Note: Descriptions are shown in the official language in which they were submitted.
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PESTICIDAL COMPOUNDS
The present invention relates to the use of certain 1,2,3,4-substituted
naphthalene
compounds as pesticides active, inter alia, against whitefly and certain
fungi; to methods
for preparation of these compounds; to compositions containing them and to use
of the
compounds and compositions for the control of whitefly, Lepidoptera and fungal
pests.
US 2,572,946 discloses a composition for the control of mites and aphids in
which
the active ingredient is a compound of the general formula (P 1)
0
/ OH
l I (Pl)
~ R
0
where R is a radical, containing from 6 to 15 carbon atoms, selected from
alkyl, cyclohexyl
and cvclohexylalkyl groups; n-alkyl, iso-alkyl, alkvlcycloalkyl and aralkyl
groups being
exemplified. No specific miticidal or aphicidal data is given for these
compounds and thus
no indication is given as to which of the many compounds is best or, indeed,
whether these
are useful for control of pests other than mites and aphids.
DE 2641343 Al generically discloses compounds of the general formula (P2)
X 0 0
II
O-C-R2 (P2)
CR1
Y 0
in which Rl is a straight, branched or cyclic C8-14 alkyl group, R2 is a
straight or branched
C1_17 alkvl, C2-17 alkenvl, C3-6 cvcloalkyl, C1-4 alkoxy, -CH-)OCH3, -CH2OCH-
)CH3
or -CH=CH-COOH group, and X and Y represent a hydrogen, fluorine. chlorine or
bromine
atom or a methyl or methoxy group. These compounds are said to exhibit
acaricidal and
aphicidal activity but only compounds where R1 is a linear Cg or C11-14 alkyl
group are
shown to have such activity.
-1-
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US 4,110,473 concerns a method for protecting plants from mites (acarids)
which
comprises treating the plant with a compound of the general formula (P3)
0
R
/ I I 1 (P3)
OR2
Y 0
where Y is hydrogen, fluorine, chlorine or bromine; R1 is branched, cyclic or
straight
chain C8-14 alkyl; R2 is branched or straight chain C1-12 saturated alkyl or
C3-12 unsaturated alkyl optionally substituted by one or two chlorine,
bromine, methoxy
or ethoxy substituents, or C3-6 cycloalkyl.
GB 1553424 discloses compound of general formula (P3) wherein R2 is H and R1
is optionally substituted cyclohexyl, for use as an active agent for treatment
of infection of
cattle with theilerosis, while EP 0123238 and EP 0123230 relate to similar
such compounds
for use as anti-protozoan and anti-coccodiosis agents.
DE 3801743 Al generically discloses compounds of the general formula (P4)
0
CO( OR'
(CH2)n - R2
0
in which n is 0 to 12, R1 represents hydrogen or an optionally substituted
alkyl, aralkyl,
alkylcarbonyl, (hetero)arylcarbonyl, alkoxycarbonyl, alkylsulphonyl or
arylsulphonvl
group, and R2 represents a haloalkyl, optionally substituted (hetero)aryl or
substituted
cycloalkyl group. These compounds are said to exhibit acaricidal and
fungicidal activity.
Ten compounds are specifically disclosed of formula (P4) in which n is 0. R1
is a
hydrogen atom and R2 is a 4-(t-butyl)cyclohexyl, 4-(trimethylsilyl)cyclohexyl,
4-(cyclohexyl)-cyclohexyl, 2-trifluoromethylcyclohexyl or 3,5-
di(trifluoromethyl)-
cyclohexyl group or n is 0, R1 is an ethanoyl group and R2 is a 4-(1-
butyl)cyclohexyl,
4-(cyclohexyl)cyclohexyl, 2- or 3-trifluoromethylcyclohexyl or 3,5-
di(trifluoromethyl)-
cyclohexyl group. Of these, acaricidal activity is demonstrated for two
compounds of
-2-
CA 02209998 1997-07-09
F \I36\918`MOOISPEC\AM970312 WPD
formula (P4) in which n is 0, R1 is a hydrogen atom and R2 is a 4-(t-
butyl)cyclohexyl or
4-(trimethylsilyl)-cyclohexyl group.
EP 0077550 discloses compounds of general formula (P5)
0
OH
CH3
(P5)
CH2 R
0 CH3
in which R is an alkyl group of from 1 to 10 carbon atoms and describes their
use in
veterinary formulations, particularly for prophylaxis against protozoan
infection.
Copending international application No. PCT/GB95/00953 relates to naturally
occurring compounds of the general formula (P6)
0
R
` I ( (P6)
C (CH3)2- CH = CH2
0
in which R represents a hydrogen atom or a hydroxyl or an ethanoyloxy group,
and relates
to their use as pesticides, especially fungicides, insecticides and/or
acaricides.
These compounds were previously disclosed as plant metabolites by Chamy et
al.,(1993)
Bol. Soc. Chil. Quim. 38 187-190.
DE 2520793 Al generically discloses compounds of the general formula (P7)
0
11
O-C-R2
I (P7)
RI
0
in which R1 is a straight, branched or cyclic C8-14alkyl group, and R2 is a
straight or
branched C1-6 alkyl group or a C3-6 cycloalkyl group. These compounds are said
to
exhibit acaricidal and aphicidal activity but only compounds where R1 is a
linear C11 or
C 12 alkyl group are shown to have such activity.
-3-
~,;r;~,~~EB SHEET
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F U3619181W001SPEC1AM970312 WPD
EP 0002228 generically discloses compounds of the general formula (P8)
0
O.P" R'
I ~ (P8)
OH
0
in which R1 is a substituted or unsubstituted C3-12 cycloalkyl group. The
compounds are
said to be active against Theileria in cattle and sheep, though only the
compound in which
R1 is cycloheptyl is shown to have such activity.
Numerous 2-hydroxy or 2-alkoxy 3-substituted naphthalene-1,4-dione compounds
have been disclosed by Fieser et al. and other workers for use in treatment of
malaria (see
eg. US 2553647, US 3578685 and JACS (1948) Vol 70 pp. 3151, 3156-3165) or as
antitumour agents (see FR 2085660). These include a number of 3-isoalkyl
substituted
compounds. In US 2398418, Fieser shows how to prepare 2,3-disubstituted
naphthalene-
-1,4-dione compounds from the corresponding 2-substituted compound.
