CA2049475A1 - Substituted 3-thioacryloyl coumpounds and their use as antimicrobial agents - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Use as microbicides of thioacryloyl compounds of the formula I

wherein Z is selected from the group consisting of OR, R and NR1 R2;
R is selected from the group consisting of hydrogen;
(C1-C18)alkyl; (C1-C8)alkenyl; (C1-C8)haloalkynyl;
2-(5-chlorothienyl)methyl; phenyl optionally substituted with one or more substituents selected from the group consisting of halo-, (C1-C3)alkoxy; nitro; and (C1-C3)alkyl; phenacyl optionally substituted with one or more substituents selected from the group consisting of ring halo-, (C1-C3)alkoxy-, nitro-, and (C1-C3)alkyl; arylalkyl optionally substituted with one or more substituents selected from the group consisting of ring halo-, (C1-C3)alkoxy-, nitro-, and (C1-C3)alkyl;
R1 and R2 are independently selected from (C1-C8)alkyl and phenyl, or R1 and R2 may be joined together with the nitrogen atom to which they are attached to form a ring containing 4 to 5 carbon atoms with or without an oxygen heteroatom;

X is selected from the group consisting of hydrogen, halogen, phenyl, CO2CH3, and (C1-C3)alkyl; and Y is selected from the group consisting of CN, CH(COCH3)2, CH2COCH3, CH2CN, CH2Co2C2H5, propargyl, SCH=CHCO2CH3, C(=NH)NH2 hydrochloride, 2-(5-chlorothienyl)methyl and a saturated or unsaturated heterocyclic 5- or 6-membered ring with 1 to 4 heteroatoms selected from the group consisting of S, O, or N, said ring being unsubstituted or substituted wtih substituents independently selected from the group consisting of unsubstituted or halosubstituted alkyl of 1 to 8 carbon atoms, unsubstituted or halosubstituted alkenyl or alkynyl of 2 to 8 carbon atoms, nitro, cyano, halo, (C1-C8)alkoxy, amino, alkylamino, dialkylamino, and benzyl; or optionally fused to a benzene ring which is optionally substituted with substituents independently selected from the group consisting of unsubstituted or halosubstituted alkyl of 1 to 8 carbon atoms, unsubstituted or halosubstituted alkenyl or alkynyl of 2 to 8 carbon atoms, nitro, cyano, halo, (C1-C8)alkoxy, amino, alkylamino, and dialkylamino; or said nitrogens in the nitrogen-containing heterocycles possibly being N-oxides;

provided that when Z is NR1R2, Y is CN; and provided that when Z is R, X is hydrogen, and Y is CN, R is not phenyl.
Compounds and compositions are also disclosed.

Description

PATENT APPLICATION
OF

Peter Osei-Gyimah, Samuel E. Sherba, Raj J. Mehta, Barry C. Lange, and Rhoda W. Joseph FOR

COMPOUNDS AND THEIR USE AS ANTIMICROBIAL AGENTS
DN89-09lA MBF:meb BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to the field of antimicrobial agents.

2. Description of the Prior Art Certain classes of thioacrylates and thioacrylamides have been prepared as antimicrobials but no compound within those classes has achieved commercial success.
US Patents 4,115,103; 4,123,254; 4,169,850; and 4,198,304 to Kao Soap ~o., disclose alkyl substituted beta-thioacrylamides and beta-thioacrylic acids (and salts thereof) and the corresponding alkyl sulfone and alkyl sulfoxide derivatives as germicidal herbicides, antibiotics, and as antimicrobial agents in non-food or medicinal compositions.
German patent DE 2536252 to Bayer AG discloses beta-thiocyanovinyl aryl ketones as antimicrobial agents. Thioalkyl-and thiocyano-alkyl- alpha-substituted acrylic acids (and esters thereof) are disclosed as plant growth regulators in Japanese Kokai J 50-036622 to Mitsubishi Chemical. German unexaminecl patent application 2821639 to Hoechst AG discloses S-substitutedalkyl-beta-thioacryloyl compounds as fungicides and bactericides.
Methyl 3-thiocyanoacrylate and dimethyl alpha-thiocyanofumarate are known compounds (Tetrahedron, 41(4), 801 (1985)), but have not been disclosed as antimicrobial compounds.
Cis-3-thiocyanoaaylic acid is a known compound (Tustus Liebigs Annalen der Chemie, ~, 1249 (1977)) but has not been disclosed as an antimicrobial compound. Beta-carbomethoxyvinylisothiurium chloride is a known compound (J. Amer. Chem. Soc., 101(21), 6306 (197g)) but has not been disclosed as an antimiaobial compound.
Methyl 3-thio(propan-2-on-1-yl)acrylate is a known compound (Berichte, 97(8), 2109-17 (1964)) but has not been disclosed as an ~f ~9~ ~
antimicrobial compound. N,N-Dimethyl-3-thiocyanoacrylamide is a known compound (T. Org. Chem. 30, 2660-2665 (1965)) but has not been disclosed as an antimicrobial compound.
Summary of the Invention Many of the antimicrobials of the prior art have toxicity and/or environmental problems.
It is an object of the present invention to provide novel antimicrobial compounds which have improved toxicity profiies and are not harmful to the environment.
These objects, and others which will become apparent from the following disclosure, are achieved by the present invention which comprises the use as a microbicide of an effective amount of a thioacryloyl compound of the formula X

Y-S-C=CH-C-Z

wherein Z is selectecl from the group consisting of OR, R and NRIR2;

R is selected from the group consisting of hydrogen;
(Cl-Clg)alkyl; (Cl-Cg)alkenyl; (Cl-Cg)haloalkynyl;

