Note: Descriptions are shown in the official language in which they were submitted.
~8~
The present invention relates to novel compounds and
to processes for the preparation of such compounds which are
useful for the control of certain parasitic weeds. The inven-
tion also includes weed control compositions suitable for this
purpose. More particularly the invention relates to novel com-
pounds and herbicidal compositions prepared therefrom which
are useful for controlling the weeds Striga hermonthica, Striga
asiatica (lutea), Orobanche crenata, Orobanche ramosa or
Orobanche aegyptiaca which are parasitic on certain economically
important crops such as sorghum, maize, sugar cane and/or broad
beans. These compounds and compositions also show some activity
against Alectra vogelii, a parasite plant which attacks cowpea
in certain African territories, especially Tanzania.
It is known that certain compounds and herbicidal com-
positions containing such compounds, described in British patent
specification No. 1,470,097, are useful in the control of para-
sitic weeds of the genera Striga and Orobanche. Some of these
compounds suffer from the disadvantage that they tend to be
slightly unstable in the locus where they are intended to be
used as herbicides.
The present invention is based on the discovery that
related novel compounds possess improved stability or more
effective herbicidal activity than the foregoing known compounds
and these novel compounds are able to act as effective germina-
tion stimulants for the seeds of Striga hermonthica, Striga
asiatica, Orobanche crenata, Orobanche ramosa or Orobanche
aegyptiaca. They are also active against Alectra vogelii.
According to the invention there is provided a com-
pound of the formula I:
R' R2 R
RrXX XCH~O~O
- 1 -
~ 1~8~6~
wherein -X- represents a direct single bond or a -CH2- linkage,
and wherein when RL and R2, which may be the same or different,
stand for hydrogen, an alkyl radical of one to five carbon
atoms or an aryl radical, substituted or unsubstituted, then
R' and R" are joined, together with the adjacent two carbon
atoms, to form a ring structure of the formula:
~ or ~ or ~
or wherein when Rl and R2 are joined, together with the adjacent
two carbon atoms, to form a ring structure of the formula:
then R' and R", which may be the same or different, stand for
hydrogen, an alkyl radical of one to five carbon atoms or an
aryl radical, substituted or unsubstituted, or they may be joined,
together with the two adjacent carbon atoms, to form a ring
structure of the formula:
R''' R''' L¦ B
or ~ or ~ or
R'''
wherein Y represents two hydrogen atoms, an additional bond or
an epoxy group; R''' stands for hydrogen, an alkyl radical of
one to five carbon atoms or an aryl radical, substituted or un-
substituted and the benzene rings A and B may be substituted by
one or more substituents, the same or different, or one or both
of the benzene rings A and B may have fused thereto a benzene
ring or a heterocyclic ring.
As representative compounds of the invention there may
6~
be mentioned compounds corresponding to one of the formulae II,
III, IV, V, VI, VII, VIII and IX:
X ~ CH-o ~ R' X X ~ CH-~
II III
~~0 R~ol ~0
IV V
~[~~ ~Rl ~
R H-O R''' X CH-O O
VI VII
~o~o R2 R~
R''' H-O ~ o R''' H O 0 ~0
VIII IX
wherein Rl, R2, R', R", R' " , X, Y, A and B have the meanings
stated above.
As a particular substituent for the alkyl radical Rl,
R2, R', R" or R " ' there may be mentioned a methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or pentyl
radical and of these, methyl is preferred. The substituent Rl,
R2, R'~ R" or R''' may be an aryl radical such as a phenyl or
naphthyl radical optionally substituted by one or more alkyl, al-
-- 3 --
~ 8$~4
koxy or halogen radicals. The representation X- is preferably
a direct single bond and the representation -Y- is preferably
an additional bond. The benzene rings A and B may be substi-
tuted by one or more substituents selected from alkyl or alkoxy
radicals of one to 8 carbon atoms, such as methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy or butoxy, halogen such as chlo-
rine or bromine, aryl, such as phenyl or naphthyl, or aralkyl,
such as benzyl. As stated above, one or both of the benzene
rings A and B may have fused thereto a benzene ring or a hetero-
cyclic ring whereby the said benzene ring A and/or benzene ring
B becomes enlarged to a naphthalene ring or a benzo-heterocyclic
ring thus providing a compound of higher molecular weight.-
Particularly useful compounds falling within the abovestated formula I are compounds represented by formulae IIA, IIIA,
IVA, VA, VIA, VIIA, VIIIA, IXA and XA as follows:
~c}~-o~o ~C~-o~O
IIA IIIA
3 ~ ~
~ O CH-O ~ o
IVA VA
3 0 ~H ~o ~1 _o~
VIIA
-- 4 --
~8~64
~C}~ -0~ C~ o
IXA
VIIIA
~ ~ CH
~` l
CH-O
XA
Of the compounds indicated above, those compounds of
formulae VIA and VIIIA are particularly preferred compounds.
