CA2056672A1

CA2056672A1 - Halopropargyl mercaptotriazole compounds, compositions, uses and processes of preparation

Info

Publication number: CA2056672A1
Application number: CA002056672A
Authority: CA
Inventors: Adam Chi-Tung Hsu
Original assignee: Individual
Current assignee: Individual
Priority date: 1990-12-10
Filing date: 1991-11-29
Publication date: 1992-06-11
Also published as: JPH0543558A; AU8891191A; KR920012050A

Abstract

ABSTRACT OF THE INVENTION
Compounds of the formula (I) wherein A is selected from the group consisting of hydrogen, alkyl, aryl, and heterocyclic;
R is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heterocyclic; and X is selected from the group consisting of halogen.

Description

2~5~
PATENT APPLICATION OF
Adam Chi-Tung Hsu FOR
HALOPPIOPARGYL MERCAPTOTRIAZOLE
COMPOUNDS, COMPOSITIONS, USES AND PROCESSES OF
PREPARATION
DN90-063 MBF:meb Ba~kground of th~ Invention Field of the Invention This invention relates to control of microorganisms.
Description of the Prior Art Certain classes of heterocyclic iodopropargyl compounds have been proposed as fungicides or microbicides but no compound within those classes has achieved commercial success.
Chemical Abstracts ~2:31696X(1970) shows synthesis of 2-(3-iodo-2-propynyl-thio)benzimidazole, -benzothiazole, and benzoxazole of the formula ~,~;, I
X = NH, O, S

U.S. Patent No. 4,170,704 to Brandmal1 et al. shows iodopropargyl pyridyl and picolinyl ethers anà thioethers as antifungal agents.
U.S. Patent No. 4,616,004 to Edwards discloses fungicidal activity for compounds of the fornnula Il .
R~,~N~ C~---I

/ =
RIS
U.S. Patent No. 4,639,460 to Rose shows compounds of the formula R~ ~--a-I
N

R>R3~0 as fungicides.
U.S. Patent No. 4,520,023 to Schmitt shows 3-(3-iodopropargyl)-benzo-1,2,3-triazolin-4-ones and their use as microbicidal agents.

~6~2 There was no suggestion in the prior art that compounds within the formula of the present invention would have utility in controlling microorganisms.
Summary of the Invention It is an object of the present invention to provide new compounds for controlling microorganisms.
A further object is to provide methods of making such compounds, methods of using them, compositions comprising such compounds, and uses of such compositions.
These objects, and others which will become apparent from the following clisclosure, are achieved by the present invention which comprises in one aspect compounds of the formula ~\
N S ,~-X

R (I) wherein A is selected from the group consisting of hydrogen, alkyl, aryl, and heterocyclic;
R is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, 2 ~ 7 ~

substituted or unsubstituted phenyl, and substituted or unsubstituted heterocyclic; and X is selected from the group consisting of halogen.
In another aspect the invention comprises a method of preparing such compound comprising reacting compound of the formula A~ ~\
N S~-H

R (IV) with a halogenating agent.
A further aspect comprises using a composition comprising the compounds, or the compound itself, to protect a material se!ected from the group consisting of wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water from microorganisms.
Detailed Description of tbe Invention and the Preferred Embodiment The compounds of the invention are of formula ~1) as set forth above. The more preferred embodiments are those wherein A is selected from the group consisting of hydrogen; (C1-C18) straight or branched alkyl; (C3-C8) cycloalkyl; (C3-C6) alkenyl; (C3-C5) alkynyl; (C7-C12) aralkyl; (C6-C12) aryl; (C6-C12) aryl substituted with 1 to 3 2 ~ .~ fi ~ 7 ~
substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, nitro, cyano, carboxyl (C1-C4) alkoxycarbonyl, (C1-C4) alkyl thio, -S(O)nR2 where n is 1 or 2 and R2 is (C1-C4) alkyl; and a halo-substituted, nitro-substituted, or un-substituteci moiety selected frorn the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
Preferred examples of A are hydrogen, 4-chlorophenyl,