The present inventors have determined that many of the prior art
naphthoquinones
do not have high activity against whitefly, and particularly that most of the
aphicidal and
acaricidal compounds specifically disclosed in the prior art have
disappointing efficacy
when tested against whitefly of resistant and susceptible types.
The present inventors have now determined that certain synthetic
naphthoquinones
-3 a-
A",=',c~~CED SHEE~
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and related 1,4 derivatized compounds have advantageous pesticidal properties
over those
disclosed for such use in the prior art, particularlv as applied to treatment
of whitefly.
Preferred synthetic compounds for the use of the invention have excellent
pesticidal activity
against, inter alia, whitefly and/or fungi, with most preferred compounds also
showing
good activity against mites and/or aphids. The compounds identified by the
present
inventors have particular use against strains of whitefly and fungi that have
become
resistant to one or more of the currently commerciallv available pesticides.
According to a first aspect of the present invention there is provided the use
of acompound of general formula (I)
R' R2
1 Z R3
(R)n I 3I (I)
(A)m CHR4 R5
R8 R7
or a salt thereof as a pesticide against whitefly, Leptidoptera and/or fungal
pests, in which
n represents an integer from 0 to 4; m represents an integer 0 or 1;
each R independently represents a halogen atom or a nitro, cyano, hydroxyl,
alkyl, alkenyl,
haloalkyl, haloalkenyl, alkoxy, haloalkoxy, haloalkenoxy, amino, alkylamino,
dialkylamino, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl,
alkylsulphonyl, carbamoyl, alkylamido, cycloalkyl, aryl or aralkyl group;
RI and R2 each independently represent an optionallv substituted alkoxy group
or together
represent a group =0, =S or =N-OR9, where R9 represents a hydrogen atom or an
optionally substituted alkyl group;
R3 represents a hydroxyl group, or a group -OL where L is a leaving group, or
a group
which in vivo is transformed into a group -OL 1 where L I is a leaving group;
R7 and R8 independently represent an optionally substituted alkoxy group or
together
represent a group =0, =S or =N-OR9, where R9 is as previously defined; and
wherein R4 and R5 independently represent a hydrogen or halogen atom or an
optionally
substituted alkyl or alkenyl group, or together with the interjacent carbon
atom represent
an optionally substituted C4-8 cycloalkyl or cycloalkenyl ring; and A
represents a straight
or branched chain alkyl or alkenyl group, which may be optionally substituted,
preferably
-4-
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WO 96/21354 PCT1GB96100041
with halogen, an acyclic carbon chain of which links the 3 position of the
naphthalene ring
shown and the moiety -CHR4R5 and wherein A does not include a quaternary
carbon atom
in that chain; and wherein the total number of carbon atoms in the longest
carbon chain
running from the 3- position of the naphthalene ring shown is no more than 8.
Preferably the total number of carbon atoms in the longest chain running from
the
3-position is from 4 to 8, more preferablv from 5 to 7. Where the number of
carbon atoms
is restricted to 1 or 2 whitefly activity is lost but antifungal activity
remains high. Where
=CHR4R5 form a carbocvclic ring this is preferably directly attached to the
naphthalene 3-
position as increasing numbers of carbon atoms between the naphthalene ring
and the
naphthalene ring result in decreased whitefly activity.
The present use particularly provides compounds for use against whitefly,
particularlv of species of Bemisia, and/or fungi, particularly of species of
Rhizoctonia,
Aspergillus and Pyricularia eg. R. solani, P. oryzae and A. niger, that have
developed
resistance to one or more commercially available non-naphthoquinone based
pesticides. and
most preferably for use against whitefly of species Bemisia tabaci such as Ned
1/2, Ned 7,
and Pak types; these having been determined by the present inventors to be
particularly
susceptible to the pesticidal actions of the presently identified compounds as
compared to
those of, for example, those compounds specifically tested in US 2572946, US
4110473
and DE 2641343. Although DE 3801743 lists some of the presently used compounds
per
se and describes them as usefiil against many different species of insect and
fungi, no
indication is given as to the significantly advantageous application of such
compounds to
combatting whitefly.
When the compounds of formula I contain a group defined as an alkyl, alkenvl
or
alkynyl substituent group otherwise undefined, this may be linear or branched
and may
contain up to 12, preferably up to 6 and especially up to 4, carbon atoms. A
cycloalkyl or
cycloalkenyl group may contain from 3 to 10, but most preferably contains 5 to
8 carbon
atoms. An aryl group may be any aromatic hydrocarbon group, especially a
phenyl or
naphthyl group. An aralkyl group may be any alkyl group as defined above which
is
substituted by an aryl group as defined above, especially a benzvl group, or
may be an aryl
group substituted by an alkyl group.
When any of the foregoing substituents are designated as being optionally
= -5-
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substituted, the substituent groups which are optionally present may be any
one or more of
those customarily employed in the development of pesticidal compounds and/or
the
modification of such compounds to influence their activity, persistence,
penetration or other
property. Specific examples of such substituents include, for example, halogen
atoms,
nitro, cyano, hydroxyl, alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy,
haloalkoxy, amino,
alkylamino, dialkylamino, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio,
alkylsulphinvl,
alkylsulphonyl, carbamoyl, alkylamido, cycloalkyl, phenyl and benzvl groups.
Typically,
0-3 substituents may be present. When any of the foregoing substituents
represents or =
contains an alkyl substituent group, this may be linear or branched and may
contain up
to 12, preferably up to 6, and most preferably up to 4, carbon atoms. When any
of the
foregoing substituents represents or contains an aryl or cycloalkvl moiety,
the arvl or
cycloalkyl moiety may itself be substituted by one or more halogen atoms,
nitro, cyano,
alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy or haloalkoxy groups.
Preferably, the aryl
moiety is a phenvl moiety and the cycloalkyl moiety contains from 3 to 8,
preferably 4 to 7,
carbon atoms.
It is preferred that R, if present, represents a halogen atom or a nitro,
cyano,
hydroxyl, C I-4 alkyl, C I-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C 1-q,
alkoxy,
C 1-4 haloalkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxycarbonyl,
C 1-4
alkylthio, C 1-4 alkylsulphinyl or C 1-4 alkylsulphonyl group.