According to a further feature of the invention there
i8 provided a process for the manufacture of a compound of the
above stated formula I which comprises reacting a derivative of
an enol compound represented by the formula IA: -
R ~ O ~ O
R' 1 X ~ CH-OH
IA
with an appropriate butenolide derivative of the formula IB:
2~r=====~
Z O
IB
wherein Rl, R2, R', R" and -X-have the meanings stated above
and Z stands for a halogen atom, a methanesulphonate radical
(CH3S02O-) or a tosylate radical (CH3C6H4.SO2O-).
The said derivative of the enolic form of an ~-formyl-
butenolide is preferably a metallic derivative thereof in the
form of a salt of the enol such as an alkali metal salt for
-- 5 --
example the sodium salt. Suitable salts for use in the prepar-
ation of the preferred compounds are the sodio-enolate salt of
3~hydroxymethylene-1,4-butyrolactone, the sodio-enolate salt
of the ~-lactone of 4-hydroxycyclopentenyl-5-(~-formylacetic
acid), l:he sodio-enolate salt of the ~-lactone of indan-2-ol-1-
(~-formylacetic acid), the sodio-enolate salt of the ~-lactone
of indan-1-ol-2(~-formylacetic acid) and the sodio-enolate salt
of the ~-lactone of 3-cyclopentenyl-4-(~-formylacetic
acid).
A suitable synthesis for the preparation of the enol
compound, in the form of its sodium salt, used as starting mat-
erial for the preparation of compound IVA or VA is as follows:
~ ,
~I Br2/H20
Br
OH `
~ NaCH(COOEt)2
~ H
CH(COOEt)2
OH ; H
' heat
COOH
50%H2 4 3
~0
¦ H.COOEt-Na
6~
~ CH-O Na
Suitable syntheses for the preparation of the enol
compound, in the form of its sodium salt, used as starting mat-
erial for the preparation of compound VIA, VIIA or XA are as
follows:
OH & ' 2)2
Br ~
¦ CrO3 ~ H.CHO/NaHCO3/H
~ Hr
\ NaCH(COOEt)2 ~
~ OH /H ~ conc.H2SO4
~CH2COOH
¦ NaBH4-NaOH;
~ H
~ O + ~ CH2COOH
2o~6H2so4-HoAc/Et2o
. H.COOEt-Na
,~,
~0
CH-O Na
-- 7 --
~,8~164
A suitable synthesis for the preparation of the enol
compound, in the form of its sodium salt, used as starting mat-
erial for the preparation of compound VIIIA or IXA is as follows:
CH2 . C02H : '
I2/KI
~ ~ .
I :
~0 ' ~:
,
¦ DBU(1,5-Diazabicyclo[5,4,0]undec-5-ene)
~
Na/H.COOEt + Et2O
~ ~ .
CH-OeNa~
-- 8 --
- :
~,t8~6~
The said butenolide derivative of formula IB, as
stated above, may be in the form of the methanesulphonate or
a tosylate or in the form of a halogen derivative such as the
chloro derivative (Z=Cl) or the bromo derivative (Z = Br).
Suitable butenolide derivatives for use in preparation of
the preferred compounds are 3-bromophthalide, 5-chloro-3-methyl-
but-2-enolide, 3-methyl-but-2-enolide-5-methanesulphonate, 3-
methylbut-2-enolide-5-p-toluenesulphonate and 5-bromo-4-methyl-
but-2-enolide.
The said process may be conveniently carried out in
the presence of a suitable solvent or diluent such as an or-
ganic solvent or diluent for example 1,2-dimethoxyethane. The
process conveniently may take place at a temperature over the
range of 0 to ambient temperature until reaction is complete
and the period of reaction may be of the order of 10 to 20
hours.
The said butenolide derivative of formula IB, may
be prepared by known means according to preparative details
described in the literature. Alternatively, the compound, 5-
chloro-3-methylbutenolide or 5-bromo-3-methylbutenolide, can
conveniently be prepared by an improved process which provides
3-methylbutenolide in a single stage process. This important
intermediate can now be prepared by heating 3-methyl-y-butyro-
lactone with a mixture of bromine and phosphorus to give 3-
methylbutenolide which can then be chlorinated or brominated,
by known means, to give 5-chloro-3-methylbutenolide or 5-
bromo-3-methylbutenolide according to the reaction scheme:
CH3 CH3 3
~ ~ ~ O > z ~ O
_ g
8~64
wherein Z stands for chlorine or bromine. This novel prepara-
tive route provides the useful intermediate, 3-methylbutenolide,
more conveniently and in better yield than by those processes
already descrihed in the literature.
