Note: Descriptions are shown in the official language in which they were submitted.
10~ 3
The present invention relates to novel l-substituted
aralkyl imidazoles, and acid addition salts thereof, and
also metal salt complexes thereof, and to processes for
the preparation of such compounds.
The l-substituted aralkyl imidazoles of this invention
possess eradicant fungicidal properties which are unique
in that they kill phytophathogenic fungi in infected plant
tissues and therefore can be utilized after fungal infection
has already occurred. The systemic properties of these
compounds are equally unique in that the compounds will move
both acropetally and basipetally in plant tissues. Further-
more, these compounds possess protectant properties against
phytophthogenic fungi when applied to the plants prior to
infection.
This invention is concerned with the preparation and
use of l-substituted aralkyl imidazoles of the formula:
IRl ~ N
Z-(A) -C-(B) -N ~ (X)a (I)
R
wherein 2 is a (C6-C14) aryl or a substituted (C6-C14) aryl
group, Rl is a hydrogen atom, a (Cl-C10) alkyl group; a
(C2-C12) alkyl group; a (C2-C12) alkenyl group, a (C7-C9)
aralkyl or substituted (C7-Cg) aralkyl group; a phenyl or
substituted phenyl group, a (C3-C7) cycloalkyl group, or a
(C5-C7) cycloalkenyl group; R2 is a (Cl-C10) alkyl group,
a (C2-C12) alkenyl group, a (C7-Cg) aralkyl or substituted
(C7-Cg) aralkyl group; a phenyl or substituted phenyl group,
a (C3-C7) cycloalkyl group, or a C5-C7) cycloalkyl group;
A and B are divalent (Cl-C5) alkylene groups; X is a (Cl-C4)
alkyl group, a halogen atom or a nitro group; a is an
integer from 0 to 3; n is the integer 0 or 1;
.~ -2-
10~53;~.3
n' is the integer O or l; and the sum of n plus n' is equal to l
or 2; or when Z is an unsubstituted phenyl group, R is a hydrogen
atom, A is methylene, and n' is O, then R2 is a (C4-C10) alkyl
group, a (C2-Cl2) alkenyl group, a (~C7-Cg) aralkyl or substituted
(C7-Cg) aralkyl group, a phenyl or substituted phenyl group, a
(C3-C7) cycloalkyl group or a (C5-C7) cycloalkenyl group.
A further embodiment of this invention is the metal salt
complexes of the above l-substituted aralkyl imidazoles having
the formula: Rl _ N
(X) . MY (II)
l2 ~ a m
wherein Z, A, B, Rl, R2, n, n', X and a are the same as above and
M is a metal cation which can be selected from Groups IIA, IVA, VA,
IB, IIB, VIB, VIIB and VIII of the Periodic Table. Y is a solubi-
lizing anion counterion and m is 1-4.
In the above description of Z the term "aryl" refers to
a phenyl, naphthyl, biphenyl, acenaphthenyl, indanyl, indolyl,
pyridyl, pyrimidyl, pyrryl, furyl or thienyl group, preferably a
phenyl group, which can be unsubstituted or substituted with up to
three substituents, preferably two substituents, selected from the
group consisting of (Cl-C4) alkyl, methoxy, ethoxy, chloro, fluoro,
bromo, iodo, nitro, amino, methylthio and the like.
The terms "A" and "B" are divalent alkylene groups of
from l to 5 carbon atoms which can be branched or straight chained.
The term "alkyl" in the description of R and R2 above
refers to a straight or branched chain alkyl group of from 1 to
10 carbon atoms. The term "alkenyl" refers to a straight or
branched chain alkenyl group of from 2 to 12 carbon atoms.
lo~s~3
The term "cycloalkyl" refers to a cycloalkyl group of from 3 to 7
carbon atoms and the term "cycloalkenyl" refers to a cycloalkenyl
group of from 5 to 7 car~on atoms.
The term "aralkyl" refers to an aralkyl group of from 7
to 9 carbon atoms, preferably ~enzyl or phenethyl, which can be
substituted with up to two substituents selected from the group
consisting of (Cl-C4) alkyl, methoxy, ethoxy, chloro, fluoro,
bromo, iodo, nitro, amino, methylthio and the like.
By the term substituted phenyl as used in the definition
of R and R2 is meant a phenyl group which can be substituted with
up to two substituents selected from the group consisting of
(Cl-C4) alkyl, methoxy, ethoxy, chloro, fluoro, bromo, iodo, nitro,
amino, methylthio and the like.
The preferred compounds of this invention are those in
which n' in Formulas I and II is one. The more preferred com-
pounds of this invention are those in which n' is one and n is
zero. The most preferred compounds of this invention are those
in which n' is one, n is zero; Rl is a hydrogen atom; a is zero;
Z is a substituted phenyl group having up to three substituents
selected from the group consisting of (Cl-C4) alkyl, methoxy,
ethoxy, chloro, fluoro, bromo, iodo, nitro, amino and methylthio,
and R is an alkyl group of from 4 to lO carbon atoms, an alkenyl
group of from 2 to 12 carbon atoms, an aralkyl group of from 7 to
9 carbon atoms which can be substituted with up to two substituents
selected from the group consisting of (Cl-C4) alkyl, methoxy,
ethoxy, chloro, fluoro, bromo, iodo, nitro, amino and methylthio;
a phenyl group which can be substituted with up to two substituents
selected from the group consisting of (Cl-C4) alkyl, methoxy,
ethoxy, chloro, fluoro, bromo, iodo, nitro, amino and
-- 4 --
10653;~;~
methylthio; a cycloalkyl group of from 3 to 7 carbon atoms or a
cycloalkenyl group of from 5 to 7 carbon atoms.
Typical compounds encompassed by this invention include:
1-[~-(2,4-dichlorophenyl)hexyl]imidazole
1-[~-(2-chlorophenyl)hexyl]imidazole
1-[~-(4-bromophenyl)hexyl]imidazole
l-[B-(3-iodophenyl)hexyl]imidazole
1-[~-(2,6-dichlorophenyl)decyl]imidazole
1-[~-(2,4-dichlorophenyl)~-(p-chlorophenyl)
ethyl]imidazole
1-[~-(2,4-dichlorobenzyl)pentyl]imidazole
1-[~-(2,4-dichlorobenzyl)hexyl]imidazole
1-[~-(2-methyl-4'-chlorophenyl)heptyl]imidazole
1-[~-(2,4-dichlorophenethyl)hexyl]imidazole
1-[~-(2,4-dichlorophenyl)nonyl]imidazole
1-[~-(2,4-dimethylthiophenyl)hexyl]imidazole
1-[~-(4-(nitrophenyl)hexyl]imidazole
1-[~-(3,4-dichlorophenyl)hexyl]imidazole
1-[~-(4-tolyl)hexyl]imidazole
1-[~-(4-anisyl)hexyl]imidazole
1-[~-(2,4-dichlorophenyl)-~-cyclopropyl ethyl]
imidazole
1-[~-(2,4-dichlorophenyl)-~-cyclopentyl ethyl]
imidazole
1-[~-(2,4-dichlorophenyl)-~-cycloheptyl ethyl]
imidazole
l-[~,~-trimethylene-~-(2',4'-dichlorophenyl)ethyl]
imidazole
O l-[~,~-pentamethylene-~-(2',3'-dibromophenyl)ethyl]
3 imidazole
l-[~,~-heptamethylene-~-(3',5'-difluorophenyl)ethyl]
imidazole
10~;53Z;~
The compounds of this invention can be prepared by
standard methods of synthesis. Typical methods of preparation
which can be utilized in the preparation of these compounds
include the following general syntheses, the temperatures given
unless indicated otherwise are in degrees centigrade.
-substituted alkyl) imidazole
l~hen the proper acetate derivative (III) is reacted with
sodium hydride in tetrahydrofuran or glyme it forms the correspon-
ding sodio salt (IV). The reaction of (IV) with an organic halide
10affords the ester (V).
Z-CH2C02C2H5 NaH ~Z-CHNaC02C2H5
(III) (IV)
~ RX
Z-cHRcH2oH T.i~1~4 Z-CHRC02C2H5
~VI) \ (V)
CH3S02Cl/(c2H5)3 \
2 2 3 \SOC12 or PC15
(VII)
(X)a ~
20N~;~3 ZCHRCH2Cl
H
Z-CHRCH2N 3 (X)a N
(VIII) Na
-- 6 --
i()~;53;~3
These esters (V) are converted to the corresponding carbinol derivatives (VI)
by a reduction with reagents such as lithium alu~inum hydride (LiAlH4) in
ether or bis(2-methoxyethoxy~ aluminum hydride in benzene. The subsequent
treatment of (VI) with methane sulfonyl chloride in the presence of triethyl
amine in an aromatic hydrocarbon solvent such as benzene or toluene provides
the sulfonate (VII). Treatment of (VI) with thionyl ch~oride or phosphorus
pentachloride in an aromatic hydrocarbon such as benzene or toluene provides
the chloride (VIIa). The reaction of (VII) with excess of an imidazole or
(VIIa) with the sodium salt of an imidazole either neat or in the presence
10 Of such 901vents as benzene, glyme, N,N-dimethylformamide, etc., gives the
aIkylated imidazole products (VIII).
-substituted aIkYl~ imidazole
The 1-(a-substituted alkyl) imidazoles are synthesized by a differ-
ent route.
Z-CH2Cl _ Mg ~ Z-CH2MgCl RCH0 Z-CH2CHROH
(IX) (X)a (X)
" N ~ CH3S0 Cl/
~ N H (C2H5~3N
Z-CH2CHR-N ~ ( )a -CH2CHROS02CH3
(XI)
The Grignard reagent (IX) is formed from the reaction of magnesium
metal with the appropriate organic chloride in ether. This reagent (IX) sub-
sequently reacted with the desired aldehyde to provide the carbinol derivati~e(X). The formation of the sulfonate or chloride followed by its reaction
with an imidazole or its sodio salt is carried out by the previously described
route to give the product (XI).
1()t;53;~;~
Methylene Chain Extension - Malonate Route
A malonate synthesis is utilized to provide the starting materials
for some other closely related analogues where the methylene chain is ex-
tended.