2 ~J '1" ~
2-(5-c~lorothienyl)methyl; phenyl optionally substituted with one or more substituents selected from the group consisting of halo-, (Cl-C3)alkoxy-, nitro-, and (Cl-C3)alkyl; phenacyl optionally substituted with one or more substituents selected from the group consisting of ring halo-, (Cl-C3)alkoxy-, nitro-, and (Cl-C3)alkyl; arylalkyl optionally substituted with one or more substituents selected from the group consisting of ring halo-, (Cl-C3)alkoxy-, nitro-, and (Cl-C3)alkyl;
Rl and R2 are independently selected from (Cl-C8)alkyl and phenyl, or Rl and R2 may be joined together with the nitrogen atom to which they are attached to form a ring containing 4 to 5 carbon atoms with or without an oxygen heteroatom;
X is selected from the group consisting of hydrogen, halogen, phenyl, CO2CH3, and (Cl-C3)alkyl; and Y is selected from the group consisting of CN, CH(COCH3)2, CH2COCH3, CH2CN, CH2CO2C2H~i, propargyl, SC'H=CHCO2CH3, C(=NH)NH2 hydrochloride, 2-(5-chlorothienyl)methyl, and a saturated or unsaturated heterocyclic 5- or 6-membered ring with 1 to 4 heteroatoms selected from the group consisting of S, O, or N, said ring being unsubstituted or substituted wtih substituents independently ~J ~ A ~

selected from the group consisting of unsubstituted or halosubstituted alkyl of 1 to 8 carbon atoms, unsubstituted or halosubstituted alkenyl or alkynyl of 2 to 8 carbon atoms, nitro, cyano, halo, (C1-C8)alkoxy, amino, alkylamino, dialkylamino, and benzyl; or optionally fused to a benzene ring which is optionally substituted with substituents independently selected from the group consisting of unsubstituted or halosubstituted alkyl of 1 to 8 carbon atoms, unsubstituted or halosubstituted alkenyl or alkynyl of 2 to 8 carbon atoms, nitro, cyano, halo, (C1-C8)alkoxy, amino, alkylamino, and dialkylamino; or said nitrogens in the nitrogen-containing heterocycles possibly being N-oxides;
provided that when Z is NRI R2, Y is CN; and provided that when Z is R, X is hydrogen, and Y is CN, R is not phenyl.
A preferred aspect of the invention comprises the use of methyl cis-3-thiocyanoacrylate, iodopropargyl cis-3-thiocyanoacrylate, methyl trans-3-thiocyanoacrylate, and cis-4-thiocyano-3-buten-2-one at concentrations from about 5 to about 300 ppm in compositions for ~?.,~ J~

controlling microorganisms in cooling tower water and paper rn~ll systems.
Detailed Description of the Invention and the Preferred Embodiments The compounds of the invention have been discovered to be unexpectedly effective antimicrobials.
Sorne representative compounds include the following:
1. Methyl cls-3-thiocyanoacrylate 2. Cis-3-thiocyanoacrylic acid 3. Ethyl cis-3-thiocyanoacrylate 4. n-Butyl cis-3-thiocyanoacrylate 5. Phenyl cis-3-thiocyanoacrylate 6. Iodopropargyl cis-3-thiocyanoacrylate 7. Dimethyl alpha-thiocyanofumarate 8. 2,5-Dinitrobenzyl cis-3-thiocyanoacrylate 9. 5-Chloro-thien-2-yl-methyl cis-3-thiocyanoacrylate 10. Benzyl cis-3-thiocyanoacrylate 11. 4-Chlorobenzyl cis-3-thiocyanoacrylate 12. p-Chloroacetophenyl cis-3-thiocyanoacrylate 13. 3-Methoxybenzyl cis-3-thiocyanoacrylate 14. 2,~Dichlorobenzyl cis-3-thiocyanoacrylate 15. Cis-beta-carbomethoxyvinylisothiouronium chloride 16. Methyl cis-3-thio(l-acetylpropan-2-on-1-yl)acrylate 17. Methyl cis-3-thio(propan-2-on-l-yl)acrylate 18. Bis-cis-(carbomethoxyvinyl)disulfide 19. Methyl trans-3-thiocyanoacrylate 20. Methyl cis-3-propargylthioacrylate 21. Methyl cis-3-(5-chlorothien-2-yl-methyl)acrylate 22. Methyl 3-bromo-3-thiocyanoacrylate 23. N,N-Dimethyl cis-3-thiocyanoacrylamide 24. N-(_~-3-thiocyanoacryloyl)piperidine 25. N-(cis-3-thiocyanoacryloyl)morpholine 2 i~

26. N-Methyl-N-n-butyl cis-3-thiocyanoacrylamide 27. N-Methyl-N-phenyl cis-3-thiocyanoacrylamide 28. Cis-4-thiocyano-3-buten-2-one 29. Methyl c -3-(cyanomethylthio)acrylate 30. Methyl cis-3-(ethylcarboxymethylthio)acrylate 31. Cis-5-thiocyano-4-penten-3-one 32. Cis-8-thiocyano-7-octen-6-one 33. 4-Phenyl-4-thiocyano-3-buten-2-one 34. 4-(2-Mercaptobenzothiazolyl)-3-buten-2-one 35. Cis-4-(5-mercapto-1-methyltetrazolyl)-3-buten-2-one 36. Cis-4-(2-mercaptothiazolinyl)-3-buten-2-one 37. Trans-4-(2-mercaptothiazolinyl)-3-buten-2-one 38. Cis-4-(2-mercaptopyridinyl)-3-buten-2-one 39. Trans-4-(2-mercaptopyridinyl)-3-buten-2-one 40. Cis-4-(2-mercaptopyridinyl-N-oxide)-3-buten-2-one 41. Cis-4-(2-mercaptothiazolyl)-3-buten-2-one 42. Trans-4-(2-mercaptothiazolyl)-3-buten-2-one 43. 1-Mercaptoimidazolyl-3-buten-2-one 44. C~s-4-(2-mercapto-1-methylimidazolyl)-3-buten-2-one 45. 4-(2-Mercapto-l-methylimidazolyl)-3-buten-2-one 2 ~ 7 Table 1 Structures and Physical Data of Representative Compounds of Formula I, Z = OR
Comp. R X Y Melting or No. Boiling Point 3 CH2CH3 H CN 72C/0.5mm 4 CH2CH2CH2CH3 H CN 85C/0.3mm Ph H CN 79-83C
6 CH2CJC-I H CN 141-143.2C

8 CH2Ph(2,5-di-NO2) H CN 138-140C
9 CH2(5-Cl-Thien-2-yl) H CN 57-59.5C
lQ CH2Ph H CN 48.5-50.5C
11 CH2Ph(4-Cl) H CN 69-70C
12 CH2COPh(4-Cl) H CN 127-129C
13 CHzPh(3-OCH3) H CN 64 66C
14 CH2Ph (2,5-di-Cl) H CN 135-138C
CH3 H C(=NH)NH2 166-167C
(hydrochloride salt) 16 CH3 H CH(COCH3)2 61-64C

18 CH3 H ~CH=CH-COOCH3 133-136C
19 CH3 H CN 70C/0.3mrn CH3 H CH2C¦C-H 85C/0.25mm 21 CH3 H 5-Cl-Thiophene-2-methylene 49.5-52C
22 CH3 Br CN 139-142.5C

~H3 H CH2CO2C2Hs Oil Table 2 Structures and Physical Data of Representative Compounds of Formula I, Z = NRl R2, X = H, Y = CN
Comp. R1 R~ Melting Point No.