3-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 3-methylphenyl, 2-thienyl, 2-nitrophenyl, 3-nitrophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-bromophenyl, 2-fluorophenyl, 2-chloro-4-nitrophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4,5-trichiorophenyl methyl, iodopropargyl, t-butyl, phenyi, 4-nitrophenyl, 3-fluorophenyl, 1-naphthyl, 2-naphthyl, 3-phyridyl, 3-bromophenyl, 3-ethoxyphenyl, n-propyl, 2-chlorophenyl, cyclohexyl, and 2-furyl.
Suitable examples of R are methyl, ethyl, isopropyl, n-butyl, phenyl, 4-chlorophenyl, allyl, 2-propynyl, 2-furyl, 2-thienyl, 3-iodo-2-propynyl, 3-nitrophenyl, methoxyphenyl, and 4-methylphenyl. R can also be hydrogen; (C1-G1a) straight or branched alkyl; (C3-Ca) cycloalkyl; (C3-C6) alkenyl; (C3-C5) alkynyl; (C7-C~2) aralkyl; (C6-C12) aryl; (C6-C12) aryl ~'3 substituted with 1 to 3 substituents selected from the group consisting of halogen, (Cl-C4) alkyl, (C1-C4) alkoxy, nitro, cyano, carboxyl (C1-C4) alkoxycarbonyl, (C1-C4) alkyl thio, -S(O)nR2 where n is 1 or 2 and R2 is (C1-C~4) alkyl; and a halo-substituted, nitro-substituted, or unsubstituted moiety selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl.
The iodopropargyl compounds, i.e., those wherein X is 1, are preferred.
As stated above, compositions comprising a compound according to formula (I) and either an agronomically acceptable carrier, a cosmetic agent, a cutting oil, a soap or synthetic detergent, a stabilizer, a film forming material, or the like have a wide range of utility for protecting against or controllins microorganisms from a wide variety of classes includin~ fungus, bacteria, algae, viruses and yeasts. The preferred utilities of the compositions are to protect wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water from microorganisms.
The following lists specific industries and applications of the compounds or compositions:

2 ~ ~3 Industrv Appliça~
Adhesives, sealants adhesives caulks sealants Agriculturelfood chain adjuvant preservation agricultural active ingredient agricultural chemical preservative agricultural formulations preservation animal feed preservation dairy chemicals fertilizer preservation food preservation food processing chemicals grain preservation post-harvest produce protection sugar processing tobacco Construction products asphalt / concrete cement modifiers construction products roof mastics synthetic stucco wall mastics joint cement Cosmetics and toiletries cosmetics raw materials for cosmetics, toiletries toiletries Disinfectants, antiseptics antiseptic disinfectant ~ ~ '3 Emulsions, dispersions aqueous dispersion dispersed pigments latex photographic emulsions pigment slurries polymer latices Formulated household fabric softeners products polishes waxes hand dish detergents raw materials li~uid dete~ents hand soaps Industrial processing, misc electrodeposition paint, baths, rinses.
electrodeposition pre-treatment, post rinses industrial fluids preservation pasteurization baths process aid preservation Industrial water treatment air washers cooling towers cooling water water cooling preservation/treatment of wooden cooling tower slats and structural members can warmers brewery pasteurization closed loop water cooling systems Laundry household laundry products laundered goods laundry wash water sanitizers-laundry 2 ~

Leather, leather products leather and hide leather and hide products Lubricants, hydraulic aids automotive lubricants and fluids conveyor lubricants greases hydraulic flwids lubricants Medical devices diagnostic enzymes diagnostic kits medical devices Metalworking ~ related app's cutting fluids metal cleaning metalworking fluids dor control (active ingredient) air conditioning animal bedding cat litter chemical toilet prep'ns deodorizers humidifiers industrial deodorants sanitary formulations toilet bowls aints and coatingscoating emulsions paints Paper and wood pulp, absorbant materials of paper and wood their products pulp packaging materials of paper and wood pulp paper paper products paper treatment soap wrap 2 ~ 7 ~

wood puip wood pulp products Paper mill paper mill slimicides pulp and paper slurries Petroleum refining, fuels aviation fuels (jet fuel, aviation gas) crude oils burner, diesel and turbine fuel oils coal slurries diesel fuel additives diesel fuels fuels gasoline heating oils hydrocarbons kerosene liquefied petroleum gas petrochemical feedstocks petroleum products, storage, transportation and production recycled petroleum products residual fuel oils turbine oils Photographic chemicals photographic processing - wash water, and process rinses photoprocessing photoplate processing chemicals (deveiopers, stabilizers etc) Printing fountain solutions (printing) ink components (pigments, resins, solvents, etc) inks 2 ~ r~ 2 Sanitizers (active) sanitizers sanitizers-dairy sanitizers-dental sanitizers-fermentation sanitizers-food preparation sanitizers-food processing sanitizers-medical sanitizers-rendering sanitizers-veterinary Soaps, detergents, cleaners cleaners detergents household cleaners industrial cleaners liquid soaps oil and grease remover powdered soaps raw materials for cleaning products soaps surfactants Textiles, textile products bonded fabrics burlap canvas canvas goods carpet backing carpets . clothing coated fabrics curtains draperies engineering textiles fibers geotextiles ~oods made of textiles knitted fabrics nets nonwoven fabrics 2 ~ 7 2 rope rugs textile accessories textile products textiles upholstery woven fabrics yarn Textile processing dye fixatives dyes fiber lubricants hand modifiers sizes textile processing fluids Therapeutic (active or animal health/veterinary preservative) aquaculture dental human health pharmaceutical /therapeutic Water purification charcoal beds deionization resins filters membranes reverse osmosis membranes ultrafilters water purification water purification pipes, tubing Wood applications lazures (wood stains) wood wood products 2 ~ 7 ~