More preferably, R, if present, represents a halogen atom or a C 1-4 alkyl,
C 1-4 haloalkyl, C24 alkenyl, C2-4 haloalkenyl, C 1-4 alkoxy or C 1-4
haloalkoxy group.
Preferably, n is 0, 1 or 2 and it is especially preferred that n is 0.
It is also preferred that RI and R2 each independently represent a C 1-4
alkoxy'
group, especially a methoxy group, or together represent a group =0 or =N-OR9,
where R9
represents a hydrogen atom or a C 1-4 alkyl, especially a methyl, group. It is
especially
preferred that R 1 and R2 are both methoxy or together represent a group =0.
When R3 is a group -OL where L is a leaving group, or a group which in vivo is
transformed into a group -OLlwhere L1 is a leaving group, the leaving group
may be any
group customarily employed as a leaving group. It is preferred that the
leaving group is
such that the pKa value of the acid LOH or LIOH in water is from 1 to 7, more
preferably
from I to 6 and especially from I to 5.
-6-
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WO 96121354 PCTIGB96100041
When R3 represents a group which in vivo is transformed into a group -OL 1
where
L is a leaving group. it is preferred that the transformation is carried out
in a plant to be
protected or a pest to be combated, preferably by action of enzymes within the
plant or pest.
For instance, if R3 represents a p-acid group, such as -O-CH2CH2CO-OH where
-CH?CH2CO-OH is not a leaving group, it may be subjected to enzymatic
oxidation in vivo
to form a group -O-CO-CH2-CO-OH, e.g. by a(3-oxidase, where -CO-CH2-CO-OH is a
leaving group.
Preferably, R) represents a group -ORIO where RIO represents a hydrogen atom,
an optionally substituted alkyl, alkenyl, aryl or aralkyl group or a group -CO-
R11, -CO-O-
Rl l, -SOR11, -SOI-RI 1. -P(X)(OR12)(OR13), -p(X)(R12)(OR13), -P(OR12)(OR133)
or
-P(R12)(OR13) where RI I represents a hydrogen atom. an optionally substituted
alkyl,
alkenvl, aryl or aralkvl group or a group -NR12RI3; R12 and R13 independentlv
representing a hydrogen atom or an optionally substituted alkyl group and X
represents an
oxygen or sulphur atom. Where R10 or RI I represents an optionally substituted
aryl or
aralkyl group, it is preferred that the aryl group or moiety is a phenyl group
or moiety and
that the optional substituents are selected from halogen atoms. nitro and C 1-
4 alkyl groups.
Substitution at the 4-position of the phenyl ring is particularly preferred.
For the purposes
of R3, the term optionally substituted includes, e.g.. substitution with
silicon containing
groups, e.g.. trialkylsilyl groups such as trimethylsilyl, as a substituent on
R10, R11 or RI2.
Preferably R3 represents a hydroxyl group or. a group -O-CO-Rl l or -O-CO-ORl
1
where R 11 represents a hydrogen atom or a C I-12 alkyl, C I-12 haloalkvl,
C 1-12 hydroxvalkvl, C 1-12 carboxylalkyl, phenyl or benzyl group.
It is particularly preferred that R3 represents a group -OH or -O-CO-R11,
where
R11 represents a hydrogen atom or a C1-6 alkyl, C 1-6 haloalkyl, phenyl or
benzvl group.
Most preferred for Rl I is a methyl, ethyl, propyl or butyl group.
Preferably, R7 and R8 independently represent a C 1-4 alkoxy group or together
represent a group =0 or =N-OR9, where R9 represents a hydrogen atom or a C 1-4
alkvl
group, but it is especially preferred that R7 and R8 are both methoxy or
together represent
a group =0.
It will be realised bv those skilled in the art that compounds wherein RI and
R2.
and R7 and R8 are each alkoxy, or in pairs =S or a group NOR9, will be
potential
-7-
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biological precursors for the corresponding naphthoquinones; the
naphthoquinones being
the preferred compounds of the invention.
Preferably, R4 and R5 each independently represent hydrogen, or a C 1-7 alkyl,
C 1-
7 haloalkyl, C2-7 alkenyl or C2-7 haloalkenyl group or, together with the
interjacent carbon
atom, represent a C4-8 cycloalkyl or cycloalkenyl ring which is optionally
substituted with
substitutents selected from halogen and methyl, ethyl, ethenyl, halomethyl,
haloethyl and =
haloethenyl groups. More preferably R4 and R5 are independently selected from
CI-q.
alkyl, C 1-4 haloalkyl, C2-4 alkenyl and C2 -4 haloalkenyl groups or form a
ring.
The compounds of formula I may form salts, e.g. when R3 represents a hydroxyl
group. Suitable bases for forming such salts include inorganic bases, such as
sodium
hydroxide, potassium hydroxide or sodium carbonate, and organic bases, for
example
tertiarv amines such as triethylamine and cyclic amines such as pyrrolidine.
It will be appreciated by those skilled in the art that many of the compounds
for the
use of the present invention will exist as different geometric isomers and
diastereomers.
The invention thus includes both the individual isomers and mixtures of these.
In a first preferred distinct group of compounds for the use of the first
aspect of the
invention the moiety -CHR4R5 is provided immediately adjacent the naphthalene
ring
wherein R4 and R5 independently represent a hydrogen, halogen or an optionally
halo-
substituted alkyl or alkenyl group.
In this first preferred group compounds of general formula (II)
R' R2
1 R3
~ I 2 (II)
(R)n 31
CHR4 R5
R$ R7
or a salt thereof are used
in which R, RI, R2, R', R7 and R8 and n are as defined for formula I and R4
and R5
independently represent a hvdrogen or halogen or an alkyl or alkenyl group
that is
optionally halo-substituted while remaining within the limits for carbon chain
length set out
for formula I.
More preferred compounds of the general formula (II) are those where n is 0,
-8-
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R1 with R2, and R7 with R8 are both =0; wherein one of R4 and R5 represents
hydrogen,
C 1-7 alkyl or C 1-7 haloalkyl or a C2-7 alkenyl or C2-7 haloalkenyl group and
the other is
independently selected from C I-7 alkyl or C 1-7 haloalkyl or a C2-7 alkenvl
or C2-7
haloalkenyl group. R3 is preferably -OH, -O-CO-RI I or -O-CO-O-RI I where RI I
is C1-3
alkyl; and most preferably -OH. Most preferably -CHR4R5 contains from 2 to 5
carbons.