Another process leading to the required butenolide
derivative of formula IB, for example 5-chloro- or 5-bromo-3-
butenolide, involves an alternative improved process for 3-
methylbutenolide. The latter can be prepared by reaction of
an ester of pyruvic acid, such as ethyl pyruvate, with a vinyl
derivative, such as vinyl acetate, in the presence of a tita-
nium salt, such as titanium tetrachloride, and subsequent cy-
clisation to form a 5-substituted-3-methylbutenolide, for ex-
ample 5-ethoxy-3-butenolide. The latter can then be converted
into 5-chloro- or 5-bromo-3-methylbutenolide by known means,
for example by heating with thionyl chloride to provide 5-
chloro-3-methylbutenolide as follows: ~ CH3
CH3 OH Et ~ O
/ CH2 IC CH3 ~
CH + ¦ C1 OCOCH3 Cl ~ H3
CH3COO
It is to be understood that the compounds of the pre-
sent invention may exist in different stereoisomeric forms.
Each compound has an optically active centre in the right
hand ring structure of its formula. In addition, any compound
which has more than one ring in the left hand ring structure
of its formula has a second chiral feature as illustrated by
reference to the structures of compounds IVA and VIIIA wherein
the asymmetric centres are shown below:
H H
H CH-O ~ ~ ~
IVA VIIIA
-- 10 --
.
8~64
In view of the cis fusion of the rings, each of the
said compounds may exist only in two diastereoisomeric forms
which can be separated one from another. For example, compound
IVA has been separated into its two diastereoisomeric forms,
identified conveniently as the "slow" isomer and the "fast"
isomer respectively according to the rate at which each isomer
is eluted from a silica column (see Example 3 hereinafter).
Likewise, compound VIIIA has been separated into its two dias-
tereoisomeric forms identified as the "slow" isomer and the
"fast" isomer. Each such diastereoisomeric form of each of
these compounds may be further separated into its dextrorota-
tory (D)-form and its laevorotatory (L)-form.
It is therefore to be further understood that the
compounds of the present invention include all possible stereo-
isomeric forms of each compound.
According to a further feature of the invention, there
is provided a method for controlling at least one of the para
sitic weeds, Striga hermonthica, Striga asiatica (lutea),
Orobanche crenata, Orobanche ramosa and Orobanche aegyptiaca
which comprises contacting dormant seeds thereof with a com-
pound corresponding to the formula I, wherein Rl, R~, R', R",
R''', X, Y, A and B have the meanings stated above.
In carrying out the method for controlling said weeds,
it is generally preferred that the host plant, i.e. the plant
on which the germinated weed seeds attach themselves and grow,
is absent from the soil containing the parasitic weed seeds
being treated, or that the host plant has substantially reached
maturity so that any infestation of the host plant by the para-
sitic weed following germination of the seeds thereof will
have a minimal effect on the host plant and harvesting of the
latter or natural death at the end of the growing season will
prevent the parasitic weed from reaching maturity and conse-
quently re-seeding itself. It is however to be understood
that the said method may conveniently be carried out at other
periods during the life of the host plant. Thus, it may be
convenient to carry out the said method using one of the com-
pounds of the present invention in admixture with a selective
herbicidal agent after the sowing of the host plant or during
the period of active growth of the host plant.
It may also be advantageous to give the seeds of
Orobanche or Striga species a preliminary treatment with a
solution of gibberellic acid before treatment with one of the
compounds of the present invention as a method of controlling
these parasitic weeds.
The invention therefore consists of the provision
of a herbicidal composition comprising as an active ingredient
a compound of the formula I wherein Rl, R2, R', R", R''', X, Y,
A and B have the meanings stated above, in association with a
suitable carrier or diluent therefor.
The compound of formula I is preferably applied to
the soil containing the dormant parasitic weed seeds in the
form of a composition containing the active compound in admix-
ture with a suitable carrier or diluent. Suitable carriers or
diluents are particularly finely divided solid inert carriers
or diluents such as powdered chalk, powdered clays, or powdered
conventional fertilizers. Also suitable are liquid carriers or
diluents such as water or an organic liquid. Pre-mixes of a
relatively high concentration of the active agent with a car-
rier may be formulated for ease of handling, particularly for
ease in preparing the final herbicidal composition to be applied
to the soil. For instance, such a pre-mix may take the form
of a solution of the active compound in an inert organic sol-
vent, such solution optionally containing a surface active
agent selected to promote the formation of an aqueous emulsion
- 12 -
~8~
when the concentrate is diluted with a large volume of water
for application to the soil.
The active compound to be used in the above method
for controlling weeds or the above herbicidal compositions is
preferably a compound of formula II, III, IV, V, VI, VII, VIII
or IX. Such a compound may be applied to the soil containing
the parasitic weed seeds in amounts of from 100 to 5000 grams/
hectare or from 0.01 to 0.5 gram/cubic meter of soil, and for
this purpose compositions may be used containing from 0.001
to 1000 parts per million of the active compound, the balance
of such compositions being essentially diluent or carrier as
described above. Too little of the active compound may se-
cure insufficient germination of the parasitic weed seeds to
afford effective control. Naturally, temperature and moisture
conditions in the soil should be suitable for the germination
of the parasitic weed seed.
