Certain 3-alkoxyisothiazole-4-carboxylic acids and derivatives thereof

Disclosed are certain novel 3-alkoxyisothiazoles. The 3-alkoxyisothiazoles and compositions containing them exhibit useful biocidal properties.

This invention relates to novel 3-alkoxyisothiazoles (hereinafter referred 
to at times as "isothiazoles" or "alkoxyisothiazoles"), to biocidal 
compositions containing them, and to their utilization in the control of 
living organisms. 
These novel 3-alkoxyisothiazoles can be represented by the formula 
##STR1## 
wherein Y is an alkyl group of 1 to 18 carbon atoms; a cycloalkyl group of 
3 to 8 carbon atoms; an aralkyl group of up to 8 carbon atoms; a halogen-, 
lower alkyl-, or lower alkoxy-substituted aralkyl group of up to 10 carbon 
atoms; a carbalkoxyalkyl group of up to 12 carbon atoms; a 
dialkylaminoalkyl group of up to 12 carbon atoms; a haloalkyl group of up 
to 12 carbon atoms; an alkoxyalkyl group of up to 12 carbon atoms; an 
alkylthioalkyl group of up to 12 carbon atoms; an alkenyl group of up to 
12 carbon atoms; or an alkynyl group of up to 12 carbon atoms; 
Z is hydrogen, halogen, a nitro group, a cyano group, a carboxy group, a 
carbalkoxy group of up to 8 carbon atoms, a carbamoyl group, an amino 
group, an aralkyl group of up to 8 carbon atoms, or a lower alkyl group; 
and 
Z' is hydrogen, halogen, an alkyl group of up to 8 carbon atoms, an aralkyl 
group of up to 8 carbon atoms, a lower alkylsulfinyl group, an 
aralkylsulfinyl group of up to 8 carbon atoms, a lower alkylsulfonyl 
group, an aralkylsulfonyl group of up to 8 carbon atoms, or an alkylamino 
group of up to 8 carbon atoms. These 3-alkoxyisothiazoles can form novel 
salts with strong organic or inorganic acids. The salts also exhibit 
biocidal activity. 
Where the expression "lower" is employed in conjunction with terms, such as 
for example, alkyl, alkylsulfinyl, alkylsulfonyl or haloalkyl, it is 
intended to indicate that the alkyl portion of the substituent group has a 
carbon content of 1 to 4 carbon atoms. Typically, the alkyl or alkyl 
portion may be methyl, ethyl, propyl, ispropyl, butyl, t-butyl, and the 
like. 
Representative Y substituents include methyl, ethyl, propyl, isopropyl, 
butyl, hexyl, octyl, dodecyl, octadecyl, cyclohexyl, benzyl, 
4-chlorobenzyl, trichlorobenzyl, carbethoxymethyl, carbethoxyethyl, 
diethylaminoethyl, diethylaminomethyl, chloroethyl, chloromethyl, 
bromomethyl, allyl, propargyl, methoxymethyl, 2-ethoxyethyl, 
methylthiomethyl, and 4-octynyl. 
Representative Z substituents include hydrogen, methyl, ethyl, propyl, 
isopropyl, butyl, benzyl, chloro, bromo, iodo, cyano, carboxy, carbethoxy, 
carbamoyl, amino, and nitro. 
Representative Z' substituents include hydrogen, methyl, ethyl, propyl, 
isopropyl, butyl, octyl, benzyl, chloro, bromo, methylsulfinyl, 
ethylsulfinyl, butylsulfinyl, benzylsulfinyl, methylsulfonyl, 
ethylsulfonyl, propylsulfonyl, benzylsulfonyl, ethylamino, and 
n-butylamino. 
Typical compounds which fall within the scope of this invention include, 
for example, 
3-methoxyisothiazole, 
3-ethoxyisothiazole, 
3-isopropoxyisothiazole, 
3-n-hexyloxyisothiazole, 
4-bromo-3-methoxyisothiazole, 
4-iodo-3-methoxyisothiazole, 
4-nitro-3-methoxyisothiazole, 
4-cyano-3-methoxyisothiazole, 
4-carbamoyl-3-methoxyisothiazole, 
4-carboxy-3-methoxyisothiazole, 
4-bromo-3-n-hexyloxyisothiazole, 
3-n-dodecyloxyisothiazole, 
3-benzyloxyisothiazolone, 
3-trichlorobenzyloxyisothiazole, 
3-carbethoxymethoxyisothiazole, 
3-[2-(N,N-diethylamino)ethoxy]isothiazole, 
3-(2-chloroethoxy)isothiazole, 
3-allyloxyisothiazole, 
3-(2-propynyloxy)isothiazole, 
3-methoxymethoxyisothiazole, 
5-chloro-3-methoxymethoxyisothiazole, 
4-cyano-3-n-dodecyloxyisothiazole, 
4-cyano-3-n-hexyloxyisothiazole, 
3-n-propoxyisothiazole, 
4-carboxy-3-n-dodecyloxyisothiazole, 
3-n-butoxyisothiazole, 
4-carboxy-3-n-butoxyisothiazole, 
4-carboxy-3-n-hexyloxyisothiazole, 
4-bromo-3-n-propoxyisothiazole, 
4-cyano-3-n-propoxyisothiazole, 
4-carbamoyl-3-n-propoxyisothiazole, 
4-amino-3-n-propoxyisothiazole 
4-chloro-3-methoxyisothiazole, 
5-benzyl-3-methoxyisothiazole, 
5-bromo-3-methoxyisothiazole, 
5-chloro-3-methoxyisothiazole, 
4,5-dichloro-3-methoxyisothiazole, 
4,5-dibromo-3-methoxyisothiazole, 
4-chloro-5-bromo-3-methoxyisothiazole, 
4-bromo-5-chloro-3-methoxyisothiazole, 
4-chloro-5-benzyl-3-methoxyisothiazole, 
4-bromo-5-benzyl-3-methoxyisothiazole, 
4-methyl-3-methoxyisothiazole, 
4-ethyl-3-methoxyisothiazole, 
4-butyl-3-methoxyisothiazole, 
4-methyl-5-ethyl-3-methoxyisothiazole, 
4,5-dimethyl-3-methoxyisothiazole, 
4-methyl-5-chloro-3-methoxyisothiazole, 
4-propyl-5-chloro-3-methoxyisothiazole, 
4-butyl-5-chloro-3-methoxyisothiazole, 
4-methyl-5-bromo-3-methoxyisothiazole, 
4-ethyl-5-bromo-3-methoxyisothiazole, 
4-ethyl-5-benzyl-3-methoxyisothiazole, 
4-propyl-5-benzyl-3-methoxyisothiazole, 