~H2CH2OCH2CH2- 89-91.5 26 CH3 n-Bu Oil 27 CH3 Ph 60-62 Table 2A
Structure and Physical Data of Representative Compounds of Formula I, Z = R, Y = CN
Comp. _ _ Melting Point No. (~C) 31 CH2CH3 H Oil 32 CH2CH2CH2CH2CH3 H Oil 33 CH3 Ph Oil Table 2B
Structure and Physical Data of Representative Compolmds of Formula I, Z = CH3, X = H
Comp. Melting Point No. y (C) N~,~, 34 ~<s~ 85-88.5 N--N
,`N

N

36(cis)~s~ 69-72 N~
37(trans) ~s~ Oil 38(cis) ~3 57-58.5 39(trans) ~3 Oil O 139-143.5 2 ~ r~

41(cis) ~3 43 5~5 5 N

42(trans) ~ Oil N;~3~

43(cis and trans) H 117-120 N;~9 44(cis) CH3 Oil N~9 45(cis and trans~ CH3 Oil The compounds of Formula I, where Z = OR; R = alkyl, phenyl and substituted phenyl, arylalkyl and substi~uted arylalkyl; X = H; and Y = CN, can be prepared by the esterification of cis-3-thiocyanoacrylic acid, Compound 2, as follows:

NC-S-CH=CH=COOH Esterification NC-S-CH=CH-COO-R
Compound 2 R = alkyl, phenyl, arylalkyl, substituted phenyl or aryl alkyl, haloalkynyl Various esterification methods known in the literature may be used to prepare the compounds. Two useful procedures are described here. A suspension of compound 2 in anhydrous solvents such as acetonitrile, dioxane or toluene is treated with 1,8-diazabicyclo-(5.4.0)undec-7-ene, (DBU), at temperatures ranging from 0-25C. The resulting solution is allowed to react with commercially available alkyl, arylalkyl, and substituted arylalkyl halides (Aldrich Chemical Company) at temperatures ranging from 0-25C. The reaction generally takes place within 1 - 24 hours.
Alternatively, compound 2 may be converted to the mixed anhydride and then treated with alcohols or phenols to give the esters. Thus, compound 2 may be suspended in dry solvents such as toluene, acetonitrile, or dioxane and treated with triethylamine at temperatures ranging from 0-25C. The resulting solution is treated with ethyl S ;~ .q h ~ ` i cl chloroformate or methane sulfonyl chloride at 0-25C. The resulting mixed anhydride is allowed to react with commercially available alcohols or phenols at temperatures ranging from 0-25C. The reaction usually takes place within 1 to 24 hours.
Iodopropargyl alcohol is prepared by a published procedure (Bulletin of the Chemical Societv of Tapan), Ando, T.; Shioi, S.;
Nakagawa, M., (1972), 45, 2611).
Cis-3-thiocyanoacrylic acid, compound 2, which serves as the starting material for esterification into many of the compounds of Structure I is known in the literature (G. Simchen and G. Entenmann, Tustus Liebigs Annalen der Chemie, No. 8,1249 (1977). The compound is prepared by treating commercial propiolic acid with sodium or ammonium thiocyanate in aqueous sulfuric acid solution at 0C and then allowing the mixture to warm to room temperature to precipitate the compound.
The chemistry of the thiocyano group and its addition to triple bonds are discussed in the text: "The Chemistry of Cyanates and their Thio Derivatives", parts 1 and 2, (Ed. S. Patai), Wiley and Sons, (1977).

r~

Methyl cis-3-thiocyanoacrylate, compound 1, is cited in the following literature:
1. M. Giffard, J. Cousseau and L. Gouin, Tetrahedron, 41(4), 801 (1985).
2. G. F. Dvorko, N.M. Soboleva, and T. F. Karpenko, Dokl Acad.
~ ,184(4), 850 (1969); (CA70:96122k).
The compound is readily prepared by treating commercial methyl propiolate with ammonium thiocyanate in aqueous sulfuric acid solution at 0C and then allowing the mixture to warrn up to room temperature to precipitate the compound.
A useful procedure for preparing the ~substituted compounds of Formula I, Z=OCH3, X = H, and Y = CH(COCH3)2, CH2CN, CH2CO2C~H5, CH2COCH3, alkynyl, and arylalkyl (Compounds 16, 17, 20, 21, 29 and 30) starts with cis-beta-carbomethoxyvinylisothiouronium chloride, Compound 15, which is prepared and hydrolyzed to the mercaptide according to literature procedure: H.R. Pfaendler, J. Costell, and R. B. Woodward, Tournal of the American Chemical Society, 101(2~), 6306(1979). The mercaptide, which is not isolated, is treated with commercially available halides of Y at temperatures ranging from 2 ~ ~ 9 !~ 7 ~
-10 to 25C in aqueous ethanol solution as shown below. The reaction usually takes place within 1- 24 hours.
H2N+ C1 1N Sodium O
Hydroxide .
~-S-CH=CH-C-OCH3 -- ~ Na+ S-CH=CH-C-OCH3 Ethanol .

Compound 15 Y-M ll ~ Y-S-CH=CH-C-OCH3 Ethanol Y= substituted alkyl, alkynyl, arylalkyl M= halide (Compound 16, 17, 20, 21, 29 and 30) Methyl trans-3-thiocyanoacrylate, compound 19, is prepared from commercially available trans-3-chloroacrylic acid (Aldrich Chemical Company) as follows: An aqueous hydrochloric or sulfuric acid solution of ammonium thiocyanate is treated with trans-3-chloroacrylic acid methanol at temperatures ranging from 25-50C. The mixture is then heated to reflux for a period of 1 to 24 hours. The mixture is extracted with chloroform which is washed with aqueous sodium bicarbonate solution. Compound 19 is obtained upon evaporation of the solvent.

