Note: Descriptions are shown in the official language in which they were submitted.
l- 1339599
EPOXIDE DERIVATIVES
This invention relates to triazole and imidazole
compounds ~seful as funqicides, to a process for preparina
them, to fungicidal compositions containing them, and to a
method of combating fungal infections in plants using
them.
The triazole and imidazole compounds have the general
formula (I):
R6 oR3 R4
Az C C X R2
R7 ll 15 (I)
wherein Rl and R2, which may be the same or different,
are hydrogen, alkyl, optionally substituted cycloalkyl,
cycloalXylmethyl, alkenyl, heterocyclyl, aryl or aralXyl
optionally substituted with halogen,. nitro, alky~, halo-
alkyl, alXoxy, phenyl, phenoxy, benzyl, benzyloxy, halo-
phenyl or haloalkoxy; R3 is hydrogen, alkyl, alkenyl,
alkynyl, aralkyl or acyl; R4 and R5, which may be the
same or different, are hydrogen, alkyl, alkenyl or
optionally substituted aryl; R6 and R7, which may be
,he same or different, are hydrogen, alkyl, alkenyl or
optionally substituted aryl; X is oxygen or sulphur or is
SO or SO2 and Az is a l,2,4- or l,3,4-triazole or
imidazole ring, and isomers, acid addition salts and metal
complexes thereof.
The compounds of the invention contain at least one
chiral centre. Such compounds are generally obtained in
the form of isomeric mixtures. However, these and other
25 mixtures can be separated into the individual isomers by
methods known in the art. *
- 2 - 1339599
The alkyl groups may be straight or branched chain
groups having 1 to 6, e.g. 1 to 4, carbon atoms, examples
are methyl, ethyl, propyl (n- or Lso-propyl) and butyl (n-,
sec-, iso- or t-butyl). Cycloalkyl groups may be, for
_
example, cyclopropyl, cyclopentyl or cyclohexyl.
Examples of suitable substituents for the aryl and
aralkyl groups, which are preferably optionally
substituted phenyl and benzyl, are halogen (e.g. fluorine,
chlorine or bromine), Cl 5 alkyl [e.g. methyl, ethyl,
propyl (n- or ~so-propyl) and butyl (n-, sec-, ~so-or t-
butyl], Cl 4 alkoxy (e.g. methoxy and ethoxy), halo-
Cl 4 alkyl (e.g. trifluoromethyl or 1, 1, 2, 2-
tetrafluoroethyl), halo- Cl 4 alkoxy (e.g. trifluoro-
methoxy or 1, 1, 2, 2-tetrafluoroethoxy), nitro, cyano,
phenyl, phenoxy, benzyl, benzyloxy (ahy of the latter four
groups may be ring substituted, e.g. with halogen),
alkylenedioxy, haloalkylenedioxy (e.g. difluoromethylene-
dioxy), amino, acetylamino, mono- or di- Cl 4 alkylamino
(e.g. dimethylamino), hydroxy, morpholino and carboxy (and
alkyl esters thereof).
The alkyl moiety of a benzyl group can be
substituted with, for example, one or two alkyl groups
(e.g. methyl or ethyl). When substituted the phenyl and
benzyl groups may bear one, two or three substituents as
defined above.
Preferably the phenyl and benzyl groups have a
substituent in the 2-, 3- or 4- position. Examples of
these groups are phenyl, benzyl, ~_-methylbenzyl, 2-, 3- or
4-chlorophenyl, 2,4- or 2,6-dichlorophenyl, 2-, 3- or 4-
fluorophenyl, 2,4-or 2,6-difluorophenyl, 2-, 3- or 4-
bromophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chloro-
phenyl, 2-chloro-6-fluorophenyl, 2-, 3- or 4-
methoxyphenyl, 2, 4-dimethoxyphenyl, 2-, 3- or 4-ethoxy-
phenyl, 2-, 3- or 4-nitrophenyl, 2-chloro-4-nitrophenyl,
2-chloro-5-nitrophenyl,
2-, 3- or 4-methylphenyl, 2,4-di-methylphenyl, 2-, 3- or
4-t-butylphenyl, 2-, 3- or 4-tri-fluoromethylphenyl, 2-,
3- or 4-trifluoromethoxyphenyl, 2-, 3- or 4-(1,1,2,2-
tetrafluoroethyl)phenyl, 2,3-(difluoromethylenedioxy)-
133!~99
-- 3
phenyl, 2-fluoro-4-methoxyphenyl, 2-methoxy-4-fluoro-
phenyl, 2-methoxy-4-chlorophenyl, 2-methoxy-4-fluoro-
phenyl, 2-, 3- or 4-phenoxyphenyl, 2-, 3- or 4-phenyl-
phenyl (2-, 3- or 4-biphenylyl), 2-, 3- or 4-benzyl-
phenyl, 2-, 3- or 4-benzyloxyphenyl, 2-, 3- or 4-(4-
chloro- or 4-fluorobenzyloxy)phenyl, 2-, 3- or 4-amino-
phenyl, 2-, 3- or 4-(N,N-dimethylamino)phenyl, 2-, 3- or
4-hydroxyphenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-
(methoxycarbonyl)phenyl, 2-, 3- or 4-morpholinophenyl and
the corresponding ring substituted benzyl and -methyl
benzyl groups.
Heterocyclic groups may be, for example, pyridyl,
furyl or thienyl.
In a further aspect the invention provides the
triazole and imidazole compounds having the general
formula (I):
R6 oR3 ~4
Az C C C X R2
R7 11 R5 (I)
wherein Rl is hydrogen, alkyl, optionally substituted
cycloalkyl, cycloalkylmethyl, alkenyl, heterocyclyl, aryl
or aralkyl optionally substituted with halogen, nitro,
alkyl, haloalkyl, alkoxy, haloalkoxy, phenyl, phenoxy,
benzyl, benzyloxy, halophenyl, haloalkoxy; R2 is any of
the values for Rl except optionally substituted phenyl
when X is oxygen and R3 to R7 are hydrogen; R3 is
hydrogen, alkyl, alkenyl, alkynyl, aralkyl or acyl; R4
and R5, which may be the same or different, are hydrogen,
alkyl, alkenyl or optionally substituted aryl; R6 and
R7, which may be the same or different, are hydrogen,
alkyl, alkenyl or optionally substituted aryl; X is oxygen
or sulphur or is S0 or S02 and Az is a 1,2,4- or 1,3,4-
triazole or imidazole ring; and isomers, acid additionsalts and metal complexes thereof.
_ 4 _ i339599
In another aspect the invention provides triazole and
imidazole compounds having the general formula (I):
R6 oR3 ~4
I
Az . C C C - X ~ R2
~7 ~1 15 (I)
wherein Rl and R2, which may be the same or different,
are alkyl, cycloalkyl, phenyl or benzyl optionally sub-
stituted with halogen, alkyl, alkoxy, phenyl, halophenyl,R3 is hydrogen or Cl_6 alkyl; R4 and R5, which may
be the same or different are hydrogen, C1-6 alkyl or
allyl; R6 and R7 are hydrogen; X is oxygen and Az is a
1,2,4-triazole ring; and acid addition salts and metal
complexes thereof.
The invention further includes compounds as defined
in the preceding paragraph but wherein R2 is other than
optionally substituted phenyl when X is oxygen and R3 to
R7 are hydrogen.
In a still further aspect the invention provides
triazole and imidazole derivatives as claimed in the claim
1 wherein in formula I Rl is Cl_6 alkyl, phenyl or
halophenyl; R2 is Cl 6 alkyl, cycloalkyl or phenyl,
both of which may be substituted with alkyl, alkoxy,
phenyl, halogen or halophenyl; R3 is hydrogen or C1 6
alkyl; R4, R5, R6 and R7 are hydrogen or Cl-6
alkyl; and X is oxygen.