Z-(CH2)nX +NaCH(C02C2Hs)2 1~Z-(cH2)ncH(co2c2H5)2
(XII) (XIII)
1. NaH
~ 2. RX
1. KOH
Z-(cH2)ncHRco2H ~-~ 2 HCl z_( ,H2)nCR(c02c2Hs)2
~XV) 3 160, -C02 (XIV)
¦ LiAlH4
CH3S02Cl/(C2H5)3N
Z-(CH2)nCHRCH20H _ ~ Z-(CH2)n--CHRCH20S02CH3
(XVI) I ~ a
~ NH ~ N
Z-(cH2)ncHRcH2N~ J( X )
(XVII)
10 The reaction of an aIkyl halide (XII) with sodio ethyl malonate in a solvent
such as THF or glyme gives the substituted malonate (XIII). A further re-
action of (XIII) with first sodium hydride in THF followed by the addition
of the appropriate organic halide affords the disubstituted ester (XIV). A
basic hydrolysis of (XIV) and a subsequent acidification and decarboxylation
15 gives the mono acid (XV). The reduction of (XV) with LiAlH4 gives the cor-
responding carbinol derivative (XVI). The alkylated imidazole product (XVII)
is then formed by the usual route.
i5~;~3
Methylene Chain Extension
The methylene chain can be extended from the methane sulfonate (VII)
via the preparation of the nitrile (XVIII).
Z-cHRcH2oso2cH3 NaCN Z-cHRCH2CN
(VII) ~ (XVIII)
~/ 1 H2S04
5Z-cHRcH2cH2oH LiAlH4 Z-CHRCH2COOH
(XX) (XIX)
2cl/(c2Hs)3N ~ a
I _ Z-cHRcH2cH2oso2cH3 H ~ Z-cHRcH2cH2N ~ (X)a
This sulfonate (VII) in DMF is treated with sodium cyanide in DMF
to give the nitrile derivative (XVIII). The hydrolysis of (XVIII) in boiling
50% sulfuric acid provides the acid (XIX) which is subsequently reduced with
LiAlH4 to provide the alcohol (XX). m e imidazole derivative is then formed
via the sulfonate in the usual way or the sulfonate can be recycled through
the process for further chain extension.
Phen.yl Analo~ues
The synthesis of the phenyl substituted analogue involves a
Darzenls reaction. A substituted benzophenone is reacted with ethyl
chloroacetate in the presence of sodium hydride to give the glycidic
ester (X~I).
~()65;~'~3
Z - C = O +NaH ClCH2C2H5 Z-c-cHco2c2H5
C6H5 C6H5
(XXI)
¦ Hydrolysis
~ OH
Z-fHCHO 1600 Z ~ C = CC02H
C6H5 C6H5
(XXII)
~ LiAlH4
Z-cHCH20H 2 2 5 3 ~ Z-lcHcH2oso2cH
6 5 C6H5
(xxlII) (X)~
.1
rN
., z_
C6H5
(XXIV)
A hydrolysis and a subsequent decarboxylation of (XXI) gives the diarylacetaldehyde (XXII). This aldehyde (XXII) is reduced to the corresponding
alcohol (XXIII) by LiAlH4, and it is then converted to the aIkylated
imidazole product (XXIV) by the usual route.
--10--
10~:;53;~;~
Disubstituted alkylimidazole
The Friedel-Craft acylation of a substituted aromatic
hydrocarbon with an acyl halide in the presence of aluminum
chloride either neat or with a halogenated hydrocarbon provides
the desired product (XXV).
O O
ll AlCl ll
Z + ClCR 3 Z-CR
(XXV)
2 2 2 5
2. NaH
1. NaOH ~ f \
Z-CHRCHO _ z_f_CHCo2c2H5
(XXVII) 2. HCl R (XXVI)
1 3. 140
1 RlMgX
Z-CHRCHR OH CH3SO2Cl/(C2H5)3N (X)
(XXVIII) I H
1 /~
Z-CHRCHR N ~ (X)a
(XXIX)
Treatment of (XXV) with an excess of ethyl chloracetate and sodium
hydride gives the glycidic ester (XXVI) which upon saponification
with base and hydrolysis with hot mineral acid followed by decar-
boxylation gives the aldehyde (XXVII). A Grignard Reaction with
an alkyl or aryl magnesium halide yields the alcohol (XXVIII).
The formation of the sulfonate followed by its reaction with an
imidazole as previously described gives the product XXIX.
-- 11 --
;53;~;~
disubstituted alkyl imidazole
When the appropriate sodio alkyl acetate derivative (XXX) pre-
pared as previously described is reacted at elevated temperatures in a
solvent such as ether, tetrahydrofuran or dimethylformamide with an
iodoalkane the desired trisubstituted acetate (XXXI) is obtained.
Z-CHR1NaC02C2H5 R2X
(XXX) (XXXI)
J LiAlH4
R1 1~1
Z-l CH2oso2cH3 ~ CH3S02Cl/(C2H~)3N Z-ccH2oH
R2N~ 12
t N ~ (XXXII)
~ H
Z~ ~ ~ ~ (X)a
(XXXIII)
Reduction of (~XXI) with LiAlH4 in anhydrous ether gives the alcohol (XXXII).
Formation of the sulfonate followed by the imidazole reaction as previously
described gives the desired product (XXXIII).
-12-
l()~;S;~;~3
Alternate Routes to PhenYl An _o~ues
The reduction of a substituted phenylacetic acid (XXXIV) with
LiAlH4 in tetrahydrofuran gives the alcohol (XXXV).
Z-lcHCO2H
C6H5-nRn ~ Z-CIHCH20H
(XXXIV) C6H5 R
(X~V)
(X)a ¦ CH SO Cl/
N~ ~ (C2HS)3N
5Z-cHcH2N ~ a ~ _ N Z_ HcH2oso2cH3
6 s-n n 6 5-n n
(XXXVI)
Formation of the sulfonate by reaction with an imidazole gives the desired
product (XXXVI).
substituted diar~lalkYl) imidazole
m e reaction of chloroacetaldehyde diethylacetal with a sub-
stituted aromatic hydrocarbon in the presence of sulfuric acid at room tem-
perature gives the substituted arylethylchloride (XXXVII). The reaction of
(XXXVII) with the sodium salt of an imidazole as previously described affords
the product (XXXVIII).
Z + (c2H5o)2cH2cl H2S04 Z-~CHCH2Cl
(XXXVII)
(X)a
l N~
Na ~ N
Z-~CHCH2N ~ (X)a
-13_ (XXXVIII)
iO~5;~3
-(substituted aryl) hexyl~imidazole
When a substituted aromatic hydrocarbon is treated with
1,2-epoxyhexane in the presence of lithium aluminum hydride the
rearranged hexanol (XXXIX) is obtained.
~\
Z + CH-CH2 LiAlH4 Z-fH(CH2)40H
C4Hg (X) CH3
I a (XXXIX)
N~3 1
r N H 1CH3SO2C1/(C2H5)3N
Z-CH(CH2)4N ~ (X) ~ ~ _ Z-IH(CH2)40S02CH3
CH3 CH3
(XL)
Formation of the methane sulfonate followed by the
reaction with an imidazole gives the product (XL).
When a benzene substituted with electron donating groups
is treated with 1,2-epoxyhexane in the presence of stannic
chloride the hexanol (XLI) is obtained.
o
/ \ SnCl
Z + CH-CH2 4 ~ Z-CHCH20H
C4Hg C4Hg
(XLI)
The imidazole derivative is formed via the above route
from the methane sulfonate.
- 14 -
;53Z;~
l-[~-(alkylthio or alkylsulfonyl substituted phenyl) alkyl]
imidazoles
The alkylthio and alkylsulfonyl derivatives are prepared
from the aldehyde (XLII).
RS ~ HO LiAlH~ RS
_~ ~H20H
(XLII) (XLIII)
~H3SO2Cl/(c2H5)3
R ~ CH2CN NaCN RS ~ CH20SO2CH3
(XLV) 1. NaH
(XLIV)
2. R'X
RS ~ ~
C~N 254 R ~ CHCO2R"
(XLVI) R
(XLVII)
RS ~ N 1 LiAlH
1. CH3so2cl/(c2H5)3N 4
~CH2 ~ a~ (X) RS ~
Rl 2-N~ ~ a ~ ~HCH2OH
( XLIX) (XLVIII)
H
The aldehyde (XLII) is reduced to the alcohol (XLIII) with LiAlH4.
The alcohol (XLIII) is reacted with methane sulfonyl chloride in
the presence of triethylamine to form the sulfonate (XLIV).
Treatment of the methane sulfonate (XLIV) with sodium cyanide
gives the benzyl nitrile derivative (XLV). Alkylation of the
nitrile (XLV) via NaH metallation followed by treatment with alkyl-
halide gives the ~-alkyl benzylnitrile derivative (XLVI). Hydro-
lysis of the nitrile (XLVI) with sulfuric acid in an alcoholic
solvent gives the ~-alkyl phenylacetic acid ester (XLVII) which
upon reduction with LiAlH4 gives the phenethyl alcohol (XLVIII).
The imidazole product is formed via the methane sulfonate as shown
- 15 -
53;~;~
above. When the imidazole (XLIX) is oxidized with hvdrogenperoxide in acetic acid the alkylsulfonyl derivative (L) is
formed.
(XLIX) H202/HOAC RSO ~ HCH2N ~ (X~ a
(L)
l-[~-(nitro substituted phenyl) alkyl] imidazole
The nitro substituted phenyl derivatives (LII) are formed
by nitration of the unsubstituted or substituted analogs (LI).
(R ~ CHCH2 ~ (X) 3/ 2 4~ ~ HCH2N ~ (X)a
R' N
(LI) (LII)
l-[~-(amino substituted phenyl) alkyl] imidazole
The amino substituted phenyl derivatives (LIII) are formed
by reduction of the nitro substituted phenyl derivative.
N
(LII) Fe/HCl/CH30H (R)n ~ CHCH2 ~ X) a
(LIII)
Substituted l'midazole derivatives
The analogs in which the imidazole rings itself is substi-
tuted (LV) are prepared by reacting the appropriate methane sul-
fonate (LIV) with either an excess of the substituted imidazole or
the sodium salt of the imidazole.
+ Z-(A) -C-(B)n,-0S02CH3 _ Z (A)n I ( n~ ~ (X)a
H (LIV) ~
~ (LV)
J~ cH3oNa/DMF
(X)a
N ~ (LIV)
~a - 16 -
10~
Acid Addition Salts
__
R ~(X) a IIA, ~ ~ (A) - ~ ) n ~(X ¦ A
(LVI) (LVII)
The salts of aralkyl imidazole derivatives are prepared
by treating an ether solution of the imidazole (LVI ) with an
equivalent amount of the desired inorganic or organic acid dissolved
in ether or alcohol followed by filtration or concentration then
filtration to give the desired salt.
Metal Complex
Z-(A)n-c-(l~)n~-N~3--(x)a ~ ~A)-nC-(l~)n~ y
(LVI) III)
The metal complex salts of the aralkyl imidazole deriva-
tives (LVIII) are prepared by the treatment of an alcoholic or
aqueous solution of the imidazole (LVI) with a metal salt at
temperatures from about 15C to about 60C.