Methyl 3-bromo-3-thiocyanoacrylate, compound 22, is prepared by allowing methyl bromopropiolate to react with ammonium thiocyanate in sulfuric acid solution at temperatures ranging from 25C. The reaction takes place in 1 to 5 hours. The starting material, methyl bromopropiolate, can be prepared according to a published procedure: W. Chodkiewicz, Ann. Chim. (Paris), 2(13), 819 (1957).
Cis-beta-thiocyanovinyl ketones, e.g., compounds 28, 31, 32 and 33, are prepared by allowing acetylenic ketones to react with ammonium thiocyanate in sulfuric acid solution at temperatures ranging from 0-25C. The reaction takes place in 1 to 2 hours.
Cis-4-(5-mercapto-1-methyl tetrazolyl)-3-buten-2-one, compound 35, is prepared by allowing 5-mercapto-1-methyl tetrazole sodium salt hydrate to react with cis-4-thiocyano-3-buten-2-one (compound 28, prepared as above) in aqueous ethanol at 25C. The reaction takes place in 18 hours.
Cis- and trans-4-(2-mercatothiazolinyl)-3-buten-2-one, compounds 36 and 37, are prepared by allowing 2-mercaptothiazoline to react with 3-butyn-2-one in aqueous ethanol at temperatures raI~ging from reflux to 25~C. The reaction takes place in 20 hours.

7 ^ ~

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 controlling microorganisms from a wide variety of classes including fungus, bacteria, algae, viruses and yeasts. The preferred utilities of the compositions are to protect wood, paint, adhesive, glue, paper, pulp/paper slurries, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water from microorganisms.
Especially preferred compounds are methyl cis-3-thiocyanoaaylate, iodopropargyl cis-3-thiocyanoacrylate, methyl trans-3-thiocyanoacrylate, and cis-4-thiocyano-3-buten-2-one. Preferred concentrations are about 5 to about 300 ppm based on weight of material being protected. Preferred applications for controlling microorganisms are in industrial cooling water and paper mill systems.
For example, especially preferred is using the compounds about at about 5-125 ppm in cooling tower water systems and at 15-250 ppm in pulp and paper slurries.

The following lists specific industries and applications of the compounds and compositions.
Industry Application Adhesives, sealants adhesives caulks sealants Agriculture/food chain adjuvant preservation agricultural active ingredient agricultural chemical preservative agricultural formulations preservation animal feed preservation dairy chemicals fertilîzer 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 Emulsions, dispersions aqueous dispersions dispersed pigments latex photographic emulsions pigment slurries polymer latices Formulated consumer ~ industrial air fresheners products fabric softeners hand cleaners polishes, floor, furniture, shoe sponges & towelettes spray strach waxes Industrial processing, misc dry cleaning fluids preservation 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 Laundry household laundry products laundered goods laundry rinse water pre-washers sanitizers-laundry removers, spot & stain Leather, leather products leather and hide leather and hide products Lubricants, hydraulic aids automotive lubricants and fluids conveyor lubricants greases hydraulic fluids hydraulic oils lubricants Medical devices diagnostic enzymes diagnostic kits medical devices Metalworking & related app's cutting fluids metal cleaning metalworking fluids Odor control (active ingredient) air conditioning animal bedding cat litter chemical toilet prep'ns deodorizers humidifiers industrial deodorants sanitary formulations toilet bowls Paints and coatings coating emulsions paints Paper and wood pulp, their products absorbant materials of paper and 2 !~
wood pulp packaging materials of paper and wood pulp paper paper products paper treatment soap wrap wood pulp wood pulp products Paper mill paper mill slimicides pulp and paper slurries ri ~J

Petroleum refining, fuels aviation fuels (jet fuel, aviation gas) 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 and process photographic processing - wash water, rinses photoplate processing chemicals (developers, stabilizers etc) Printing fountain solutions (printing) ink components (pigments, resins, solvents, etc) inks Sanitizers (active) sanitiæers sanitizers-dairy sanitizers-dental sanitizers-fermentation sanitizers-food preparation sanitizers-food processing sanitizers-medical ,~ J ~ 5 sanitizers-rendering sanitizers-veterinary Soaps, detergents, cleaners cleaners detergents, hand automatic laundry, other household cleaners industrial cleaners liquid soaps, hand, dish, laundry 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 goods made of textiles knitted fabrics nets nonwoven fabrics rope rugs textile accessories textile products textiles upholstery woven fabrics yarn Textile processing dye fixatives dyes fiber lubricants hand modifiers siæes textile processing fluids Therapeutic (active or preservative) animal health/veterinary 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 Miscellaneous alcohols bedding incorporating water or gels ceramic contact lens cases-leaching ~19 ~ ~
electronic circuitry electronics chemicals enzymes-food production enzymes-industrial gel cushions laboratory reagents marine antifoulants mildewcides mining applications natural rubber latex oil field applications pipes plastics polymer systems polymers and resins (synthetic and natural) reagent preservation rubber rubber products skin remover solid protective/decorative films swimming pools waste treatment water beds The amoun~s of the compound to be used depend on the application. The useful amounts for a particular application are similar to amounts used for other microbicidal compounds.
The compound can be used in combination with other microbicides. The term "microbicide" is considered equivalent to "antimicrobial" as used herein.

2 ~

Suitable methods of application of compounds of formula I to control fungi, bacteria, algae, viruses, yeasts, and the like are in amounts and with carr~ers, etc., as are well known in the art~
The following examples are presented to illustrate a few embodiments of the in~ention, but are not to be considered as limiting.
Example 1 Phenyl cis-3-Thiocyanoacrylate (Compound 5) Triethylamine (2.3 g., 0.031 mole) in 5 ml of dry toluene was added dropwise to a stirred suspension of compound 2 (4.0 g., 0.031 mole) in 30 ml of dry toluene at 0C. To the resulting solution, methanesulfonyl chloride (3.55 g., 0.031 mole) in 15 ml of dry toluene was added dropwise at 0C and stirred for 30 minutes. A solution of phenol (2.9 g., 0.031 mole) and dimethylaminopyridine (DMAP) (3.5 g., 0.028 mole) in 40 ml of dry toluene was added dropwise with stirring at 0C. The mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The mixture, consisting of yellowish gum in a two-phase mixture with toluene, was diluted with methylene chloride, poured into water and the organic phase was separated. The aqueous phase was extracted with methylene chloride. The combined 2 ~ '' ` ~
organic phase was washed with sodium bicarbonate solution, water, dried tMgSO4) and concentrated. The residue was column-chromatographed on silica gel using hexane/ether (4:1) as eluant to give product as white crystals, 2.9 g: mp 79-83C; IR (KBr) 1700, 2175 cm-1.
Example 2 Benzyl cis-3-Thiocyanoacrylate (Compound 10) To a stirred suspension of compound 2 (3.0 g., 0.023 mole) in dry acetonitrile (40 ml), a solution of DBU (3.54 g., 0.023 mole) in 10 ml of dry acetonitrile was added dropwise, keeping the temperature of the mixture below 25C. To the resulting solution was added dropwise a solution of benzyl bromide (4.0 g., 0.023 mole) in 15 ml of dry acetonitrile at room temperature. After stirring for 5 hours, the mixture was poured into water, and extracted with ether. The ether extract was washed with water, dried (MgS04) and concentrated to give an oil which solidified upon standing, 4.3 g. The solid recrystalliæd from ethanol/hexane mixture as plate-like crystals: mp 48.5-50.5C; IR
(KBr) 1695, 2180 cm.-l.