4-cyano-5-methylsulfinyl-3-methoxyisothiazole, 
4-cyano-5-ethylsulfinyl-3-methoxyisothiazole, 
4-cyano-5-benzylsulfinyl-3-methoxyisothiazole, 
4-cyano-5-methylsulfonyl-3-methoxyisothiazole, 
4-cyano-5-butylsulfonyl-3-methoxyisothiazole, 
4-cyano-5-benzylsulfonyl-3-methoxyisothiazole, 
4-carboxy-5-methylthio-3-methoxyisothiazole, 
4-carbamoyl-5-methylthio-3-methoxyisothiazole, 
4-cyano-5-n-butylamino-3-methoxyisothiazole, 
4-cyano-5-ethylamino-3-methoxyisothiazole, 
4-carbethoxy-3-methoxyisothiazole, 
4-nitro-5-chloro-3-methoxyisothiazole, and 
4-cyano-5-methyl-3-methoxyisothiazole. 
The 3-alkoxyisothiazoles of the invention can be prepared by reacting with 
a halogenating agent a disulfide-imidate hydrochloride having the formula 
##STR2## 
wherein R and R' are hydrogen, saturated alkyl groups, or araalkyl groups 
and Y is as defined above. Typical halogenating agents include chlorine, 
bromine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide, 
n-bromosuccinimide, iodine monochloride and the like. Chlorine and 
sulfuryl chloride are the preferred halogenating agents. 
Temperature is not critical to the cyclization reaction process, and any 
desired temperature may be utilized. Generally and preferably the 
cyclization will be carried out in the range of about 0.degree. to 
60.degree. C. 
The reaction is generally carried out in an inert nonaqueous solvent, such 
as benzene, toluene, xylene, ethyl acetate, ethylene dichloride, 
2-nitropropane, and the like. 
The isothiazoles may be obtained as their isothiazolium salts during the 
cyclization process. Such salts have the following structure: 
##STR3## 
wherein Y, R, and R' are as defined above, and A is halogen. Where desired 
or necessitated, an acid acceptor can be incorporated in the reaction 
medium to avoid isothiazolium salt formation. Typical acceptors which can 
be utilized include t-amine bases, such as, for example, pyridine and 
triethylamine. It should be noted at this point that the isothiazolium 
salts can also be transformed or neutralized to free isothiazoles by being 
contacted with water or bases. Such procedures are, of course, well known 
to those skilled in the art. 
To separate, if desired, the products prepared by the novel process of the 
invention from the reaction solution, any of the known techniques may be 
employed. Generally, separation will involve one or more of the steps of 
distillation, crystallization, filtration and the like. 
For the cyclization of each mole of the disulfideimidate, three mole 
equivalents of the halogenating agent are required. When more than three 
mole equivalents of the halogenating agent are provided, the halogenation 
can occur at the 5-position and at both the 4- and 5- positions. Thus, 
when five mole equivalents of the halogenating agent are present, a 
5-monohalogenated alkoxyisothiazole can be prepared, and when seven mole 
equivalents of the halogenating agent are present, a 4,5-dihalogenated 
alkoxyisothiazole can be obtained. 
The 4-halo and 4,5-dihalo-3-alkoxyisothiazoles can also be prepared by 
halogenation of a 3-alkoxyisothiazole. Preparation of alkoxyisothiazoles 
having the 4- and 5- positions substituted with different halogen atoms is 
achieved by the halogenation of an isothiazolone already halogenated at 
one of the two positions in question. For example, a 
4-bromo-5-chloro-3-alkoxyisothiazole can be obtained by bromination of a 
5-chloro-3-alkoxyisothiazole. The starting isothiazole can, of course, be 
prepared by the cyclization of a disulfide-imidate as described herein. 
The disulfide-imidates which are cyclized to form the 3-alkoxyisothiazoles 
are generally prepared from .beta., .beta.'-dithiodipropionitriles which 
are in turn prepared from the reaction of acrylonitriles with ammonium 
tetrasulfide. The reaction of olefins with ammonium tetrasulfide to form 
disulfides is a reaction well known in the art. A .beta.,.beta. 
'-dithiodipropionitrile prepared from acrylonitriles in the manner stated 
above is then reacted with a suitable alcohol in the presence of hydrogen 
chloride to give the disulfide-imidate hydrochloride. The reaction is 
generally carried out in the presence of an inert non-aqueous solvent. The 
reaction can be run over a wide temperature range, with -20.degree. C. to 
100.degree. C. being the preferred range. 
Salts of the novel 3-alkoxyisothiazoles of the invention are also 
biocidally active. Preparation of the salts of these 3-alkoxyisothiazoles 
is readily achieved by reacting a 3-alkoxyisothiazole with a strong acid. 
The salts can be represented by Formula III, above, wherein A represents 
an anion of the strong acid. Typical strong acids include hydrobromic, 
nitric, sulfuric, perchloric, chlorosulfuric, chloroacetic, maleic, 
p-toluenesulfonic, hydrochloric, and the like. Separation of these salts 
from the reaction medium can be accomplished by any convenient means. 