It is found by the inventors that compounds of this first preferred group
generally
have good activity against whitefly and, when the longest 3 position chain is
7 carbons or
less, fungi, eg. R. solani, P. oryzae and A. niger, while retaining activity
against mites.
In a second preferred distinct group of compounds provided for the use of the
first
aspect of the invention the moiety -CHR4R5 is provided as part of a cycloalkyl
or
cycloalkenyl ring and thus this second group of preferred compounds of formula
(I) are of
preferred formula (III)
R' R2
(III)
1 R3
(R)n 1 31 /R`'
(A)m CH ~
wherein R8 R7 R5
n, A, R, RI, R2, R', R7 and R8 are as defined for general formula (I);
m represents an integer 0 to 1;
and R4 and R5 together with the interjacent carbon atom represent an
optionally substituted
C5-7 cycloalkyl or cycloalkenyl ring.
More preferably the compounds of this group are of formula (III) wherein R1
with
R2, and R7 with R8 are both =0; n and m are 0; and R4 and R5 together with the
interjacent carbon atom represent a fully saturated C5-7 cycloalkyl ring which
is optionally
substituted.
Still more preferably R4and R5 together with the interjacent carbon atom
represent
a C5-7 saturated cycloalkyl ring substituted with halogen, most preferably
chlorine or
fluorine, or with C I-q. alkyl or haloalkyl or C2-4 alkenyl or haloalkenyl
group R20. Most
preferably R4 and R5 together with the interjacent carbon atom represent a
cyclopentyl or
cyclohexyl ring substituted in one or more of the 2, 3 or 4 positions with a
group R20.
Preferred compounds of this second preferred group of the invention are
-9-
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exceptionally effective against whitefly, especially species of B. tabaci,
when the
cycloalkyl or cycloalkenyl ring is directly attached to the naphthalene ring,
ie. m = 0.
In a third distinct group of compounds of the first aspect of the invention
the moiety
-CHR4R5 does not represent a cycloalkyl or cycloalkenyl ring and is provided
spaced by
between 1 and 6 carbon atoms length awav from the naphthalene ring, and most
preferably
between 2 and 4 carbon atoms length away from the naphthalene ring.
Thus in this distinct group of compounds for the use of the inventiori the
compounds of formula (I) are of preferred formula (IV)
R' R2
R3 (IV)
z
(R)n 4 3~
A-CHR4R5
wherein R a R7
n. A. R, R1, R2, R3, R7 and R8 are as defined for general formula (I);
and
R4 and R5 each independently represent a halogen or optionally substituted
alkyl or alkenyl
group.
More preferred compounds of this group are of formula (IV) wherein n is 0, Rl
with
R2, and R7 with R8 are both =0; A is a C 1 -6 alkvl, C 1-6 haloalkyl, C2-6
alkenyl or C2-6
haloalkenyl chain, which may be substituted by a halogen or a branch chain
which may be
halogenated. Preferably R4 and R5 are C2-6 alkyl or haloalkyl or C2-6 alkenyl
or
haloalkenyl. R3 is preferably -OH, -O-CO-RI 1 or -O-CO-O-RI I where Rl 1 is C1-
3 alkyl,
and most preferably OH.
Preferred compounds of this group are those where A is a group -(CH2)a where a
is an integer of 1 to 6, more preferably 1 to 4, or -(CH2)a CH=CH-(CH2)b-
where a and
b are integers which add up to 0 to 4, and analogues of these wherein one or
more of the
carbon atoms in the these groups are substituted bv alkyl, haloalkyl, alkenyl,
haloalkenyl
or halogen.
Particularly effective compounds of formula (III) for the use of the invention
are
those wherein one or more of A, R4 and R5 includes a haloalkyl or haloalkenyl
group,
particularly a trifluoromethyl group. Preferred compounds include those where
-10-
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W O 96/21354 PCT/GB96100041
-A-CHR4R5 is an isofluoroalkvl group, eg. such as 2-trifluoromethylpropyl or
2,2-di-
trifluoromethylethyl. Both unsubstituted and halogenated compounds have good
activity
against the aforesaid fungi when the longest chain at the 3 position is up to
7 carbons.
A second aspect of the present invention provides novel compounds of formula
(I),
wherein -CHR4R5 forms a 2-substituted cycloalkyl ring, preferably 2-
substituted by C1-4
alkyl or C1-4 haloalkyl; or -(A)m-CHR4R5 is an isohaloalkyl group.
Preferred 2-substituted cycloalkyl compounds, such as 2-hydroxy-3-(2-methyl-
cyclohexyl)-naphthalene-1,4-dione, are not only novel, but have surprisingly
high activity
against whitefly as compared to the 3- and 4- substituted cycloalkyl
compounds.
Thus this aspect of the invention particularly provides a compound of formula
(VI)
0
/ , R3 R20
(R)n \ ,4 3~ (VI)
(A)m
0
wherein n, m, A, R, Rl, R2, R3, R7 and R8 are as defined for general formula
(I) and R20
is selected from C1-4 alkyl, C1.4 haloalkyl, C2-4 alkyl and C2-4 haloalkyl.
This aspect of the invention further particularly provides a compound of
formula
(VII)
0
/ ~ 2 R3
(R~n ~ ~ 4 3I (A) CHR4R5 (VII)
0
wherein n, m, A, R, Rl, R2, R', R7 and R8 are as defined for general formula
(I) and one
or more of A, R4 and R5 is or includes a haloalkyl group. Preferred such
compounds have
A as a C 1-4 alkylene group and one or both of R4 and R5 is trifluoromethyl.
Preferred isohaloalkyl compounds of formula (VI), such as 2-hydroxy-3-(2-
-11-
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trifluoromethylpropyl)-naphthalene- 1,4-dione, are not only novel, but have
high activity
against mites as well as whitefly.
Further novel compounds of the invention are those of formula (I) where RI
with
R2 and/or R7 with R8 are not both =0.
A third aspect of the present invention provides a method of combatting
whitefly,
Lepidoptera and/or fungal pests at a locus which comprises treating the locus
with a
compound of the general formula (I), preferably of general formula (II), (III)
or (IV).
