Rs and R6 are each independently of the other phenyl or naphthyl, which is
optionally substituted by one to three substituents independently selected from
Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6haloalkyl, C,-C6hydroxyalkyl, C2-C6aIkenyl,
C2-Cealkynyl, C2-C6haloalkenyl, Ci-Cealkylcarbonyl, Q-Cealkoxycarbonyl,
benzyloxycarbonyl or benzyloxycarbonyl substituted by one to three R9, nitro,
cyano, formyl, carboxyl, halogen, azido, thiocyanato, tri(Ci-C6alkyl)silyl, mercapto,
ph.enyltb.io or phenylthio substituted by one to three R9, phenylsulfinyl or phenylsulfinyl
substituted by one to three R9, -SF5, Ci-Cgalkylthio, Ci-Cgalkylsulfinyl, Cj-
C6alkylsulfonyl, d-C6alkyl-SO(NH)-, Ci-C6alkyl-SO(NCH3), d-Cghaloalkylthio,
Ci-Cehaloalkylsulfinyl, CpCehaloalkylsulfonyl, benzylsulfonyl or benzylsulfonyl
substituted by one to three R9, phenylsulfonyl or phenylsulfonyl substituted by one
to three R9, hydroxyl, Ci-Cgalkoxy, Ci-C6haloalkoxy, Cj-Cealkylsulfonyloxy, Cj-
Cehaloalkylsulfonyloxy, phenoxy or phenoxy substituted by one to three R9,
benzyloxy or benzyloxy substituted by one to three R9, -CONH-SCVCi-CgalkyI,
-CONH-SO2-Ci-C6haloalkyl, -NHCO-d-C6alkyl, -NHCO-Ci-C6haloalkyl,
-NHCO2-C1-C6alkyl, -NHCO2-Ci-C6haloalkyl, -OCO-C,-C6alkyl, -OCOCi-
Cghaloalkyl, -OCO-phenyl or -OCO-phenyl substituted by one to three R9,
-OCONH-Ci-C6alkyl, -OCONH-Ci-C6haloalkyl, -OCONH-phenyl or -OCONHphenyl
substituted by one to three R9, or by -CONR7R8 wherein R7 and R8 are each
independently of the other hydrogen, Q-C6alkyl, Ci-Qhaloalkyl, Ca-Cecycloalkyl,
phenyl or phenyl substituted by Ci-Cghaloalkyl, nitro, cyano or by halogen, or R7
and R8 together form a Cs-Cgalkylene group which optionally contains one oxygen
or sulfur atom or one to two amino or Ci-Cealkylamino groups, or
R5 and R6 are each independently of the other a 5- to 10-membered heterocycle
containing one to three nitrogen, oxygen or sulfur atoms, which is optionally benzofused,
and which is optionally substituted by one to three substituents independently
selected from Ci-Csalkyl, Cs-Cecycloalkyl, Cj-Cehaloalkyl, Ci-Cs-hydroxyalkyl,
C2-C6alkenyl, C2-C6alkynyl, Cz-Cghaloalkenyl, Ci-Cealkylcarbonyl, Ci-Cealkoxycarbonyl,
benzyloxycarbonyl or benzyloxycarbonyl substituted by one to three R9,
phenylthio or phenylthio substituted by one to three R9, phenylsulfinyl or phenylsulfinyl
substituted by one to three R9, nitro, cyano, formyl, carboxyl, halogen,
azido, thiocyanato, tri(Ci-C6alkyl)silyl, mercapto, -SFs, Ci-Cgalkylthio, Ci-Cgalkylsulfinyl,
Ci-C6alkylsulfonyl, Ci-C6haloalkylthio, d-C6haloalkylsulfmyl, Ci-C6halo-
alkylsulfonyl, benzylsulfonyl or benzylsulfonyl substituted by one to three R9,
phenylsulfonyl or phenylsulfonyl substituted by one to three R9, hydroxyl, C\-
Cealkoxy, Ci-C6haloalkoxy, Ci-Cgalkylsulfonyloxy, Ci-Cehaloalkylsulfonyloxy,
phenoxy or phenoxy substituted by one to three R9, benzyloxy or benzyloxy
substituted by one to three R9, -CONH-SO2-Ci-C6alkyl, -CONH-SO2-Ci-C6haloalkyl,
-NHCO-C,-C6alkyl, -NHCO-Ci-C6haloalkyl, -NHCO2-C,-C6alkyl, -NHCO2-