The fOllowing examples are provided merely to illustrate
the methods of preparation of the l-substituted imidazoles and
their metal complex salts. These examples are not to be considered
in any ways as limitations of the scope of this invention.
EXAMPLE 1
lrB-(2,4-dichlproph~nyl~ hexyllimidaz~le
1. ethvl-B-(2,4-dichloro~henvl) hexanoate
To 58.6g (1.22 mole) of 50% sodium hydride in 1 liter of
anhydrous tetrahydrofuran (THF) is added at 40, 50.0g (0.215 mole)
of ethyl-2,4-dichlorophenyl acetate, and the mixture is stirred
for 10 min. When the evolution of H2 gas begins the temperature
of the reaction is lowered to 10, and 200.0 g (0.858 mole) of
- 17 -
10~;53~;~
additional ester is added dropwise. When this addition is com-
plete~ the reaction is allowed to stir and to slowly warm up to
ambient temperature. The reaction is then heated at 40 for 1
hour and then it is cooled to ambient temperature. To the mixture
is added at 20, 198.0 g (1.076 mole) of l-iodobutane, and when
this addition is complete, the reaction is stirred at 40 for 16
hours. The mixture is cooled, stripped down in volume, and poured
into 1.5 liters of water. The insoluble oil is separated, and the
aqueous layer is extracted with ether. The extract is combined
with the oil. The ether solution is washed with 100 ml. of dilute
hydrochloric acid, 100 ml. of sodium bicarbonate and finally 100 ml.
of water. The solution is dried and concentrated to give 324.3 g.
of crude product. Distillation of the product gives 223.0 g.
(72~) of pure ester (115-20/.25mm). The material is identified
by ir and its purity is determined by glc.
2. 2-~2,4-dichlorophenyl) hexan-l-ol
To 11.7 g. (0.308 mole) of lithium aluminum hydride in
one liter of anhydrous ether at 5-10 is slowly added 140.0 g.
(0.486 mole) of the prepared ethyl-~-(2,4-dichlorophenyl) hexanoàte.
When the addition is complete, the reaction is allowed to stir
and slowly warm to ambient temperature. The slurry is slowly
added to iced water as H2 gas vigorously evolves. When this
addition is complete, the mixture is made acidic with concentrated
hydrochloric acid. The organic layer which forms is separated,
and the aqueous layer is extracted with ether. This extract is
combined with the organic phase, and the solution is washed with
water and then with dilute sodium bicarbonate solution. After
drying over anhydrous magnesium sulfate, the ether solution is
concentrated and distilled (118-23/.2 mm) to give 110.8 g. (92%)
of product.
- 18 -
10~i~3~3
3 2-(2.4-dichlorophenYl) hexyl methane sulfonate
To 24.7 g. (0.1 mole) of the 2-(2,4-dichlorophenyl) hexan-
2-ol and 13.8 g. (0.12 mole) of methane sulfonyl chloride in 200
ml. of benzene at 10 is slowly added 14.2 g. (0.14 mole) of
triethylamine. T~hen the addition is complete, the reaction is
stirred, and allowed to come up to ambient temperature over a 30
minute period. The reaction slurry is then heated to reflux for
30 minutes, cooled and poured into water. The organic solution is
washed with dilute hydrochloric acid then with water and finally
with dilute sodium bicarbonate solution. After drying over anhy-
drous magnesium sulfate, the benzene is stripped off to yield 31.8
g. (98%) of the crude product. This material is identified by ir
and nmr. The purity is determined by glc.
4. Imidazole Reaction
To 27.2 g. (0.4 mole) of imidazole at 95 is added 31.8 g
(0.098 mole) of the 2-(2,4-dichlorophenyl) hexyl methane sulfonate,
and the materials are stirred at 95 for 16 hours. At the end of
this period the reaction is cooled, and poured into 500 ml. of
water. After stirring for one hour the organic material is
separate, and aqueous layer is extracted with ether. The ether
is combined with the organic phase, and after a water wash is
dried and concentrated to give 24.4 g. (88%) of product. The
imidazole product is identified by ir, nmr, and elemental analysis.
Its purity of greater than 95% is determined by glr.
EXAMPLE 2
In 30.0 g (0.101 mole) of 1-[~-(2,4-dichlorophenyl)hexyl]
imidazole dissolved in 200 ml of ether is bubbled dry hydrogen
chloride gas until the mixture is acidic to litmus. A colorless
solid forms which is separated by filtration to give 24.5 g. of
the hydrochloride salt which is identified by nmr.
-- 19 --
1(~t;53~;~
EXAMPLE 3
1-rR-(2.4-dic~lQxophenvl) hexyllimidazole zinc chloride
Method A
To a solution of 2.0 g (0.0067 mole) of 1-[~-(2,4-dichlo-
rophenyl)hexyl] imidazole in 10 ml of absolute ethanol is added
dropwise a solution of 0.46 g (0.0036 mole) of zinc chloride in
30 ml of absolute ethanol. The reaction mixture is stirred at
room temperature for 10 minutes and the solvent is removed under
vacuum. A white glass-like solid is isolated as the product and
is identified by nmr.
Method B
l-rB-(2,4-dichlorophenyl) hexyl]imidazole 2.0 g (0.0067
mole) and zinc chloride 0.92 g (0.0067 mole) are mixed in an
acetone: methanol: water (1:1:2) solvent system, 40 ml. This
preparation is immediately applied to plant foliage.
EX8M~LE 4
l-rB-2,4-dichloro~henYll hexYllimidazole oxalate
To a solution of 4 g (0.0135 mole) of 1- B-(2,4-dichloro-
phenyl)hexyl] imidazole in ether is added dropwise a solution of
1.7 g (0.0135 mole) of oxalic acid dissolved in 10 ml of methanol.
A white precipitate forms immediately. The precipitate is collected
by filtration and dried under vacuum to give 3.37 g of a solid,
m.p. 126-128.
- 20 -
1~653Z3
ExamPle 26
~ P-methylthioPhen~l)hexyl]imidazole
1. P-MethYlthio~henYl methanol
To 19.8g (0.521 mole) of lithium aluminum hydride
(LiAlH4) in 750 ml of anhydrous ether is slowly added 98g.
(0.64 mole) of p-methyl mercaptobenzaldehyde in 250 ml of
anhydrous ether at less than 10C. When the addition is
complete the reaction is stirred for 0.5 hour at 10C. and
then the reaction is stopped by slowly adding 100 ml of acetone
to remove unreacted LiAlH4.
To this mixture is added 500 ml of water and the
reaction is made acidic by the addition of conc. hydrochloric
acid. The ether layer is separated, dried over anhydrous
magnesium sulfate, and concentrated to give 89.6g of the crude
product. This residue is crystallized from ether-hexane to
give 75.8g, mp 38-400 (76% yield).
2. ~-Methylth~2phenYl acetonitrile
To 73.0g (0.47 mole) of p -methylthiophenyl methanol
and 59.6g (0.52 mole) of methane sulfonyl chloride in 250 ml
of benzene is slowly added 59.6g (0.59 mole) of triethylamine
over a period of one hour at less than 15C. When the addition
is complete, the reaction is stirred for one hour and allowed
to warm up to ambient temperature.
The reaction mixture is combined with 400 ml of dilute
hydrochloric acid. The benzene layer is separated, washed with
250 ml of H20, dried and concentrated to give 74.7g of the crude
mesylate product.
This residue is added to 25.5g (0.52 mole) of sodium
cyanide in 300 ml of dimethyl sulfoxide, and allowed to stir fo
3o one hour. The reaction is poured into iced water and the yello~
-21-
10~;53~;~
tinted solid which fOrIIIS i'i liltered and re(~ryst~lliz~d ~ OIII
benzene-hexane to give 60.8g (79%) of the product, mp ~4-5.
3. 2-(P-MethYlthio~henyl)hexanenitril e
To 12.5g (0.25 mole) of 50% sodium hydride in ~00 ml
of anhydrous, distilled tetrahydrofurane is added 60.0g (0.258
mole) of the p-methylthiophenyl acetonitrile over a period of
one hour. me reaction mixture is allowed to stir for one hour
then 48.8g (0.265 mole) of l-iodobutane is slowly added. When
the addition is complete, the reaction is stirred for two hours.
The mixture is combined with 500 ml of water and the organic
phase is separated, washed with water and concentrated to give
80.1g of crude product. Upon distillation 65.7g (85%) of the
product is isolated (126-30/.01 r~m.).
The imidazole derivative is then prepared by the
method of Example 68 parts 2, 3, 4 and 5.
Example 27
1- L~ (p-methYlsulfonYlPhenYl)hexyllimidazole
To 7.0g (0.021 mole) of l-L~-(p-methylthiophenyl)
hexyl]imidazole nitric acid salt in 75 ml of glacial acetic
acid is added dropwise at less than 10, 8.og (0.083 mole) of
35% hydrogen peroxide. When the addition is complete, the
reaction is stirred for one hour heated on a steambath for a
second hour and then poured into iced water. The solution is
made basic to litmus with sodium hydroxide and the product is
extracted out with ether.
me ether extract is treated with nitric acid and the
salt settles out an oil. ~his material is treated with aqueous
sodium hydroxide to give the product. An extraction with ether
and concentration of that extraction gives 2.lg (25%) of the
-22-
10~;53;~3
methylsulfonyl product.
Example 29
1-1 ,B-(P-nitrophenyl)hexyllimidazole
To a mixture of 20 ml of nitric acid and 10 ml of
sulfuric acid at 5O is slowly added lO.Og (0.0~4 mole) of
l-L~-phenylhexyl]imidazole in 10 ml of sulfuric acid. As soon
as the addition is complete, the reaction is poured into iced
water and the oil product settles out. The acidic solution is
decanted and the remaining oil is washed with water, and then
made basic with dilute sodium hydroxide. m e product is
extracted out with ether, dried and treated with nitric acid to
precipitate the salt. The salt is recrystallized from acetone-
ether to give 4.8g mp. 98-100. Treatment of the salt with
dilute sodium hydroxide gives the free base product.
Example ~0
-(P-aminophen.Yl)hexYl]imidazole
To 5.0g L0.0183 mole) of l-L~-(p-nitrophenyl)hexyl~-
imidazole in 50 ml of methanol is added 2.0g of conc. hydrochloric
acid. The solution is heated to reflux and ~ one gram
portions of iron filings are added at five min. intervals.