A more preferred compound to be used in the method
for controlling the said weeds or to be used in the herbicidal
compositions is a compound of the formula IIA, IIIA, IVA, VA,
VIA, VIIA VIIIA, IXA or XA. Of these, the compounds present-
ly of choice are the compounds of formulae VIA and VIIIA which
are particularly effective against Orobanche crenata and Striga
hermonthica.
It is known that a compound of the formula XIA:
CH3
CH-O ~ O
XIA
8~36~
~is active as a germination stimulator and may be used as a her-
bicidal agent in the control of parasitic weeds of the genera
Strig and Orobanche. In comparison with the known compound
XIA, the preferred compounds VIA and VIIIA of the present in-
vention show an improvement over the said compound XIA as ger-
mination stimulators in laboratory tests and it has also been
found that a comparable improvement or advantage was obtained
when the compounds of the present invention were used as her-
bicides against Striga and Orobanche weeds.
- 14 -
~8~4
- The invention is illustrated by, but not limited by,
the following Examples describing the preparation of compounds
of for~ula I:
Exam21e 1
Preparation of Compound IIA
Br~O ~
IIA
A mixture of the sodio-enolate salt (0.87 g) and 3-
bromophthalide (1.07 g) in anhydrous 1,2-dimethoxyethane (20 ml)
was stirred at room temperature for 18 hours and then diluted
with ice-cold water (80 ml). The precipitated solid product was
collected and recrystallized from a mixture of dichloromethane
and hexane. The product, compound IIA, in the form of mixed
diastereoisomers, had m.p. 212-213 (Found: C, 67.6; H, 4.3;
C16H12O5 requires C, 67-6; H~ 4.25).
Example 2
Preparation of Compound IIIA
H-O ~a~ ~ ~ CH-o
IIIA
3-Bromophthalide (1.07 g) was added to a suspension
of the sodio-enolate salt of 3-hydroxymethylene-1,4-butyrolac-
tone (0.68 g) in anhydrous 1,2-dimethoxyethane (lS ml) and the
mixture stirred at room temperature for 18 hours. The mixture
was then diluted with water (100 ml) and extracted with dichlo-
romethane (3 x 30 ml). The combined organic extract was washedwith water (50 ml) followed by saturated salt solution (50 ml),
dried over sodium sulphate and evaporated to dryness. The solid
~8~364
residue crystallized from methylene chloride-hexane mixture to
give compound IIIA as colourless needles, m.p. 185-189. (Found:
C, 63.45; H, 4.15; C13HloO5 requires C, 63.4; H, 4.05).
Example_
Preparation of Compouncl IVA
(i) 2-Bromoindan-l-ol
This was prepared from indene according to the known
procedure. The n.m.r. spectrum in deuteriochloroform confirmed
that the product was trans-2-bromoindan-1-ol.
(ii) Trans-indan-2-ol-1-acetic acid
This was prepared by modification of the known proce-
dure. Sodium (0.46 g) was added in small pieces to a stirred
solution of diethyl malonate (3.2 g) in 1,2-dimethoxyethane
(15 ml) at room temperature (3 hours). The resulting solution
was treated with a solution of 2-bromoindan-1-ol (2.13 g) in 1,2-
dimethoxyethane (12 ml) and the mixture stirred at room tempera-
ture overnight. It was then heated under reflux for 1 hour,
cooled and evaporated to dryness.
The mixture of crude diester and excess diethylmalo-
nate was saponified by boiling with 2N sodium hydroxide (60 ml)
- for 1.5 hours. The resulting solution was cooled, washed with
ethyl acetate (30 ml x 2), acidified with 6N hydrochloric acid
and saturated with salt. Continuous extraction with ether for
24 hours followed by removal of the solvent gave a solid pro-
duct which crystallized from benzene-alcohol, when it had m.p.
116-118.
The hydroxy-diacid was decarboxylated by heating in
an oil bath to about 130 with stirring under an atmosphere of
nitrogen for 1 hour. The resulting oil solidified on cooling
and was crystallized flom benzene-hexane. It had m.p. 124-132.
(Found: C, 68.6; H, 6.25; CllH12O3 requires C, 68.75; H, 6.25%).
- 16 -
8~i4
The n.m.r. spectrum of the compound clearly showed it to be
trans-indan-2-ol-1-acetic acid; double irradiation studies
at 220 MHz showed the presence of -CH2-CH-CH-CH2- carbon
skeleton, inconsistent with the previous structural assign-
ment.
(iii) Lactonisation of trans-indan-2-ol-1-acetic acid
The hydroxy-acid (2.5 g) (above) was dissolved in
65% concentrated sulphuric acid in acetic acid (10 ml) and
kept at room temperature for 24 hours. It was then poured
onto cracked ice (300 g) and the aqueous solution extracted
with dichloromethane (60 ml x 4). The combined organic ex-
tract was washed with water (100 ml x 2) followed by 5%
sodium bicarbonate (50 ml x 2) and then saturated salt solu-
tion (30 ml). After drying over sodium sulphate, the organ-
ic solution was filtered and evaporated to give an oil which
slowly crystallized. Recrystallization from dichloromethane-
hexane mixture gave the desired lactone as colourless need-
les, m.p. 73-74. (Found: C, 75.85; H, 5.75. CllH10O2 re-
quires C, 75.8; H, 5.7%).