Ci-Cehaloalkyl, -OCO-Ci-C6alkyl, -OCO-Ci-C6haloalkyl, -OCO-phenyl or -OCOphenyl
substituted by one to three R9, -OCONH-CrC6alkyl, -OCONH-Ci-C6haloalkyl,
-OCONH-phenyl or -OCONH-phenyl substituted by one to three R9, or by
-CONR7R8 wherein R7 and R8 are each independently of the other hydrogen,
Cj-Cealkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, phenyl orphenyl substituted by
Ci-Cehaloalkyl, nitro, cyano or by halogen, or R7 and R8 together form a €3-
Cgalkylene group which optionally contains one oxygen or sulfur atom or one to two
amino or Ci-Cealkylamino groups, and
R6 may additionally be hydrogen, cyano, Ci-C6alkyl or CpCealkoxycarbonyl, or
Rs and R6 together with the carbon atom to which they are bonded form a 3- to 10-
membered ring, which optionally contains one to three nitrogen, oxygen or sulfur
atoms, and which is optionally substituted by one to four substituents independently
selected from Cj-Cealkyl, Q-Cehaloalkyl, Cj-Cgalkoxy, Ci-Cgalkoxycarbonyl, Ci-
Cgalkylcarbonyl, Cj-Cealkylsulfonyl, Ci-Cehaloalkylsulfonyl, Ci-Cghaloalkylcarbonyl,
Ci-Cealkenyl, halogen, cyano, nitro, phenyl or phenyl substituted by
Ci-Cehaloalkyl, nitro, cyano or by halogen, phenylcarbonyl or phenylcarbonyl
substituted by Q-Cghaloalkyl, nitro, cyano or by halogen, or
R5 and R6 together with the carbon atom to which they are bonded form a group of
the formula C=CR10RU wherein R10 and R11 are independently selected from
hydrogen, Ci-C6alkyl, Ci-C6alkoxy, -NH(Ci-C6alkyl), -N(Ci-C6alkyl)2, Ci-
C6alkoxy-Ci-C2alkyl, Ci-C6alkylcarbonyloxy, Ci-C6alkylcarbonyloxy-Ci-C2alkyl,
Ci-C6alkoxy-Ci-C2alkylcarbonyloxyorCi-C6alkylcarbonyloxy-Ci-C2alkylcarbonyloxy;
m is 0,1 or 2;
nis 1,2 or 3;
Y is hydrogen, Ci-Cealkyl, Ca-Cecycloalkyl, Ci-C6haloalkyl, C2-C6alkenyl,
C2-C6alkynyl, C2-C6haloalkenyl, C]-C6alkylcarbonyl, Ci-C6alkoxycarbonyl, nitro,
cyano, formyl, hydroxyl, carboxyl, halogen, azido, thiocyanato, tri(Ci-C6a!kyl)silyl,
Ci-Cealkylthio, Cj-Cgalkylsulfinyl, Cr-Cgalkylsulfonyl, benzylsulfonyl or benzylsulfonyl
substituted by one to three R9, or
Y is phenylsulfonyl or phenylsulfonyl substituted by one to three R9, or
Y is Ci-Cgalkoxy, Ci-Cshaloalkoxy, Ci-Cealkylsulfonyloxy, Ci-Cehaloalkylsulfonyloxy,
phenoxy or phenoxy substituted by one to three R9, or
Y is benzyloxy or benzyloxy substituted by one to three R9, or
Y is -CONH-SO2'-Ci-C6alkyl or -CONH-SO2-CrC6haloalkyl, or
Y is phenyl, naphthyl or tetrahydronaphthyl, which is optionally substituted by one
to three substituents independently selected from Ci-Cgalkyl, Cj-Cecycloalkyl,
CrC6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy-Ci-C6alkyl, C2-C6aIkenyl,
C2-C6alkynyl, C2-Cehaloalkenyl, Ci-Cealkylcarbonyl, Ci-Cghaloalkylcarbonyl, C|-
Cealkoxycarbonyl, benzyloxycarbonyl, nitro, cyano, formyl, carboxyl, halogen,
azido, thiocyanato, tri(Ci-C6alkyl)silyl, mercapto, phenylthio, phenylsulfinyl, -SFs,
Ci-C6alkylthio, Ci-C6haloalkylthio, Ci-C6haloalkylsulfinyl, Ci-C6haloalkylsulfonyl,
Ci-Csalkylsulfinyl, Ci-C6alkylsulfonyl, benzylsulfonyl or benzylsulfonyl substituted
by one to three R9, phenylsulfonyl or phenylsulfonyl substituted by one to three R9,