Miscellaneous alcohols bedding incorporating water or gels ceramic contact lens cases-leachlng electronic circuitry electronics chemicals enzymes-food production en2ymes enzymes-industrial gel cushions marine antifoulants mildewcides wood plastics laundry mining natural rubber latex oil field injection waters including enhanced recover injection fluids, drilling, fracturing and completion fluids pipes plastics polymer systems polymers and resins (synthetic and natural) reagent preservation rubber rubber products skin remover solid protective/decorative films stains swimming pools waste treatment water beds 2~6~7~
The amounts of the compound to be used depend on the application. The useful amounts for a particular applicalion are similar to amounts used for other microbiocide compounds.
The compound can be used in combination with other microbicides. The term "microbicide" is considered equivalent to "antimicrobial`' as used herein.
Compounds of formula I can be prepared by a variety of methods.
One suitable method comprises reacting a compound of the formula A~ ~\~
N S~-H

F~ ~IV) with an iodinating or brominating agent.
Suitable iodinating or brominating agents include, for example, iodine, bromine, an iodine-amino compound such as morpholine-iodine complex, morpholine-bromine complex, N-bromosuccinimide ("NBS") and N-iodosuccinimide ("Nl~,n), the latter being the most preferred.
When an iodine, bromine, or iodo amino compound is used, base should also be used, preferably sodiurn or potassium hydroxide, and solvent such as methanol, ethanol, and aqueous ethanol should also be used.

2 ~

When NIS or NBS is useci, a catalyst such as, for example, silver nitrate, or the like, should be used in presence of solvent such as acetone, methyl ethyl ketone, tetrahydrofuran, and the like.
Reaction times of about 20 minutes to about 24 hours have been utilized successfully with reaction temperatures of about 0C to about 2~oc.
Another suitable method to obtain sompounds of formula (1) is from compounds of Formula (Il) using a halopropargylating agent such as Formula (111) in the presence of a base such as potassium carbonate and a solvent such as acetone:

A~ + L~ N~S~X

(Il) (111) (1) The meanings of A, R, and X have been defined before. L is a leaving group such as bromine, chlorine, or 0-S02-R where R is methyl or phenyl or p-tolyl. Examples of Formula (111) include 3-iodopropargyl chloride, 3-iodopropargyl mesylate, and 3-iodopropargyi p-toluenesulfonate. The reagants of Formula (111) may be prepared by methods described in literature.

Suitable methods of application of compounds of formula (I) to control fungi, bacteria, algae, viruses, yeasts, and the like are in amounts and with carriers, etc., as well known in the art.
The following examples are presented to illustrate a few embodiments of the invention. All parts and percentages are by weight unless otherwise indicated.
.EXAMPL~S
Some representative compounds of the invention are the following:
Compound #

1. 3-(3-lodopropargyl)mercapto-4-phenyl-1,2,4-triazole 2. 3-(3-lodopropargyl)mercapto-4~t4-chlorophenyl)-1,2,4-triazole 3. 3-(3-lodopropargyl)mercapto-4-methyl-5-phenyl-1,2,4-triazole