2 ~

Example 3 Methyl cis-3-Thio(1-Acetylpropan-2-on-1-yl) Acrylate (Compound 16) To a stirred solution of cis-beta-carbomethyoxyvinylisothiouronium chloride (compound 15) (3.92 g., 0.02 mole) in 80 ml of 95% ethanol, a pre-cooled solution of sodium hydroxide (lN, 40 ml, 0.04 mole) was added within 5 minutes at -10C. To the white precipitate which formed immediately, consisting of sodium cis-beta-carbomethyoxyvinylmercaptide, urea and sodium chloride, was added a solution of 3-chlor~2,4-pentanedione (2.68 g., 0.02 mole) in 30 ml of 95% ethanol at -10C. After allowing the mixture to warm to room temperature, it was stirred for an additional 5 hours and then poured into water, followed by extraction with chloroform. The chloroform extract was washed with water, dried (MgSO4), and concentrated. The residual oil was purified by column chromatography using hexane/ether (2:3) as eluant. The resulting oil, 2.1 g, solidified on standing and was recrystallized from ethanol/hexane mixture: mp 61-64C; NMR (CDCl3) 17.1 (s, lH); 6.8 (d, lH, l=9-3 cps); 5.95 (d, lH, J=9.3 cps); 3.8 (s, 3H); 2.35 (s, 6H).

2 3~
Example 4 Methyl trans-3-Thiocyanoacrylate ~Compound 19) To a stirred solution of ammonium thiocyanate (7.2 g., 0.095 mole) in 4N sulfuric acid solution (50 ml) at 40C, a solution of trans-3-chloroacrylic acid (10.0 g., 0.095 mole) in 35 ml of methanol was added dropwise within 5 minutes. The mixture was refluxed for 18 hours, cooled and poured into water which was extracted thoroughly with ether. The ether extract was washed with saturated sodium bicarbonate solution and then with water. After drying (MgS04), the solution was concentrated to give an oil which distilled at 70C/0.3 mm; yield, 7.2 g.;
NMR (CDC13) 7.3 (d, lH, J=14.4 cps); 6.35 (d, lH, J=14.4 cps); 3.8 ~s, 3H);

IR(KBr) 2180, 1725 cm-l.
Example 5 Methyl 3-Bromo-3-Thiocyanoacrylate (Compound 22) To a stirred solution of ammonium thiocyanate (3.06 g., 0.04 mole) in 2M aqueous sulfuric acid (20 ml) at 0C, methyl 3-bromopropiolate (3.26 g., 0.02 mole) was added dropwise, neat, over 5 minutes. After keeping the temperature at 0C for 1 hour, the mixture, consisting of a solid precipitate in the aqueous solution, was extracted 7 ~
with ether which was washed with water, dried (MgSO~), and concentrated. The residual solid was suspended in hexane and removed by filtration, yielding 2.4 g. of product. The solid recrystallized from ethanol as yellowish microcrystals; mp 139-142.5C;
IR (KBr) 2170, 1680 cm-l.
Example 6 N-(cis-3-Thiocyanoacryloyl)piperidine (Compound 24) To a stirred suspension of compound 2 (3.06 g., 0.023 mole) in 60 ml of dry toluene, triethylamine (2.35 g., 0.023 mole) in 10 ml of dry toluene was added dropwise, keeping the temperature of the mixture at 0-5C. To the resulting solution was added dropwise, ethyl chloroformate (2.53 g., 0.023 mole) in 15 ml of dry toluene at 0-5C.
After stirring the mixture for 15 minutes, piperidine (2.0 g., 0.023 mole) in 15 ml of dry toluene was added dropwise at 0-5C. The mixture was allowed to warm to room temperature, stirred for an additional 2 hours and filtered. The filtrate was washed with water, dried (MgSO4) and concentrated to give an oil which solidified, 2.6 g. l~e solid was recrystallized from ethanol: mp 88-90C; IR (KBr) 2175, 1630 cm-Example 7 _-4-Thiocyano-3-buten-2-one (Compound 28) To a stirred solution of ammonium thiocyanate (7.6 g., 0.1 mole) in 2M sulfuric acid solution (50 ml) at 0C, 1-butyn-3-one (3.4 g., 0.05 mole) was added neat over 5 minutes. The resulting solid suspension was stirred at 0C for 15 minutes and then allowed to warm to room temperature and then stirred for an additional hour. The solid was removed by filtration and washed with water. After drying, the brown solid was purified by column chromatography on silica gel using hexane/ether (1:4) as eluant. The resulting solid, 3.6 g recrystallized from hexane/ethanol mixture as needles upon standing in the refrigerator: mp 44-46C; IR (KBr) 2150, 1665 cm-l.