(iv) Formylation of the lactone of indan-2-ol-1-acetic
acid
Sodium (0.23 g) was added to a solution of the
foregoing lactone (1.74 g) in a mixture of ethyl formate
(1.11 g) and ether (20 ml) and the reaction stirred at room
temperature for 18 hours. The light-tan sodio-enolate salt
was filtered, washed quickly with a small amount of ether
and dried overnight in a desiccator.
(v) Reaction of sodio-enolate salt with 5-chloro-3-
methylbutenolide
-
~; + ~ C!33
5-Chloro-3-methylbutenolide (0.66 g) was added to
a suspension of the foregoing sodio-enolate salt (1.12 g) in an-
- 17 -
~ ~ .
hydrous 1,2-dimethoxyethane (20 ml) and the mixture stirred
for 16 hours at room temperature. At the end of this period
the mixture was diluted with water (50 ml) and extracted with
chloroform (60 ml x 3). The combined chloroform extract was
shaken with saturated salt solution, dried over sodium sul-
phate, filtered and evaporated to dryness. The residual
light brown solid was crystallized from chloroform-ether to
give compound IVA as a colourless product (mixed isomersj,
m.p. 200-214. (Found: C, 68.45; H, 4.85; C17H14O5 requires
C, 68.45; H, 4.7~). The product, which is a diastereoisomeric
mixture, was separated on a silica column (activity III; 84
x 2.5 cm) eluting with 2% ethyl acetate in ether. The "slow"
isomer which had the lower RF value on a silica plate, eluted
with ethyl acetate-ether mixtures and had m.p. 205. The
"fast" isomer had m.p. 119-120.
The 5-chloro-3-methylbutenolide used as starting mat-
erial above can be prepared from 3-methyl-~- butyrolactone by
heating with bromine and phosphorus to yield 3-methyl-3-buten-
olide which can then be converted into 5-chloro-3-methylbuten-
olide by known means. Alternatively, the 3-methyl-3-butenolide
can be converted, if desired, into 5-bromo-3-methylbutenolide,
by direct bromination as described in the literature, which
can also be used as starting material.
Preparation of 3-methyl-3-butenolide
CH3 CF~3
~0 ~ ~0
In a 1 litre three-necked round-bottomed flask equipped with
a dropping funnel, magnetic stirrer, and an efficient reflux
condenser, were introduced 100 g of a-methyl-y- butyrolactone
and 11.6 g of red phosphorus. Over an interval of 30 minutes,
168 g of bromine was added, the mixture being stirred and cooled
- 18 -
8~64
by an ice bath. The mixture was heated to 70 in an oil bath,
and an additional 168 g of bromine was added over an interval
of 30 minutes. After the bromine addition, the temperature
was raised to 80 and the mixture held at that temperature for
3 hours. Air was then blown into the cooled reaction product
until the excess bromine and hydrogen bromide were removed [a
trap to catch the resulting vapours is desirable].
The aerated reaction mixture was then heated to 80
on an oil bath and water (20 mll was added cautiously with
stirring. On cessation of the reaction (which takes about 30
minutes), an additional 300 ml of water was added and the mix-
ture was refluxed (using a heating mantle) vigorously for 4
hours. The product was cooled, water (50 ml) was added and
then the aqueous layer was saturated with sodium chloride and
extracted with methylene chloride (4 x 100 ml). The combined
extracts were dried (sodium sulphate) and the solvent was re-
moved under reduced pressure. The resulting dark-red residue
was distilled under reduced pressure to afford 52 g (53%) of
3-methyl-3-butenolide, b.p. 52/1.5 mm; 82/7 mm, 97-98.6/20
mm.
The 5-chloro-3-methylbutenolide used as starting
material can also be prepared conveniently in a three-stage
process by reacting ethyl pyruvate with vinyl acetate in the
presence of titanium tetrachloride followed by ring cl~sure
and subjecting the 5-ethoxy-3-methylbutenolide so obtained to
chlorination with thionyl chloride as follows:
OH
/CH3 CH2 - I CH3 CH3 CH3
llH2 t CH _~ ~ Cl O
CH3COO
Titanium tetrachloride (8.1 g, 43 m.moles; freshly
distilled) in methylene dichloride (60 ml, dried over moie-
. - . -.. : : :
~8~36~
cular sieves) was cooled and stirred in an ice bath and then
a solution of ethyl pyruvate (4.94 g, 43 m.moles) and vinyl
acetate (3.66 g, 43 m.moles) in dry methylene dichloride (30
ml~ was added dropwise over 2 hours to the cooled and stirred
reactio~ mixture. Stirring was continued for another 2 hours
at 0. Water (40 ml) was then added, the layers separated and
the aqueous layer extracted with further methylene dichloride
(2 x 30 ~1). The combined methylene dichloride extract was
washed with water (30 ml), dried over sodium sulphate and eva-
porated to give a colourless oil (7.50 g) which showed n.m.r.(CDC13) signals at ~1.40 (s, tertiary Me), 6.63 (m) and 2.00
and 2.08 (diastereoisomeric acetates).