4. 3-(3-lodopropargyl)mercapto-4-(2-chlorophenyl)1,2,4-triazole

5. 3-(3-lodopropargyl)mercapto-4-(4-methoxyphenyl)-1,2,4-triazole

6. 3-(3-lodopropargyl)mercapto-4-(4-methylphenyl)-1,2,4-triazole

7. 3-(3-lodopropargyl)mercapto-4-(3-chlorophenyl)-1,2,4-triazole

8. 3-(3-lodopropargyl)mercapto-4-(n-hexyl)-1,2,4-triazole

9. 3-(3-lodopropargyl)mercapto-4-(n-butyl)-1,2,4-triazole

10. 3-(3-lodopropargyl)mercapto-4-(4-chlorophenyl)-5-methyl-1,2,4- triazole

11. 3-(3-lodopropargyl)mercapto-4-phenyl-5-methyl-1,2,4-triazole

12. 3-(3-lodopropargyl)mercapto-4,5-diphenyl-1,2,4-triazole

13. 3-(3-lodopropargyl)mercapto-4-(n-heptyl)-1,2,4-triazole

14. 3-(3-lodopropargyl)mercapto-4-(n-octyl)-1,2,4-triazole

15. 3-(3-lodopropargyl)mercapto-4-cyclohexyl-1,2,4-triazole Table 1 shows the structures and the physical data of these representative compounds.

16 2 ~ 7 ~

Table 1 Physiçal Data Melting Point ~oC) or NMR Chemical Compound $~ A R Shift (ppm!
1. H ph 161 -163C
2. H 4-CI-ph 174-175C
3. ph Me 142-146C
4. H 2-CI-ph 65-70C
5. H 4-MeO-ph 125-136C
6. H 4-Me-ph 165-170C
7. H 3-CI-ph 170-173C
8. H n-C6H13 8.70 (1H, s) 4.07 (2H, s) 4.00 (2H, t) 1.70 (2H, m) 1.40-1.10 (6H, m) 0.86 (3H, t) 9. H n-C4Hg 8.24 (1 H, s) 4.08 (2H, s) 4.00 (2H, t) 1.80 (2H, tt) 1.50-1.10 (2H, m) 0.90 (3H, t) 10. Me 4-CI-ph 7.78-7.50 (4H, q) 4.04 (2H, s) 2.26 (3H, s) 11. Me ph 165-167C
12. ph ph 164C

13. H n-C7H15 8.24 (1H, s) 4.08 (2H, s) 4.00 (2H, t) 1.80 (2H, tt) 1.50-1.10 (8H, m~
o.go (3H, t) 14. H n-C8H17 8.22 (1H, s) 4.10 (2H, s) 4.00 (2H, t) 1.79 ~2H, tt) 1.50-1.10 (10H, m) o.go (3H, t) 15. H cyclohexyl 120-1 25C

Example 1 Preparation of 3-(3-iodopropargyl)mercapto-4-methyi-5-phenyl-1,2,4-triazole (Compound #3) (a) Preparation of 1-Bçnzoyl-4-methyl-thiosemicarbazide:
To the suspension of benzoic acid hydrazide (6.8 g, 0.05 mole) in tetrahydrofuran (75 mL) at room temperature with magnetic stirring was added a solution of methyl isothiocyanate (3.7g, 0.05 mole) in tetrahydrofuran (5 mL) from a dropping funnel. After addition, 3 drops of triethyl amine was added as catalyst. The reaction rnixture turned to a very thick paste after 5 min. The reaction mixture was stirred at room temperature for one hour. Hexane (100 ml) was added and the resultant white precipitate was collected by suction-filtration and washed with some hexane to give 7.0 g (yield: 66.6 %) of 2 ~ ,7 ~

1-benzoyl-4-methyl-thiosemicarbazide, mp= 197-200C. An NMR spectrum (in DMSO-d6) showed the desired compound.

(b) Preparation of 3-phenvl-4-methyl-1 2~4-triazolin-5-thione:
Sodium hydroxide (1.15 g, 28.7 mmol) was dissolved in water (50 mL).
To the above basic solution was added 1-benzoyl-4-methyl- thiosemicarbazide (6 g, 28.7 mmol). The resultant clear solution was gentiy refluxed on a heating mantle for 2 hours with magnetic stirring. The reaction mixture was cooled down to room temperature and was neutralized by conc. HCI to pH=~5. The white precipitate was collected by suction-filtration and was washed with water to give 4.1 9 (yield: 74.8 %) of triazolin-5-thione as white powders. mp= i66-168C. An NMR spectrum (in DMSO-d6) showed the desired compound.

(c) Preparation of 3-propar~vlme~capto-4-methyl-5-phenyl-1.2.4-triazole:
To the solution of 3-phenyl-4-methyl-1,2,4-triazolin-5-thione above (3.1 g, 16.23 mmol) in acetone (40 mL) at room temperature under nitrogen with magnetic stirring was added anhydrous potassium carbonate (2.76 9, 2û
mmol), followed by propargyl bromide (2.7 9 of 80 % toluene solution, 18 mmol). The reaction mixture was refluxed on a heating mantle for 16 hours.
The mixture was cooled down to room temperature and the $olid was filtered off by suction. The filtrate was concentrated on a rotary evaporator to a oily residue. The residue was further purified by a short column silica gel eluted 2 ~ 7 with ethyl acetate-hexane (1:1 to 3:1, total 800 ml) to give 2.8 g ~yield: 75.3 %) of 3-propargylmercapto-4-methyl-5-phenyi-1,2,4-triazole as yellow viscous oil.
An NMR spectrum (in DMSO-d6) showed the desired compound.