The 4-cyano, 4-carboxy, 4-carbalkoxy, 4-carbamoyl, 4-nitro, and 
4-amino-3-alkoxyisothiazoles are all prepared by various classical 
reactions from the appropriate 3-alkoxyisothiazoles. A 
4-bromo-3-alkoxyisothiazole, prepared as described above, is reacted with 
an equimolar or excess amount of cuprous cyanide, in a polar, 
non-hydroxylic solvent such as dimethylformamide, to give the 
4-cyano-3-alkoxyisothiazole. The 4-carbamoyl-3-alkoxyisothiazoles are 
prepared by the hydrolysis of 4-cyano-3-alkoxyisothiazoles with sulfuric 
acid. When the carbamoyl derivative is hydrolyzed with nitrous acid, a 
4-carboxy-3-alkoxyisothiazole is obtained. In the hydrolysis reactions, an 
equimolar amount or an excess of sulfuric acid or nitrous acid is used, 
and the reactions can be carried out in a wide variety of solvents. The 
5-halo and 5-alkyl-4-carboxy and 4-carbamoyl-3-alkoxyisothiazoles are 
prepared from the corresponding 4-cyano-3-alkoxyisothiazole, which is in 
turn prepared from 3-alkoxyisothiazole. 
The 4-nitro-3-alkoxyisothiazoles are prepared by a classical nitration of 
3-alkoxyisothiazole in a nitric acid-sulfuric acid mixture, generally 
using an equimolar amount of nitric acid and excess sulfuric acid. The 
4-amino-3-alkoxy-isothiazoles can be prepared by reacting a 
4-carbamoyl-3-alkoxyisothiazole with aqueous sodium hypobromite or sodium 
hypochlorite, the well-known Hofmann rearrangement. 
The 3-alkoxyisothiazoles of this invention can also be prepared by 
alkylation of a 3-hydroxyisothiazole. This reaction can be represented as 
follows: 
##STR4## 
wherein Y, Z, and Z' are as defined above and X is a halogen, such as 
bromine, chlorine, or iodine. This reaction may also yield 
3-isothiazolones having the formula 
##STR5## 
wherein Y, Z and Z' are as defined above, as well as the 
3-alkoxyisothiazoles. Generally, an acid acceptor is used to facilitate 
the alkylation reaction. Among the suitable acid acceptors which can be 
used are inorganic bases, such as alkali and alkaline earth metal 
hydroxides, alcoholates, hydrides, amides, and carbonates, and organic 
bases, such as trialkylamines and pyridine. The ratio of the reactants - 
3-hydroxyisothiazole, alkylhalide, and acid acceptor - will usually be 
equimolar. However, an excess of any of the reactants can be used. 
The alkylation reaction can be carried out in almost any solvent which will 
not interfere with reaction, including water, alcohols, aliphatic and 
aromatic hydrocarbons, ethers, esters, amides, nitriles, and the like. The 
alkylhalide reagent itself can also be used as a solvent for the reaction. 
The alkylation reaction will proceed over a broad temperature range and 
temperature is not critical to the reaction. Generally, the alkylation 
will be carried out in the range of about 0.degree. to 100.degree. C. 
The 3-hydroxyisothiazoles which are used as starting materials in the 
alkylation reaction can be prepared by several methods. 
3-Hydroxyisothiazoles having the formula 
##STR6## 
wherein M and M' are hydrogen, halogen, or saturated alkyl groups can be 
prepared by the cyclization of a disulfide-amide having the formula 
##STR7## 
wherein M" and M"' are hydrogen or saturated alkyl groups. The cyclization 
is accomplished by reacting the disulfide-amide with a halogenating agent 
under conditions similar to the disulfideimidate cyclization described 
above. Halogenated 3-hydroxyisothiazoles can be prepared by a method 
similar to the halogenation of 3-alkoxyisothiazoles described above. The 
methods of W. D. Crow and N. J. Leonard, J. Org. Chem., 30, 2660-2665 
(1965), Goerdeler and Miller, Chem. Ber. 96, 944-954 (1963), and W. R. 
Hatchard, J. Org. Chem. 28, 2163-2164 (1963), and an extension of the 
method of Goerdeler and Keuser, Chem. Ber., 97, 3106 (1964), which 
involves the cyclization of a substituted .alpha.-cyanothiomalonamide with 
a halogenating agent, are also useful. 