Example 7A
_-~(5-mercapto-1-methyl tetrazolyl)-3-buten-2-one (Compound 35) To a stirred solution of 5-mercapto-1-methyl tetrazole sodium salt hydrate (1.1 g., 0.008 mole) in aqueous ethanol (15 ml), a solution of ~-4-thiocyano-3-buten-2-one (Compound 28) in ethanol was added dropwise over 5 minutes. A solid suspension was observed forming 2 ~

over the next 2 hours which was stirred at 25 C for 18 hours. The volatiles were removed in vacuo and the residue was extracted into ethyl acetate and washed thoroughly with water. After drying (MgSO4), the solution was concentrated. The solid residue was purified via column chromatography on silica gel using hexanes/ethyl acetate (3:2) as eluant to yield 1.1 g of a white solid, mp 112-114 C IR (nujol) uc=o 1660 cm-1.
Example 7B
Cis and trans-4-(2-mercaptothiazolinyl)-3-buten-2-one (Coumpounds 36 and 37) To a stirred solution of 2-mercaptothiazoline (3.7 g., 0.03 mole) in aqueous ethanol (35 ml) at 35C, a solution of 3-butyn-2-one (2.0 g., 0.03 mole) in ethanol (10 ml) was added dropwise over 10 minutes.
The resulting solution was refluxed for 2 hours and stirred at ambient temperature for 18 hours. The volatiles were removed in vacuo and the residue was extracted into ethyl acetate and washed thoroughly with water. After drying (MgSO4), the solution was concentrated to an amber oil consisting of the cis and trans isomers. Purification and '' r'`) isolation of the isomers was accomplished via column chromatography on silica gel using hexanes/ethyl acetate (4:1), yielding 2.7 g cis-isomer as a white solid, mp 69-72 C IR.(nujol) uc=o 1660 cm-1.
The trans-isomer was recovered as an amber oil, 0.2 g IR (neat) uc=o 1660 cm-1.

Example 8 Biological Activity A. Biocidal Activitv:
Biocidal evaluations (bactericidal, algicidal, and fungicidal) were carried out.
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 500 ppm compound.

When the test is ready to be done, each vesse~;3 t~ tion series, except the first vessel, contains an equal volume of cornpound 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 second vessel. After being mixed, one half the resulting volume is removed from the second vessel and transferred to the third vessel. The entire cycle is repeated sufficien~Lly to give a series of concentrations amounting to 500, 250,125, 63, 31, 16, 8, and 4 ppm (or 100, 50, 25, 12.5, 6.2, 3.1, 1.6, and 0.8), respectively.
Each vessel is then inoculated with a cell suspension of the appropriate test organism. Bacteria are grown in broth, fungi on agar slants for a time and at a temperature appropriate to the species being tested, and algae are a mixture of green algae and blue-green bacteria grown in a nutrient media. At the end of the growth period, in the case of bacteria, 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, 2 ~ 9~
temperature, and the volume of the diluent. The suspension is then used to inoculate the vessels containing the broth compound.
The algae culture contains green algae and blu~green bacteria, and is obtained from a cooling tower in Spring House, Pennsylvania.
The algae culture is grown in Allen's medium on a rotary shalcer under flourescent room lighting. This culture is further diluted with Allen's medium and then added to the test vessel.
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.

2 ~

The organisms tested to demonstrate biocidal activity include:
BACTERIA:
Pseudomonas fluorescens (PSFL), gram negative Pseudomonas aerugenosa (PSAE), gram negative Escherichia coli (ECOL), gram negative Staphylococcus aureus (SAUR), gram positive _UNGI:
Aspergillus niger (ANIG) Aureobasidium pullulans (APUL) The results of the minimum inhibitory concentration (MIC) and SOK tests of compounds of this invention are shown in Table 3 against the microorganisms shown in Table 6.
B. In-Vitro Plant Fungicidal Tests:
In-vitro tests of plant diseases were carried out.
The organisms employed in the test are:
PYlJ Pythium ultimum (Oomycete) PHY Phytophthora capsici (Oomycete) PIR Piricularia oryzae (Ascomycete) HEL Cochliobolus sativus (Ascomycete) BOC Botrytis cinerea ~Ascomycete) FUS Fusarium roseum ~Ascomycete) SEP Septoria nodorum (Ascomycete) RHI Rhizoctonia solani (Basidiomycete) XAN Xanthomonas campestris (bacterium) Methods:
1. Culture maintenance: Transfers in steps 1 and 2 are done in a laminar flow hood. All 8 fungi and the bacterium used in this test are transferred and maintaned on potato dextrose agar plates each week (2 plates~organism). Organisms are used when they are the following ages: a. 1 week old: PYU, PHY, RHI; b. 2 weeks old: XAN, PIR, BOC, HEL, FUS, SEP. Pythium ultimum and Phytophthora capsici are transferred to asparagine-sucrose broth shake cultures (ASB).
Rhizoctonia solani, Fusarium roseum, and Zanthomonas campestris are mainted in yeast extract-dextrose broth (YDB) on a shaker. Culture flasks are inoculated with 6 mycelial plugs each (except for Pythium which is inoculated with only 3 plugs) taken from PDA plates. All liquid shaker cultrues are used after 2 days growth.

29 ~7~

2. Inoculum preparation. Conidia and mycelium from PIR, BOC, HEL, and SEP are lightly scraped off into YDB so that mos~dy conidia are used as inoculum. The conidial suspension is strained through a double layer of cheesecloth to remove mycelial clumps. One plate produces enough conidia or mycelium to inoculate 100 ml of YDB. XAN broth culture is poured (lml culture/100 ml broth) into YDB. PYU, PHY, RHI and FUS cultures are ground up (2-3 5 second bursts in a blender) and all but Pythium and Phvtophthora are filtered through a dobule layer of sterile cheesecloth to remove large mycelial clumps. Ten ml of the culture solutions of R. solani and F. roseum are added to 90 ml of YSB and 10 ml of the P. capsici is added to 90 ml ASB.
Two ml of the culture solution of P. ultimum is added to 98 ml of ASB.
Care must be made not to overinoculate (e.g., solutions should appear fairly clear to the eye, yet when held up to light a faint cloudiness should be visible) or standards will not behave properly. The inoculum mixtures are placed in microtiter plates using a 12-tipped pipet. 175 ~l (single dose) or 100111 (dose-response test) of inoculum broth is placed in each well of the microtiter plates. The plates with inoculated media are placed in the refrigerator overnight. There a~e two replications per treatment.
3. Addition of compounds. This operation is carried out in a hood. Six microtiter plates have 245 microliters of sterile water added to their wells ahead of time. 10 Mg a.i. of the compounds are placed in 1 ml 1:1 acetone:methanol. 5 Microliters of this solution is pipetted into the microtiter plates containing the sterile water according to the grid. There are 45 compounds and 3 control treatments per plate.
There are 2 replicates per treatment. 25 Microliters of solution is transferred to the inoculated plates with a 96 well replicator. The replicator is flame sterilized with alcohol, rinsed with sterile water, and blotted on sterile paper towels between each transfer.
The results of ~0 control of plant fungi at a certain concentration of some of the compounds of this invention are shown in Table 4.
C. Greenhouse Tests of Plant Disease Control:
Several compounds of this invention were tested for fungicidal activity in vivo against tomato late blight (TLB), wheat powdery mildew (WPM) and wheat leaf rust (WLR) and the results are shown in Table 5. In tests on cereals 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~.
Tomato Late Blight (TLB):
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 plants which had been sprayed previously with experimental fungicides. The inoculated plants were placed in a 2 ~ s humidity cabinet 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.
Wheat Powdery Mildew (WPM):
Erysiphe graminis (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.
Wheat 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.