(d~ PreparatiQn of 3-(~-iodopropar~Ll)merca,~t~-4-melhvl-5-phen 1,2,4-triazole (Compound #3):
To the solution of 3-propargylmercapto-4-methyl-5-pheny!-1,2,4-triazole (2 g, 8.73 mmol) in dry acetone (20 mL) at room temperature with magnetic stirring was added silver nitrate (100 mg, 0.~8 mmol), followed by N-iodosuccinimide (2 g, 8.8 mmol). After stirring for one hour, the resultant cloudy mixture was diluted with some acetone and the solid was filtered off by suction. The filtrate was ooncentrated to a residue. Ethyl acetate (200 mL) was added and was washed with water (2 x 50 ml) and brine (3 x 50 ml~. The organic layer was dried over sodium sulfate. After filtering and concentrating a yellow residue was obtained. The residue was made a slurry with hexane and suction-filtered to give 1.9 g (yield: 61.5 %) of 3-(3-iodopropargy!)rnercapto-4-methyl-5-phenyl-1,2,4-triazole (Compound #3) as a yellow solid, mp = 142-146C. An NMR spectrum (in DMSO-d6) showed the desired structure.

2~3~6~2 Example 2 Preparation of 3-(-3-iodopropargyl)merc:apto-4-(n-octyl)-1,2,4-triazole (Compound #14):
(a) Preparation of 3-iodo,cropargvl mesvlate:
To the solution of 3-iodopropargyl alcohol (~ 9, 27.5 mmol) in methylene chloride (150 mL) at 0C under nitrogen was added triethylamine (2.8 9, 27.5 mmol). To the above solution was dropwise added methanesulfonyl chloride (3.2 g. 27.5 mmol) with magnetic stirring. The reaction mi~ture was stirred at Q
to 5C for 2 hrs. The reaction mixture was washed with 0.5 N HCI (50 mL), diluted sodium bicarbonate (50 mL), water (3x50 mL), and brine. The organic phase was dried over MgSO4 and filtered. The filtrate was concentrated on a rotary evaporator to afford 5.5 g (yield: 76.9 %) as a tan oil. An 1 H NMR
spectrum (CDCI3) was consistent with the desired compound. This compound was used for the following step without further purification.
(b) Preparation of 3-t3-iodopropargyl)mercapto-4-(n-octyl!-1.2.4-triazole (Compound #141:
To the solution of 4-n-octyl-1,2,4-triazolin-5-thion (2 g,.12.55 mmol) in dry acetone (mL) was added potassium carbonate (1.8 9,13.0 mmol), followed by 3-iodopropargyl mesylate (3.4 g, 13.18 mmol) at room temperature. The 2~tJ~7 reaction mixture was stirred at room for 20 hrs. The resultant solid was filtered off by suction-filtration and the filtrate was washed with water and brine. The organic phase was dried over MgSO4 and filtered. The filtrate was concentrated on a rotary evaporator to give a brown oil. The pure compound was obtained by column silica gel eluted with ethyl acetate affording 1.8 g (yield: 38 %) as a light brown oil. An NMR spectrum showed the desired compound. Elemental Analysis: Calcd for C13H201N3S: C = 41.4%, H=5.30%, S=8.30%, I=33.6%;
Found: C=42.03%, H=5.46%, S=8.56%, I=33.4%.
Example 3 Biocidal Evaiuations of Compounds A minimum inhibitory concentration (MIC) value is obtained using a broth, two-fold serial dilution test performed as follows: A stock solution or dispersion of the test compound, typically at a concentration of 1%, is made in a 5:3:2 solvent solution of acetone, methanol, and water. A volume of the stock solution is dispensed into culture media to give an initial starting test concentration of 250 ppm compound.
When the test is ready to be done, each vessel in the dilution series, except the first vessel, contains an equal volume of compound free broth. The first vessel contains twice the volume of broth with the starting concentration of test compound. One half of the broth from the first vessel is transferred to the s~