In a yet further aspect the invention provides
triazole and imidazole derivatives as defined in the
preceding paragraphs wherein R2 is other than optionally
substituted phenyl when Az is a 1,2,4-triazole or
imidazole ring, X is 0, Rl is alkyl, optionally
substituted phenyl or optionally substituted cycloalkyl
and R3, R4, R5, R6 and R7 are hydrogen.
- 5 - 1339~99
The salts can be salts with inorganic or organic
acids e.g. hydrochloric, nitric, sulphuric, acetic, 4-
toluene sulphonic or oxalic acid.
Suitably the metal complex is one including, as the
metal, copper, zinc, manganese or iron. It preferably has
the general formula:
/ R6 oR3 R4
I
M Az C C C X R2 Am YH2~
\ R7 Rl R5
wherein Rl, R2, R3, R4, R5, R6 and R7, Az
and X are as defined above, M is metal, A is an anion
(e.g. a chloride, bromide, iodide, nitrate, sulphate or
phosphate anion), n is 2 or 4 and y is O or an integer of
1 to 12, and m is an integer consistent with valency.
Examples of the compounds of the invention are shown
in Table I below. These compounds correspond to the
general formula:-
/
-
- 6 - 1339599
C) N
o 1'
CO I ~
~I r~ ~ O ~O O
a) o ~ ~ ~
X O O O O O O O O
~ ~ ~ X X 3: ~; ~ ,~
d' 1~ a: I ~--1
--U--~ z~ E- ~ ~
. a~ a a
o~--C~--Z ~ ~ ~ ~ ~1~ ~ ~ ~ ;
o ~ I C o o ~ o
~ o O L~ h
/ \ O S~ O
r C I I I ~ --~
U ~-' ~ U
_~ 5
Q ~ Q ,~
O O~~
1339~99
. L~
~o
C ~ ~ I' ~D O
~ ~ , , , ,
_1 ~ ~ O~9 L ~
G~ O ~ ~ O
~: P~ E
L~
X OOOOOOO ~
t' C
~ ,
LO C
X ~ ~ ~ ~ 3
U .,~
C o
O
O O ~ ~ O ~ ~O ~1 ~ - \
U C ~ X
O ~ O ~ O O
E
U ~ ~ ~ U
I E
a a ~ ~ E
r ~ r ~, .
O ~ 0 5C C~
L~ L ,~ C
O O O I I O I ~~'
S ~ ~ ,1
U U U ~ ~J
--I O
~ N
o ~a
Z ~
~ ,'
Z ~; E
~ * ~ ,,
O o ~ o ~ ~ ~ ~ Ln
~ z ~ ~ c
O ., ~
- 8- 1339~99
~ o L~
C ~
9 1 *
a) o ~ ~ ~ O o
o o
$ ~ ~ $
~g
U~
,
z
o
H C ~ ~ ~ ~ ~ >1 1-
4~ 4 ~ ' a.
O O ~ O
~; O 'I h .~ ~ ~/ O h
.C ~ O ~ O O O ,C O
s r
J
~q
L
C C
~, ~ a
,~ s ~ o
coooo~c,a
) ~ h h ~ ' a) ~ h
S O O O O O I S O
U SU -I ~ ~Cu
.,J
o
~ a)
:~ h
~ O ~D r co ~ O ~ ~ ~ ~ J
1~39~99
~ _ _ _ ~
C C C ~ C
o o o o o
.,, .,~ .,, .~ .,,
.. , .,,.,. .,, .
rr~ ~ 0
C~ (, .. ~, o
C ~ ~ ~ o o , o
C ,, , 1 0 , ... ... ...
0 n~ O ~ ~1 ~ UJ d' nl ~ C~ d'
a) o ~ ~ r o ~r: o ~r _I o
O O O O O O O
X rQ U~ rQ rQ rQ rQ rQ O
.7
r~
z
z
o
H ~ ~ ~ >1 >1
~ J ,~
C Q, ~ S
O O,C ~ ~ ~O
_I ~ J 5 ~ I E
S S"~ S~:
U U ~ ~ UV
n
>1 >1 ~ ~ I
~J ~ 4, 4
~ ~ ~ ~ r' ~ ,
--~ O ~ C ~ ~ O ~ ~ O
h ,n aJ -~ ~ h,~ l
O I ,~ O O O I :) h
U ~ ~ V 0
~:5
Z O
O O
O
*
-- 10 --
13~9599
U~
C~ .
t~7 ~ ~D r-l ~9 ~ ~ 1'
C ~ o ~ o ~ ~ ~ o
r~ ~ CO r~ I r~ r~ ~r-l r~~ _I r~
'r'l 'r'~
O O O
~IJ O CO O ~ O r~ ~ ~ o
r~ CO r-~ r-~ r-1 r~
X O O O O O O O O O O O O
X
~D
Lr
z
_l
O . ,~
I ~ C C ~ ~
r-l r-l
O ,C>1 ~ ~ Q~
E- ~ 4 ~,~ ,~ r-l r-~ ~r-/ r-l ! O O O
O~ 1 0 ~ 1 4
r~ v ,C ~ , ~ C :L, ~ ~1, Q~
,c ': E E J ~ ~ a~ ~ I I I I
U O ,c aJS ~ ,' I.,~ I ,~ I -,~ I
I S ~ E
N Q
r~ r~ r~ r-l
O :~ ~ >1 ~ I
h ' C - O
--I O 1. r~~ ~ r-lr~l r~ 1 4
~ r~ _Ir~ ~ ~ ~ ~1 ~ r~ O
J S ~ r~
-- ~ U C O ~ O ~ O
t~ rJ a) 4 ,~ V ~
O I O I ~ I . '- O ~ r~ ~J
- ~ ~ U ~ d'
I I I I
a
z
~ ~ o r~
i;
1339
rn
u ~ r~
~o ~ o
O O O
~J O ~ n,
C4 --4 ~;
X O O O O O O O O O O O O
'9
~; ~ U U U 5~ U U U U
tr: U U U ~ ~ ~ :~ U U U U
z
O O O ~ O ~ O ~ ~ ~ O
cl ~I cl cl cl
c
--Ir1 r-l r~
~ ~ I ' ~ ~ I O
f_ O _ _ O _ _ O ~
'J ~ k
.~,; O ~,~ O ' , O O
,~ r ~ S >
U C C-I -~ U ~ U -. ~
o o ~ o -~ J o
-- ~ ~3 S S
I ~ ~S --I I ~ ~ r r~
U ~ ~ ~ ~1 ~ _I
~ ~ ~ ~ ~ d ~ d ~ ~ n
a
~ s~
o o ~ ~ r ~ ~o ~ J
-
r~ ~c
1339~99
-- 12 --
C~ o ~ Cr~
o --~
o c~ ~ o
o ~ _~ ~ CO t'
X o o o o o o o o o o o o
UUUUUUUUUUU U
Z ~ I C I ~ I C I
o
u
,_
~ s~ s~ s~ s~ s s~ s~ c s~ c ~ JsJ
) o o
r~ r-- s
, J ,~ J ~ S
O O ,C S _ C O ~ ,C ,' r~
~-1 r-l ~ J I ~ S ~ r~
,1 S O aJ ,'- S r-l
Z
~ z ~
1339~99
C~ o
~ E~
E~ Zi
o
X o o o o o o o o o o o o
X ~ ~ 3 s !r. ~ X ~
U U U U U ~ U U U U U U
o
S ~ ~ 5
E~ kE~
O ~ O ~
O _~ O --I O ~ I O r5 ~5
~5
U ~ U ~ U U
z ~
o _~ ~ ~d'U~ ~ I' ~ ~ o
_
Z ,
- 14 - 133g~99
~ o
H E-l
E~ 'Z
~2
X o o o o o o o o o o
X 5: 5: X
~g
U~
Z C~ ~ ~ ~ ~ I , , , , ~
~ U ~, ~, U , ~ ~ , ~ I
o
C~
.,,
, , , II,,,,, ~
s ~ ~ ~ ~ ~ ~ ~ ~ ~ o
E E~ ~ ~
~ ,~
o o ~ ~ ~ c l l ~ ~
1 ~ a a o o ~~
o o ~ - ~ C'
~ I a~_I ~ ~ h O--~ O--I
~ S. ~ S ~ O r' O,S'>1 ~ O O ~
u c c c~ s_ s: a
a) ~_ a) o_, o~ c o u
s. s s. s~
U ~ ~ I I C'
~ N N F~ N E~ ~ d ' ' ' ~r~
Z ~
N ~ ~ ~ 9 t' Ct) ~ O
. . ~
~ ~ ~ ~ ~ ~ J
-- 15 --
1339~99
C~ o
Z
H E~
~ O
,~ H
~0 ~
X O O O O O O O O O O O
~9
C~
H ~ ~ )CJ U C,)
