WO1994002451A1

WO1994002451A1 - Halo alkynyl urea derivatives, a method for their production and fongicidal compositions containing them

Info

Publication number: WO1994002451A1
Application number: PCT/US1993/007024
Authority: WO
Inventors: Rainer Gruening
Original assignee: Troy Chemical Corporation
Priority date: 1992-07-24
Filing date: 1993-07-26
Publication date: 1994-02-03
Also published as: AU4786593A

Abstract

Novel fungicidal compounds are urea derivatives of iodo alkynyls, having formula (I), in which R is H or an alkyl group having one to not more than 20 carbon atoms, Ra to Rc are H or a substituted or unsubstituted alkyl, aryl, aralkyl or cycloalkyl group having from one to not more than 20 carbons and Rc is H or alkyl when Ra or Rb is aryl, n and m are a whole number integers between 1 and 3, and X is I or Br. These compounds have shown great fungicidal activity, particularly when used in surface coating compositions, such as paint formulations, and for the protection of wood and wood type material.

Description

HALO ALKYNYL UREA DERIVATIVES, A METHOD FOR

THEIR PRODUCTION AND FUNGICIDAL COMPOSITIONS

CONTAINING THEM

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

This invention is directed to novel fungicidal agents. More particularly, this invention is directed to urea derivatives, the preparation thereof, and their use as fungicidal and algaecidal agents. REVIEW OF RELATED ART

One of the most effective and efficient classes of fungicides now known is generally considered to be the organically substituted mercury compounds. They have been particularly valuable because they control attack by a wide spectrum of micro-organisms, may be used at low concentration, and have

considerable permanence when this characteristic is desirable (as in surface coatings). However, the reputation of these compounds has deteriorated recently because of toxic and environmental hazards, and they are being eliminated or phased out as commercial fungicides. Other fungicides which have been developed and which have been placed on the market from time to time as mercurial substitutes are listed below, but none of these has proved to be entirely satisfactory. a. Captan - not stable to hydrolysis, particularly in alkaline systems; b. trans, di-n-propyl-l,2-ethene - not stable in aqueous systems; c. 4-methyl sulfonyl tetrachloropyridine - not stable in alkaline

systems; d. 2-(4 Thiazolyl)-benzimidazole - expensive and relatively ineffective against Alternaria sp. (a prevalent organism in the south); e. p-chloro (or methyl) phenyl diiodomethyl sulfone - causes yellowing, ineffective in oil-based systems and relatively susceptible to degradation due to weathering; f. octylisothiazolone - expensive, relatively susceptible to degradation due to weathering, and requires zinc oxide as a synergist.

Certain halogenated acetylenic alcohols and derivatives therefrom have been described for various uses.

U.S. Patent No. 1,841,768 teaches the preparation of chloro and bromo substituted ethine carbinols. They are disclosed as pharmaceutically valuable and for therapeutic use. U.S. Patent No. 2,989,568 also relates to the preparation of chloro and bromo-substituted acetylenic alcohols. The compounds are described as useful as corrosion inhibitors and inhibitors for plating baths. U.S. Patent No. 2,791,603 is directed to carbamates (urethanes) of tertiary acetylenic carbinols useful as anti-convulsants. U.S. Patent No. 3,436,402 teaches certain halogenated carbamates of diaryl substituted alkynes.

In U.S. Patent 3,923,870, Singer disclosed iodopropargyl carbamate and

taught the use of this compound as a fungicide. Others confirmed the use of halopropargyl carbamate and its derivatives as fungicides (Versfelt, et al. (1984), GB 2,140,299; Morell (1987), J. Wood Fiber Sci. 19:388-391; Leathers, et al. (1989), U.S. Pat. 4,806,263; Gertjejansen, et al. (1989), For. Prod. J.. 39:15-19; Kusaba, et al. (1989), U.S. Pat. 4,841,088; and Rayudu (1990), EP 0 365 121). Bacteriocidal activity has also been reported for propargyl ethers by Makhsumov, et al. (1968, Izv. Akad. Nauk. SSSR. Ser. Khim.. No. 11, 2591-2593). N-(3-iodopropargyl) carbazole was disclosed by Shklover, et al. (1990, Mol. Cryst. Liq. Crvst.. Vol. 180B, pp. 417-423), but no utility was suggested for the compound.

Despite the number of alternatives to organo-mercurial fungicides, there remains a need for novel compounds with fungicidal activity. SUMMARY OF THE INVENTION

It is the object of the invention to provide novel fungicidal and algaecidal

agents.

It is also an object of the invention to provide halo alkynyl ureas of the formula:

I

[XC ^~≡ C-[C]_n-N-CO-NH]_mR

I I

R_b R_c

where m and n are whole number integers between 1 and 3 and may be the same or different, R., R,, and R,. are independently H or an unsubstituted or substituted alkyl, aryl, arylalkyl, alkenyl, alkylaryl or cycloalkyl group having from one to not more than 20 carbon atoms, R is H or a substituted or unsubstituted alkyl group having from one to not more than 20 carbons and having from one to three linkages (valences) corresponding to m, and X is I or Br.