second vessel. AHer being mixed, one half the resulting volume is removed from the second vessel and transferred to the third vessel. The entire cycle is repeated sufficiently to give a series of concentrations amounting to 250, 125, 63, 31,16, 8, and 4, 2,1, 0.5, n.25 and 0.12 ppm.
Each vessel is then inoculated with a cell suspension of the appropriate test organism. Bacteria are grown in broth and fungi on agar slants for a lime and at a temperature appropriate to the species being tested. At the end of the growth period, the broth is vortexed to disperse the cells. In the case of fungi, the spores are harvested by pipetting water onto the slant and dislodging the spores with a sterile loop. The cell/spore suspension is standardized by controlling incubation time, temperature, and the volume of the diluent. The suspension is then used to inoculate the vessels containing the broth compound. The vessels are then incubated at the appropriate temperature.
After the incubation, the vessels are examined for growth/no growth. The minimum inhibitory concentration (MIC) is defined as the lowest concentration of compound that results in complete inhibition of growth of the test organism.
The organisms tested to demonstrate biocidal activity include:
BACTERIA:

Pseudomonas aerugenosa (Psae), gram negative Escherichia coli (Ecol), gram negative Staphvlococcus aureus (Saur), gram positive 2~6~7~

FUNGI:
Asperaill_s niaer (Anig) Aureobasidium pullulans (Apul) ALGAE:
Chlorella Dvroidenosa (Chlor) Table 2: Bioçidal Evaluation The Result of Minimum Inhibitorv Concentration (MIC! Tests MlC(ppm) Compound # Psae Ecol Saur Aniq Apul Chlor >250 >250 >250 8 4 <0.1 2 2 ,250 >250 2 2 1 ~250 3 250 >250 125 2 8 4 >250 >250 32 250 16 >250 >250 250 1 0.25 8 6 ,250 >250 250 125 63 >250 7 >250 >250 >250 63 8 8 >250 >250 32 <0.12 <0.12 32 9 >250 >250 63 1 1 4 1 0 >250 >250 125 1 6 1 25 1 25 11 >250 >250 32 1 0.25 8 1 2 >250 >250 32 125 2~0 250 1 3 >250 >250 <0.12 1 32 1 4 >250 >250 >250 <0.12 <0.12 1 5 1 25 >250 32 1 <0.12 2 ~

Example 4 Aqricultural Funaicide ~valuations of Compounds The compounds of this invention were tested for fungicidal activity in vivo against rice blast (RB), tomato late blight (TLB), wheat powdery mildew (WPM), botrytis on tomato (BOT), cucumber anthracnose (CA), rice helminthosporium (RH), wheat glume blotch (SNW) and wheat leaf rust (WLR) and the results are shown in Table 3. In tests on cereals (except for rice plants used for testing rice blast), the plants were trimmed about 24 hours prior to the application of the fungicide compound to provide a uniform plant height and to facilitate uniform application of the compound and inoculation with the fungus. The compounds were dissolved in a 2:1:1 mixture of water, acetone, and methanol, sprayed onto the plants, allowed to dry (four to six hours), and then the plants were inoculated with the fungus. Each test utilized control plants which were sprayed with the water, acetone, and methanol mixture and inoculated with the fungus. The remainder of the technique of each of the tests is given below and the results are reported as percent disease control (percentages of plants treated with the compounds of the present invention lacking disease signs or symptoms compared to the untreated control plants).

2 ~

Rice~last (F~BI:
Nato rice plants were inoculated with Piricularia oryzae (about 20,000 conidia per ml) by spraying the leaves and stems with an airbnush until a uniform film of inoculum was observed on the leaves. The inoculated plants were incubated in a humid environment (7~F to 85F) for about 24 hours, then placed in a greenhouse environment (70F to 75F). Seven to eight days after inoculation, the percent disease control was determined.
Io~L~):
Phvtophthora infestans was cultured on four week old Pixie tomato plants in a controlled environment room (65F to 70F and 100%
relative humidity). After storage, the spores were washed from the leaves with water and dispersed by DeVilbiss atomizer over three week old Pixie tomato piants which had been sprayed previously with experimental fungicides. The inoculated plants were placed in a humidity ca~inet at 70F and constant mist for 24 hours for infection. The plants were then moved to the controlled environment room as above and scored after three more days incubation. Disease control levels were recorded as percent control four days after inoculation and five days after spraying the compounds.