hydroxyl, Ci-Cealkoxy, Cs-Cgcycloalkyloxy wherein one of the CEfe groups is
optionally replaced by an oxygen atom, Ci-Cshaloalkoxy, C2-C6alkenyloxy,
CrCealkynyloxy, Q-Cealkylsulfonyloxy, Cj-Cahaloalkylsulfonyloxy, phenoxy or
phenoxy substituted by one to three R9, benzyloxy or benzyloxy substituted by one
to three R9, -CONH-SO2-C]-C6alkyl, -CONH-SO2-Ci-C6haloalkyl, -NH-SO2-
CrC6alkyl, -NH-SO2-Ci-C6haloalkyl, -NHCO-Ci-C6alkyl, -NHCO-Ci-C6haloalkyl,
-NHCO2-CrC6alkyl, -NHCO2-Ci-C6haloalkyl, -OCO-Ci-C6alkyl, -OCOCi-
Cehaloalkyl, -OCO-phenyl or -OCO-phenyl substituted by one to three R9,
-OCONH-Ci-C6alkyl, -OCONH-Ci-C6haloalkyl, -OCONH-phenyl or -OCONHphenyl
substituted by one to three R9, or by -CONR7R8 wherein R7 and R8 are each
independently of the other hydrogen, Ci-Cealkyl, Ci-Cghaloalkyl, Cs-Qcycloalkyl,
phenyl or phenyl substituted by Ci-Cehaloalkyl, nitro, cyano or by halogen, or R7
and R8 form a Ca-Cgalkylene group which optionally contains one oxygen or sulfur
atom or one to two amino or Ci-Csalkylamino groups, or
Y is a 5- to 10-membered heterocycle containing one to three nitrogen, oxygen or
sulfur atoms, which is optionally benzo-fused, and which is optionally substituted by
one to three substituents independently selected from Ci-Cealkyl, Cs-Cecycloalkyl,
CrCehaloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy-Ci-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, Cz-Cehaloalkenyl, Ci-Cealkylcarbonyl, Cj-Cshaloalkylcarbonyl, C\-
Cgalkoxycarbonyl, nitro, cyano, formyl, carboxyl, halogen, azido, thiocyanato,
tri(Ci-C6alkyl)silyl, mercapto, -SF5, Ci-C6alkylthio, Ci-C6alkylsulfinyl, C]-C6alkylsulfonyl,
Ci-Cahaloalkylthio, Ci-Cahaloalkylsulfinyl, Ci-Cehaloalkylsulfonyl,
benzylsulfonyl or benzylsulfonyl substituted by one to three R9, phenylsulfonyl or
phenylsulfonyl substituted by one to three R9, hydroxyl, Ci-Cealkpxy,
C3-C6cycloalkyloxy wherein one of the CH2 groups is optionally replaced by an
oxygen atom, Ci-Cehaloalkoxy, Ci-Cealkenyloxy, C2-C6alkynyloxy, Ci-C6alkylsulfonyloxy,
Ci-Cehaloalkylsulfonyloxy, phenoxy or phenoxy substituted by one to
three R9, benzyloxy or benzyloxy substituted by one to three R9, -CONH-SO2-
Ci-C6alkyl, -CONH-SO2-CrC6haloalkyl, -NH-SOj-d-Cealkyl, -NH-SO2-
Ci-C6haloalkyl, -NHCO-Ci-C6alkyl, -NHCO-CrC6haloalkyl, -NHC02-Ci-C6alkyl,
-NHCO2-Ci-C6haloalkyl, -OCO-CrC6alkyl, -OCO-d-C6haloalkyl, -OCO-phenyl or
-OCO-phenyl substituted by one to three R9, -OCONH-Ci-C6alkyl, -OCONHCi-
C6haloalkyl, -OCONH-phenyl or -OCONH-phenyl substituted by one to three R9,
or by -CONR7R8 wherein R7 and R8 are each independently of the other hydrogen,
Q-Cealkyl, Ci-Cehaloalkyl, Ca-Cecycloalkyl, phenyl or phenyl substituted by
Ci-Cehaloalkyl, nitro, cyano or by halogen, or R7 and R8 together form a €3-
Cgalkylene group which optionally contains one oxygen or sulfur atom or one to two
amino or Ci-Cgalkylamino groups;
R9 are independently from each other Q-Cshaloalkyl, Ci-Cealkoxycarbonyl, nitro,
cyano, formyl, carboxyl or halogen;
and to N-oxides, salts and optical isomers of compounds of formula I.