The crude colourless oil so obtained (7.12 g) was
dissolved in absolute ethanol (80 ml), concentrated hydrochlo-
ric acid (4 ml) was added and the mixture heated under reflux
for 4 hours. Water ~100 ml) was then added, the ethanol was
removed by distillation and the remainder heated under reflux
for a further 45 minutes. The reaction mixture was then ex-
tracted with ethyl acetate (3 x 50 ml) and the extract dried
over sodium sulphate and evaporated. The product was a yellow-
brown gum (2.39 g) which showed n.m.r. (CDC13) signals at ~1.90
(vinyl Me) and 6.00 and 6.38 ( 2x m, 1 proton each).
The crude yellow-brown gum was heated with thionyl
chloride (20 ml) under reflux for 1 hour and then the excess
reagent removed by distillation. The residue was distilled
under reduced pressure to give a colourless mobile oil (1.4 g)
b.p./62/2 mm. which was identified as 5-chloro-3-methylbuten-
olide.
Example 4
Preparation of Compound VA
CH-O~a~ ~
VA
- 20 -
3-Bromophthalide (0.7 g) was added to a suspension of
the foregoing sodio-enolate salt (0.75 g), prepared as for
compound IVA in Example 3 above, in anhydrous 1,2-dimethoxy-
ethane (15 ml) and the mixture stirred for 18 hours at room
temperelture. At the end of this period the mixture was poured
into ice (50 g~ and the solid product filtered and dried in
desiccator. A further crop of the product was obtained by
extracting the aqueous mother liquor from above with chloro-
form (30 ml x 3), the extract being dried over sodium sulphate,
filtered and evaporated to dryness. Crystallization from di-
chloromethane-hexane mixture gave compound VA as a crystal-
line product (mixed diastereoisomers) m.p. 161-168. (Found:
C, 71.55; H, 4.28. C20H14O5 requires C, 71.85; H, 4.19~).
Example 5
Preparation of Compound VIA
Lactonisation of trans-indan-1-ol-2-acetic acid
Trans-indan-1-ol-2-acetic acid (3.4 g) was dissolved
in 25% aqueous sulphuric acid (25 ml) and ether (150 ml) was
added, the mixture being stirred vigorously at room tempera-
ture for 18 hours. The ether layer was separated, shaken withsaturated salt solution (25 ml) and dried over sodium sulphate.
Filtration and removal of the solvent in vacuo gave an oily
product which crystallized on standing. Recrystallization
from ether-light petroleum (b.p. 60-80~) yielded the desired
cis-lactone as colourless needles, m.p. 64-65.
Formylation of the lactone of cis-indan-1-ol-2-acetic acid
The foregoing cis-lactone ~2.61 g) was added to a sus-
pension of sodium (0.345 g) in anhydrous ether (50 ml) follow-
ed by ethyl formate (1.8 g) and anhydrous ethanol (1.0 ml).
The mixture was stirred at room temperature under nitrogen
for 18 hours. The precipitated sodio-enolate salt was fil-
tered, washed quickly with dry ether (25 ml) and dried overnight
- 21 -
in a vacuum desiccator.
Reaction of sodio-enolate salt with 5-chloro-3-methylbutenolide
¢~ + C~oH ~X~-o~CoB3
5- Chloro-3-butenolide (0.663 g) was added to a suspen-
sion of the foregoing sodio-enolate salt (1.12 g) in anhydrous
1,2-dimethoxyethane (20 ml) and the mixture stirred for 19
hours at room temperature. Crushed ice (40 g) was then added
and the aqueous solution extracted with chloroform (60 ml x 4).
The combined chloroform extract was washed with saturated salt
solution (20 ml), dried over sodium sulphate, filtered and eva-
porated to dryness ln vacuo. The crystalline solid so obtained
was recrystallized from dichloromethane-hexane and gave com-
pound VIA (mixed diastereoisomers) as colourless needles, m.p.
116-124. (Found: C, 68.45; H, 4-7- C17H14Os requires C~
68.45; H, 5.05%).
Example 6
Preparation of Compound VIIA
~CB-O Na CB-O~
A mixture of the sodio-enolate salt (0.75 g), prepared
as for compound VIA in Example 5 above, and 3-bromophthalide
(0.71 g) in anhydrous 1,2-dimethoxyethane (10 ml) was stirred
at room temperature for 19 hours. Ice (20 g) was added and
the crystalline solid so obtained was separated and dried.
The product was compound VIIA (mixed diastereoisomers) which
had m.p. 163-173. The mass spectra showed peaks at 334, 316,
201 and 133. The infra red spectra (KBr disc) showed peaks
- 22 -
~ . :
3~
at 1788 cm 1, 1740 cm 1 and 1680 cm 1. The nuclear magnetic
resonance (NMR) spectra (CDC13) showed ~, 3.5 m, 4.3 m, 6.35
d, 7.1 s and 8.0 m.