This invention provides halo alkynyl urea derivatives of the formula:

R.

I

[XC ≡ C-[C]_n-N-CO-NH]_mR Formula I

where R, R., R_b, -R_<., X, m and n are as defined above. The various groups R„ R_b and R_c may be the same or different, but R,. is H or alkyl when either R_a or R_b or both are aryl. Preferably, none of R, R,, R_b, and R,. have

more than 8 carbons.

These compounds have shown fungicidal activity, particularly when used in surface coating compositions, such as paint formulations, and for the

protection of wood and wood type material.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to halo alkynyl urea derivatives according to

formula I. This invention is also directed to the preparation of the compounds of the formula I by reacting an amine of the formula:

R.

I

HC ≡ C-CC -NHR_c Formula II

I R_b

with an equimolar amount of a suitable isocyanate of the formula:

R[NCO]_m Formula III

where m, R and R, to -R, are defined as above and, in a second step, halogenating the product to form the compounds of the general formula of the invention: R.

I

[XC≡C-[C]_n-N-CO-NH]_mR

Examples of R,, R_b or R,. include hydrogen and linear or branched alkyl groups of from 1 to 6 carbon atoms represented by any of methyl, ethyl, propyl,

isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and hexyl groups and branched isomers thereof, or alkenyl groups of from 2 to 8 carbon atoms represented by vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl groups and the respective isomers of the alkenyls mentioned having 4-8, preferably, 5 or 6 carbon atoms, including cycloalkenyls. Examples of R„ R_b or R_«. also include cycloalkyl radicals with from 4 to 8 carbon atoms, including cyclopentyl, cyclohexyl and cycloheptyl groups, and arylalkyl and alkylaryl groups of 6 to 10 carbon atoms such as phenyl, tolyl, naphthyl, and benzyl. Such moieties also can be substituted with radicals that do not adversely affect the process for making the halo alkynyl urea of the above formula or its use as a fungicide or algaecide. Preferred substituents include hydroxyl, cyano or nitro groups or halogen atoms. Compounds of formula I in which both R, and R_b are either hydrogen or methyl, as well as those compounds in which one or both of R, and R_b is hydrogen or one is methyl are preferred.

Examples of linear or branched alkyl groups of from 1 to 20 carbon atoms represented by R, include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups as well as the branched isomers of the alkyls having from 5 to 12 carbon atoms. It is preferred if R represents a group having 8 or fewer carbons. If R is a cycloalkyl of from 4 to 8 carbon atoms it may, for example, be a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group. Compounds in which R represents a lower alkyl of from 1

to 6 carbon atoms are more preferred. Especially preferred compounds are those which R represents, for example, propyl, butyl, or cyclohexyl group. R may also represent linear or branched alkenyl groups or cycloalkenyl groups, such as propenyl, butenyl, pentenyl and hexenyl groups and the respective isomers of the alkenyls mentioned having 4-8, preferably, 5 or 6 carbon atoms, including cycloalkenyls. The moieties represented by R also can be substituted with radicals that do not adversely affect the process for making the halo alkynyl urea of the above formula or its use as a fungicide or algaecide. Preferred substituents include hydroxyl, cyano or nitro groups or halogen atoms.

The isocyanates of Formula III may include any R group that will form a compound according to Formula I upon reaction with an amine of Formula II. Such isocyanates include, for example, methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, isobutyl isocyanate, and cyclohexylisocyanate. The alkynyl ureas of this invention may also be synthesized by the reaction of amines of Formula II with alkyl di-isocyanates or alkyl tri-isocyanates c ormula in to produce an alkyl group substituted with two or three alkynyl ure, Oieties. Such polyisocyanates are well known in the polyurethane art, and include hexamethylene-l ,6-diisocyanate, tetramethylene-l,4-diisocyanate, cyclohexane 1,4-diisocyanate, 4,4'- dicyclohexylmethyl diisocyanate, and the like.

Based on antifungal efficacy, the preferred halo alkynyl ureas of this invention are iodo alkynyl ureas. The iodo alkynyl ureas of Formula I may be synthesized by reacting primary or secondary amines of Formula II with equimolar amounts of the isocyanates of Formula HI and iodinating the resultant alkynyl urea according to standard procedures. It will be apparent to the skilled worker that bromo alkynyl ureas of Formula I may be prepared similarly.

The synthesis of alkynyl urea is carried out at temperatures from about 0° to 100°C, preferably from about 20° to 70°C, usually in an inert solvent. Suitable solvents include ethylene chloride, dimethyl formamide, toluene, chlorobenzene, methylene chloride, and tetrahydrofuran and the like. The reaction can be accelerated with catalysts such as, for example, dibutyltin carboxylates of fatty acids. Catalysts that may be used also include tertiary bases such as triethylamine. A preferred method of halogenating the alkynyl

urea is the procedure for halogenation of alkynes taught in Singer, U.S. Patent 3,923,870 incorporated herein by reference. Surprisingly, the procedure of this invention can be used to produce an unsubstituted halo alkynyl urea from an alkynyl amine. An alkynyl amine according to formula II is reacted with hydrocyanic acid to form alkynyl urea which can then be halogenated in a second step. The halogenation reaction selectively substitutes the alkynyl carbon in preference to the urea nitrogen.