Preferably, the locus comprises the pests, i.e. whitefly, Lepidoptera and/or
fungi,
per se or environments subject to or subjected to attack by pests. More
preferably, the
locus comprises the pests per se, stored food material, plants or animals
subject to or
subjected to attack by pests, seeds of such plants or the medium in which such
plants are
growing or are to be grown. Specifically, compounds of formula I may be used
in a
domestic environment for spraying rooms to combat infestation by houseflies or
other
insects, acarids or fungi, in a horticultural or agricultural environment for
treatment of
stored crops, especially cereals, or to spray growing crops such as cotton or
rice to combat
infestation by pests, particularly whitefly and related species, and in a
medical or veterinary
environment, for instance, as a cattle spray to prevent or treat infestation
the pests.
In a fourth aspect the present invention also provides processes for the
preparation
of compounds of formula (I) and particularly of formula (II), (III) and (IV)
as defined
above.
In a preferred process for preparing compounds of formula (I), (II), (III) and
(IV),
a compound of the general formula (V)
0
R3
(R)n (V)
0
in which n, R and R' are as defined above, is reacted with a carboxylic acid
CHR4R5-(A)m COOH where R4 and R5 are as defined above, in the presence of a
free
radical initiator, such as ammonium peroxvsulphate and silver nitrate in a
suitable solvent,
such as aqueous acetonitrile, to form a compound of the general formula (I),
(II), (III) or
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(IV). Compounds of formula (V) are commercially available but in any case may
be
prepared from corresponding available benzoquinones and substituted alkenes
using eg.
Diels Alder conditions.
In a still further process for preparation of the compounds of the present
invention
the compound of formula (V) is reacted with a compound of formula X-(A)m
CHR4R5
wherein R4, R5, A and m are as defined for formula I and X is a leaving group
that will
leave the compound to give a charged radical +(A)m CHR4R5; eg. X may be a
halogen
atom or tosyl group. This reaction is carried out in the presence of an acid,
eg. a Lewis acid
such as aluminium chloride, using conditions broadly as described by Fieser
and Gates (J.
Am. Chem. Soc. (1941) 63, 2943-2953.
Compounds of formula (1) obtained by these processes may then be further
reacted
using the derivatisation processes described above or combinations thereof to
obtain further
compounds of formula (I), as desired.
For use in this alternative method, in the case where R4 and RS together with
their
interjacent carbon atom form a cycloalkyl or cycloalkenyl ring of from 3 to 10
carbons,
many of the cycloalkyl and cycloalkylenecarboxylic acids are commercially
available and
the carboxylic acid groups thereon may be extended by known techniques to give
access
to longer carbon chain lengths, and then substituted if required using
techniques well
known to those skilled in the art. For example the Arnst-Elstert reaction may
be used to
give a -CH2- extension (see e.g.. Meier and Zeller (1975) Angew. Chem. Int.
Ed. Ewgl., .14,
32). Alternatively compounds where m is I may be accessed by the reaction of
the
corresponding cycloalkanone with ethyl cyanoacetate and subsequent reaction
with a
Grignard reagent, followed by hydrolysis to yield the cycloalkyl acetic acid
(see e.g. Amsterdamsky et al (1975) Bull. Soc. Chim. Fr. (3-4 Part 2), p635-
643 and
Muhs M. A. PhD Thesis, University of Washington, Diss Abst. 14, 765 (1954) to
increase
the carbon chain length in increments of 1.
For preparation of compounds containing R4 RS rings having higher numbers of
carbons, the corresponding monobromo-substituted cycloalkyl or cycloalkenyl
compounds
may be converted to the carboxylates bv formation of the Grignard compound
using
magnesium and then treating this with CO2), e.g.. in the form of dry ice. The
carboxylic
acid so formed may be converted to the alkyl carboxylate by alkylation using,
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WO 96/21354 PCT/GB96/00041
e.g. a compound R6-I, e.g. methyl iodide, in the presence of butyl-lithium,
where R6 is
a group as defined above that is stable under these conditions.
Substitutions, e.g. alkylation, of the cycloalkyl/cycloalkylene ring at
positions other
than the 1-position to the carboxylate may be accomplished by methods known to
those
skilled in the art. Starting from the ring mono-unsaturated cycloalkylene
carboxylic alkyl
esters, alkylation may be directed at the desired position as previously
described and then,
using light as initiator, reaction with e.g. CF3X allows introduction of CF3-
groups with
reduction using palladium carbon catalysis conditions allowing saturation of
the
unsaturated bond. Many other manipulations will occur to those skilled in the
art for
the purposes of accessing other compounds of the general formula (I).
Compounds of formula (I) in which R3 represents a leaving group as defined
above
~
may be prepared by reacting a compound of formula (I) in which R' represents a
hydroxyl
group with a compound X-L, where X represents a halogen atom, in the presence
of an
organic base, preferably a tertiary amine such as triethylamine, or an
inorganic base such
-, -
as sodium carbonate. For instance compounds of formula I in which R'
represents a group =
-O-CO-Rl 1, where RI I is as defmed above, may be prepared by acylation of the
hydroxy
group in a suitable compound of formula I, for instance, by using an acyl
chloride R11-CO-
Cl in a suitable solvent, such as dichloromethane, in the presence of a base,
such as
~
triethylamine. Alternatively compounds of formula I in which R-1 represents a
hydroxyl
group may be reacted with a compound HO-L where L is as defined above and
includes the
acid C=O, in the presence of a dehydrating agent such as
dicyclohexylcarbodiimide.
A further route to such compounds is provided by reacting a metal salt of a
compound of
formula (I) in which R3 represents a hydroxyl group, that is, R3 represents a
group -OM
where M is a metal ion, with a compound X-L as defined above.
Compounds of formula (I) in which RI with R2 and/or R7 with R8 each
independently represent an optionally substituted alkoxy group may be prepared
by
ketalisation of one or both carbonyl groups in a suitable compound of formula
(I) or(
V), for instance, by using a suitable alcohol in basic or acidic conditions,
such as by aise
of a solution of potassium hydroxide in methanol.
Compounds of formula (I) in which RI with R2 together and/or R7 with R8
together represent a thiocarbonyl group =S mav be prepared by treating a
suitable
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CA 02209998 1997-07-09
WO 96121354 PCTIGB96100041
compound of formula (I), wherein Riwith R2 and R7 with RS are both =0, with a
thiating
agent, such as Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-
diphosphetane-2,4-disulphide), using protecting groups where required.