'.
- 22a -
,. . - : ,
8~64
~xample 7
Preparation of Compound VIIIA
Iodolactonisation of Cyclopent-2-enyl-1-acetic acid
A solution of iodine (30 g) and potassium iodide (50
g) in water (200 ml) was added to a mixture of cyclopent-2-enyl-
l-acetic ~cid (12.6 g) in 0.5M sodium bicarbonate (400 ml) and
chloroform (300 ml) and the mixture stirred vigorously at room
temperature in dark for two days. At the end of this period
the chloroform layer was separated, washed with a solution of
10% sodium thiosulphate, followed by a saturated solution of
sodium chloride. The resulting chloroform solution was dried
over sodium sulphate, filtered and evaporated to dryness to
give a thick yellow oil which crystallized on standing. There
is thus obtained the desired compound (23.8 g) with the struc-
ture
I
~~CO
Preparation of Cyclopent-3-ene-2-ol-1-acetic acid lactone
A mixture of the foregoing iodolactone (22.66 g) and
1,5-diazabicyclo[5:4:0]-undec-5-ene (DBU) (13.69 g) in anhyd-
rous tetrahydrofuran (200 ml) was stirred at 50 for 2 hours
and heated under reflux for 1-1/2 hours~ It was then cooled
to room temperature, diluted with water (100 ml) and extracted
with dichloromethane (3 x 60 ml). The combined organic extracts
were shaken with saturated salt solution, dried over sodium
sulphate, filtered and concentrated to give cyclopent-3-ene-
2-ol-1-acetic acid lactone (10.3 g) which was purified by dis-
tillation at 69/0.4 mm. (Found: C, 68.08; H, 6.51, C7H8O2
requires C, 67.74; H, 6.45%).
Form~lation of the lactone of Cyclopent-3-ene-2-ol-1-acetic acid
Sodium (0.~6 g) was added to a solution of the fore-
- 23 -
.
~8g6~
going lactone (2.48 g) in a mixture of ethyl formate (2.22 g)
and ether (25 ml) and the reaction stirred at room temperature
for 18 hours. The light tan sodium salt was filtered, washed
with a small amount of anhydrous ether and dried overnight in
a desiccator.
Reaction of sodium salt with 5-chloro-3-methylbutenolide
~ 013~1a~ Cl~O e~_O~
VIIIA
5-Chloro-3-methyl~utenolide (1.33 g) was added to a
suspension of the foregoing sodium salt (1.74 g) in anhydrous
1,2-dimethoxye~hane (20 ml) and the mixture stirred at 5 for
16 hours. It was then diluted with cold water (20 g) and ex-
tracted with dichloromethane (3 x 25 ml). The combined di-
chloromethane extract was shaken with saturated salt solution,
dried over sodium sulphate, filtered and evaporated to dryness
to give a viscous oil which solidified on standing. Crystalli-
zation from ether gave a colourless crystalline product; m.p.
140-188 (mixed diastereoisomers) (Found: C, 62.81; H, 4.89.
C13H12O5 requires C, 62.90; H, 4.84%) which was identified as
compound VIIIA.
Example 8
Preparation of Compound IXA
~e+~
CH-O Na B CH-o O
3-Bromophthalide (1.07 g) was added to a suspension
of the sodium salt (0.87 g), prepared as for compound VIIIA in
Example 7, in anhydrous 1,2-dimethoxyethane (20 ml) and the
mixture stirred at room temperature for 18 hours. It was then
~ 24 -
diluted with ice-cold water and extracted with dichloromethane
(3 x 25 ml). The combined dichloromethane extract was shaken
with saturated salt solution, dried over sodium sulphate, fil-
tered and evaporated to dryness to give a solid (1.45 ~) which
was crystallized from ether. The product was a colourless
crystalline solid, m.p. 178-200 (dec) (mixed diastereoisomers)
(Found: C, 67.47; H, 4.28. C16H12O5 requires C, 67.61; H,
4.23~) which was identified as compound IXA.
Example 9
Preparation of compound XA
C~-O Na X~ C~-O
A mixture of the sodio-enolate salt (prepared as for
compound VIA in Example 5 but using 4 g of lactone) and S-
bromo-4-methyl-3-butenolide (5 g) in dry tetrahydrofuran (100
ml) was stirred overnight in an atmosphere of nitrogen at room
temperature. Most of the solvent was removed under reduced
pressure at room temperature and the residue poured into water
and extracted several times with methylene chloride. The com-
bined extracts were washed with saturated sodium chloride so-
lution, then aqueous sodium bicarbonate and water. After re-
moval of the solvent from the dried solution, the residue was
crystallized from ether-chloroform to give the product as
colourless crystals, m.p. 188-189 which was identified as
compound XA. The observed n.m.r. spectrum is in accord with
the structure given to compound XA. The infra red spectra
(I~Br disc) showed peaks at 1795 cm 1, 1740 cm 1 and 1680 cm 1.