When the additions are complete, the reaction slurry is stirred
at reflux for 1~ hours. The reaction is cooled, and then poured
into water. The organic material is extracted out with toluene,
dried and concentrated to give ~.5g of the crude product.
The oil is dissolved in ether, and the solution is
treated with nitric acid. The salt settlesout as an oil. The
oil is treated with dilute sodium hydroxide, extracted with
ether, dried and concentrated to give 3.5g of the imidazole
product.
~~3-
10~;5;~3
Example ~1
,~,4-dichloro-5-nitroPhenyl)hexyllimidazole
To a solution of 40 ml of nitric acid and 10 ml of
sulfuric acid, 14.8g (0.0498 mole) of 1-L~-(2,4-dichlorophenyl)-
hexyl~imidazole in 30 ml of sulfuric acid is added at less than5. ~he reaction is stirred for 1/2 hour and then it is poured
into iced water. ~he oily solid which separates is isolated by
decanting off the dilute acid solution. ~he residue is washed
and then treated with ammonium hydroxide solution.
The organic product is extracted out with ether, and
the extract is dried and treated with dry hydrogen chloride.
The hydrochloride salt precipitates out and is filtered to give
9.4g of the crude product. A recrystallization of 2.7g of this
material from methanol gives 1.8g of the purified hydrochloride
salt, mp 99-100.
Example 46
1-[~-(2 4-d ~ethYlPhenYlphenyl)hexyllimidazole
1. ?-(2,4-dimethylphenYl)hexan-l-ol
~o a stirred, OoC mixture of m-xylene 173g (1.63 mole)
and anhydrous stannic chloride 78.0g (0.30 mole) which is
constantly swept with nitrogen, is added dropwise, 1,2-ePo
hexane, 30.0g (0.30 mole) in 50 g m-xylene. ~he exothermic
temperature is maintained at 3OC by the rate of addition.
After the addition is completed, the reaction which now contains
223 g (2.0 mole) m-xylene is stirred for 30 minutes at 0C
then poured into iced concentrated hydrochloric acid. ~he
aqueous and organic layers are separated. After extracting
the aqueous portion with ethyl ether, this organic layer is
-24_
10~5;~3
combined with the previous organic fraction. This combined
organic material is washed successively with water, sodiu~
bicarbonate and again water. The dried organic solvent mixture
of ethyl ether and excess unreacted m-xylene is then removed
on rotory evaporator. The concentrated residue is fractionally
distilled in vacuo. The third fraction, 112C/.5 mm, is
shown to be the desired product by spectral and analytical
data. The yield is 35.6g (57.6~ theory).
2. 1-i~-(2~4-dimethylphenyl)hexYllimidazole
The imidazole is formed from the alcohol by the method
of Example 1 parts 3 and 4.
Exam~le 6?
l-~a-(2~4-dimethox.Yphen.Yl)hexYllimidazole
1. 2-(2~4-dimethoxyphenyl)hexan-1-ol
To a stirred, 5OC mixture of m-dimethoxybenzene
27.6g (0.20 mole), anhydrous stannic chloride 52.1g (0.20 mole)
and 200 ml of methylene chloride which is constantly swept with
nitrogen, is added dropwise, 1,2-epoxyhexane, 20.0g (0.20 mole)
in 50 ml of methylene chloride. The exothermic reaction
temperature is maintained at 3C by the rate of addition. After
the addition is complete, the reaction is stirred at 5OC for
30 minutes, at which time it is poured into iced concentrated
hydrochloric acid. The layers are separated and the aqueous
layer is extracted with methylene chloride. The combined
organic layers are washed with water followed by 5% sodium
bicarbonate solution and finally water. The last water wash
is neutral to pH paper. The methylene chloride solvent is
removed on a rotory evaporator at 400C bath temperature. This
residue is then fractionally distilled in vacuo. The third
-25-
iS3~;~
fraction, 140-142C/.2 mm, is shown by nmr and ir to be the desired
product. The yield is 25.32g (55%, theory1.
2. 1-[~-(2,4-dimethoxyphenyl~hexyl] imidazole
The above alcohol forms the methane sulfonate via the
method of Example 1 part 3. However, upon reacting the methane
sulfonate with imidazole by the method of Example 1 part 4, a
rearrangement takes place and the a-substituted product is obtained
which is identified by ir and nmr.
Example 66
1-~-(2,4-dichlorobenzvl)~entvllimidazole
1. ~-(2,4-dichlorobenzvl)pentan-1-ol
To 7.5g (0.384 mole) of magnesium turnings in 150 ml of
ether is added a lO.Og (0.051 mole) portion of ~, 2,44trichloroto-
luene and a few crystals of iodinè. When the iodine color has
dissipated, the reaction is warmed to reflux, and 58.0g (0.297
mole) of additional ~,2,4-trichlorotoluene in 50 ml of ether is
added at such a rate that the refluxing is maintained. When the
addition is complete, the reaction is stirred at reflux for 2 hours
and cooled. To this reaction mixture is added 17.0g (0.197 mole)
of valeraldehyde, and the reaction is heated again at reflux for
2 hours. The reaction is cooled and poured into ice cold dilute
hydrochloric acid, and the organic phase is separated. The aqueous
solution is extracted with ether, and the extract is combined with
the organic phase. After a water wash, the organic solution is
dried over anhydrous magnesium sulfate and stripped of solvent to
give 57.2g of crude product. A distillation provides 11.3g (23%)
of the product. Purity is determined by glc.
- 26 -
1()~;5323
2. 1-(2.4-dichlorobenzvl)pentYl methane sulfonate
The methane sulfonate is prepared according to the method
of Example 1 part 3, is identified by ir, and its purity determined
by glc.
3. 1-[a-(2,4-dichlorobenzvl)pentyllimidazole
The imidazole is prepared according to the method of
Example 1 part 4, is identified by ir, nmr and elemental analysis
and its purity of greater than 95% determined by glc.
Exam~le 67
1- rR- r2.4--dichlorc~ zyl )hP~yl 1 ;mid;~lP
. ethyl a-(2.4-dichlorobenzvl)malonate
To 4.6g (0.095 mole) of 50~ NaH in 250 ml of anhydrous
THF is added with stirring 16.0g (0.1 mole) of ethylmalonate, and
the reaction slurry is allowed to stir for one hour, and then
heated at reflux for three hours. The reaction is cooled, and to
it is added 17.5g (0.09 mole) a,2,4-trichlorotoluene. The
resulting reaction slurry is heated to reflux for 16 hours. The
reaction is cooled, and the THF is stripped off. The concentrate
is stirred with water, and the ester product is extracted out with
ether. The ether solution is washed with water, dried over anhy-
d~OUS magnesium sulfate and concentrated to give the crude product.
The residue is heated up to 110 under 0.1 mm pressure, and the
excess ethyl malonate is distilled off leaving 27.1g (94%) of the
product. The purity of the material is greater than 95% by glc.
2. ethYl,a-butvl-a-(2,4-dichlorobenzyl) malonate
To 6.7g (0.14 mole) of 50~ sodium hydride in 500 ml
of anhydrous THF is added at reflux 44.2g (0.139 mole) of the
ethyl, a-(2,4~dichlorobenzyl) malonate, and the resulting slurry
is stirred at reflux temperature for 16 hours. The reaction is
cooled, and 26.6g (0.14 mole) of l-iodobutane is added. This
mixture is heated, with stirring, at reflux for 6 hours.
- 27 -
10~;53;~;~
The solvent is stripped off, and the concentrate is
stirred with 500 ml of water. The product which separates is
extracted out with ether and the ether is washed twice with 100 ml
of water. After drying over anhydrous magnesium suIfate, the
ether is stripped to yield 60g ( 100%) of the crude product. By
glc this sample is 95~ pure.
3. a-(2.4-dichlorobenzvl)hexanoic acid
To 45.0g (0.40 mole) of 50% potassium hydroxide is added
52.4 g (0.14 mole) of the ethyl a-butyl-a-(2,4-dichlorobenzyl)
malonate, and the mixture is stirred at reflux for 16 hours. The
reaction is cooled, and washed twice with 75 ml of benzene. The
aqueous solution is treated with concentrated hydrochloric acid,
and the malonic acid derivative settles out. The oil is separated,
and the aqueous solution is extracted with xylene. The extract
is combined with the oil phase, dried over anhydrous magnesium
sulfate and heated up to reflux. After two hours, the xylene is
distilled off until the pot temperature reaches 180. The
reaction is cooled to give 46.0g of crude product.
4. 2-(2.4-dichlorobenzyl) h~xan~-l-ol
To 9.4g (0.248 mole) of lithium aluminum hydride in 600 ml
of THF is slowly added, at less than 10, 46.0 g of the crude a-
(2,4-dichlorobenzyl) hexanoic acid. The reaction is allowed to
stir, and slowly warm up to ambient temperature. After 2 hours,
the slurry is heated to reflux and held there for 16 hours. At
the end of this period, the reaction is cooled and carefully
poured into ice water to decompose the excess LiAlH4. The mixture
is then made acidic by treatment with concentrated hydrochloric
acid. The ether solution is separated, and the aqueous phase is
extracted three times with 200 ml of ether. The extracts and the
ether solution are combined and washed with 100 ml of dilute sodium
bicarbonate and then with 100 ml of ~ater. The solution is dried over.
- 28 -
10~;53;~;~
anhydrous magnesium sulfate and the ether is stripped off to give
35.9 g of the crude alcohol product. Distillation (86.8 /.15 mm)
provides 34.2 g (93%) of pure alcohol. The material is identified
by ir and its purity is determined by glc.
5. 2-~2,~ _____obenzyl) hexyl methane sulfonate
The methane sulfonate is prepared according to the
method of Example 1 part 3, the product is identified by ir and
its purity determined by glc.
6. l-rR-(2.4-dichl~he~yl) hexyll;m;dazQlp
The imidazole is prepared according to the method of
Example 1 part 4, the product is identified by ir, nmr and elemental
analysis and its purity determined to be greater than 95% by glc.
EXAMPLE 68
- r~- (2.4-dichloro~henvl) heptyllimidaz~le
1. 2-(2,4-dichloroPhenvl)hexvl cYanide
To a suspension of 11.3 g (0.23 mole) of sodium cyanide
in 100 ml of dry dimethyl formamide (DMF) is added dropwise a
solution of 50 g (0.154 mole) of 2-(2,4-dichlorophenyl)-hexyl-
methane sulfonate in 50 ml of DMF. The reaction mixture is
stirred at 70 overnight. It is then poured into 500 ml of
water and extracted with ether. The combined ether extracts are
washed with water, then saturated saline solution and finally
dried over magnesium sulfate. Solvent is evaporated under reduced
pressure to give 37 g of crude product which is further purified
by vacuum distillation (107.5-110/0.05 mm) to give 33.9 g (86%)
of expected product.