E~
o
H ~
.C S S S S
E ~ E
-- : O
. I J O ~ '- . L
, _ Ll ,~ _ ~ O ,
L~ C ~
O O U ~ O O ~ O ~ O O
' S ~ R
I U ~ ~ I ~ ~ ~ ~ o
N ~ ~) d '
N
Z
O r~ _I N ~ d~ u~ ~ I' CO ~ O ~
, _ cs~ ~ ~ a~ ~ ~ cs~ c~ ~ o o
' Z
- 16 - 1339~99
o
Z ~ o l~
~ E~ ~ t' I'
E~ Z
,~ H ~ cr~
O ~ ~9 1'
X OOO OOOOOO O
~9
U~
~ d'
H I ~ ~ $
z
O
H t~
~ :~ ~ ~ ~ ~ X
J J
~ S ~ ~ ~ ,C ,~
~1_1 _.1 _
-- - O ~ O
~ ~ O ~ ~ J
'
o ~ o ~ o
u I ~ ~ u~1 u
~z ~
o ~ ao ~ O --
~ -- o o o o o o o o --l ~
~ z
v
- 17 - 1339~99
eJ~ o *
C In
.,, ~ c
C
,.,.
~ O a~
X oo oooo oo,o o
U~
~ U ~ C ~ ~ X
" U
L
Z ~; :C X 5
o
U
~ ~f~
a a I I ~
~ o ~ ~ ~ f ,
C ~; ~ h ~ _ ~ ~ X
C C ~ O
U
~ ~ ~ ~ u
o
~ o
r ~ ~_ o ~
O O OO ~ ~ I F
C I ~1 ~1~1 _ ,~ ~J I ~h
U
I . II
~ ~ ~~f~ ~
a h
'Z
~ o ~ ~ ~ ~ ~r~o ~ o ~
. ~ Z ~ ~ ~ f~ ~ ~
r.)
1339~9g
- 18 -
The compounds of the invention having the general
formula I wherein Rl, R2 R3 R4 R5 R6 R7
are as defined above can be made by treating the epoxides
of general formula (II)
R6 R7
\C/
0 R4
Rl_ C I _ X R2
(II)
with l,2,4-triazole or imidazole either in the presence of
an acid-binding agent or in the form of one of its alkali
metal salts in a convenient solvent, and, thereafter,
oxidising those compounds wherein X=S to obtain those
compounds wherein X is S0 or S02. A suitable oxidising
agent is m-chloroperbenzoic acid and the oxidation process
is by normal such procedures. In the main process suitably
a compound of general formula (II) is reacted at 20-lO0
with the sodium or potassium salt of l,2,4-triazole or
imidazole (the salt can be prepared by adding either
sodium hydride, a sodium alkoxide or potassium t-butoxide
to l,2,4-triazole or imidazole) in a convenient solvent
such as acetonitrile, methanol, ethanol or dimethyl-
formamide. The product can be isolated by pouring the
reaction mixture into water and extraction into a suitable
solvent.
The epoxides of general formula (II) wherein R6 =
R7 = hydrogen are made by reacting a ketone of general
formula (III)
- 1~3~99
~ -- 19 --
O R4
Rl I C X--R2
(III)
with dimethyl oxosulphonium methylide (Corey and
Chaykovsky, J.Amer. Chem. Soc. 1965, 87, 1353-1364) or
dimethyl sulphonium methylide (Corey and Chaykovsky, J.
Amer. Chem. Soc. 1962, 84, 3782) using methods set out
in the literature. The epoxides of general formula (II)
may also be made by the epoxidation of an olefin of
general formula (IV)
R7 R6
\ C/ ~4
Rl-- C C X R2
~5
(IV)
with the standard oxidising agents such as hypochlorous
acid, hydrogen peroxide or peracids (e.g. peracetic or
perbenzoic acid). The olefin (IV) is made by treating
the ketone of general formula (III) with a Grignard
reagent (V)
R6
\
CH MgY
(V)
133g599
- 20 -
where Y is halogen, for example, chlorine, bromine or
iodine, in a convenient solvent such as ether, tetrahydro-
furan or anisole and dehydrating the intermediate alcohol.
The ketones of general formula (III) may be made by a
variety of methods many of which are well known in the
literature.
(a) Alkylation of the corresponding~ -hydroxy ketones as
in Houben Weyl 7/2e p.2232. The ~-hydroxy ketones
are made by literature methods - Houben ~eyl 7/2e
pp. 2173-2242.
(b) Grignard reaction of RlMgY on the appropriate
nitrile, R2XCR4R5CN, as in Organic Syntheses
Collective Volume 3, pp 562-563.
(c) Grignard reaction of RlMgY on the appropriate acid
chloride, R2XCR4R5COCl, as in Fumie Sato et al.,
Tet. Letters, 1979, 44, pp.4303-4306.
(d) Grignard reaction of RlMgY on the appropriate
aldehyde, R2XCR4R5CHo, to give the secondary
alcohol followed by oxidation to give the ketone.
~0 (e) Treatment of the epoxide Rl - CH ~ R4R5, or the
halohydrin Rl- CHoHCYR4R5, with R2 ~ as in
W.S. Emerson, J. Amer. Chem. Soc. 1945, 69, 516-518
fol lowed by ox idat ion as in A . Kael in Helv . Chim . Acta,
1947, 30, 2132-41 to give the ketone.
(f) Reaction of the ~-halo ketone Rl- C- CR4R5Y with
R2~)~ ~
1339~99
- 21 -
oR8
(g) Treatment of the halo-ketal Rl OR9
wherein R8 and R9 are alkyl or together form a
ring with R~ followed by acid hydrolysis.
(h) The ketones where Rl is alkyl or aralkyl can also be
R4
made by alkylating the acetylenic alcohol HO- C - _ - R10
R5
wherein R10=H, alkyl, or aryl, followed by hydrolysis
as in B D Tiffinay et al., J.Amer.Chem.Soc., 1957, 79,
1682-7.
(i) The ketones where Rl=aryl can be made by Friedel-
Crafts reaction between a substituted benzene and the
R4 o
acid chloride R2X- C- C- Cl.