Among the 3-hydroxyisothiazoles which can be reacted with alkyl halides to 
produce the 3-alkoxyisothiazoles of the invention are: 
3-hydroxyisothiazole, 
4-bromo-3-hydroxyisothiazole, 
4-chloro-3-hydroxyisothiazole, 
5-benzyl-3-hydroxyisothiazole, 
5-bromo-3-hydroxyisothiazole, 
5-chloro-3-hydroxyisothiazole, 
4,5-dichloro-3-hydroxyisothiazole, 
4,5-dibromo-3-hydroxyisothiazole, 
4-chloro-5-bromo-3-hydroxyisothiazole, 
4-bromo-5-chloro-3-hydroxyisothiazole, 
4-chloro-5-benzyl-3-hydroxyisothiazole, 
4-bromo-5-benzyl-3-hydroxyisothiazole, 
4-methyl-3-hydroxyisothiazole, 
4-ethyl-3-hydroxyisothiazole, 
4-butyl-3-hydroxyisothiazole, 
4-methyl-5-ethyl-3-hydroxyisothiazole, 
4,5-dimethyl-3-hydroxyisothiazole, 
4-methyl-5-chloro-3-hydroxyisothiazole, 
4-propyl-5-chloro-3-hydroxyisothiazole, 
4-butyl-5-chloro- 3-hydroxyisothiazole, 
4-methyl-5-bromo-3-hydroxyisothiazole, 
4-ethyl-5-bromo-3-hydroxyisothiazole, 
4-ethyl-5-benzyl-3-hydroxyisothiazole, 
4-propyl-5-benzyl-3-hydroxyisothiazole, 
4-cyano-5-methylsulfinyl-3-hydroxyisothiazole, 
4-cyano-5-ethylsulfinyl-3-hydroxyisothiazole, 
4-cyano-5-benzylsulfinyl-3-hydroxyisothiazole, 
4-cyano-5-methylsulfonyl-3-hydroxyisothiazole, 
4-cyano-5- butylsulfonyl-3-hydroxyisothiazole, 
4-cyano-5-benzylsulfonyl-3-hydroxyisothiazole, 
4-carboxy-3-hydroxyisothiazole, 
4-carbamoyl-3-hydroxyisothiazole, 
4-nitro-3-hydroxyisothiazole, 
4-carboxy-5-methylthio-3-hydroxyisothiazole, 
4-carbamoyl-5-methylthio-3-hydroxyisothiazole, 
4-cyano-5-n-butylamino-3-hydroxyisothiazole, 
4-cyano-5-ethylamino-3-hydroxyisothiazole 
4-iodo-3-hydroxyisothiazole, 
4-cyano-3-hydroxyisothiazole, 
4-carbethoxy-3-hydroxyisothiazole, 
4-nitro-5-chloro-3-hydroxyisothiazole, 
4-cyano-5-methyl-3-hydroxyisothiazole 
5-methyl-3-hydroxyisothiazole, 
4-bromo-5-methyl-3-hydroxyisothiazole, 
4-cyano-5-methylthio-3-hydroxyisothiazole, 
5-phenyl-3-hydroxyisothiazole, 
4-carbamoyl-5-anilino-3-hydroxyisothiazole, and 
4-cyano-5-anilino-3-hydroxyisothiazole. 
By way of demonstration, the following examples are offered to illustrate 
this invention and are not to be construed as limitations thereof. 
Examples 1 to 30 are tabulated in Table I, which lists their formulas, 
elemental analyses, and melting points. Specific preparations of Examples 
1, 6, 8, 13, 15, 16, 17, 18, 19, and 20 are set out below to illustrate 
the various methods of preparing the 3-alkoxyisothiazoles of the invention 
.

EXAMPLE 1 
Preparation of 3-methoxyisothiazole 
To a solution of 43 g. (0.25 mole) of .beta.,.beta.'-dithiodipropionitrile 
and 80 g. (2.5 mole) of methanol in 250 ml. of ethylene dichloride was 
added at 0.degree.-5.degree. C. 55 g. (1.5 mole) of anhydrous hydrogen 
chloride over 1 hour. The solution was then allowed to stand for several 
days at 5.degree.-10.degree. C., during which time dimethyl 
.beta.,.beta.'-dithiodipropionimidate dihydrochloride precipitated as a 
white solid. Filtration and drying gave 68 g. (88% of product.) 
To a suspension of 61.8 g. (0.2 mole) of dimethyl 
.beta.,.beta.'-dithiodipropionimidate dihydrochloride in 650 ml. of ethyl 
acetate at 25.degree. C. was added over 1 hour 44.7 g. (0.63 mole) of 
chlorine. After chlorination, the reaction mixture was stirred for 1 hour, 
then filtered to give 44.4 g. of 3-methoxyisothiazole hydrochloride as a 
white solid. This material was dissolved in 100 ml. of water, neutralized 
with solid sodium bicarbonate and extracted thoroughly with ether. The 
ether extracts were dried over anhydrous magnesium sulfate and evaporated 
to give an oil residue which on distillation yielded 26.8 g. (58%) of 
3-methoxyisothiazole, b.p. 147.degree.-50.degree. (760 mm). 
EXAMPLE 6 
Preparation of 3-dodecoxyisothiazole 
To a slurry of 10.7 g. (0.25 mole) of sodium hydride (56% mineral oil 
dispersion) in 60 ml. of dimethylsulfoxide was added slowly at 25.degree. 
C. a solution of 3-hydroxyisothiazole in 60 ml. of dimethylsulfoxide. 
Hydrogen gas was evolved vigorously and after addition 5.3 liters had been 
collected. To the resulting slurry was then added over 15 minutes 49.8 g. 
(0.2 mole) of 1-bromododecane. After stirring for 18 hours at 25.degree. 
C., the reaction was heated to 80.degree. C. for 1.5 hours. The reaction 
mixture was then diluted with 300 ml. of water and was extracted 
thoroughly with ether. The combined ether extracts were washed with water, 
dried over anhydrous magnesium sulfate, and evaporated to give an oil 
residue. This latter product on vacuum distillation gave 11.1 g. (21%) of 
3-dodecoxyisothiazole, b.p. 142 (0.6 mm). 
EXAMPLE 8 
Preparation of 3-benzyloxyisothiazole 
To a solution of 20.2 g. (0.2 mole) of 3-hydroxyisothiazole in 100 ml. of 
methanol was added 47.5 g. (0.22 mole) of 25% methanolic sodium methoxide 
solution, maintaining the temperature at 25.degree.-30.degree. C. To the 
resulting solution was then added dropwise at 25.degree. C. 25.2 g. (9.2 
mole) of benzyl chloride in 50 ml. of methanol. The reaction solution was 
then heated at reflux for 5 hours, during which time sodium chloride 
precipitated as a white solid. The resulting slurry was evaporated to an 
oil-solid mixture, which was slurried in ether and filtered. The ether 
solution was evaporated, and the oil residue was vacuum distilled to yield 
18.7 g. (49%) of 3-benzyloxyisothiazole, b.p. 110.degree. C. (0.3 mm). 