2 ~
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 (9.5 rnillion) 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 tl8-20~ 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.

2 jnJ1 ~ n ~
Table 3 - Biocides Secondary MIC/SOK Test Data (in PPM) for Compounds of Formula I
Cpd# SOK PSFL PSAE ECOL SAUR ANIG APUL
>500 63 125 250 125 16 8 2 >250 >250 >250 250 >250 >250 >250 4 250 250 >250 >250 >250 63 32 >250 16 250 125 16 2 4 6 125 16 250 250 16 <.13 7 250 >250 >250 >250 >250 >250 125 8 250 32 >250 >250 >250 63 >250 9 32 8 >250 >250 125 8 16 32 16 >250 >250 125 8 32 11 32 16 >250 >250 125 8 32 12 250 >250 >250 >250 >250 8 63 13 125 32 >250 >250 63 32 16 14 125 >250 >250 >250 >250 >250 >250 >250 >250 >250 >250 >250 >250 125 16 >250 >250 >250 >250 >250 >250 0.63 17 >1000 >250 >1000 >1000 >1000 >1000 >1000 18 >250 >250 >250 >250 >250 >250 63 19 >250 16 63 63 63 4 2 >1000 >250 >1000 >1000 1000 1000 1000 21 >250 >250 250 >250 >250 250 250 22 >250 32 >125 250 250 63 16 23 >250 >250 >250 >250 >250 250 63 24 >250 >250 >250 >250 >250 250 125 >250 >250 >250 >250 >250 250 125 26 >250 >250 >250 >250 >250 125 63 27 >250 >250 >250 >25Q >250 32 63 29 >250 250 >250 >250 >250 >250 >250 >250 250 >250 >250 >250 >250 >250 31 63 - 63 63 >250 2 32 >250 - 32 >250 >250 63 63 33 >250 - >250 >250 16 16 8 Table 3A - Biocides Secondary MIC Test Data (in PPM) for Compounds of Formula I
Cpd. # SOK PSFL PSAE ECOL SAUR ANIG APUL
34 - - 500 >500 32 - -- - >500 S00 250 Table 4 In-Vitro Plant Fungicide Test Results for Compounds of Formula I
% control at 25 ppm Cpd.# PYU PIR PHY BOC HEL RHI FUS SEP XAN

6 10~ 100 100 100 100100 100 100 0 Table 5 Green House Test Results of Plant Disease Control for Compounds of Formula I
% Control Comp. # Rate (p~m) TLB WLR WPM

.?

Microorganisms Used in the Biocides Tests Name GRAM ATCC NO! Abbreviation used BACTERIA
1. Pseudomonas aeruginosa (-) 15442 PSAE
2. Staphylococcus aureus (+) 6538 SAUR
3. Escherichia coli (-) 11229 ECOL
4. Pseudomonas fluorescens (-) 948 PSFL
FUNGI
1. Aspergillus niger 6275 ANIG
2. Aureobasidium pullulans 9348 APUL

Claims (9)

1. A process of inhibiting the growth of microbials comprising introducing a microbicidally effective amount of one or more thioacryloyl compounds onto, into, or at a locus subject to microbial attack, said thioacryloyl compounds being of the formula wherein Z is selected from the group consisting of OR, R and NR1R2;
R is selected from the group consisting of hydrogen;
(C1-C18)alkyl; (C1-C8)alkenyl; (C1-C8)haloalkynyl;

2-(5-chlorothienyl)methyl; phenyl optionally substituted with one or more substituents selected from the group consisting of halo-, (C1-C3)alkoxy-, nitro-, and (C1-C3)alkyl; phenacyl optionally substituted with one or more substituents selected from the group consisting of ring halo-, (C1-C3)alkoxy-, nitro-, and (C1-C3)alkyl; arylalkyl optionally substituted with one or more substituents selected from the group consisting of ring halo-, (C1-C3)alkoxy-, nitro-, and (C1-C3)alkyl;

R1 and R2 are independently selected from (C1-C8)alkyl and phenyl, or R1 and R2 may be joined together with the nitrogen atom to which they are attached to form a ring containing 4 to 5 carbon atoms with or without an oxygen heteroatom;
X is selected from the group consisting of hydrogen, halogen, phenyl, CO2CH3, and (C1-3)alkyl; and Y is selected from the group consisting of CN, CH(COCH3)2, CH2COCH3, CH2CN, CH2CO2C2H5, propargyl, SCH=CHCO2CH3, C(=NH)NH2 hydrochloride, 2-(5-chlorothienyl)methyl, and a saturated or unsaturated heterocyclic 5- or 6-membered ring with 1 to 4 heteroatoms selected from the group consisting of S, O, or N, said ring being unsubstituted or substituted wtih substituents independently selected from the group consisting of unsubstituted or halosubstituted alkyl of 1 to 8 carbon atoms, unsubstituted or halosubstituted alkenyl or alkynyl of 2 to 8 carbon atoms, nitro, cyano, halo, (C1-C8)alkoxy, amino, alkylamino, dialkylamino, and benzyl; or optionally fused to a benzene ring which is optionally substituted with substituents independently selected from the group consisting of unsubstituted or halosubstituted alkyl of 1 to 8 carbon atoms, unsubstituted or halosubstituted alkenyl or alkynyl of 2 to 8 carbon atoms, nitro, cyano, halo, (C1-C8)alkoxy, amino, alkylamino, and dialkylamino; or said nitrogens in the nitrogen-containing heterocycles possibly being N-oxides;
provided that when Z is NR1 R2, Y is CN; and provided that when Z is R, X is hydrogen, and Y is CN, R is not phenyl.
2. The process of claim 1 wherein said compound is selected from the group consisting of methyl cis-3-thiocyanoacrylate;
cis-3-thiocyanoacrylic acid;
ethyl cis-3-thiocyanoacrylate;
n-butyl cis-3-thiocyanoacrylate;
phenyl cis-3-thiocyanoacrylate;
iodopropargyl cis-3-thiocyanoacrylate;
dimethyl alpha-thiocyanofumarate;
2,5-dinitrobenzyl cis-3-thiocyanoacrylate;
5-chloro-thien-2-yl-methyl cis-3-thiocyanoacrylate;

benzyl cis-3-thiocyanoacrylate;
4-chlorobenzyl cis-3-thiocyanoacrylate;
p-chloroacetophenyl cis-3-thiocyanoacrylate;