R5
The compounds (I) of the invention can also be prepared by
treating the epoxide of general formula (VI)
\ /
l\o
Rl C/
R6 _ C- R7
I
Az (VI)
with the alkali metal salt of an oxygen or sulphur
nucleophile (VII)
- 22 - 1339~99
R2 - ~ M0
(VII)
in a convenient solvent such as dimethyl formamide and
dimethyl sulphoxide at temperatures of 20-100~. The
epoxides of general formula (VI) wherein R4 = R5 = H
can be prepared by reacting a ketone of general formula
5 (VIII) Rl
I
C - O
R6 C R7
Az (VIII)
with dimethyl oxosulphonium methylide (Corey and
Chaykovsky, J.Ameer. Chem. Soc. 1965, 87, 1353-1364) or
dimethyl sulphonium methylide (Corey and Chaykovsky,
J.Amer. Chem.Soc. 1962, 84, 3782) using methods set out in
the literature.
The ketones of general formula (VIII) can be made
by methods set out in the patent literature (British
Patents Nos. 1533705/6).
The salts and metal complexes of the compounds of
general formula (I) can be prepared from the latter in
known manner. For example, the complexes can be made by
reacting the uncomplexed compound with a metal salt in a
suitable solvent.
The compounds, salts and metal complexes are active
fungicides, particularly against the diseases:-
Puccinia recondita, Puccinia striiformis and other rustson wheat, Puccinia hordei, Puccinia striiformis and other
rusts on barley, and rusts on other hosts e.g. coffee,
apples, vegetables and ornamental plants
133~
- 23 -
Plasmopara viticola on vines
Erysiphe graminis (powdery mildew) on barley and wheat and
other powdery mildews on various hosts such as
Sphaerotheca fuliginea on cucurbits (e.g. cucumber),
Podosphaera leucotricha on apples and Uncinula necator on
vines
Helminthosporium spp. and Rhynchosporium spp. on cereals
Cercospora arachidicola on peanuts and other Cercospora
species on for example sugar beet, bananas and soya beans
Botrytis cinerea (grey mould) on tomatoes, strawberries,
vines and other hosts
Venturia inaequalis (scab) on apples
Some of the compounds have also shown a broad range
of activities against fungi in vitro. They have activity
against various post-harvest diseases on fruit (e.g.
Penicillium digatatum and italicum on oranges and
Gloeosporium musarum on bananas). Further some of the
compounds are active as seed dressings against: Fusarium
spp., Septoria spp., Tilletia spp. (i.e. bunt, a seed borne
disease of wheat), Ustilago spp., Helminthosporium spp. on
cereals, Rhizoctonia solani on cotton and Corticium sasakii
on rice.
The compounds can move acropetally in the plant
tissue. Moreover, the compounds can be volatile enough to
be active in the vapour phase against fungi on the plant.
The compounds, and their derivatives as defined
above, also have plant growth regulating activities.
The plant growth regulating effects of the compounds
are manifested as,for example, by a stunting or dwarfing
effect on the vegetative growth of woody and herbaceous
mono- and di-cotyledonous plants. Such stunting or
dwarfing may be useful, for example, in peanuts, cereals
and soya bean where reduction in stem growth may reduce
the risk of lodging and may also permit increased amounts
of fertiliser to be applied. The stunting of woody
species is useful in controlling the growth of undergrowth
under power lines etc. Compounds which induce stunting or
- 24 -
1 339~99
dwarfing may also be useful in modifying the stem growth
of sugar cane thereby increasing the concentration of
sugar in the cane at harvest; in sugar cane, the flowering
and ripening may be controllable by applying the
compounds. Stunting of peanuts can assist in harvesting.
Growth retardation of grasses can help maintenance of
grass swards. Examples of suitable grasses are
Stenotaphrum secundatum (St. Augustine grass), Cynosurus
cristatus, Lolium multiflorum and perenne, Agrostis
tenuis, Cynodon dactylon (Bermuda grass), Dactylis
glomerata, Festuca spp. (e.g. Festuca rubra) and Poa spp.
(e.g. Poa pratense). The compounds may stunt grasses
without significant phytotoxic effects and without
deleteriously affecting the appearance (particularly the
colour) of the grass; this makes such compounds attractive
for use on ornamental lawns and on grass verges. They may
also have an effect on flower head emergence in, for
example, grasses. The compounds can also stunt weed
species present in the grasses; examples of such weed
species are sedges (e.g. Cyperus spp.) and dicotyledonous
weeds (e.g. daisy, plantain, knotweed, speedwell, thistle,
docks and ragwort). The growth of non-crop vegetation
(e.g. weeds or cover vegetation) can be retarded thus
assisting in the maintenance of plantation and field
crops. In fruit orchards, particularly orchards subject
to soil erosion, the presence of grass cover is important.
However excessive grass growth requires substantial
maintenance. The compounds of the invention could be
useful in this situation as they could restrict growth
without killing the plants which would lead to soil
erosion; at the same time the degree of competition for
nutrients and water by the grass would be reduced and this
could result in an increased yield of fruit. In some
cases, one grass species may be stunted more than another
grass species; this selectivity could be useful for
example for improving the quality of a sward by
preferential suppression of the growth of undesirable
species.
- 25 - 1339~99
The dwarfing may also be useful in miniaturising
ornamental, household, garden and nursery plants (e.g.
poinsettias, chrysanthemums, carnations, tulips and
daffodils).
As indicated above, the compounds can also be used to
stunt woody species. This property can be used to control
hedgerows or to shape fruit trees (e.g. apples). Some
coniferous trees are not significantly stunted by the
compounds so the compounds could be useful in controlling
undesirable vegetation in conifer nurseries.
The plant growth regulating effect may (as implied)
above) manifest itself in an increase in crop yield.
In the potato, vine control in the field and
inhibition of sprouting in the store may be possible.
Other plant growth regulating effects caused by the
compounds include alteration of leaf angle and promotion
of tillering in monocotyledonous plants. The former
effect may be useful for example in altering the leaf
orientation of, for example, potato crops thereby letting
more light into the crops and inducing an increase in
phytosynthesis and tuber weight. By increasing tillering
in monocotyledonous crops (e.g. rice), the number of
flowering shoots per unit area may be increased thereby
increasing the overall grain yield of such crops. In
-grass swards an increase in tillering could lead to a
denser sward which may result in increased resilience in
wear.
The treatment of plants with the compounds can lead
to the leaves developing a darker green colour.
The compounds may inhibit, or at least delay, the
flowering of sugar beet and thereby may increase sugar
yield. They may also reduce the size of sugar beet
without reducing significantly the sugar yield thereby
enabling an increase in planting density to be made.
Similarly in other root crops (e.g. turnip, swede,
mangold, parsnip, beetroot, yam and cassava) it may be
possible to increase the planting density.
- 26 - 1~3~99
The compounds could be useful in restricting the
vegetative growth of cotton thereby leading to an increase
in cotton yield.
The compounds may be useful in rendering plants
resistant to stress since the compounds can delay the
emergence of plants grown from seed, shorten stem height
and delay flowering; these properties could be useful in
preventing frost damage in countries where there is sig-
nificant snow cover in the winter since then the treated
plants would remain below snow cover during the cold
weather. Further the compounds may cause drought or cold
resistance in certain plants.
~ Jhen applied as seed treatments at low rates the
compounds can have a growth stimulating effect on plants.
15 ~ In carrying out the plant growth regulating method
of the invention, the amount of compound to be applied to
regulate the growth of plants will depend upon a number
of factors, for example the particular compound selected
for use, and the identity of the plant species whose
growth is to be regulated. However, in general an
application rate of 0.1 to 15, preferably 0.1 to 5, kg per
hectare is used. However, on certain plants even
application rates within these ranges may give undesired
phytotoxic effects. Routine tests may be necessary to
determine the best rate of application of a specific
compound for any specific purpose for which it is
suitable.
The compounds are also useful for the treatment of
candidiasis and human dermatophyte infections.
The compounds may be used as such for fungicidal
or plant growth regulating purposes but are more
conveniently formulated into compositions for such usage.
The invention thus provides also a fungicidal composition
comprising a compound of general formula (I) or a salt or
complex thereof as hereinbefore defined, and a carrier or
diluent.