Compounds of formula (I) in which Rl and R2 together and/or R7 and R8 together
represent an oxime group =N-OR9, where R9 is as defined above, may be prepared
by
treating a suitable compound of formula (I), wherein Rland R2 and R7 and R8
are both =0,
with a hydroxylamine or alkoxylamine of formula R90-NH-), where R9 is as
defined
above, in the presence of a base, such as pyridine.
Combinations of the above derivatisation processes may be performed to achieve
the desired compound of formula (I).
In a fifth aspect of the present invention an insecticidal and/or fungicidal
composition is provided which comprises a compound of formula (I) and
preferably of
formula (II), (III) or (IV), as defined above, in association with at least
one carrier. Such
a composition may contain a single compound or a mixture of several compounds
of the
present invention. It is also envisaged that different isomers or mixtures of
isomers may
have different levels or spectra of activity and thus compositions may
comprise individual
isomers or mixture of isomers.
The compositions of the invention typically contain from 0.001 to 95% by
weight
of the active ingredient of formula I. Preferably the compositions contain
from 0.001 to
25% by weight of the active ingredient when they are in ready-to-use form.
However,
higher concentrations, for instance, up to 95%, mav be present in compositions
to be sold
as concentrates for dilution before use.
The compositions of the invention may be mixed with a variety of appropriate
inert
carriers such as solvents, diluents and/or surface-active agents to form
dusts, granular
solids, wettable powders, mosquito coils or other solid preparations or
emulsions,
emulsifiable concentrates, sprays, aerosols or other liquid preparations.
Suitable solvents
and diluents include water, aliphatic and aromatic hydrocarbons such as xylene
or other
petroleum fractions and alcohols such as ethanol. Surface-active agents may be
of an
anionic, cationic or non-ionic type. Anti-oxidants or other stabilisers mav
also be included
as well as perfumes and colourings. These inert carriers may be of the type
and in
proportions such as are conventionally used in pesticidal compositions. These
inert carriers
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WO 96/21354 PCT/GB96/00041
may be of the type and in proportions such as are conventionally used in
pesticidal
compositions and thus are conveniently inert with respect to the physiology of
a plant to
be treated.
Examples of carriers known to be suitable for use in compositions
incorporating
naphthalene-1,4-diones for pesticidal use include those described in the
specifications, and =
more specifically the Examples, of US 2572946, US 4110473, US 4970328 and JP
90/152943 (the latter to Agro-Kanesho KK).
In addition to these inert carriers, the compositions of the invention may
also
contain one or more further active ingredients: These further active
ingredients may be
other compounds which exhibit pesticidal activity and these other compounds
may exhibit =
a synergistic effect with the compounds of the present invention.
The present invention will now be described further by way of illustration
only by
reference to the following non-limiting Examples and Comparative Examples.
Further
embodiments of the invention will occur to those skilled in the art in the
light of these.
EXAMPLES
Example 1:
Pryparation of 2-cvclohexyl-3=h ydroxv-naphthalene-l.4-dione
To a stirred solution of 2-hydroxynaphthalene-1,4-dione (1.00 g, 5.74 mmol),
cyclohexane carboxylic acid (1.10 g, 8.61 mmol) and silver nitrate (520mg) in
acetonitrile
(1 5ml) and water (20ml) heated at 65-70 C was added an aqueous solution of
ammonium
persulphate (1.77g, 7.77mmo1) in water ( l Oml). After heating for 1 hour the
mixture was
cooled. diluted with water (50ml) and extracted with ether (3 x 40ml). The
combined ether
fractions were washed with water (3x25m1), saturated sodium chloride solution
(25m1) and
dried over magnesium sulphate. Filtration and evaporation of solvents under
reduced
pressure and silica gel chromatography yielded the title compound (364 mg,
m.p. 133 C).
This compound is listed as compound 12 in the Tables below.
Example 2:
PSgparation of 2-hvdroxv-3-(4-methylcyclohexvl)-naphthalene-1.4-dione.
The method of Example I was followed using lawsone, ie. (2-hydroxynaphthalene-
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WO 96121354 PCTIGB96100041
1,4-dione (1.00 g), and 4-methvlcyclohexanecarboxylic acid (1.23 g), and
yielded the title
compound (100 mg, m.p. 101 C).
This compound is listed as compound 19 in the Tables below.
Example 3:
Preparation of 2-hvdroxv-3-(1-meth ly butvl -naphthalene-1.4-dione.
The method of Example 1 was followed using 2-acetyloxynaphthalene-1,4-dione
(1.24 g, 5.74 mmol) and 2-methylpentanoic acid (1.00 g) yielded the title
compound (608 '
mg) after hydrolysis in. 30 ml THF using potassium hydroxide (5 x exess) in
water (8ml)
(mp 82-83 C). This compound is listed as compound 3 in the Tables below.
Example 4:
Preparation of 2-hvdroxv-3-(2-trifluoromethvlFropyl)-1.4-na hp thoouinone
2-acetyloxynaphthalene- 1,4-dione (1.24 g) and 3-trifluoromethylbutanoic acid
(1.08
g) were reacted using the method as descibed in Example 3 yielding the title
compound (353 mg) (mp 168 C). This compound is listed as compound 11 in the
Tables
below.
Other compounds set out in the tables below were produced using these general
methods.
Example 20 is Example 1 of Table 1 of DE 3801743 Al which is 2-hydroxy-3-(4-t-
-
butylcyclohexyl)naphthalene-l,4-dione (Formula I: n = 0; m=O, RI + R2 together
and R7
+ R8 together both represent =0; R3 =-OH; -CHR4R5- = 4-1-butylcyclohexyl)s
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CA 02209998 1997-07-09
WO 96/21354 PCT/GB96/00041
U .-. -- M M ~ ~ cf ~ N 00
.-= ~O 00 00 p p ~ ~ ^ ~ -
O oo N N ~ fV O .--~
Ul 00 00 Q ~
-
=
N N
_ ^ Q
f~. .i~. ~ ..M .='~ U-U .M ...,M
L.