3-methoxybenzyl cis-3-thiocyanoacrylate;
2,5-dichlorobenzyl cis-3-thiocyanoacrylate;
cis-beta-carbomethoxyvinylisothiouronium chloride;
methyl cis-3-thio(1-acetylpropan-2-on-1-yl)acrylate;
methyl cis-3-thio(propan-2-on-1-yl)acrylate;
bis-cis-(carbomethoxyvinyl)disulfide;
methyl trans-3-thiocyanoacrylate;
methyl cis-3-propargylthioacrylate;
methyl cis-3-(5-chlorothien-2-yl-methyl)acrylate;
methyl 3-bromo-3-thiocyanoacrylate;
N,N-dimethyl cis-3-thiocyanoacrylamide;
N-(cis-3-thiocyanoacryloyl)piperidine;
N-(cis-3-thiocyanoacryloyl)morpholine;
N-methyl-N-n-butyl cis-3-thiocyanoacrylamide;
N-methyl-N-phenyl cis-3-thiocyanoacrylamide;

cis-4-thiocyano-3-buten-2-one;
methyl cis-3-(cyanomethylthio)acrylate;
methyl cis-3-(ethylcarboxymethylthio)acrylate;
cis-5-thiocyano-4-penten-3-one;
cis-8-thiocyano-7-octen-6-one;

4-phenyl-4-thiocyano-3-buten-2-one, 4-(2-mercaptobenzothiazolyl)-3-buten-2-one;
cis-4-(5-mercapto-1-methyltetrazolyl)-3-buten-2-one;
cis-4-(2-mercaptothiazolinyl)-3-buten-2-one;
trans-4-(2-mercaptothiazolinyl)-3-buten-2-one;
cis-4-(2-mercaptopyridinyl)-3-buten-2-one;
trans-4-(2-mercaptopyridinyl)-3-buten-2-one;
cis-4-(2-mercaptopyridinyl-N-oxide)-3-buten-2-one;
cis-4-(2-mercaptothiazolyl)-3-buten-2-one;
trans-4-(2-mercaptothiazolyl)-3-buten-2-one;
1-mercaptoimidazolyl-3-buten-2-one;
cis-4-(2-mercapto-1-methylimidazolyl)-3-buten-2-one; and 4-(2-mercapto-1-methylimidazolyl)-3-buten-2-one.

3. A compound of formula I except compounds wherein (a) X is hydrogen, Y is CN and Z is hydrogen, methoxy or dimethylamino;
(b) X is hydrogen, Z is methoxy and Y is CH2COCH3 or C(=NH)NH2 hydrochloride; and (c) X is CO2CH3, Y is CN and Z is methoxy.
4. The compound according to claim 3 wherein said compound is selected from the group consisting of ethyl cis-3-thiocyanoacrylate;
n-butyl cis-3-thiocyanoacrylate;
phenyl cis-3-thiocyanoacrylate;
iodopropargyl cis-3-thiocyanoacrylate;
2,5-dinitrobenzyl cis-3-thiocyanoacrylate;

5-chloro-thien-2-yl-methyl cis-3-thiocyanoacrylate;
benzyl cis-3-thiocyanoacrylate;
4-chlorobenzyl cis-3-thiocyanoacrylate;
p-chloroacetophenyl cis-3-thiocyanoacrylate;
3-methoxybenzyl cis-3-thiocyanoacrylate;

2,5-dichlorobenzyl cis-3-thiocyanoacrylate;
methyl cis-3-thio(1-acetylpropan-2-on-1-yl)acrylate;
bis-cis-(carbomethoxyvinyl)disulfide;
methyl cis-3-propargylthioacrylate;
methyl cis-3-(5-chlorothien-2-yl-methyl)acrylate;
methyl 3-bromo-3-thiocyanoacrylate;
N-(cis-3-thiocyanoacryloyl)piperidine;
N-(cis-3-thiocyanoacryloyl)morpholine;
N-methyl-N-n-butyl cis-3-thiocyanoacrylamide;
N-methyl-N-phenyl cis-3-thiocyanoacrylamide;
cis-4-thiocyano-3-buten-2-one;
methyl cis-3-(cyanomethylthio)acrylate;
methyl cis-3-(ethylcarboxymethylthio)acrylate;
cis-5-thiocyano-4-penten-3-one;
cis-4-thiocyano-7-octen-6-one;
4-phenyl-4-thiocyano-3-buten-2-one;
4-(2-mercaptobenzothiazolyl)-3-buten-2-one;
cis-4-(5-mercapto-1-methyltetrazolyl)-3-buten-2-one;

cis-4-(2-mercaptothiazolinyl)-3-buten-2-one;
trans-4-(2-mercaptothiazolinyl)-3-buten-2-one;
cis-4-(2-mercaptopyridinyl)-3-buten-2-one;
trans-4-(2-mercaptopyridinyl)-3-buten-2-one;
cis-4-(2-mercaptopyridinyl-N-oxide)-3-buten-2-one;
cis-4-(2-mercaptothiazolyl)-3-buten-2-one;
trans-4-(2-mercaptothiazolyl)-3-buten-2-one;
1-mercaptoimidazolyl-3-buten-2-one;
cis-4-(2-mercapto-1-methylimidazolyl)-3-buten-2-one; and 4-(2-mercapto-1-methylimidazolyl)-3-buten-2-one.
5. A composition useful as a microbicide comprising an effective amount of a compound according to claim 3.

6. A process comprising according to claim 1 wherein said locus is selected from the group consisting of wood, paint, adhesive, glue, paper, pulp/paper slurries, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed, and industrial cooling water from microorganisms.

7. The process of claim 6 wherein the compound is selected from the group consisting of methyl cis-3-thiocyanoacrylate, iodopropargyl cis-3-thiocyanoacrylate, methyl trans-3-thiocyanoacrylate, and cis-thiocyano-3-buten-2-one.

8. The process of claim 7 wherein said is selected from the group consisting of pulp/paper slurries and industrial cooling water.

9. The process of claim 6 wherein the amount of said compound is about 5 to about 300 ppm based on weight of said locus.