- 27 - 1339599
The invention also provides a method of combating
fungal diseases in a plant, which method comprises applying
to the plant, to seed of the plant, or to the locus of the
plant or seed, a compound, or a salt or complex thereof,
as hereinbefore defined.
The invention further provides a method of combating
fungal diseases in a plant, which method comprises
applying to the plant, to seed of the plant or to the
locus of the plant or seed, a compound, or a salt or
complex thereof, as hereinbefore defined.
The compounds, salts and complexes can be applied in
anumber of ways, for example they can be formulated or
unformulated, directly to the foliage of a plant, to seeds
or to other medium in which plants are growing or are to be
planted, or they can be sprayed on, dusted on or applied as
a cream or paste formulation, or they can be applied as a
vapour. Application can be to any part of the plant, bush
or tree, for example to the foliage, stems, branches or
roots, or to soil surrounding the roots, or to the seed
before it is planted.
The term "plant" as used herein includes seedlings,
bushes and trees. Furthermore, the fungicidal method of
the invention includes preventative, protectant,
prophylactic and eradicant treatment.
The compounds are preferably used for agricultural and
horticultural purposes in the form of a composition. The
type of composition used in any instance will depend upon
the particular purpose envisaged.
The compositions may be in the form of dusting powders
or granules comprising the active ingredient and a solid
diluent or carrier, for example fillers such as kaolin,
bentonite, kieselguhr, dolomite, calcium carbonate, talc,
powdered magnesia, Fuller's earth, gypsum, Hewitt's earth,
diatomaceous earth and China clay. Such granules can be
preformed granules suitable for application to the soil
without further treatment. These granules can be made
either by impregnating pellets of filler with the active
- 28 - 1339~99
ingredient or by pelleting a mixture of the active
ingredient and powdered filler. Compositions for dressing
seed, for example, may comprise an agent (for example a
mineral oil) for assisting the adhesion of the composition
to the seed; alternatively the active ingredient can be
formulated for seed dressing purposes using an organic
solvent (for example ~-methylpyrrolidone or
dimethylformamide).
The compositions may also be in the form of
dispersible powders, granules or grains comprising a
wetting agent to facilitate the dispersion in liquids of
the powder or grains which may contain also fillers and
suspending agents.
The aqueous dispersions or emulsions may be prepared
by dissolving the active ingredient(s) in an organic
solvent optionally containing wetting, dispersing or
emulsifying agent(s) and then adding the mixture to water
which may also contain wetting, dispersing or emulsifying
agent(s). Suitable organic solvents are ethylene
dichloride, isopropyl alcohol, propylene glycol, diacetone
alcohol, toluene, kerosene, methylnaphthalene, the xylenes,
trichloroethylene, furfuryl alcohol, tetrahydrofurfuryl
alcohol, and glycol ethers (e.g. 2-ethoxyethanol and 2-
butoxyethanol).
The compositions to be used as sprays may also be in
the form of aerosols wherein the formulation is held inaa
container under pressure in the presence of a propellant,
e.g. fluorotrichloromethane or dichlorodifluoromethane.
The compounds can be mixed in the dry state with a
pyrotechnic mixture to form a composition suitable for
generating in enclosed spaces a smoke containing the
compounds.
Alternatively, the compounds may be used in a micro-
encapsulated form.
By including suitable additives, for example additives
for improving the distribution, adhesive power and
- 29 ~ 1339~99
resistance to rain on treated surfaces, the different
compositions can be better adapted for various utilities.
The compounds can be used as mixtures with fertilisers
(e.g. nitrogen-, potassium- or phosphorus-containing
fertilisers). Compositions comprising only granules of
fertiliser incorporating, for example coated with, the
compound are preferred. Such granules suitably contain up
to 25% by weight of the compound. The invention therefore
also provides a fertiliser composition comprising the
compound of general formula (I) or a salt or metal complex
thereof.
The compositions may also be in the form of liquid
preparations for use as dips or sprays which are generally
aqueous dispersions or emulsions containing the active
ingredient in the presence of one or more surfactants e.g.
wetting agent(s), dispersing agent(s), emulsifying agent(s)
or suspending agent(s). These agents can be cationic,
anionic or non-ionic agents. Suitable cationic agents are
quaternary ammonium compounds, for example cetyltrimethyl-
ammonium bromide.
Suitable anionic agents are soaps, salts of aliphaticmonoesters of sulphuric acid (for example sodium lauryl
sulphate), and salts of sulphonated aromatic compounds (for
example sodium dodecylbenzenesulphonate, sodium, calcium or
ammonium lignosulphonate, butylnaphthalene sulphonate, and
a mixture of sodium diisopropyl- and triisopropyl-
naphthalene sulphonates).
Suitable non-ionic agents are the condensation
products of ethylene oxide with fatty alcohols such as
oleyl or cetyl alcohol, or with alkyl phenols such as
octyl- or nonyl-phenol and octylcresol. Other non-ionic
agents are the partial esters derived from long chain fatty
acids and hexitol anhydrides, the condensation products of
the said partial esters with ethylene oxide, and the
lecithins. Suitable suspending agents are hydrophilic
- 30 - 1339~99
colloids (for example polyvinylpyrrolidone and sodium carb-
oxymethylcellulose), and the vegetable gums (for example
gum acacia and gum tragacanth).
The compositions for use as aqueous dispersions or
emulsions are generally supplied in the form of a con-
centrate containing a high proportion of the active
ingredient(s), the concentrate to be diluted with water
before use. These concentrates often should be able to
withstand storage for prolonged periods and after such
storage be capable of dilution with water in order to form
aqueous preparations which remain homogeneous for a
sufficient time to enable them to be applied by convent-
ional spray equipment. The concentrates may conveniently
contain up to 95%, suitably 10-85%, for example 25-60%, by
weight of the active ingredient(s). These concentrates
suitably contain organic acids (e.g. alkaryl or aryl
sulphonic acids such as xylenesulphonic acid or dodecyl
benzenesulphonic acid) since the presence of such acids can
increase the solubility of the active ingredient(s) in the
polar solvents often used in the concentrates. The
concentrates suitably contain also a high proportion of
surfactants so that sufficiently stable emulsions in water
can be obtained. After dilution to form aqueous prepar-
~ ations, such preparations may contain varying amounts of
the active ingredient(s) depending upon the intendedpurpose, but an aqueous preparation containing 0.0005% or
0.01% to 10% by weight of active ingredient(s) may be
used.
The compositions of this invention can comprise also
other compound(s) having biological activity, e.g. com-
pounds having similar or complementary fungicidal activity
or compounds having plant growth regulating, herbicidal or
insecticidal activity.
The other fungicidal compound can be for example one
which is capable of combating ear diseases of cereals (e.g.
- 31 - 1339S99
wheat) such as Septoria, Gibberella and Helminthosporium
spp., seed and soil borne diseases and downy and powdery
mildews on grapes and powdery mildew and scab on apple etc.
These mixtures of fungicides can have a broader spectrum of
activity than the compound of general formula (I) alone;
further the other fungicide can have a synergistic effect
on the fungicidal activity of the compound of general
formula (I). Examples of the other fungicidal compound are
imazalil, benomyl, carbendazim, thiophanate-methyl,
captafol, captan, sulphur, triforine, dodemorph, tride-
morph, pyrazophos, furalaxyl, ethirimol, dimethirimol,
bupirimate, chlorothalonil, vinclozolin, procymidone,
iprodione, metalaxyl, forsetyl-aluminium, carboxin, oxy-
carboxin, fenarimol, nuarimol, fenfuram, methfuroxan,
nitrotal-isopropyl, triadimefon, thiabendazole, etridi-
azole, triadimenol, biloxazol, dithianon, binapacryl,
quinomethionate, guazitine, dodine, fentin acetate, fentin
hydroxide, dinocap, folpet, dichlofluanid, ditalimphos,
kitazin, cycloheximide, dichlobutrazol, a dithiocarbamate,
a copper compound, a mercury compound, 1-(2-cyano-2-
methoxyiminoacetyl)-3-ethyl urea, fenapanil, ofurace, pro-
piconazole, etaconazole and fenpropemorph.