V
Cs. ~~. ~-' -,`~' U_ = U_ x U U U U U
U U w U :. ~ x o
U U
00
^ ^ r=~. i--~. ~ vUi
N .O
CC
co
u U WU U U U U v
a/ V =
Q 'O
ct
Q -~
y ~
U M -T" - - - - - U -
fL
CD
~ 0
~
O N ~
~ w
+-= X
CIS Q c c = _ _ _ _ _ _ _ ~
-
v,
~ z0 =--~ N M v> ~O [~ 00 Q~ ~ Q
O
U
zI
-~s-
CA 02209998 1997-07-09
W O 96121354 PCT/G1I96/00041
TABLE 2
In all the following examples n = 0, RI + R2 together and R7 + R8 together
both represent
-,
=O;R'=OHandm=0.
Compound -CHR4R5- M.pt
No. ( C)
12 cyclohexyl 133
13 cyclopentyl 98-99
14 cyclobutyl 125-127
cycloheptyl 94-95
10 16* cyclopropyl 86-87
17 2methvlcvclohexyl 89-90
18 3methylcyclohexyl 104-5
19 4methylcyclohexyl 101-2
4t-butylcyclohexyl 96-97
15 *Comparative Example = Compound No 16.
Pesticidal Activitv
Pesticidal activity was assessed against houseflies, mustard beetles. mites
and
whitefly using the following methods.
Houseflies (MD) (Musca domestfca
20 Female flies were treated on the thorax with a one microlitre drop of test
compound
dissolved in acetone. Two replicates of 15 flies were used at each dose rate
and 6 dose
rates were used per compound under test. After treatment, the flies were
maintained at a
temperature of 20 + 1 C and kill was assessed 24 and 48 hours after
treatment. LD50
values were calculated in micrograms of test compound per fly (see Sawicki et
al..
Bulletin of the World Health Organisation, 35, 893 (1966) and Sawicki et al..
Entomologia and Exp. Appli 10, 253, (1967).
IVlustard beetles (PC) (Phaedon cochleariae Fab)
A one microlitre drop of an acetone solution of the test compound was applied
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WO 96/21354 PCT/GB96/00041
ventrally to adult mustard beetles using a micro drop applicator. The treated
insects were
maintained for 48 hours after which time kill was assessed. Two replicates
each of 20
to 25 mustard beetles were used at each dose level and 5 dose levels were
treated
comparably. LD50 values were calculated as for houseflies.
Mites (TU) (Tetranvchus urticae)
25 adult female mites were immersed in 35 l of a solution of the test
compound
in a 1:4 acetone-water mixture for 30 seconds. The treated insects were
maintained
at 21 20C and kill was assessed 72 hours after treatment. Mites exhibiting
repetitive
(non-reflex) movement of more than one locomotory appendage after this period
were
recorded as alive. Three replicates of 25 mites each were used at each dose
rate and 5
or 6 dose rates were used per compound under test. LC50 values were calculated
in ppm
of the solution of the test compound per insect. The test was carried out
using a susceptible
strain of mites (GSS) supplied by Schering, AG, Berlin.
Whiteflv (BT) (Bemisia tabaci)
Acetone solutions (0.100 ml) of the test compounds were placed in 10 ml glass
vials
and evaporated with rotation to deposit a film of the compound. Thirty adult
whiteflies
were placed inside the vial, then after 60 minutes, the treated insects were
transferred onto
untreated cotton leaf discs which were kept moist on a bed of agar gel. The
temperature
was maintained at 25 C and mortality assessed after 48 hours. Three replicates
were used
at each of 5 to 7 dose levels per compound. LC50 values were calculated by
using a
computer software package ("Polo-PC available from LeOra Software, Berkeley,
California). (See M.R. Cahill and B. Hackett in Proceedings Brighton Crop
Protection
Conference, 1992). The test was carried out using a susceptible strain of
whitefly (SUD-S)
which was collected in Sudan in 1978 from cotton.
The results of these tests are set out in Tables 3 and 4 below. The values
given are
LD50 ( g/insect) or LC50 (ppm solution of test compound) unless otherwise
specified.
= -20-
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CA 02209998 1997-07-09
P.11361918\WOOI SPEC1M197012. WPD
TABLE 3
Compound MD PC PX TU(GSS) BT(SUD-S)
No. (LD50) (LD50) (LD50) (LC50) (LC50)
1 c.2.5 3.0 - 29 19
2 1.6 1.9 - 82 18
3 c. 1.5 c.4.0 - c.500 12
4 c. 3.5 c. 0.8 - 80 23
2.8 5.8 - c.500 10
6 - >20 - - -
7 c10 c5 - 65 13
8 NA c7 - 16 17
9 c20 c7 NA 170 9.4
1.9 0.78 - c 1000 19
11 NA 12 - 8 4.8
A >>20 0.36 - 64 82
Compound A Example 1, page 5 of DE 2641343 A1 which is
2-n-dodecyl-3-ethanoyloxynaphthalene-1,4-dione
(Formula I: n = 0; m = 1; Rl + R2 together and R7 + R8 together
are both=0; R3=-0-CO-CH3; A=-CH2-; -CR4R5- = nC11H23)
-21-
r...,;.~:~~Ci SHE~~
CA 02209998 1997-07-09
WO 96/21354 PCT/GB96/00041
TABLE 4
Compound MD PC TU(GSS) BT(SUD-S)
No. (LD50) (LD50) (LC50) (LC50)
12 < 20 < 2 c.50 6.8
~
13 2.5 < 2 40 6.1
14 > 10 c. 10.0 150 25
2.6 0.9 37 3.0
16* > 10 > 10 c. 500 c.50
17 1.2 0.53 12 1.1
10 18 1.5 0.86 7.4 3.9
19 2.0 c 1 7.3 4.5
15.5 0.53 44 18
* Compound 16 = Comparative Example
Activity resistant whitefly (BT) (Bemisia tabaci)
15 The whitefly test on (BT (SUD-S)) was repeated using a resistant strain of
whitefly (Ned
1/2). The Ned 1/2 strain is a composite collection which was collected in the
Netherlands
in 1992 from Gerbera and Bouvardia by ICI Netherlands and exhibits high
resistance to
pyrethroid insecticides, such as cypermethrin, organophosphate and carbamate
insecticides
and the insect growth regulator buprofezin. The result of this test is set out
in Table 5
20 below. The value given ise LC50 (ppm solution of test compound).
TABLE5
Compound BT (Ned 1/2)
No. (LC50)
12 6.4
20 100
In addition to activity against whitefly, the presently investigated compounds
were also
found to have activity against Diabrotica (Western Corn Root worm), and
Lepidoptera.