EXAMPLE 13 
Preparation of 3-allyloxyisothiazole 
To a slurry of 10.7 g. (0.22 mole) of sodium hydride (56% mineral oil 
dispersion) in 60 ml of dimethylformamide was added slowly at 25.degree. 
C. 20.2 g. (0.2 mole) of 3-hydroxyisothiazole in 60 ml. of 
dimethylformamide. Hydrogen gas was evolved vigorously and at the 
completion of addition 5.2 liters had been collected. To the resulting 
solution was then added dropwise at 25.degree. C. 24.2 g. (0.2 mole) of 
allyl bromide. After stirring at 25.degree. C. for several hours, the 
reaction solution was diluted with water and extracted thoroughly with 
ether. The ether extracts were washed with water, dried over anhydrous 
magnesium sulfate, and evaporated to an oil residue. This latter material 
was vacuum distilled to give 7.3 g. (26%) of 3-allyloxyisothiazole, b.p. 
60.degree. (18 mm). 
EXAMPLE 15 
Preparation of 4-bromo-3-methoxyisothiazole 
To a solution of 9.2 g. (0.08 mole) of 3-methoxyisothiazole in 20 ml. of 
glacial acetic acid was added dropwise at 25.degree. C. a solution of 12.8 
g. (0.08 mole) of bromine in 20 ml. of glacial acetic acid. After stirring 
overnight the slurry which has formed was poured into 400 g. of ice-water 
and allowed to stand. The precipitated solid was extracted into ether, and 
the aqueous phase was neutralized with solid sodium bicarbonate and 
extracted with ether again. The combined ether extract was dried over 
anhydrous magnesium sulfate and evaporated to leave an oil residue. This 
material was distilled to give 11.1 g. (72%) of 
4-bromo-3-methoxyisothiazole, b.p. 70.degree. C. (5 mm), which solidified 
on cooling in ice. 
EXAMPLE 16 
Preparation of 4-iodo-3-methoxyisothiazole 
To a solution of 1.15 g. (0.01 mole) of 3-methoxyisothiazole in 5 ml. of 
glacial acetic acid was added dropwise over 10 minutes 1.80 g. (0.011 
mole) of iodine monochloride. After standing for several days the reaction 
solution was poured onto ice to precipitate an oil, which on continued 
washing with water gave after filtering and drying 1.0 g. (42%) of 
4-iodo-3-methoxyisothiazole as a tan solid. Crystallization from hexane 
gave this product as a white solid, m.p. 61.degree.-63.degree. C. 
EXAMPLE 17 
Preparation of 4nitro-3-methoxyisothiazole 
To a solution of 10 ml. of concentrated sulfuric acid and 2 g. (0.022 mole) 
of 70% nitric acid was added over several minutes 2.3 g. (0.02 mole) of 
3-methoxyisothiazole. The temperature rose to 40.degree. C. and was 
controlled at that point by cooling. After stirring for 5 hours the 
reaction solution was poured into 30 ml. of ice-water to precipitate 0.5 
g. (16%) of 4-nitro-3-methoxyisothiazole as a white solid, m.p. 
118.degree.-122.degree. C. 
EXAMPLE 18 
Preparation of 4-cyano-3-methoxyisothiazole 
To a solution of 38.8 g. (0.2 mole) of 4-bromo-3-methoxyisothiazole 
prepared as in Example 15 in 80 ml. of dimethylformamide was added 54 g. 
(0.6 mole) of cuprous cyanide. The mixture was stirred and heated at 
reflux for 1 hour. Then the reaction mixture was cooled to 25.degree. C., 
and 40 g. (0.81 mole) of sodium cyanide in 120 ml. of water was added in 
portions. The mixture exothermed to 60.degree.-70.degree. C. and was 
allowed again to cool to 25.degree. C. The reaction solution was then 
extracted thoroughly with ether. The ether extracts were washed with 10% 
sodium cyanide solution and then water. After drying over anhydrous 
magnesium sulfate and evaporation 23.4 g. (83%) of 
4-cyano-3-methoxyisothiazole was obtained as a white solid, m.p. 
60.degree.-62.degree. C. after crystallization from ligroin 
(90.degree.-120.degree.). 
EXAMPLE 19 
Preparation of 4-carbamoyl-3-methoxyisothiazole 
A solution of 2.8 g. (0.02 mole) of 4-cyano-3-methoxyisothiazole prepared 
as in Example 18 in 30 ml. of 75% sulfuric acid was heated at 70.degree. 
C. for 0.5 hour. The solution was then cooled and poured into ice to give 
after filtration and drying 0.95 g. of 4-carbamoyl-3-methoxyisothiazole, 
m.p. 165.degree.-168.degree. C. By continuous ether extraction of the 
aqueous filtrate an addition 1.13 g. of 4-carbamoyl-3-methoxyisothiazole 
was obtained to give a total yield of 2.08 g. (66%). 
EXAMPLE 20 
Preparation of 4-carboxy-3-methoxyisothiazole 
To a solution of 7.9 g. (0.05 mole) of 4-carbamoyl-3-methoxyisothiazole 
prepared as in Example 19 in 90 ml. of 80% sulfuric acid at 
10.degree.-15.degree. C. was added slowly beneath the surface of the 
liquid a solution of 9.5 g. (0.137 mole) of sodium nitrite in 13 ml. of 
H.sub.2 O. When addition was complete the solution was allowed to come to 
25.degree. C., and then was heated to 60.degree. C., for several minutes. 
After cooling to 25.degree. C. the reaction solution was poured onto ice 
to precipitate 3.64 g. (46%) of 4-carboxy-3-methoxyisothiazole as a white 
solid, m.p. 182.degree.-185.degree. C. 
TABLE I 
__________________________________________________________________________ 
3-Alkoxyisothiazole Examples 
##STR8## 
Analysis** 
Ex. 
No. 
Z Z' 
b.p./m.p. 