The compounds of general formula (I) can be mixed with
soil, peat or other rooting media for the protection of
plants against seed-borne, soil-borne or foliar fungal
diseases.
Suitable insecticides are Pirimor, Croneton, dimeth-
oate, Metasystox and formothion.
The other plant growth regulating compound can be one
which controls weeds or seedhead formation, improves the
level or longevity of the plant growth regulating activity
of the compounds of general formula (I), selectively
controls the growth of the less desirable plants (e.g.
grasses) or causes the compound of general formula (I) to
act faster or slower as a plant growth regulating agent.
Some of these other agents will be herbicides.
- 32 - 1339599
Examples of suitable plant growth regulating compounds
are the gibberellins (e.g. GA3, GA4 or GA7, the
auxins (e.g. indoleacetic acid, indole-butyric acid, naph-
thoxyacetic acid or naphthylacetic acid), the cytokinins
(e.g. kinetin, diphenylurea, benzimidazole, benzyladenine
or benzylaminopurine), phenoxyacetic acids (e.g. 2,4-D or
MCPA), substituted benzoic acids (e.g. triiodobenzoic
acid), morphactins (e.g. chlorfluorecol), maleic
hydrazide, glyphosate, glyphosine, long chain fatty
alcohols and acids, dikegulac, fluoridamid, mefluidide,
substituted quaternary ammonium and phosphonium compounds
(e.g. chlormequat or chlorphonium), ethephon, carbetamide,
methyl-3,6-dichloranisate, daminozide, asulam, abscissic
acid, isopyrimol, 1(4-chlorophenyl)-4,6-dimethyl-2-oxo-
1,2-dihydropyridine-3-carboxylic acid, hydroxybenzo-
nitriles (e.g. bromoxynil), difenzoquat, benzoylpropethyl,
and 3,6-dichloropicolinic acid.
The following Example illustrates the invention; the
temperatures are give ~ _
/
1339~99
- 33 -
EXAMPLE 1
This Example illustrates the preparation of 3,3-
dimethyl-1-(4-chlorophenoxy)-2-(1,2,4-triazol-1-yl-
methyl)butan-2-ol (Compound No.l of Table I).
Stage I:
To a solution of dimsyl sodium, prepared by reacting
sodium hydride (1.1 parts) with di~ethyl sulphoxide (40 ml)
under nitrogen atmosphere at 60-70~, was added with
cooling, trimethylsulphonium iodide (9.42 parts) dissolved
in dimethyl sulphoxide (40 ml), over a period of 5 minutes.
After stirring for an additional five minutes,~ -4-chloro-
phenoxy pinacolone (lO parts) dissolved in tetrahydrofuran(80 ml) was added rapidly and kept at 0~ for about 10
minutes. The cooling bath was removed and the stirring
was continued for another hour. The reaction mixture was
then poured into water (300 ml) and the aqueous solution
was extracted three times with petroleum ether (30-40~).
The combined organic extract was washed with water, dried
(K2C03) and the solvent was removed to obtain the
oxirane.
Stage II:
To a suspension of potassium tertiary-butoxide (1.9 parts)
in dimethylformamide (30 ml) was added 1,2,4-triazole
(1.15 parts) in dimethylformamide (30 ml) dropwise at room
temperature and the mixture was kept at 60~ for one hour.
The solution was cooled to 0 to -5~ and the oxirane (4
parts) described in Stage I was dissolved in dimethyl-
formamide (15 ml) and added dropwise with stirring. The
reaction mixture was allowed to warm to room temperature
and then heated at 50~ for three hours.
- 34 - 1~39~99
The mixture was poured into water (200 ml) and any of the
unreacted oxirane that was precipitated was filtered off.
The filtrate was extracted with ether (50 ml) three times.
The combined ether extract was washed with water, dried
(MgS04) and the solvent removed. The yellow residue was
purified by flash chromatography over silica gel (230-400
mesh) and eluted with ethyl acetate: petroleum ether
(60-80~) (1:1) to yield the title compound as a white
solid, m.p. 85.5 - 87~.
EXAMPLE 2
This Example illustrates the preparation of 3,3-
dimethyl-1-(4-chlorophenylsulphenyl)-2-(1,2,4-triazol-1-
ylmethyl)butan-2-ol (Compound No.22 of Table I).
Dry dimethylsulphoxide (DMS0: 70 ml) was added
dropwise with stirring to a mixture of sodium hydride
15(1.73 g) and trimethylsulphoxonium iodide (15.80 g) under
nitrogen and stirred for 1 hour at room temperature. A
solution of ~-triazolylpinacolone (10.00 g) in DMS0
(30 ml) was added to the resulting ylide solution and
stirred for 5 hours at room temperature. The mixture was
poured into water and extracted with ether. The combined
extracts were washed with water, dried over MgS04, and
concentrated to give a colourless oil (4.51 g) whose
infrared spectrum showed no carbonyl absorption.
A solution of the colourless oil (4.51 g) in dry
dimethylformamide (DMF ; 10 ml) was added with stirring to
a solution of sodium 4-chlorothiophenoxide ~from sodium
hydride (0.65 g) and 4-chlorothiophenol (3.96 g)] in DMF
(40 ml) under nitrogen and stirred for 2 hours at room
temperature. The mixture was poured into water and
extracted with ether. The combined extracts were washed
with water, dried over MgS04, and concentrated to give
13~9~99
- 35 -
the title compound (6.58 g, 34~ from X-triazolylpina-
colone) as a viscous colourless oil which crystallised on
standing, m.p. 64-65~.
EXAMPLE 3
This Example illustrates the preparation of 3,3-
dimethyl-1-(4-chlorophenylsulphinyl)-2-(1,2,4-triazol-1-
ylmethyl)butan-l-ol (compound No.26 of Table I).
m-Chloroperbenzoic acid (1.40 g) was added in portions to
a stirred solution of 3,3-dimethyl-1-(4-chlorophenyl-
sulphenyl)-2-(1,2,4-triazol-1-ylmethyl)butan-2-ol (2.12 g)
in dichloromethane (100 ml) at 5~. After 0.5 hours the
reaction mixture was washed successively with aqueous
NaHC03 and water, dried over MgS04, and concentrated
to give the title compound as a white solid (1.62 g, 73%),
m.p. 140-145~ (decomp.).
EXAMPLE 4
This Example illustrates the preparation of 3,3-
dimethyl-1-(4-chlorophenylsulphonyl)-2-(1,2,4-triazol-1-
ylmethyl)butan-2-ol (compound No. 31 of Table I).
m-Chloroperbenzoic acid (4.20 g) was added in portions to
a stirred solution of 3,3-dimethyl-1-(4-chlorophenyl-
sulphenyl)-2-(1,2,4-triazol-1-ylmethyl)butan-2-ol (3.18 g)
in dichloromethane (100 ml) at room temperature. After 1
hour the reaction mixture was washed successively with
aqueous NaHC03 and water, dried over MgS04, and
concentrated to give the title compound as a white solid
(2.18 g, 62~), m.p. 114-116~ (decomp.).
1339~99
- 36 -
EXAMPLE 5
This Example illustrates the preparation of 1-(1,2,4-
triazol-l-yl)-2-(4-methylphenyl)-3-ethoxyhexan-2-ol
(compound nos. 59 and 60 of Table I).