The nuclear magnetic resonance (NMR) spectra (CDC13) showed ~,
2.15 s, 3.2 m, 3.9 m, 6.0 m and 7.4 m.
In order to demonstrate the activity of the compounds
6'~
in promoting the germination of seeds of Striga hermonthica,
Striga asiatica, Orobanche _egyptiaca, Orobanche crenata and
Orobanche ramosa, the following method was used. Seeds of the
parasitic weeds were first sterilized with a 1% aqueous so-
dium hydrochlorite solution for 10-15 minutes, and then washed
with distilled water until free of hypochlorite.
The Striga and Orobanche seeds were pre-treated by in-
cubating at 23C under moist conditions, e.g. on moist glass
fibre filter paper, for 10-14 days. Usually about 25 seeds on
10 mm discs of the filter paper were employed.
Discs carrying pre-treated seed of Striga or Orobanche
were dabbed to remove surplus moisture. Two discs were then
placed in each of two replicate dishes, so there were 4 discs
per treatment, carrying a total of about 100 seeds. The com-
pounds to be tested were dissolved in ethanol and diluted to
the required concentration with distilled water. The amount
of ethanol was never greater than 0.5% v/v in the final so-
lution. Freshly prepared solutions were always used. To each
disc was added two 16 ~1 drops of test solution. Dilution
of the test solutions by the moisture in the discs was allowed
for, so concentrations given were final concentrations. Germ-
ination was counted after 2 days at 34C in the case of Striga
and 5 days at 23C in the case of Orobanche.
- 26 -
Table 1
Germination tests on Striga hermonthica
Concentration % Germination
(P.p.m.)
Compound Compound
IIA IIIA
100 32 33
43 39
38 17
1 29 1
100.5 30 6
0.1 0 16
Control (distilled water): 6~ germination
It will be seen that both compounds are active and compound IIA
is more active than compound IIIA.
Table II
Germination tests on Orobanche ramosa
Concentration % Germination
(P.p.m-) . ,~
CompoundCompound Compound Compound
IIA IIIA IVA VA
100 O O 1 1
0 1 1 2 2
0.01 50 42 55 10
0.001 13 34 50 46
0.0001 30 21 50 9
I
Control (distilled water): 9~ germination
It will be seen that all four compounds are active and that co-
mpoulld IVA is the most active compound of the four compounds
tested.
~8~364
Table III
Germination tests on Orobanche crenata
Concentration % Germination
(p.p.m.)
Compound IVA Compound IVA Compound
("slow" mov- ("fast" mov-XIA
ing isomer) ing isomer)
1 50 66 49
0.1 18 39 14
0.01 9 8 0
Control (distilled water): 0~ germination
It will be seen that there is no marked difference between the
unresolved DL-pairs of diastereoisomers (the "slow" and "fast" ~
isomers) of compound IVA. Each of these isomers is superior in -
activity to compound XIA.
Table IV
Germination tests on Orobanche crenata
Concentration % Germination
(p.p.m.)Compound CompoundCompound
VIA VIIA XIA
100 27 18 24
37 3 ~ 18
0.01 8 6
0.001 3 16
O . 0001 1 5 O
Control (distilled water): 1% germination
Each of the compounds VIA and VIIA is superior in activity to
compound XIA over the lower range of concentration.
- 28 -
36~s
Table V
Germination tests on Striga hermonthica
Concentration I % Germination
p,p.m.)
Compound IVA Compound IVA Compound
("slow" mov- ("fast" mov-XIA
ing isomer) ing isomer)
100 9 1 1
17 3 7
9 8
1 44 23
1 60 28 24
0.5 44 10 18
0.1 7 19 12
0.05 8 20 28
0.01 10 j 22 21
Control (distilled water): 2~ germination
Both the "slow" moving isomer and the "fast" moving isomer of
compound IVA show appreciable activity. Each of these isomers
is superior in activity to compound XIA over certain ranges of
concentration.
- 29 -
8~36~
It has been demonstrated in Hyderabad, during the
Kharif (second) rains, that compound VIIIA was effective, at
a concentration of 10 p.p.m. and 1 p.p.m., in significantly
reducing Striga asiatica in a field test on a black soll,
being 39% and 36% respectively more efficient than a control
treatment. Furthermore, compounds VIA and VIIIA have been
shown to be active in germinating Orobanche ramosa seeds in
vitro, at concentrations of 0.1 to 1.0 p.p.m., having obtained
germinations of about 80 to 90~ twelve days after treatment.
Again, compound VIIIA was shown to be active in stimulating
germination of Orobanche ramosa seeds carried on glass fibre
paper discs and placed on the surface of sterilized sandy loam
soil in glass beakers, or when buried 5 cm deep in said soil
or when incorporated into said soil. Thus results show that
compound VIIIA is as active in sterilized soil as it is in
vitro.
- 30 -