2. A process for the preparation of a compound of formula I wherein R1, R2, R3, R4, R5,
R6 and Y are as defined in claim 1, m is 2, and n is 1, wherein a compound of
formula la
(Figure Removed)
wherein R1, R2, R3, R4, and Y are as defined in claim 1, and m is 2, is reacted in an
inert solvent in the presence of a base in a single step or stepwise in succession with
compounds of formula R5-X and/or R6-X, wherein R5 and R5 are as defined in claim
1 , and X is a leaving group.
3. A process according to claim 2 wherein R5 and/or R6 are halogen.
4. A process for the preparation of a compound of formula I wherein R1 , R2, R3, R4, R5
and Y are as defined in claim 1, R6 is Ci-C10alkyl or halogen, m is 2, and n is 1,
wherein a compound of formula Ib
(Figure Removed)
wherein R1, R2, R3, R4, and Y are as defined in claim 1, R6 is Ci-Cioalkyl or halogen,
and m is 2, is reacted in an inert solvent in the presence of a base with a compound
of formula R5-X, wherein R5 is as defined in claim 1, and X is a leaving group.
5. A process according to claim 4 wherein R5 is halogen.
6. A process for the preparation of a compound of formula I wherein R1, R2, R3, R4 and
Y are as defined in claim 1, R5 and R6 together with the carbon atom to which they
are bonded form a cyclopropyl ring which is optionally substituted by one to four
substiruents independently selected from Ci-Cealkyl, Ci -Cealkoxycarbonyl, Ci-
Cealkylcarbonyl, nitro or phenylcarbonyl, m is 2, and n is 1, wherein a compound of
formula VII
(Figure Removed)
wherein R1, R2, R3, R4 and Y are as defined in claim 1 , m is 2, and RD3 and R154 are
hydrogen or Ci-Cealkyl, is reacted with tri(Ci-C6alkyl)sulfonium halide or tri(Ci-
C6alkyl)sulfoxonium halide, or with a compound of the formula
(Figure Removed)
wherein RCYI and RCY2 are halogen, Ci-Cealkoxycarbonyl, Ci-Cealkylcarbonyl,
phenylcarbonyl or nitro, RCY1 additionally can be hydrogen, and XL is a leaving
group in an inert solvent in the presence of a base.
7. A process for the preparation of a compound of formula I wherein R1, R2, R3, R4, R6
and Y are as defined in claim 1, R5 is chlorine, bromine or iodine, m is 1 or 2, and n
is 1, wherein a compound of formula Ic
(Figure Removed)
wherein R1, R2, R3, R4, R6 and Y are as defined in claim 1, is reacted in an inert
solvent in succession with an N-halosuccinimide and an oxidising agent.
8. A herbicidal composition which comprises a herbicidally effective amount of a
compound of formula I in addition to formulation adjuvants.
9. A method of controlling grasses and weeds in crops of useful plants, which
comprises applying a herbicidally effective amount of a compound of formula I, or
of a composition comprising such a compound, to the plants or to the locus thereof.
10. A composition according to claim 8, which comprises a further herbicide in addition
to the compound of formula I.
11. A composition according to claim 8, which comprises a safener in addition to the
compound of formula I.