.
Boron trifluoride etherate (1.8 ml) was added to a stirred
mixture of l,l-diethoxybutane (32.1 g) and trimethylsilyl
cyanide (22.0 g) at room temperature: exotherm. After 3
hours, aqueous sodium bicarbonate was added and the mixture
was extracted with ether. The extracts were dried over
MgSO4 and concentrated to give an orange oil (36.0g)
containing 2-ethoxyvaleronitrile (Compare: K. Utimoto,
Y. Wakabayashi, Y. Shishiyama, M. Inoue and H. Nozaki,
Tetrahedron Letters, 1981, 22, 4279). A solution of part
of this crude material (9.0 g) in dry tetrahydrofuran (THF:
20 ml) was added to a stirred solution of 4-methylphenyl
magnesium bromide [from 4-bromotoluene (9.4 g) and
magnesium (1.98 g)] in dry THF (80 ml) under nitrogen and
the resulting mixture was heated under reflux for 3 hours.
After cooling, dilute sulphuric acid was added and the
mixture was extracted with ether. The combined extracts
were washed with water, dried over magnesium sulphate, and
concentrated under reduced pressure to give a red oil
(10.0 g) which was purified by column chromatography on
silica gel using dichloromethane as eluant to give 1-
ethoxy-1-(4-methylbenzoyl)butane (5.7 g, 47% from 1,1-
diethoxybutane) as an orange oil, IR: 1680 cm 1.
A suspension of sodium hydride ~0.70 g) in dry
dimethylsulphoxide (DMSO : 40 ml) was stirred at 50~ under
a nitrogen atmosphere for 2.5 hours. The resulting clear
solution was diluted with dry THF (40 ml) and cooled in an
ice-salt bath. Solutions of trimethylsulphonium iodide
(5.9 g) in DMSO (40 ml) and 1-ethoxy-1-(4-methylbenzoyl)-
butane (5.22 g) in THF (40 ml) were added successively to
the stirred dimsyl sodium solution, maintaining the
temperature of the reaction mixture at about 0~. After 15
1339~9
- 37 -
minutes the cooling bath was removed and after a further
1.5 hours the reaction mixture was diluted with water and
extracted with ether. The combined extracts were washed
with water, dried over magnesium sulphate, and concentrated
under reduced pressure to give a mixture of
diastereoisomers of 1,2-epoxy-2-(4-methylphenyl)-3-
ethoxyhexane (5.15 g, 93~) as a yellow oil.
A solution of 1,2-epoxy-2-(4-methylphenyl)-3-ethoxy-
hexane (4.7 g) in dry dimethylformamide (DMF: lO ml) was
added to a stirred solution of sodium triazole ~from 1,2,4-
triazole (2.07 g) and sodium hydride (0.72 g)] in DMF (40
ml) under nitrogen, and the mixture was heated at 50-60~
for 3 hours. Water was added, the mixture was extracted
with ether, and the combined extracts was washed with
water, dried over magnesium sulphate, and concentrated to
give a crude mixture of diastereoisomers of the title
compound (5.43 g) as a yellow oil.
Chromatography on a column of silica gel using ether
as eluant gave (i) Diastereoisomer A (2.04 g, 34~) as a
yellow oil, Rf (Et20/silica gel) 0.3; (ii) a mixture of
diastereoisomers A and B (0.80 g, 13%) as a yellow oil;
(iii) diastereoisomer B (0.87g, 14%) as a white crystalline
solid, m.p. 117-119~C, Rf (Et20/silica gel) 0.2
(found: C,67.20; H,8.02; N,14.02%. C17H25N302
requires C,67.33; H,8.25; N,13.86%).
EXAMPLE 6
This Example illustrates the preparation of 1-(1,2,4-
triazol-l-yl)-2-(4-chlorophenyl)-3-isopropoxy-propan-2-ol
(compound no.42 of Table I)
- 38 -
1339~99
Stage 1
Metallic sodium (3.0 g atoms, 69 g) was added to isopropyl
alcohol (1250 ml) at such a rate so as to maintain gentle
reflux. When all the sodium had reacted chloroacetic acid
(1.5 mol., 142 g) in isopropyl alcohol (180 ml) was added
dropwise maintaining gentle reflux. After the addition the
solution was refluxed for a further 4 hours. The isopropyl
alcohol was distilled off, the solid residue dissolved in
water (500 ml) and the solution cooled in an ice-salt bath.
Concentrated HCl (200 ml) was added dropwise, the sodium
chloride filtered off and the filtrate saturated with
sodium sulphate. The aqueous solution was extracted with
diethyl ether (5 x 250 ml) and the ether removed Ln vacuo
to give an orange liquid which distilled at reduced
pressure to give isopropoxy acetic acid (70%), b.p. 98-100~/
10 mm Hg.
Stage 2
Isopropoxy acetic acid (0.6 mol, 70.8 g) was added dropwise
to thionyl chloride (0.72 mol 86 g), stirred at 60~ for l.S
hours and heated to 100~ for half an hour to complete the
reaction. Distillation gave isopropoxy acetyl chloride
(95~), b.p. 140-141~.
Stage 3
Isopropoxy acetyl chloride (0.37 mol, 50 g) was added
dropwise with caution to 80/80 ammonia (250 ml) cooled in
an ice-salt bath keeping the temperature between 10~-15~.
After the addition the solution was stirred at room
temperature for 6 hours then reduced to dryness in vacuo.
The residue was extracted with hot ethyl acetate (3 x 250
ml) and thç solution dried over anhydrous sodium sulphate.
Removal of the solvent gave isopropoxyacetoamide (85%) as
a white crystalline solid, m.p. 41-42~.
1~39599
- 39 -
Stage 4
Isopropoxyacetoamide (0.21 mol, 25 g) and thionyl
chloride (0.26 mol, 30 g) were heated under gentle reflux
for 1 hour. Distillation at atmospheric pressure gave
isopropoxyacetonitrile (40%) as a colourless liquid b.p.
149-150~.
Stage 5
The Grignard reagent was prepared from 4-chloroiodobenzene
(0.066 mol, 15.7 g) and magnesium (0.066 g atoms, 1.6 g) in
dry diethyl ether (50 ml). To this ice-cooled solution was
added isopropoxyacetonitrile (0.055 mol, 5.5 g) in dry
ether (7 ml) and the solution allowed to stand at room
temperature for 2 hours. After cooling in an ice-salt bath
the complex was decomposed by adding water (80 ml) and
dilute H2S04 (30 ml). The ether solution was washed
with dilute H2S04 (100 ml), water (100 m), saturated
sodium bicarbonate solution (100 ml), and dried over
anhydrous sodium sulphate. Removal of the ether gave an
orange oil which was purified by medium pressure column
chromatography (silica Crosfield SD210 eluted with toluene)
to give ~-isopropoxy-4-chloroacetophenone (40%) as a golden
yellow oil.
Stage 6
50~ Sodium hydride (0.03 mol, 1.44 g) was washed with
petroleum ether, suspended in dry dimethyl sulphoxide
(30 ml) and heated at 70~ under a nitrogen atmosphere for 2
hours. After cooling to room temperature, dry tetrahydro-
furan (30 ml) was added and the solution cooled to 0~.Trimethylsulphonium iodide (0.03 mol, 6.12 g) dissolved in
dry dimethyl sulphoxide (30 ml) was added dropwise at 0~,
stirred for two minutes, and ~-isopropoxy-4-chloroaceto-
phenone (0.015 mol, 3.2 g) in dry dimethyl sulphoxide (15
ml) and dry tetrahydrofuran (15 ml) was added dropwise at
0~. The solution was stirred at room temperature for 4
hours, poured into ice water (200 ml), and extracted with
1339~99
- 40 -
(3 x 200 ml). The ether solution was washed with water (3
x 150 ml) and dried over anhydrous sodium sulphate.