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WO 96121354 PGTIGB96100042
eg. Spodoptera eg. S. littoralis and S. frugiperda. For example Compound 4 has
LC50
ppm topical of the order of 5, 10 and 20 for these three species, while
Compound 13 has
LC50 values of approximately 20, 12 and 20 respectively; Diabrotica, S.
littoralis and
S. frugiperda. Antifeedant activity is also evident in the species specified.
Fung;icidal Activity
Fungitoxicity of coded compounds to isolates of Aspergillus niger, Pvricularia
oryzae
(=Magnaporthe grisea) and Rhizoctonia solani was tested in vitro.
Each compound was incorporated into potato dextrose agar in solvent
(50/50 ethanol/acetone) at 0.5 ml solvent per 250 ml agar while the autoclaved
agar was
still molten and cooled to 50 C. Each compound was tested at a single
concentration
(100 mg 1-1).
Each test, usually of two compounds, included three control treatments: a
standard ftmgicide (carbendazim at 1 or 5 mg 1-' or prochloraz at 1 mg 1-');
ethanol/acetone only; no additions. The fungicides used as standards may be
considered
as representative of active commercially available compounds.
Each fungus was tested on agar in four Petri dishes per treatment, with three
replicate fungal colonies per plate (one colony for R. solani). A. niger and
R. solani
were incubated for 4 days at 20-25 C , and P. oryzae for 7 days. Increase in
colony
diameter was then measured and used to determine activity:
The results of these tests are set out in Table 6 below. The values given are
%
inhibition of growth in colony diameter in agar plates at a given
concentration of agent.
Compound numbers are as above with the addition of compound number 21:- 2-
methyl-3-hydroxynaphthalene- 1,4-dione, and compound number 22:- 2-ethyl-3-
hydroxynaphthalene-1,4-dione. Inhibition by standard agents is given for
comparison.
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WO 96/21354 PCT/GB96/00041
TABLE 6
Compound of Fungus Activity at Activity at Activity at
Example No. 1% 0.2% 0.1%
3 A. niger 77 42
11 A. niger 50 36
21 A. niger 100 76
22 A. niger 100 100 57
3 P. oryzae 100 -
11 P. oryzae 100 100
21 P. oryzae 100 100 23
22 P. oryzae 100 100 89
3 R. solani 100 89
11 R. solani 67 56
21 R.solani 100 63 41
22 R. solani 100 87 64
Prochloraz A. niger 97.8
Carbendazim P. oryzae 99.8 14. 7
Carbendazim R.solani 82.4 3.3
In addition, tests have shown that the compounds of formula I exhibit good
fungicidal
activity against a broad spectrum of fungi which cause diseases in both cereal
and broad
leaved crops. Particularly, good activity has been observed against fungi of
the genera
Erysiphe, especially Erysiphe graminis, and Botrvtis. especially Botrytisfabae
and
Botrytis cinerea, as well as the genera Rhizoctonia. Pvricularia and
Aspergillus as
illustrated above.
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CA 02209998 1997-07-09
WO 961213S4 PCTIGB96100042
O
u
M
n
~
C3 U
N v~i
II. Z 2 2 O O O Z
A A A
~-
cN.i U
.~ a
cz
N v
E.
z z z
w o
~
cz
t"'
c3 \
~. .
O
U V
O
z z z z z z z
~ o
cz
-~
~
co U
U ~
~ U -~b ¾ ¾ ¾ ~ u z z
z z
=U a
y
~
M ....M ~ .,.i
w II a> g ~ ~M V U U U
cz =~ M .~. o
U
U U U U U
z ; --
v,
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WO 96/21354 PCT/GB96/00041
Example-5-
Preparation of 2-hvdroxv-naphthalene-1.4-dione starting materials for
compounds
where n=1 or more.
Diels-Alder type reactions using corresponding quinone compounds yield
suitable
starting material 2-hydroxy-naphthalene- 1.4-diones for preparation of
compounds where
n=1 or more. Examples are as follows.
(a) Preparation of 6-methvl-nanhthalene-1.4-dione.
A solution of 1,4-benzoquinone (13.9 g, 128 mmol) and isoprene (13.1 ml,
131 mmol) was stirred in glacial acetic acid (44 ml) for 68 hours at room
temperature.
The mixture was diluted with water (44 ml) and refluxed for 1%2 hours. The
mixture
was cooled to room temperature and acetic acid (84 ml) and chromic acid
[chromium
trioxide (29.4 g)] in water (30 ml)] was added sequentially, before refluxing
for a further
1%z hours. After cooling, the mixture was diluted with water (200 ml) and
extracted
with ether (3 x 50 ml). The combined ether fractions were washed with dilute
sodium
hydroxide solution (2M; 2 x 50 ml), water (2 x 50 ml), saturated sodium
chloride
solution (50 ml) and dried over magnesium sulphate. Filtration and evaporation
of
solvent under reduced pressure, and repeated recrystallisation from petroleum
ether
yielded the title compound (7 g).
(b) 2-Amino-6 and 7-methvl-1.4-naphthalene-l.4-diones.
To a stirred solution of 6-methyl naphthalene-1,4-dione (2.1 g, 12 mmol) in
glacial acetic acid (60 ml) at room temperature was added a solution of sodium
azide
(1.58 g) in water (5 ml). The mixture was stirred for 2 days before diluting
with water
(200 ml) and, after stirring for a further 15 minutes, was filtered. The
filtrate was
neutralised with sodium bicarbonate and extracted with chloroform (3 x 25 mi).
The
combined chloroform extracts were washed with saturated sodium bicarbonate
solution.
brine and dried (CaSO4). Filtration and evaporation of solvent under reduced
pressure
and silica gel chromatography yielded the title compound (100 mg) as a 3:2
mixture of
isomers.
(c) 2-Hydroxy-6- and -7-methvlnanhthalene-1.4-diones.
The aminomethyl naphthalene- 1,4-dione mixture from (b)(200 mg) was refluxed
in water (20 ml) and concentrated sulphuric acid (10 ml) for 20 minutes. The
cooled
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mixture was poured into ice/water (50 g) and extracted with ether (3 x 25 ml).
The
combined ether extracts were washed with water, saturated NaHCO3, water,
saturated
NaCI solution and dried (MgSO4). Filtration and evaporation of solvent and
purification by silica gel colunm chromatography yielded the title compound
(68 mg).
-27-