2~6~72 Wheat PQwdery Mildew (WPM):
Ervsiphe araminis (f. sp. tritici) was cultured on Pennol wheat seedlings in a controlled temperature room at 65F to 75F. Mildew spores were shaken from the culture plants onto Pennol wheat seedlings which had been sprayed previously with the fungicide compound. The inoculated seedlings were kept in a controlled temperature room at 65F
to 75F and subirrigated. The percent disease control was rated 8 to 10 days after the inoculation.
heat Leaf Rust (WLR.~:
Puccinia recondita (f. sp. tritici Races PKB and PLD) was cultured on seven day old wheat (cultivar Fielder) over a 14 day period in the greenhouse. Spores were collected from the leaves with a cyclone vacuum or by settling on aluminum foil. The spores were cleaned by sieving through a 250 micron opening screen and stored or used fresh.
Storage employed sealed bags in an Ultralow freezer. When stored, spores must be heat shocked for two minutes at 40F before use. A
spore suspension is prepared from dry uredia by adding 20 mg (9.~
million) per ml of Soltrol oil. The suspension is dispensed into gelatin capsules (0.7 ml capacity) which attach to the oil atomizers. One capsule is used per flat of twenty of the two inch square pots of seven day old Fielder wheat. After waiting for at least 15 minutes for the oil to evaporate from the wheat leaves, the plants are placed in a dark mist chamber (1 8-20C and 100% relative humidity) for 24 hours. The plants are then put in the greenhouse for the latent period and scored after 10 days for disease levels. Protective and curative tests were inoculated one day after and two days, respectively, before spraying the plants with the test chemicals.
Botrytis on TomatQ (BOT):
Strains of ~3~trYtis ci~çrea to be used were inoculated singly onto tomato plants to verify virulence. In tests, spore suspensions from at least two strains were prepared and mixed in equal volume amounts. All cultures were maintained on PDA (potato dextrose agar) and incubated in closed plastic boxes at room temperature and room light for 2-3 weeks before use in tests.
The inoculum was prepared as follows: dextrose solution (1.9 g/100 ml) in tap water was prepared and poured over each culture plate of sporulating fungus. Plates were rubbed with a rubber policeman and the solution filtered through 2 layers of cheesecloth. A spore suspension of 5 - 6.5 x 105 spores/ml is desired. "Pixie" tomato plants, 3-4 weeks old and about 8-10 cm tall were placed in indirect headhouse lighting tor at ~6~72 least two days before use (inoculation). The plants were inoculated usin~ a DeVilbiss atomizer, by spraying the upper and lower leaf surfaces and the stem of the plants until near run-off. The plants were stored on a mist bench at 70F., 100% humidity in indirect room light and scored for results in 5-7 days.
Cucumber AnthraGnose ((::A):
Colletotrichum las~enarium was cultured on potato dextrose agar (PDA) in petri plates for 14 days under dark conditions. Plates were inoculated by spreading inoculum over medium with an inoculating needle. Spores were then harvested from plates by adding deionized water to the PDA plates. The agar surface was scraped with a rubber policeman and the spore suspension filtered through cheesecloth to remove mycelial and agar fragments, followed by adjustment to a concentration of 1-2 x 105 spores per ml.
Cucumber plants (var "Marketer" 14 day old seedlings) were inoculated by sprayin~ the leaves (especially the underside) until a uniform film of inoculum was observed on the plant. Inoculated plants were then incubated in a humid environment at 70-75F for 24 hours and then removed, allowed to dry and placed under greenhouse conditions.
Treatment comparisons were made 10-14 days after inoculation.

2~g~

F~Lçe Helminthocporium (RH):
Growth of the fungus was conducted on PDA under artificial light.
Spores grown for 3 weeks to 3 months were used. The plates were flooded with Dl water and scraped with a spatula and the washings filtered through a layer of cheesecloth.
Inoculation was done with a DeVilbis air inoculator by applying 100,000 to 500,000 spores per flat of 20 plants. The plants were incubated in a humidity cabinet for 24 hours at 25C and then placed in greenhouse conditions and scored after 6 days.
Wheat Glume Blotch (~NW):
Portions of inoculum from a 2 or 3 week old colony of Septoria ~Q~Qa~ (ascomycete stage, Leptosphaeria nodorum), were incubated on Czapek-Dox V-8 agar plates for 48-72 hours in the dark at 20C with alternating light and dark (12h/12h).
The spore solution for inoculation was prepared by adding deionized water (one hundred mls per 10-15 plates) to a one-half gallon jar and then transferring the fungal material from 10-20 culture plates to the jar. The jar was shaken vigorously for 15-30 seconds and allowed to stand for 5-10 minutes. The spore concentration was then filtered through cheesecloth and diluted to the appropriate concentration (approximately 3.0 x 106 spores per ml). Thi~ty to forty plates produced about 1 liter of diluted inoculum. One week old Fielder (untreated seed) wheat plants were used for disease evaluations. About 22 ml of inoculum was applied to the wheat plants (i,n a flat of 20 pots) using a DeVilbiss atomizen The flats were air-dried for 10-15 minutes and then stored at 20C, 1 2hr/12 hr lighVdark at 100% humidity in a humidity cabinet. The plants were incubated for 96 hours and then transferred to an envirornmental cabinet for disease development for 8 days before being scored for results.
Table ~
Green Hous~ Test Results of Plant dise~ses Control Compound E~Q E~2I Ç~ ~ RH SNW IL@ ~J~ YE~