Removal of the solvent gave 1-(4-chlorophenyl)-1-isopro-
poxymethyl ethylene oxide (90~) as a pale yellow oil.
Stage 7
50% Sodium hydride (0.02 mol, 0.96 g) was washed with
petroleum ether and suspended in dry dimethyl formamide (20
ml). 1,2,4-Triazole (0.02 mol 1.38 g) was added portion-
wise at room temperature and stirred at room temperature
until the effervescence ceased. 1-(4-chlorophenyl)-1-
isopropoxymethylethylene oxide (0.01 mol, 2.26 g) in
dimethyl formamide (2 ml) was added and the solution
stirred at 80~ for 5 hours. After cooling to room
temperature the solution was poured into water (200 ml),
extracted with ether (2 x 150 ml), washed with water (2 x
150 ml), and dried over anhydrous sodium sulphate. Removal
of the solvent gave a pale yellow oil which was purified by
column chromatography (silica Crosfield SD 210 eluted with
ethyl acetate) to give the title compound (70~) as an oil.
EXAMPLE 7
The compounds were tested against a variety of foliar
fungal diseases of plants. The technique employed was as
follows.
The plants were grown in John Innes Potting Compost
(No 1 or 2) in 4 cm diameter minipots. A layer of fine
sand was placed at the bottom of the pots containing the
dicotyledonous plants to facilitate uptake of test compound
by the roots. The test compounds were formulated either
by bead milling with aqueous Dispersol T or as a solution
in acetone or acetone/ethanol which was diluted to the
required concentration immediately before use. For the
foliage diseases, suspensions (100 ppm active ingredient)
were sprayed on to the soil. Exceptions to this were the
*Trade Mark
- 41 - 1339.~99
tests on Botrytis cinerea, Plasmopara viticola and
Venturia inaequalis. The sprays were applied to maximum
retention and the root drenches to a final concentration
equivalent to approximately 40 ppm a.i./dry soil. Tween
20, to give final concentration of 0.05%, was added when
the sprays were applied to cereals.
For most of the tests the compound was applied to the
soil (roots) and to the foliage (by spraying) one or two
days before the plant was inoculated with the diseases. An
exception was the test on Erysiphe graminis in which the
plants were inoculated 24 hours before treatment. After
inoculation, the plants were put into an appropriate
environment to allow infection to ta~e place and then
incubated until the disease was ready for assessment. The
period between inoculation and assessment varied from four
to fourteen days according to the disease and environment.
The disease control was recorded by the following
grading:-
4 = no disease
3 = trace - 5% of disease on untreated plants
2 = 6-25~ of disease on untreated plants
1 = 26-59% of disease on untreated plants
0 = 60-100% of disease on untreated plants
The results are shown in Table
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- 46 -
EXAMPLE 8
This Example illustrates the plant growth regulating
properties of the compounds. The compounds were applied as
an overall spray of an emulsifiable concentrate diluted to
give the concentrations shown in Table III. The plants were
grown in 3" pots in peat compost and sprayed at the 2 leaf
stage. Plant growth regulating effects were assessed 12
days after application of the compounds. Retardation of
growth was scored on a 0-3 scale where :
1 = 0-30~ retardation
2 = 31-75% retardation
3 = 75% retardation
Additional plant growth regulating properties are indicated
as follows :
G = darker green leaf colour
A = apical effect
T = tillering effect
The results are shown in Table III. If no figure is given
the compound was substantially inactive as a stunting
agent. --
/
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-- 47 --
1~3~99
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- 48 -
1339~99
Key to test species in Table I~I
AT Agrostis tenuis
CC Cynosurus cristatus
DA Dactylis glomerata
5 LT Lactaca sativa
SB Beta vulgaris
TO Lycopersicon esculentum
SY Glycine max
CT Gossypium hirsutum
10 MZ Zea mays
~J Triticum aestivum
BR Hordeum vulgare
1~33~99
- 49 -
EXAMPLE 9
An emulsifiable concentrate was made up by mixing the
ingredients, and stirring the mixture until all the
constituents were dissolved.
Compound of Example 1 10%
5 Ethylene dichloride 40%
Calcium dodecylbenzenesulphate 5%
"Lubrol" L 10%
"Aromasol" H 35
EXAMPLE 10
A composition in the form of grains readily dis-
persible in a liquid, e.g. water, was prepared by grindingtogether the first three ingredients in the presence of
added water and then mixing in the sodium acetate. The
resultant mixture was dried and passed through a British
Standard mesh sieve, size 44-100, to obtain the desired
size of grains.
Compound of Example 1 S0%
"Dispersol" T 25~
"Lubrol" APN5 1.5%
Sodium acetate 23.5%
EXAMPLE 11
20The ingredients were all ground together to produce a
powder formulation readily dispersible in liquids.
Compound of Example 3 45%
"Dispersol" T 5
"Lissapol" NX 0.5
25 "Cellofas" B600 2%
Sodium acetate 47.5%
1339599
- 50 -
EXAMPLE 12
The active ingredient was dissolved in a solvent and
the resultant liquid was sprayed on to the granules of
China clay. The solvent was then allowed to evaporate to
produce a granular composition.
Compound of Example 4 5%
China clay granules 95
EXAMPLE 13
A composition suitable for use as a seed dressing was
prepared by mixing the three ingredients.
Compound of Example 5 50%
Mineral oil 2%
China clay 48%
EXAMPLE 14
A dusting powder was prepared by mixing the active
ingredient with talc.
Compound of Example 6 5%
15 Talc 95%
EXAMPLE 15
A Col formulation was prepared by ball-milling the
constituents set out below and then forming an aqueous
suspension of the ground mixture with water.
Compound of Example 1 40%
"Dispersol" T 10%
"Lubrol" APN5 1%
Water
1339~99
- 51 -
EXAMPLE 16
A dispersible powder formulation was made by mixing
together the ingredients set out below and then grinding
the mixture until all were thoroughly mixed.
Compound of Example 2 25%
5 "Aerosol" OT/B 2%
"Dispersol" A.C. 5%
China clay 28%
Silica 40%
EXAMPLE 17
This Example illustrates the preparation of a
dispersible powder formulation. The ingredients were mixed
and the mixture then ground in a comminution mill.
Compound of Example 3 25%
"Perminal" BX 1%
"Dispersol" T 5%
15 Polyvinylpyrrolidone 10%
Silica 25%
China clay 34%
EXAMPLE 18
The ingredients set out below were formulated into a
dispersible powder by mixing then grinding the ingred-
ients.
Compound of Example 4 25%
"Aerosol" OT/B 2%
"Dispersol" A 5%
China clay 68%
- 52 - 133~99
In Examples 9 to 18 the proportions of the
ingredients given are by weight. The remaining compounds
of Table I were similarly formulated.
There now follows an explanation of the compositions
or substances represented by the various Trade Marks and
Trade Names mentioned above.
LUBROL L : a condensate of nonyl phenol
1 mole) with ethylene oxide
(13 moles)
10 AROMASOL H : a solvent mixture of alkylbenzenes
DISPERSOL T & AC : a mixture of sodium sulphate and a
condensate of formaldehyde with
sodium naphthalene sulphonate
LUBROL APN5 : a condensate of nonyl phenol
(1 mole) with naphthalene oxide
(5.5 moles)
CELLOFAS B600 : a sodium carboxymethyl cellulose
thickener
LISSAPOL NX : a condensate of nonyl phenol
(1 mole) with ethylene oxide
(8 moles)
AEROSOL OT/B : dioctyl sodium sulphosuccinate
PERMINAL BX : a sodium alkyl naphthalene
sulphonate
HGHA/bgg/SPEC220