Y C H N S Halogen 
__________________________________________________________________________ 
1 H H 72.degree. (52 mm) 
CH.sub.3 41.77(41.7) 
4.35(4.4) 
11.95(12.2) 
27.90(27.8) 
2 H H 36.degree. (0.3 mm) 
C.sub.3 H.sub.7 -n 
50.42(50.4) 
6.49(6.3) 
9.92(9.8) 
22.44(22.4) 
3 H H 95 (26 mm) 
CH(CH.sub.3).sub.2 
50.56(50.4) 
6.35(6.3) 
9.80(9.8) 
22.05(22.4) 
4 H H 42 (0.1 mm) 
C.sub.4 H.sub.9 -n 
54.06(53.5) 
7.21(7.0) 
8.76(8.9) 
20.24(20.4) 
5 H H 61 (0.4 mm) 
C.sub.6 H.sub.13 -n 
58.59(58.4) 
7.98(8.1) 
7.51(7.6) 
17.18(17.3) 
6 H H 142 (0.6 mm) 
C.sub.12 H.sub.25 -n 
68.39(66.9) 
9.90(10.0) 
4.82(4.7) 
11.72(11.9) 
7 H H 94 (0.5 mm) 
CH.sub.2 OCH.sub.3 
41.14(41.1) 
5.42(5.5) 
9.70(9.6) 
22.07(21.9) 
8 H H 110 (0.3 mm) 
CH.sub.2 C.sub.6 H.sub.5 
62.27(62.9) 
4.73(4.7) 
7.64(6.3) 
16.63(16.8) 
9 H H 66-9.degree.* 
CH.sub.2 C.sub.6 H.sub.2 Cl.sub.3 
42.53(40.9) 
2.52(2.0) 
4.22(4.7) 
9.86(10.8) 
Cl, 36.13 (36.1) 
10 H H 94.degree. (1.25 mm) 
CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
45.54(44.9) 
5.05(4.8) 
6.94(7.5) 
16.70(17.1) 
11 H H 80 (0.1 mm) 
C.sub.2 H.sub.4 N(C.sub.2 H.sub.5).sub.2 
53.38(54.0) 
7.70(8.0) 
14.05(14.0) 
16.26(16.0) 
12 H H 56 (0.35 mm) 
C.sub.2 H.sub.5 Cl 
38.07(36.9) 
4.32(3.7) 
7.79(8.6) 
19.26(19.63) 
Cl, 21.67 (21.3) 
13 H H 60 (18 mm) 
CH.sub.2 CHCH.sub.2 
51.43(51.2) 
4.95(4.9) 
9.58(9.9) 
22.59(22.8) 
14 H H 65 (0.4 mm) 
CH.sub.2 CCH 
51.37(51.7) 
3.98(3.6) 
9.75(10.1) 
23.01(23.0) 
15 Br H 70.degree. (5 mm) 
CH.sub.3 24.82(24.7) 
2.18(2.1) 
7.20(7.2) 
16.21(16.5) 
Br, 40.48 (41.2) 
16 I H 61-30* CH.sub.3 19.43(19.9) 
1.50(1.7) 
5.51(5.8) 
13.32(13.3) 
I, 52.15 (52.7) 
17 NO.sub.2 
H 118-22.degree.* 
CH.sub.3 30.13(30.0) 
2.60(2.5) 
17.49(17.5) 
19.95(20.0) 
18 CN H 60-2.degree.* 
CH.sub.3 42.40(42.8) 
2.98(2.9) 
19.98(20.0) 
22.44(22.8) 
19 CONH.sub.2 
H 165-68.degree.* 
CH.sub.3 38.16(38.0) 
3.78(3.8) 
17.60(17.7) 
20.24(20.3) 
20 CO.sub.2 H 
H 182-5.degree.* 
CH.sub.3 38.13(37.7) 
3.13(3.1) 
8.74(8.8) 
20.02(20.1) 
21 Br H 115 (0.3 mm) 
C.sub.6 H.sub.13 -n 
41.26(40.9) 
5.47(5.3) 
5.21(5.3) 
12.01(12.12) 
Br, 30.65 (30.3) 
22 CN H 40-2.degree.* 
C.sub.6 H.sub.13 -n 
56.83(57.1) 
6.51(6.7) 
13.18(13.3) 
15.13(15.2) 
23 CO.sub.2 H 
H 78-9.degree.* 
C.sub.6 H.sub.13 -n 
51.91(52.4) 
6.34(6.6) 
6.07(6.1) 
12.47(13.9) 
24 CN H 73-5.degree.* 
C.sub.12 H.sub.25 -n 
65.04(65.3) 
8.72(8.8) 
9.38(9.5) 
10.72(10.9) 
25 CO.sub.2 H 
H 87-90.degree.* 
C.sub.12 H.sub.25 -n 
61.32(61.3) 
8.78(8.6) 
5.03(4.5) 
9.91(10.2) 
26 H Cl 
46.degree. (0.05 mm) 
CH.sub.2 OCH.sub.3 
33.01(33.4) 
3.43(3.3) 
7.86(7.8) 
18.61(17.8) 
Cl, 20-46 (19.2) 
27 Br H 50.degree. (0.05 mm) 
C.sub.3 H.sub.7 -n 
33.13(32.4) 
3.79(3.6) 
6.08(6.3) 
14.14(14.4) 
Br, 35.40 (36.0) 
28 CN H 71.degree. (0.025 mm) 
C.sub.3 H.sub.7 -n 
50.02(50.0) 
5.19(4.8) 
16.34(16.7) 
19.28(19.1) 
29 CONH.sub.2 
H 97-98.degree.* 
C.sub.3 H.sub.7 -n 
43.50(45.2) 
5.62(5.4) 
14.30(15.0) 
17.37(17.2) 
30 NH.sub.2 
H 149-50.degree.* 
C.sub.3 H.sub.7 -n . HCl 
37.28(37.0) 
5.71(5.7) 
14.19(14.4) 
16.71(16.4) 
17.88 
__________________________________________________________________________ 
(18.2) 
*Melting Point 
**The number parenthesized represents the theoretical value, as 
calculated, using the empirical formula of each compound. 