6 200 75 50 0 90 0 0 o 0 200 90 80 0 95 50 0 50. 0 12 200 75 75 50 95 0 0 . 0 0 200 90 90 80 95 50 0 ~0 0 20~6672 While the invention has been described with reference to specific examples and applications, other modifications and uses for the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention defined in the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula (I) wherein A is selected from the group consisting of hydrogen, alkyl, aryl, and heterocyclic;
R is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heterocyclic; and X is selected from the group consisting of halogen.

2. Compound according to claim 1 wherein A is selected from the group consisting of hydrogen; (C1-C18) straight or branched alkyl; (C3-C8) cycloalkyl;
(C3-C6) alkenyl; (C3-C5) alkynyl; (C7-C12) aralkyl; (C6-C12) aryl; (C6-C12) aryl substituted with 1 to 3 substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, nitro, cyano, carboxyl (C1-C4) alkoxycarbonyl, (C1-C4) alkyl thio, -S(O)nR2 where n is 1 or 2 and R2 is (C1-C4) alkyl; and a halo-substituted, nitro-substituted, or un-substituted moiety selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.

3. Compound according to claim 1 wherein A is selected from the group consisting of hydrogen, 4-chlorophenyl, 3-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 3-methylphenyl, 2-thienyl, 2-nitrophenyl, 3-nitrophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-bromophenyl, 2-fluorophenyl, 2-chloro-4-nitrophenyl, 2,4-diclorophenyl, 3,4-dichlorophenyl, 2,4,5-trichlorophenyl methyl, iodopropargyl, t-butyl, phenyl, 4-nitrophenyl, 3-fluorophenyl, 1-naphthyl, 2-naphthyl, 3-phyridyl, 3-bromophenyl, 3-ethoxyphenyl, n-propyl, 2-chlorophenyl, cyclohexyl, and 2-furyl.

4. Compound according to claim 1 wherein X is 1.

5. Compound according to claim 1 wherein R is selected from the group consisting of methyl, ethyl, isopropyl, n-butyl, phenyl, 4-chlorophenyl, allyl, 2-propynyl, 2-furyl, 2-thienyl, 3-iodo-2-propynyl, 3-nitrophenyl, 3-methoxyphenyl, and 4-methylphenyl.

6. Compound according to claim 1 wherein R is selected from the group consisting of hydrogen; (C1-C18) straight or branched alkyl; (C3-C8) cycloalkyl;
(C3-C6) alkenyl; (C3-C5) alkynyl; (C7-C12) aralkyl; (C6-C12) aryl; (C6-C12) aryl substituted with 1 to 3 substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, nitro, cyano, carboxyl (C1-C4) alkoxycarbonyl, (C1-C4) alkyl thio, -S(O)nR2 where n is 1 or 2 and R2 is (C1-C4) alkyl; and a halo-substituted, nitro-substituted, or unsubstituted moiety selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl.

7. Composition comprising a compound according to claim 1 and an agronomically acceptable carrier.

8. Composition comprising a compound according to claim 1 and a cosmetic agent.

9. Composition comprising a compound according to claim 1 and a cutting oil.

10. Composition comprising a compound according to claim 1 and a soap or synthetic detergent.

11. Composition comprising a compound according to claim 1 and a stabilizer.

12. Composition comprising a compound according to claim 1 and a film-forming material.

13. Method of preparing a compound according to claim 1 comprising reacting compound of the formula (IV) with an iodinating or brominating agent.

14. Process comprising using a compound of claim 1 to control microorganisms.

15. Process comprising using a compound according to claim 1 to control fungi.

16. Process comprising using a compound according to claim 1 to control bacteria.

17. Process comprising using a compound according to claim 1 to control algae, viruses or yeasts.

18. Process comprising using a composition comprising a compound according to claim 1 to protect a material selected from the group consisting of wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water from microorganisms.