2. 2-(2.4-dichlorophenyl) heptanoic acid
A mixture of 15g (0.0596 mole) of 2-(2,4-dichlorophenyl)
hexyl cyanide and 100 ml of 50% sulfuric acid is heated at 110
overnight. The reaction mixture is cooled and diluted with 500 ml
of water. This aqueous portion is extracted with ether and the
- 29 -
10~;53~3
combined ether extracts are dried over magnesium sulfate. Solvent
is removed under reduced pressure to give 15.02g (93.7~) of a
white solid, mp 65-68.
3. 3-(2,4-dichlorophenyl)-heptan-1-ol
To a suspension of 2.07 g (0.0545 mole) of lithium
aluminum hydride 15 in 100 ml of ether is added dropwise a solution
of 15 g (0.054 mole) of 2-(2,4-dichlorophenyl) heptanoic acid in
50 ml of ether. The resulting mixture is stirred at room tempe-
rature for 3 hours. The excess lithium aluminum hydride is decom-
posed carefully with 100 ml of saturated ammonium chloride solutionfollowed by 100 ml of dilute sulfuric acid solution. The ether
layer is separated from the aqueous layer and the aqueous layer is
again extracted with ether. The combined ether layers are washed
with 10% sulfuric acid, water, saturated sodium bicarbonate
solution, saturated saline solution and dried over magnesium
sulfate. Solvent is evaporated under reduced pressure to give 12 g
of an oil which is further purified by vacuum distillation (120-
125/0.1 mm) to give 10.2 g (72%) of desired product.
4. 3-(2,4-dichlorophenyl)heptyl methane sulfonate
To 10.2 g (0.039 mole) of the 3-(2,4-dichlorophenyl)
heptan-l-~l and 4.8 g (0.042 mole) of methane sulfonyl chloride
in 100 ml of benzene at 10 is slowly added 4.4 g (0.043 mole) of
triethylamine. When the addition is complete, the reaction is
stirred and allowed to come up to ambient temperature over a 30
minute period. The reaction slurry is then heated to reflux for
30 minutes, cooled and poured into water. The organic solution
is washed with dilute hydrochloric acid, then with water and
finally with dilute sodium bicarbonate solution. After drying
over anhydrous magnesium sulfate, the benzene is stripped off to
give 10.6 g of crude sulfonate product.
- 30 -
iO~iS3'~;~
5. l-[B~2,4-dichlorophenyl~ heptyl imidazole
To 10.6 g (0.160 mole~ of imidazole at 95 is added lO.9g
(0.042 mole) of the crude 3-(2',4'-dichlorophenyl) heptyl methane
sulfo~ate. The materials are stirred at 95 for 16 hours, cooled
and poured into 500 ml of water. After stirring for l hr., the
organic material is separated and the aqueous layer is extracted
with ether. The ether is combined with the organic phase, and
after a water wash, it is dried and concentrated to give 10.6 g
of the crude product.
1- r B-(2,4-dichloro~henvl? ~henethyllimidazole
l. ~-t2.4-dichloroDhenyl! ~henyl acet~ldehy~
To 47.1 g (0.188 mole) of 2,4-dichlorobenzophenone and
36.2 g (0.289 mole) of ethyl chloroacetate is slowly added 14.9 g
(0.31 mole) of 50% sodium hydride at 15. The reaction is allowed
to stir and slowly come up to ambient temperature overnight. The
reaction is added to iced water, and made acidic with dilute
hydrochloric acid. The organic material is extracted out with
three 200 ml portions of benzene. The extracts are combined,
washed twice with lO0 ml of water and dried over anhydrous magne-
sium sulfate. The benzene is stripped off, and the crude product
is added to 35.3 g (0.53 mole) of 85~ potassium hydroxide in
350 ml of water. This mixture is refluxed for 20 hours, cooled
and washed twice with 200 ml of benzene. The aqueous solution is
acidified and the organic acid settles out as an oil. The oil is
separated and the aqueous solution is extracted twice with 200 ml
of ether. The extracts are combined with the oil, dried over
anhydrous magnesium sulfate and concentrated to give 30.7 g of the
hydroxy acid. This residue is heated for
- 31 -
iO~ S3'~
3 hours at 140 to decompose it to the crude aldehyde product (24.3 g).
Distillation (128-137/.05 mm) gives 16.3 g (33%) of the aldehyde.
2. ~-(2.4-dichloroPhenYl) phenethanol
To 2.4 g (0.0615 mole) of LiA1H4 in 140 ml of anhydrous THF is added
S dropwise, at 0, 16.3 g (0.0615 mole) of the a-(2,4-dichlorophenyl) phenyl
acetaldehyde in 60 ml of anhydrous THF. When the addition is complete, the
reaction is stirred for 2 hours at 0 and then for 16 hours at ambient tem-
perature. The reaction is then heated up to reflux for two hours, cooled
and poured into ice water. The mixture is acidified with concentrated hydro-
lO chloric acid, and the organic material is extracted out twice with 200 ml
portions of ether. The extracts are combined, dried over anhydrous magnesium
sulfate and, concentrated to give 15.5 g of crude product. Distillation
(125-39/.025 mm) gives 10.6 g (65%) of the purified alcohol product. The
material is identified by ir, and its purity is determined by glc.
~ ~ 4-dichlorophenvl) phenethYl methane sulfonste
The methane sulfonate is prepared according to the method of
Ex~mple 1 part 3, the product is identified by ir and its purity is determined
by glc.
4. ~ -(2.4-dichloroPhenyl) Phenethy~ ml- zole
,0 The imidazole is prepared by the method of Example 1 part 4, the
product is recrystallized from ether acetone to give 2.6 g (32%) of the
hydrochloride salt, mp 197-8.
EXAMPLE 70
~ (2,4-dichlorophenyl) hexyl~imidazole
l. 5-~2,4-dichlorophenYl) hexan-l-ol
A slurry of m-dichlorobenzene, 735 g. (5.0 mole) and anhydrou~
aluminum chloride~ 162 g. (1.1 mole) is cooled to 10 using an ice-water bath
and 1,2-epoxyhexane, 100 g. (1.0 mole) is added dropwise over a one hour
period. The temperature of the reaction is kept below 15. The reaction
30 mixture is allowed to come to room temperature and stirring is continued
-32-
l O ~
overnight. The reaction mixture is then poured into a 4 liter flask con-
taining ice and concentrated hydrochloric acid (50 ml.) with stirring. The
aqueous and organic layers are separated and the aqueous layer extracted
three times with ether (150 ml). The combined organic extracts are washed
5 twice with water (50 ml) and dried over magnesium sulfate. Solvent is
evaporated and vacuum distillation (160-172/0.1 mm) gives 114 g. (46~)
of product.
2. 1-E~-(2~4-dichloropherl~yl) hexYl1imidazole
The primary alcohol is converted into the sulfonate and imidazole
compound in the usual manner.
EXAMPLE 71
1- a-MethY~ ?4-dichlorophenyl )hexyl 'limidazole
1. 2,4-Dichlorovalerophenone
To 48.0 g. (0.398 le) of valeryl chloride in 100.0 g. (0.680 le)
of m-dichlorobenzene is added portionwise at less than 5, 66.7 g. (0.5 le)
of aluminum chloride. When ths addition is complete, the reaction mixture
is allowed to stir and slowly warm up to ambient temperature for 2 hours.
It is then heated at reflux for 3 hours, and stirred at room temperature for
16 hours. The reaction mixture is poured into iced water, and made acidic
with hydrochloric acid. The oil which formed separates, and the aqueous
phase is extracted twice with 200 ml. of ether. The oil and the extracts
are combined, washed with water, dried and concentrated to give 122.2 g. of
the crude product. A distillation (89-93/.05 mm) gives 55.2 g. (60%) of the
product.
2. ~-(2,4-dichlorophe~yl) hexanal
To 50.0 g (0.216 mole) of 2,4-dichlorovalerophenone in 42.4 g
(0.346 mole) of ethyl chloroacetate at 0 is added portionwise 8.7 g (0.363
mole) of sodium hydride over a 4 hour period. When the addition is complete,
the reaction mixture is stirred and allowed to slowly warm up to ambient
~33-
10~;53;~;~
temperature for 2 hours. The reaction is then poured into iced water, and
the mixture is made acidic with hydrochloric acid. The organic material is
extracted out with ether, and the extract is dried and concentrated to give
~9.2 of the crude glycidic ester. The residue is treated with 40.0 g (0.607
mole) of 85% potassium hydroxide in 400 ml of water, and the mixture is heated
for 2 hours on a steambath. The alkaline solution is washed with benzene,
and acidified with hydrochloric acid. The oil which forms is extracted out
with ether, and the ether solution is dried and concentrated. The residue
i9 dissolved in xylene, and heated at reflux for 6 hours with carbon dioxide
evolution. The solution is stripped to dryness to give 32.4 g of the crude
aldehyde. A distillation (112-7/.2 mm) gave 16.6 g (31%) of the product.
(2~4-dichloroPhen~vl) heptan-2-ol
To 14.3 g (0.088 mole) of methylmagnesium iodide in 75 ml of ether
is slowly added at less than 10, 14.5 g (0.059 mole) of the a~2,4-dichloro-
phenyl) hexanal. When the addition is complete, the reaction is stirred for
1 hour then heated up to reflux for 2 hours. The reaction is cooled and
poured into water. The mixture is acidified with hydrochloric acid and the
oil which separates is extracted out with ether. The ether solution is dried
and concentrated to give 11.7 g (76%) of the crude product.
4. _ ~-(2?4-dichlorophenyl) hePt-~-vll~lethane sulfonate
The methane sulfonate is prepared by the method of Example 1
part 3, the product is identified by ir and its purity determined by glc.
5. l-ra-rnethyl-~-(2~4-dichlorophen~yl~hexvlFimidazole
The imidazole i9 prepared according to the procedure of Example 1
part 4, the product is identified by ir and its purity determined by glc which
shows it contains about equal amounts of isomeric products.
EXAMPLE ?2
-butYl-~-(2~-dichlorophe-n ~ xyllimidazole hydroc lor de
1. ethYl~ ~_butYl-a-(2.4-dichlorophe~l) hexanoate
To 4.3 g (0.09 mole) of 50% sodium hydride in 200 ml of anhydrous
-34-
iO~i3~;~
tetrahydrofuran is added 23.6 g (Q.Q816 mole) of ethyl ~-(2,4-
dichlorophenyl) hexanoate, and the reaction is heated at reflux
for 72 hours. The reaction is then stirred for 72 hours at ambient
temperature. At the end of this period 16.6 g (0.09 mole) of
iodobutane are added, and the reaction is heated at reflux for 24
hours. The reaction is cooled and poured into iced water, and the
oil which forms is separated. The aqueous phase is extracted with
ether, and the extract is combined with the oil. The ether
solution is drièd and concentrated to give 14.2 g of crude product.