The novel alkoxyisothiazoles and salts of this invention are biocidally 
active compounds, and as such, are suitable for the control of various 
living organisms, including microorganisms. They are useful as 
bactericidal, algaecidal, fungicidal, and nematocidal agents, for example. 
Antibacterial and antifungal activity were evaluated by the Serial Dilution 
Test (Broth Titor Test) wherein a series of broths containing varying 
dilutions of a test compound and an organism are halved starting with 
1:1,000. The values obtained which are also shown in Table II represent 
the maximum dilution in parts per millions at which the compound under 
evaluation renders complete control of the organism. Staphylococcus aureus 
(S. aureus) and Escherichia coli, (E. coli) were the bacterial organisms 
employed in this test, and the fungi employed were Aspergillus niger (A. 
niger) and Rhizopus stolonifer (R. stol. ). 
TABLE II 
______________________________________ 
MICROBIOLOGICAL ACTIVITY 
(minimum microbistatic concentration, ppm) 
Ex. Bacteria Fungi 
No. S. aureus E. coli. A. niger 
R. Stol. 
______________________________________ 
1 &gt;1000 1000 &gt;500 &gt;500 
2 1000 1000 500 500 
4 1000 500 
5 250 &gt;1000 63 16 
6 500 1000 &gt;500 &gt;500 
7 125 125 
8 250 250 &gt;500 500 
9 500 &gt;1000 250 125 
10 1000 1000 &gt;500 &gt;500 
11 1000 500 &gt;500 &gt;500 
12 1000 1000 &gt;500 &gt;500 
13 1000 1000 &gt;500 &gt;500 
14 1000 500 &gt;500 500 
15 1000 1000 &gt;500 &gt;500 
16 1000 1000 250 250 
18 1000 1000 &gt;500 &gt;500 
19 500 1000 &gt;500 &gt;500 
20 &gt;1000 &gt;1000 
21 250 &gt;1000 500 31 
22 63 1000 250 31 
24 1000 1000 
25 31 &gt;1000 500 250 
26 250 250 250 125 
______________________________________ 
3-Alkoxyisothiazoles were also evaluated as algaecides by the Fitzgerald 
Test (Applied Microbiology, 7, 205-211, No. 4, 1959). 
The alkoxyisothiazoles can also be used in seed treatment applications. By 
seed treatment is meant the disseminating of a biocidally active material 
over a seed subject to the attack of microorganisms, and particularly 
fungi, in an amount which is effective to control such microorganism 
without deleteriously effecting such seed. In most circumstances, the 
biocidally active material, in this case, the alkoxyisothiazoles or 
compositions containing them, will be applied to the surface area of the 
seeds to be treated. This may be accomplished by means common to the art, 
such as slurrying, socking, dusting, spraying and the like. 
Evaluation of the alkoxyisothiazoles with regard to further pesticidal 
activity demonstrated their use as nematocides. 
For the nematode test, soil was homogeneously inoculated with a macerated 
blend of tomato roots heavily knotted with the root-knot nematode. Ten ml. 
of a test solution of the 3-alkoxyisothiazole being evaluated was added to 
200 ml. of the inoculated soil in a 16 oz. jar to give a concentration by 
volume of about 60, 30, or 15 ppm. The jar was then shaken to insure 
thorough mixing and kept capped for 72 hours. The soil was then placed 
into a 3-inch deep plastic plant pot and allowed to air for about 24 hours 
after which time 3 cucumber (Cucumis sativus) seeds were planted. About 
twenty-three days thereafter, the cucumber plants were removed from the 
soil and the root systems examined for the presence of knots. A total of 
50 knots is considered as no control (-) and less than that as a measure 
of control. 
TABLE III 
______________________________________ 
NEMATOCIDAL ACTIVITY 
Example Number of Knots 
No. 60 ppm 30 ppm 15 ppm 
______________________________________ 
2 20 -- 
4 0 -- 
5 0 47 
8 0 21 
12 8 0 20 
14 4 
26 8 
Control 50-100 
______________________________________ 
Generally, control of a living organism is achieved in accordance with this 
invention by contacting the organism with an alkoxyisothiazole in an 
amount which is effective to control the organism. Any of the techniques 
known in the art can be employed to disseminate the alkoxyisothiazoles in 
a manner so as to achieve the desired contact with the organism to be 
controlled. Spraying and fumigating are typical of such techniques. 
The compounds of this invention can be utilized as slimicides, algaecides, 
bactericides, fungicides or combinations thereof in any locus and 
particularly in aqueous media, such as water-cooling systems, swimming 
pools, paper pulp processes, water-based paints, and the like. In 
addition, these compounds and/or compositions containing them can function 
as preservatives, and especially fabric preservatives, soap additives, 
sanitizing agents, preservatives for metal working compounds, and the 
like. 
In general, a locus subject to attack by microorganisms can be protected in 
accordance with this invention by incorporating into said locus an 
alkoxyisothiazole in an amount which is effective to control said 
microorganisms. The exact amount of alkoxyisothiazole required will, of 
course, vary with the medium being protected, the microorganisms being 
controlled, the particular alkoxyisothiazoles or compositions containing 
the alkoxyisothiazoles being employed and the like. Typically, in a liquid 
medium, excellent control is obtained when the alkoxyisothiazoles are 
incorporated in the range of 0.1 to 10,000 parts per million (ppm.) or 
0.00001 to 1% based on the weight of the medium. A range of 1 to 2000 ppm. 
is preferred. 