A distillation (150-70/.25 mm) gives 13.3 g of the ester product.
2. 2-butyl-~(24-dichloroPhenyl) hexan-l-ol
The alcohol is formed by the method of Example 1 part 2,
the pure product 4.8 g distills at 133-8/0.05 mm and is identified
by nmr.
3. Imidazole Reaction
The imidazole is formed via the methane sulfonate according
to the methods of Example 1 parts 3 and 4. The final product 1.5 g
(28~) mp 103-5 is recrystallized from acetone-ether and is identi-
fied by nmr and elemental analysis.
~a~ELS 7~
1- r R.R-bis (D-chloroDhenvl) ethYllimidazole
To 15.1 g (0.397 mole) of lithium aluminum hydride in 750
ml of anhydrous tetrahydrofuran at less than 5 is added portion-
wise over a 2 hour period 95.0 g (0.338 mole) of bis (p-chloro-
phenyl) acetic acid. When the addition is complete, the reaction
is stirred at 5 for 4 hours then allowed to warm up to ambient
temperature overnight. The reaction is slowly poured into iced
water with resulting evolution of hydrogen. The mixture is made
acidic with hydrochloric acid, and the organic phase which forms
is separated. The aqueous phase is extracted twice with 200 ml
.:
!l
~ ~ - 35 -
lO~S3~;~
of ether and the extracts are combined with the organic phase.
The ether solution is dried and concentrated to give 74.9 g of
crude product. This residue is distilled (157-62/.05 mm)
- 35a -
lQf~S3;~;~
to give 35.3 g (39%) of the product.
2. Formation of Imidazole
The imidazole derivative (m.p. gO-2) is formed by the usual route.
EXAMPLE 74
1- ~-(o&p-chlorophenYl)p-chlorophenethvl~ imidazole
1. 2-~o&p-ch~oz~henyl)-p-chlorophenethyl chloride
To a mixture of 12.5 ml of 30% oleum in 25 ml of sulfuric acid is
added dropwise at less than 35, 11.6 g (0.76 mole) of chloroacetaldehyde
diethyl acetal in 34.0 g (0.30 le) of chlorobenzene. When the addition
lO is complete, the reaction is stirred for 1 hour, and warmed up to ambient
temperature. The reaction mixture i9 poured into iced water, and the organic
phase is extracted out twice with 200 ml of ether. The extracts are dried
and concentrated to give 17.3 g of the yellow-orange crude product. The
material is distilled to give 9.8 g (165-8/.4 mm) of the isomeric product.
2. Reaction with Imidazole
To 75 ml Or methanol is added 1.05 g (0.0458 mole) of sodium to
form a solution. To this solution is then added 3.1 g (0.0458 mole) of
imidazole, and the reaction is stripped to dryness. To the wet solid residue
is added 50 ml of N,N-dimethylformamide. The resulting solution is heated
20 up to 130, and the remaining methanol is distilled off. To this dimethyl-
formamide solution is added 8.7 g (0.0305 mole) of the 2-(o&p-chlorophenyl)-p-
chlorophenethyl chloride, and the reaction is heated up to 130 for 48 hours.
The reaction is cooled, poured into iced water and the organic material is
extracted out with ether. The ether extract is cooled and treated with
21 hydrogen chloride gas. The oil salt which formed is separated, and treated
with a sodiu~ bicarbonate solution. The resulting mixture is extracted with
ether and the ether solution is dried and concentrated to give 0.6 g of the
product.
-36-
10~53~;3
EXAMPLE 75
nitrate
tetramethylene-2,4-dichlorobenzyl cYanide
Into a 500 ml three-necked flask is placed 200 ml of 25%
sodium hydroxide solution and 4 g of tetraethyl ammonium bromide.
To this suspension is added dropwise a solution of 33.5g (0.2 mole)
of 2,4-dichlorobenzyl cyanide and 43g (0.2 mole) of 1,4-dibromo-
butane in 200 ml of methylene chloride under nitrogen. ~hen the
addition is over, the reaction mixture is heated to reflux for 1.5
hours. It is then poured into water and the layers are separated.
The aqueous layer is extracted with 100 ml of methylene chloride.
The combined organic extracts are washed with water, saturated
sodium chloride solution and dried over magnesium sulfate. Solvent
is evaporated to give a light yellow oil. Vacuum distillation
(130-140/0.2 mm) gives 30.4g (63~) of pure product, which is
identified by nmr.
2. ~ ~-tetramethylene-2e4-d;chloro~h~ny~ ~c~t;c ac;d
A mixture of 14g (.06 mole) of ~,~-tetramethylene-2,4-
dichlorobenzyl cyanide, 160 ml of 40% potassium hydroxide solution,
and 120 ml of diethylene glycol is heated under reflux for 3 days.
The reaction mixture is poured into water and extracted with ether.
The aqueous layer is then made acidic with hydrochloric acid
followed by extraction with ether. The combined ether extracts
from the acidic solution are washed with water, saturated sodium
chloride solution and then dried over magnesium sulfate. Solvent
is evaporated to give 12.4g of crude acid which is recrystallized
from hexane-benzene to give 8g of pure acid, m.p. 136-138.
lO~S3~;~
3. ~,~ f -tetramethYlene-2-(2~4-dichlorophenyl)-ethyl alcohol
To a suspension of 3g C0.08 mole) of lithium aluminum
hydride in 300 ml of anhydrous ether is added dropwise 13g (0.05
mole) of a,a-tetramethylene-2,4-dichlorophenyl acetic acid in 50
ml of ether under nitrogen. The reaction mixture is then heated
to reflux for one hour. Excess lithium aluminum hydride is care-
fully decomposed by dropwise addition of 10% hydrochloric acid
into the reaction mixture. The two layers are separated and the
aqueous layer is extracted with ether. The combined ether extracts
are washed with water and dried over magnesium sulfate. Solvent
is evaporated to give 9.8g of alcohol, which is identified by nmr.
4. 2,2-tetramethyle~e-~-(2.4-dichlorophe~y~lethyl methane
sulfonate
To a mixture of 9.8g (.04 mole) of 2,2-tetramethylene-
2-(2,4-dichlorophenyl) ethyl alcohol and 5g (.04 mole) of methane
suIfonyl chloride in 30 ml of benzene is added dropwise 5g (.05
mole) of triethyl amine. The reaction mixture is stirred at room
temperature overnight. The precipitate formed is filtered. The
benzene solution is washed with water then dilute hydrochloric
acid and dried over magnesium sulfate. Solvent is evaporated to
give 12g of productt which is identified by nmr.
5. 1-[B,B-tetramethylene-e-(2.4-dichloropheny~) ethyll;~;~ Le
A mixture of 12g (.037 mole) of 2,2-tetramethylene-2-
t2,4-dichlorophenyl)ethyl methane sulfonate, lOg (0.15 mole) of
imidazole, and 1 ml of dimethyl formamide is heated at 140 for
24 hours. The reaction mixture is poured into water and extracted
with ether. The combined ether extracts are washed with water
and dried over magnesium sulfate. The drying agent is filtered
- 38 -
lO~;S~
and to the etheral solution is added conc. nitric acid dropwise.
The white precipitate which forms is collected by filtrati~)rl
and dried under vacuo. A total of 3.7g of tile salt is obtained
m.p. 176-179, which is identified by nmr.
Exam~e 101
1-l~=(214-dichloro~henyl)hexyll-4-nitroimi_azole
To 1.3g (0.0307 mole) of sodium hydroxide in 150 rrll
of methanol is added 3.5g (0.0307 mole) of 4-nitroimidazole,
and the solution is heated and the methanol distilled off. To
the concentrate is added 100 ml of dimethyl formamide and the
solution is heated up to 120 to remove tlle excess methanol
and water. This dimethyl formamide solution is then cooled to
less than 90 and lO.Og (of 0.0307 mole) of 2-(2,4-dichlorophenyl)-
hexyl methane sulfonate is added. The reaction mixture is heated
up to 145 for two hours and then cooled and poured into water.
The organic material is extracted out with ether and after
drying, the extract is stripped to give 11.2g of residue. The
concentrate is triturated with hexane and then dissolved in 25
ml of methanol. The methanol solution is poured slowly into
water and a gummy solid forms. This solid is separated by
filtration, dried and recrystallized from acetone-hexane to give
4.2g (41%) of the product, m.p. 67-90.
Example 102
-(2.4-dichloro~hen.Yl)hexY114,~dichl roimidazole
To 100 ml of methanol is added 1.7g (0.0735 moles) of
sodium. When the sodium dissolves, lOg (0.0735 moles) of 4,5-
dichlorimidazole is added. The mixture is stirred until a
solution forms, and then the methanol is stripped off. The wet
residue is then added to 50 ml of dimethyl formamide and the
-39-
solution heated up to 125 to remove the remaining methanol
and water. The solution is cooled to less than 100 and 2.5g
(0.0735 moles) of 2-(2,4-dichlorophenyl)hexyl methane sulfonate
is added. The reaction is heated up to 130 for two hours and
then cooled. The reaction is poured into water and the organic
material extracted three times with 200 ml of benzene. The combined
extracts are washed twice with 50 ml of water, dried over anhydrous
magnesium sulfate and concentrated to obtain 15.8g of the crude
product. The residue is dissolved in ether, and treated with
dry hydrogen chloride gas. The ether solution is decanted from
the oil which forms and the oil is triturated twice with 150 ml
of ether. The oil is then treated with 10% sodium hydroxide, and
the product extracted out twice with 200 ml of ether. The ether
solution is dried and concentrated to give 12.6 g (47%j of the
oil product.
Ex~mple 10~
l-L,~-(2~4-dichlorophen~l)hexyl~-3-butylimidazolium iodide ,`
l-L~-(2,4-dichlorophenyl)hexyl]imidazole 5.0g
(0.0168 moles) is heated for two hours on a steambath with 3.1g
(0.0168 moles) of l-iodobutane. The reaction is cooled and
triturated three times with 50 ml of ether. The oil residue is
stripped to dryness to give 5.3g (66%) of the oil product.
Exam~le 104
1-1,~-(2~4-dichloro-~-nitro~henyl)hex~l' nltroimldazole
To l-L~-(2,4-dichlorophenyl) hexyl~imidazole 20.0g
(0.067 mole) in 40 ml of sulfuric acid is slo~Jly added 80 ml
of nitric acid and 40 ml of sulfuric acid. The reaction is
heated on a steambath for 14 hours, cooled and poured into water.
. -40-
10~iS;~;~3
The aqueous acidic solution is decanted from the oil which forms.
The residue is washed twice with 75 ml of water, and then taken up in
acetone-benzene, dried and concentrated to give 14.9g of the crude
product. To purify, 3.0g of the crude product is dissolved in hot
methanol. Upon cooling the product precipitates out is separated by
filtration and dried to give 1.6g of the nitro imidaæole derivative.
The following Tables I and II present some of the compounds
prepared by procedures presented in the preceding examples. These
tables are presented as a further illustration of the types of
compounds encompassed by the present invention and are not to be
construed in anyway as limitations of the scope of this invention.
A
;
s~
I V S~o V
{\~
\~ \ \ \ "
~d
~ l l l l l l l l l
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,
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_~
~C
v~ v`D v v v v ~ c~ v
c~ c\J (~ ~ ~\J ~\1 ~I N OJ
t~ V V V V V V V V V
I N (~I
42 -
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C
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a~ Or~ ~1 (r) ~ U~ ~) C~ 0~ ) a~ O
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m :~ ~ m m c~ m m m m m m
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H ~
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~1 _I ~r ~r ~ ~ ~ ~ er ~r
N C~ t )
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m
N r ~ ,~ O ~ ~ u
x
-- 46 --
1~3~;S3~3
o ~
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-- 48 --
~1 ~ O
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N N N N N ~ ~ N ~D X m
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-- 49 --
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--54 --
lO~S3;~;~
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--55--
10f~53~3
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-- 56 --
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o ~o o ~ o ~ o`~ ~~ ~
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.. .. .. .. .. .. .. .. .. ..
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E
~.~ . . . . . .. . . . . . . . . . . . . .
o ,i c~ 1` o o ~ r ~ ~ o a~ ~ I` co
, ~ U I ~ O I I O I I O
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o o o~ o o O co o 1` a~ O
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-- 59 --
3~3
I
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ol
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, ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
I a~ I` ~ o ~ o co u~ ~ o ~ D O
o~ o _I ~r oo er cn ~ o ~r ~ I` ~ ~~ c~ n o ~ ~ ~ ~
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Ia~ O~ N00 0~N r~~D ~D1` 1`~D ~t~ _Ia~ O CO CO (Y~ ~
_ _ _ _ _ _ _ _ _ _ _
I
_l ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
w
o ~oo oo ~~ ~o ~ x cn u~ ~ o ~ o
ol~ ~ u~~r ~~D~r a~o ~1~ ,lu~ ~0 ~D
O _l
~r o ~ o ~ o o o oo o
U ~ ~ _I U
~1 ~
Xcoo~ o ~ ~ ~ ~ u~u~ 1` 00
-- 60 --
;53;~3
~ __ _ __ _~ __
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10 0CO a~lN ~11` 1` 11'~ ~r u7 U) 1$~ ~D
o~ oo~~~ o~o oo ~ Lr o ~ D 00
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t) ~ u
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a~
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-- 61 --
10~;53~3
~r ~
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n ~ x a~ ô ~ ~ a~
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C _ _ _ _ _
a _ _ _ _ _
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n 5~ ~ x ~ o~
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7,i ~1 ~1 ~1~1
-- 62 --
The metal salt complexes of the above l-substituted
aralkyl imidazoles can be prepared by adding dropwise, with
stirring, a stoichiometric amount of a metal salt dissolved in
an appropriate solvent to a solution of the l-substituted
aralkyl imidazole dissolved in a similarly appropriate solvent.
The reaction mixture is briefly stirred and the solvent is
removed under reduced pressure to give the metal salt complex
of the respective l-substituted aralkyl imidazole. Identifi-
cation and purity are determined by elemental analysis.
The metal salt complexes can also be prepared by
mixing stoichiometric or excess amounts of the metal salt and
l-substituted aralkyl imidazole in the desired amount of solvent
containing the appropriate adjuvants just prior to spraying the
plants. Adjuvants that may be included in this "in-situ"
preparation may be detergents, emulsifiers, wetting agents,
spreading agents, dispersing agents, stickers, adhesives, and
the like which are used in agricultural applications.
Solvents that can be utilized in these procedures
include any polar solvent e.g., water, methanol, ethanol,
isopropanol or ethylene glycol and any aprotic dipolar solvent
e.g., dimethylsulfoxide, acetonitrile, dimethylformamide,
nitromethane or acetone.
The metal salt cations that may be used in these
procedures can be selected from the group consisting of calcium,
magnesium, manganese, copper, nickel, zinc, iron, cobalt, tin,
cadmium, mercury, chromium, lead and barium and the like.
Any appropriate anion e.g., chloride, bromide, iodide,
sulfate, bisulfate, phosphate, nitrate, perchlorate, carbonate~
bicarbonate, hydrosulfide, hydroxide, acetate, oxalate, malate,
citrate and the like may be utilized as the counterion in the
metal salt.
63-
10~5~
It has also been found that any metal containing fungi-
cides can also act as safening agents when used in place of metal
salts. Typical metal containing fungicides that can be utilized in
these procedures are: a) dithiocarbamates and derivatives such as:
ferric dimethyldithiocarbamate (ferbam), zinc dimethyldithiocarba-
mate (ziram), manganese ethylenebisdithiocarbamate (maneb) and its
coordination product with zinc ion (mancozeb), zinc ethylenebisdi-
thiocarbamate (zineb); b) copper-based fungicides such as : cuprous
oxide, copper naphthenate, and Bordeaux mixture; and c) miscellane-
ous fungicides such as: phenylmercuric acetate N-ethylmercuri-1,2,
3,6-tetrahydro-3,6-endomethano-3,4,5,6,7,7-hexachlorophthalimide,
phenylmercuri monoethanolammonium lactate, nickel-containing com-
pounds and calcium cyanamide.
The compounds and metal salt complexes of this invention
are excellent as systemic protectant/eradicant fungicides and possess
a high degree of activity against assorted phytopathogenic fungi.
Certain compounds are particularly effective for the control of
grey mold of faba beans (Botyrytis cinerea), rice blast (Piricularia
oryzae) on rice plants, tomato late blight (Phytophtora infestans)
on tomato seedlings, bean powdery mildew (Erysiphe polygoni) on
bean plants, barley net blotch (Helminthosporium teres) on barley
plants, grape downy mildew (Plasmopora viticola) on grape seedlings,
citrus decay (Penicilli~m digitatum) on citrus fruit, apple scab
(Venturia inaequalis) on apple seedlings, wheat powdery mildew
(Erysiphe graminis) on wheat plants, wheat black point (Alternaria
tenuis) on wheat plants, black rot of grapes (Guignardia bidwellii)
on grape seedlings, cucumber powdery mildew (Erysiphe cichoracearum)
on cucumber plants, and the organism responsible for the
-64-
;53'~3
production of aflatoxin (Asper~illus flavus).
The compounds eradicant fungicidal properties ~re
unique in that they kill Helminthosporium teres in infected
A plant tissues~a property not possessed by current fungicides
used to control diseases incited by Helminthosporium SPP. The
systemic properties possessed by these compounds are equally
unique in their ability to move both acropetally and basipetally
in plant tissues.
As the free base these compounds can be used to contlol
10 seedborne HelminthosPorium oryzae~a property which is found in
no other fungicides other than the organic mercury compounds.
These compounds as the free base possess growth
regulatory activity in both dicotyledonous and monocotyledonous
plants, the most pronounced effect being a retardation of plant
15 growth. In some cases, particularly in dicotyledonous plants,
some of the growth regulatory properties may be considered
adverse. When this occurs, the growth regulatory and phytotoxic
plant responses may be suppressed by metal salt complexation of
the imidazole compounds with elements selected from Groups IIA,
20 IVA, VA, IB, IIB, VIB, VIIB and VIII of the Periodic Table.
In evaluating these compounds, a preliminary fungicidal
evaluation is carried out using the compounds at 300 ppm and
spraying the plants to run off in a carrier volume of about
150 gallons/acre.
The general procedure is to take potted plants in
proper condition of growth for susceptibility to the fungal
disease to be evaluated to spray these on a moving belt and
allow to dry. The proper plants are then inoculated with the
fungal spores and then allowed to incubate until the disease has
3o developed and the control read or estimated. The percent
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lt)~ 5 ~
disease control is reported by the following rating system:
A = 97-100% control
B = 90-96~ control
C = 70-89% control
D = 50-69% control
E = Inactive <50% control
% disease control = disease of untreated-disease of treated X100
disease of untreated
The phytopathogenic fungi used in the evaluation of the
fungicidal activity of the compounds and salts of this invention
are described below.
BH - barley net blotch (Helminthosporium teres)
BOT - grey mold of faba beans (Botyrytis cinerea)
BPM - bean powdery mildew (ErYsiphe Poly~oni)
GDM - grape downy mildew (Plasmopora viticola)
TLB - tomato late blight (Phytophtora infestans)
RB - rice blast (P _icularia oryzae)
WSR - wheat stem rust (Puccinia ~raminis. f. sp. tritici)
WLR - wheat leaf rust (Puccinia recondita)
Table III presents the results of the application of
some of the compounds and salts of this invention at a rate of
300 ppm evaluated against the above fungi.