The term "control," as employed in the specification and claims of this 
application, is to be construed as the effect of any means which adversely 
affects the existence or growth of any living organism or microorganism. 
Such effect may comprise a complete killing action, eradication, arresting 
in growth, inhibition, reduction in number or any combination thereof. 
The alkoxyisothiazoles can also be used as agricultural fungicides. As 
such, they are particularly valuable when formulated in a fungicidal 
composition. Such compositions normally comprise an agronomically 
acceptable carrier and the compounds disclosed herein as the active agent 
or agents. Where necessary or desirable, surfactants or other additives 
may be incorporated to give uniformly formulated mixtures. By 
"agronomically acceptable carrier" is meant any substance which can be 
utilized to dissolve, dispense or diffuse the chemical incorporated 
therein without impairing the effectiveness of the toxic agent and which 
does no permanent damage to such environment as soil, equipment and 
agronomic crops. 
For use as pesticides, the compounds of this invention are usually taken up 
in an agronomically acceptable carrier or formulated so as to render them 
suitable for subsequent dissemination. For example, the alkoxyisothiazoles 
may be formulated as wettable powders, emulsion concentrates, dusts, 
granular formulations, aerosols or flowable emulsifiable concentrates. In 
such formulations, the alkoxyisothiazoles are extended with a liquid or 
solid carrier and, when desired, suitable surfactants are likewise 
incorporated. 
Thus, compounds of this invention can be dissolved in a water-miscible 
liquid such as ethanol, isopropanol, acetone, and the like. Such solutions 
are easily extended with water. 
The isothiazoles can be taken up on or mixed with a finely particled solid 
carrier, as for example, clays, inorganic silicates, carbonates, and 
silicas. Organic carriers may also be employed. Dust concentrates are 
commonly made wherein alkoxyisothiazoles are present in the range of 20 to 
80%. For ultimate applications these concentrates are normally extended 
with additional solid from about 1 to 20%. 
Wettable powder formulations are made by incorporating the compounds of 
this invention in an inert, finely divided solid carrier along with a 
surfactant which may be one or more emulsifying, wetting, dispersing or 
spreading agents or blend of these. The alkoxyisothiazoles are usually 
present in the range of 10 to 80% by weight and the surfactants in from 
0.5 to 10% by weight. Commonly used emulsifying and wetting agents include 
polyoxyethylated derivatives of alkylphenols, fatty alcohols, fatty acids 
and alkylamines; alkylarene sulfonates and dialkyl sulfosuccinates. 
Spreading agents include such materials as glycerol mannitan laurate and a 
condensate of polyglycerol and oleic acid modified with phthalic 
anhydride. Dispersing agents include such materials as the sodium salt of 
the copolymer of maleic anhydride and an olefin such as diisobutylene, 
sodium lignin sulfonate and sodium formaldehydenphthalene sulfonates. 
One convenient method for preparing a solid formulation is to impregnate 
the isothiazole toxicant onto the solid carrier by means of a volatile 
solvent, such as acetone. In this manner, adjuvants, such as activators, 
adhesives, plant nutrients, synergists and various surfactants, may also 
be incorporated. 
Emulsifiable concentrate formulations may be prepared by dissolving the 
isothiazoles of this invention in an agronomically acceptable organic 
solvent and adding a solvent-soluble emulsifying agent. Suitable solvents 
are usually water-immiscible and may be found in the hydrocarbon, 
chlorinated hydrocarbon, ketone, ester, alcohol and amide classes of 
organic solvents. Mixtures of solvents are commonly employed. The 
surfactants useful as emulsifying agents may constitute about 0.5 to 10% 
by weight of the emulsifiable concentrate and may be anionic, cationic or 
nonionic in character. Anionic surfactants include alcohol sulfates or 
sulfonates, alkylarene sulfonates and sulfosuccinates. Cationic 
surfactants include fatty acid alkyl amine salts and fatty acid alkyl 
quaternaries. Non-ionic emulsifying agents include ethylene oxide adducts 
of alkylphenols, fatty alcohols, mercaptans and fatty acids. The 
concentration of the active ingredients may vary from 10 to 80%, 
preferably in the range of 25 to 50%. 
For use as phytopathogenic agents, these compounds should be applied in an 
effective amount sufficient to exert the desired biocidal activity by 
techniques well known in the art. Usually, this will involve the 
application of the alkoxyisothiazoles to the locus to be protected in an 
effective amount when incorporated in an agronomically acceptable carrier. 
However, in certain situations it may be desirable and advantageous to 
apply the compounds directly onto the locus to be protected without the 
benefit of any substantial amount of carrier. This is a particularly 
effective method when the physical nature of the alkoxyisothiazoles is 
such as to permit what is known as "low-volume" application, that is, when 
the compounds are in liquid form or highly soluble in higher boiling 
solvents, so that they can be dissolved therein at high concentrations. 
The application rate will, of course, vary depending upon the purpose for 
such application, the alkoxyisothiazoles being utilized, the frequency of 
dissemination and the like. 
For use as bactericides and fungicides, dilute sprays may be applied at 
concentrations of 0.05 to 20 pounds of the active alkoxyisothiazole 
ingredient per 100 gallons of spray. They are usually applied at 0.1 to 10 
pounds per 100 gallons and preferably at 0.125 to 5 pounds per 100 
gallons. In more concentrated sprays, the active ingredient is increased 
by a factor of 2 to 12. With dilute sprays, applications are usually made 
to the plants until run-off is achieved, whereas with more concentrated or 
low-volume sprays the materials are applied as mists. 
The compounds of this invention can be utilized as the sole biocidal agents 
or they can be employed in conjunction with other fungicides, 
insecticides, nematocides, and other comparable pesticides. 
It is to be understood that changes and variations may be made without 
departing from the spirit and scope of the invention as defined by the 
appended claims.