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Tab l ~
_
Example No. BH BOT BPM GDM TLB RB l~lSR WLR
._
A B A B E B - A
2 A B A A B A - A
3 A A A A B B - A
4 E B A A A B - A
A C A A B E - A
6 A A A B B E - A
7 A A A A A A - A
8 A A A A B B - A
9 A A A A A A - A
A A A A B A - A
11 E E A B B B - A
12 A E A E B A - A
13 E E A - E E - E
14 A E A B A _ _ E
A E A B E B - C
16 A E E E C A - C
17 A E A B A E - B
18 A E A A A E - A
19 E E A B B B - A
A E A B A E - A
21 A B A B B B - A
22 A E A A A B - A
23 E E E E E - E
24 A C A C E - C
A C A E E - E
26 E C A E E - E
27 - E E E - - E
28 - E A E B - B
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1(1~;S;~3
Example No. BH BOT BPM GDM TLB RB WSR WLR
_ _
29 A C A C E - C
E E B C E A A
31 E C A E E _ E
32 B A A E E - C
33 E C A C B - E
34 E C A C E - B
A E A C E - E
36 E E A E E - E
37
38 A E A B A - B
39
A E A E E - E
41 E C A E - - E
42 E E A C A - C
43 E C A C E - E
44 E E A B A - E
E E A E E ~rl E
46 A E A A E - C
47 A C E E E - C
48 A C A A E A A
49 E B E C E - B
A B A B E - A
51 B A A B B _ B
52 A A A B E A A
53 E E A E E E C
54 E E A E E - E
E E A E E - E
56 A E A E E - E
57 E C A E E - E
Example No. BH BOT BPMGDM TLB RB WSR WLR
58 A A E E E C E
59 A E A E E B B
E C A E E B E
61 E C A E E _ E
62 A C A E C _ C
63 E B E C - - C
64 A E A E E - C
A E A E A B E
66 B C A A A A - C
67 A D A A B A - A
68 A E B A B E - C
69 A A A B A A - A
A E E B B B - E
71 A E A A B A _ A
72 E B A E E B - A
73 A B B E B B _ A
74 A A A A A E _ A
A A A A A A _ B
76 E E A B B B - E
77 E E A C E - E
78 A A A E B B - A
79 E B A B B - A
A E A B C B - A
81 E E A E E E - E
82 A C A A C E - E
83 A C A B B E - B
84 A E A E E E - B
E C A E E A - A
86 A C A E E B - A
-69 -
Example No. BH BOT BPM GDM TLB RB WSR WLR
87 A C E E E B - A
88 E E A E E B - A
89 E C A B B B - A
E B A B B B - A
91 A B A B B B - A
92 E E A E B B - E
93 A E A E B B - A
94 A E A E E - - A
E E A E E - - A
96 E E E E E E - E
97 E E E E E B - E
98 E E E E E B - E
99 A E A E - E - A
100 E E E E B B - E
101 E E A C E A A
102 E E A C E A A
103 E A A B B _ E
104 E E B B E A A
-7o-
l(~S~
The aralkylimidazoles and their metal salt complexes of
this invention are useful as agricultural fungicides and as such
can be applied to various loci such as the seed, the soil or the
foliage. For such purposes these compounds can be used in the
technical or pure form as prepared, as solutions or as formulations.
The compounds are usually taken up in a carrier or are formulated
so as to render them suitable for subsequent dissemination as
fungicides. For example, these aralkylimidazoles or their metal
salt complexes can be formulated as wettable powders, emulsifiable
concentrates, dusts, granular formulations, aerosols, or flowable
emulsion concentrates. In such formulations, the compounds are
extended with a liquid or solid carrier and, when desired, suitable
surfactants are incorporated.
It is usually desirable, particularly in the case of
foliar spray formulations, to include adjuvants, such as wetting
agents, spreading agents, dispersing agents, stickers, adhesives
and the like in accordance with agricultural practices. Such adju-
vants commonly used in the art can be found in the John W.
McCutcheon, Inc., publication "Detergents and Emulsifiers Annual."
In general, the compounds of this invention can be
dissolved in certain solvents such as acetone, methanol, ethanol,
dimethylformamide, pyridine or dimethyl sulfoxide and such solu-
tions extended with water. The concentration of the solution can
vary from 1% to 90~ with a preferred range being 5 to 50%.
For the preparation of emulsifiable concentrates, the
compound can be dissolved in suitable organic solvents, or a
mixture of solvents, together with an emulsifying agent which
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l~S~
permits dispersion of the fungicide in water. The concentration
of the active ingredient in emulsifiable concentrates is usually
10% to 90% and in flowable emulsion concentrates, this can be as
high as 75%.
Wettable powders suitable for spraying, can be prepared
by admixing the compound with a finely divided solid, such as
clays, inorganic silicates and carbonates, and silicas and incor-
porating wetting agents, sticking agents, and/or dispersing agents
in such mixtures. The concentration of active ingredients in such
formulations is usually in the range of 20% to 98%, preferably 40%
to 75%. A typical wettable powder is made by blending 50 parts of
1-[~-(2,4-dichlorophenyl)-hexyl]imidazole, 45 parts of a synthetic
precipitated hydrated silicon dioxide sold under the trademark
Hi-Sil~ and 5 parts of sodium lignosulfonate (Marasperse~ N-22).
In another preparation a kaolin type (Barden) clay is used in place
of the "Hi-Sil" in the above wettable powder, and in another such
preparation 25% of the "Hi-Sil" is replaced with a synthetic
sodium silico aluminate sold under the trademark Zeolex~ 7.
Dusts are prepared by mixing the aralkylimidazole or its
metal salt complex with finely divided inert solids which can be
organic or inorganic in nature. Materials useful for this pur-
pose include botanical flours, silicas, silicates, carbonates and
clays. One convenient method of preparing a dust is to dilute a
wettable powder with a finely divided carrier. Dust concentrates
containing 20% to 80% of the active ingredient are commonly made
and are subsequently diluted to 1% to 10% use concentration.
The aralkylimidazoles or their metal salt complex can
be applied as fungicidal sprays by methods commonly employed, such
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10~5~
as conventional high-gallonage hydraulic sprays, low-gallonage
sprays, air-blast spray, aerial sprays and dusts. The dilution
and rate of application will depend upon the type of equipment
employed, the method of application and diseases to be controlled,
but the preferred effective amount is usually about 0.1 lb. to
50 lbs. per acre of the active ingredient.
As a seed protectant, the amount of toxicant coated on
the seed is usually at a dosage rate of about 0.1 to 20 ounces per
hundred pounds of seed. As a soil fungicide the chemical ean be
ineorporated in the soil or applied to the surface usually at a
rate of 0.1 to 50 lbs. per acre. As a foliar fungicide, the
toxicant is usually applied to growing plants at a rate of 0.25
to 10 lbs. per acre.
Fundieides whieh ean be eombined with the fungieides
of this invention ineludes:
(a) dithioearbamates and derivatives sueh as: ferrie
dimethyldithioearbamate (ferbam), zine dimethyl-
dithioearbamate (ziram), manganese ethylenebisdi-
thioearbamate (maneb) and its eoordination produet
with zine ion (mancozeb), zinc ethylenebisdithio-
earbamate (zineb), zinc propylenebisdithiccarbamate
(propineb), sodium methyldithiocarbamate (metham),
tetramethylthiuram disulfide (thiram), and 3,5-
dimethyl-l, 3,5-2H-tetrahydrothiadiazine-2-thione
(dazomet);
(b) nitrophenol derivatives such as:
dinitro-(l-methylheptyl) phenyl crotonate (dinocap),
2-see-butyl-4,6-dinitrophenyl 3,3-dimethyl aerylate
(binapaeryl),
and
- 73 -
2-sec-butyl-4~6-dinitrophenyl isopropyl
carbonate;
(c) heterocyclic structures such as:
N-trichloromethylthiotetrahydro-phthalimide
(captan),
N-trichloromethylthiopthalimide (folpet),
2-heptadecyl-2-imidazoline acetate (glyodin),
2-octylisothiazolone-3,
2,4-dichloro-6-(o-chloroanilino)-s-triazine,
diethyl phthalimidophosphorothioate,
4-butyl-1,2,4-triazole,
5-amino-1-Lbis(dimethylamino)phosphinyl]-3-
phenyl-1,2,4-triazole,
5-ethoxy-3-trichloromethyl-1,2,4-thiadizole,
2,3-dicyano-1,4-dithiaanthraquinone (dithianon),
2,thio-1,3-dithio-L4,5-b]quinoxaline (thioquinox),
methyl l-(butylcarbamoyl)-2-benzimidazole
carbamate (benomyl),
2-(4-thiazolyl) benzimidazole (thiabendazole)~
4-(2-chlorophenylhydrazono)-3-methyl-5-isoxa-
zolone~
pyridine-2-thiol-1-oxide,
8-hydroxyquinoline sulfate,
2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiin-
4,4-dioxide,
2,3-dihydro-5-carboxanilido-6-methyl-1,4-
oxathiin,
a-(phenyl)-a-(2,4-dichlorophenyl)-5-pyrimidinyl-
methanol (triarimol),
cis-N-L(1~1~2~2-tetrachloroethyl)thio]-4-cyclo-
hexene-1,2-dicarboximide,
-74-
;S3'~;~
3-L2~ 5-dimethyl-2-oxycyclohexy~-2-hydroxyl -
glutarimide (cycloheximide),
dehydroacetic acid,
N-(1,1,2,2-tetrachloroethylthio)-3a,4,
7,7a-tetrahydropthalimide (captafol),
5-butyl-2-ethylamino-4-hydroxy-6-methylpyrimi-
dine (ethirimol),
acetate of 4-cyclododecyl-2,6-dimethylmorpho-
line (dodemorph), and
6-methyl-2-oxo-1,3-dithioloL4,5-b~-quinoxaline
(quinomethionate).
(d) miscellaneous halogenated fungicides such as:
tetrachloro-p-benzoquinone (chloranil),
2,3-dichloro-1,4-naphthoquinone (dichlone),
1,4-dichloro-2,5-dimethoxybenzene (chloroneb),
3,5,6-trichloro~o-anisic acid (tricamba),
2,4,5,6-tetrachloroisophthalonitrile (TCPN),
2,6-dichloro-4-nitroaniline (dicloran),
2-chloro-~-1-nitropropane~
polychloronitrobenzenes such as:
pentachloronitrobenzene (PCNB) and
tetrafluorodichloroacetone;
(e) fungicidal antibiotics such as:
griseofulvin,
kasugamycin and
streptomycin;
(f) copper-based fungicides such as:
cuprous oxide,
basic cupric chloride,
basic copper carbonate,
copper naphthenate, and
-75-
lO~S;~
Bordeaux mixture; and
(g) miscellaneous fungicides such as:
diphenyl,
dodecylguanidine acetate (dodine),
phenylmercuric acetate,
N-ethylmercuri-1,2,3,6-tetrahydro-3,6-endo-
methano-3,4,5,6,7,7,-hexachlorophthalimide,
phenylmercuric monoethanol ammonium lactate,
p-dimethylaminobenzenediazo sodium sulfonate,
methyl isothiocyanate,
l-thiocyano-2,4-dinitrobenzene,
l-phenylthiosemicarbazide,
nickel-containing compounds,
calcium cyanamide,
lime sulfur,
sulfur~ and
1,2-bis(3-methoxycarbonyl-2-thioureido)benzene
(thiophanate-methyl).
The compounds and metal salt complexes of this
invention can be advantageously employed in various ways.
Since the metal salt complexes possess inherent systemicity and
broad spectrum fungicidal activity, they can be employed in
the storage of cereal grain. These complexes can also be
employed as fungicides in turf and fruit orchard applications.
Other applications of the metal salt complexes of this invention
will suggest themselves to those skilled in the art of
agriculture and horticulture.
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