Due to their microbiostatic and microbiocidal effect, the compounds according to the invention are suitable, for example, for the preservation of technical products, such as paints, glues, dispersions, or cold lubricants, or for the antimicrobial treatment of joint caulking compounds, such as silicon caulks. They are also suitable for the elimination of mold, for example, mold on wet walls, ceilings, or floors, for the preservation of wood, and for the antimicrobial treatment of plastics, such as polyolefm or polyvinyl chloride (PNC) foils. Furthermore, the compounds according to the invention can be used as disinfectants or as preservatives for cosmetics. The antimicrobial compositions described herein are particularly effective as fungicidal compositions.

For use in antimicrobial compositions, one or more compounds according to the invention can be incorporated by a known method into liquid, paste, or solid preparations that are in the form of solutions, suspensions, or emulsions. In preparations ready for use, the compounds of the invention should be present in a fungicidally or algaecidally effective amount and preferably will be present in amounts of from about 0.01 to 5% by weight based upon the weight of the total antimicrobial preparation, although other concentrations are possible depending upon the specific application. Concentrates for the make-up of such ready-for-use preparations may conveniently contain the compounds of the invention in amounts of up to 50% by weight, based upon the weight of the total concentrate. The remainder of the antimicrobial composition will contain conventional formulation ingredients, such as, for example, water, organic solvents such as, for example ethanol, isopropanol, acetone, toluene and ethyl acetate, surfactants and binders.

When the antimicrobial or fungicidal compositions are admixed with a desired substance to preserve the substance, the compounds according to the invention should comprise from about 0.001 to 5% by weight, preferably from about 0.01 to 3% by weight, based upon the weight of the total preparation. In most instances an antimicrobial composition such as that described above will be admixed with the desired substance. However, it is within the scope of the invention that one or more compounds of Formula I could be added directly.

The examples below are intended to illustrate the invention and should not be construed as limiting the invention thereto. Example 1; 3-Iodo-2-Propynyl-n-bιιtyI-Urea

0.1 mol. (5.5g) of propargylamine was placed in a reaction flask and dissolved in 20g of tetrahydrofuran (THF), then 0.1 mol. (9.9g) of n-butyl isocyanate was added dropwise. The exothermic reaction was controlled by cooling so that the temperature did not exceed 50'C. After a reaction time of 10 minutes, the urea precipitated out. For an additional 30 minutes, the reaction mixture was kept at 50'C, then the solvent was evaporated under vacuum, and the slight yellow propargyl butyl urea was used without further purification (15. lg = yield 98%).

In a second step the propargyl butyl urea was iodinated in the presence of solvents (for example, hydrocarbons, aromatics, ethers, esters, alcohols) according to literature procedures. (See, e.g., Singer, U.S. Patent 3,923,870, incorporated herein by reference.)

Then the residual solvent was removed by vacuum drying procedure, and

24.3g (87.9% yield of the theory) were obtained as a creme yellow powdery substance which was recrystallized into a white crystallinic substance (melting point 131 to 133°C). The substance has a moderate overall solubility, with good solubilities in alcohols and slight solubility in hydrocarbons. It is practically insoluble in water.

Molecular Formula: C_gH₁₃IN₂O

Molecular Weight: 280.11

Analysis % C H I

calculated 34.27 4.64 45.30 found 34.52 4.68 44.01

IR (film: cm^ IC ≡C: 2175; (HC≡C: 2115) MS:

254 I₂ (recombination)

Example 2; 3-Iodo-2-Propynyl Propyl Urea

The procedure described in Example 1 was followed. The reaction was set up using 5.5g (0.1 mol) of propargylamine, which was placed in a reaction flask and dissolved in 20g of THF, then 8.5g (0.1 mol) of propyl isocyanate was added dropwise. After holding for further 30 minutes at 50°C, the solvent was evaporated, and the resulting cremish yellow solid powder (yield: 13.6g = 97.1 %) was used for the iodination without further purification. The iodinated product (yield: 22.3g = 86%) was a white crystalline powder which melted at 138-139°C.

Molecular Formula: C₇H_nIN₂O Molecular Weight: 266.09

Analysis % H

calculated 31.45 4.12 47.51 found 31.63 4.20 46.85

Example 3; Fungicidal Activity

The fungicidal activity of the iodopropargylalkyl urea derivatives were determined by standard microbiological test methods, as well as international norms (MIC, ASTM, DIN). As an example of a very effective alkyl derivative the butyl compound was evaluated.

Efficacy of 3-iodo-2-propynyl-butyl urea:

A modified MIC petri dish method according to Schultz et al., 1990

Phytochem.. 29: 1501-1507 (incorporated herein by reference) revealed the following approximate values of concentration for 100% inhibition of growth:

Aureobasidium pullulans 100 ppm

Chαetomi m globositm ( 50 ppm x spergill s niger 250 ppm

The fungicidal efficacy was determined according to the ASTM Standard

Method D1413 -76 (Reapproved 1986) (incorporated herein by reference) as well as DIN Standard Method EN 113 (published February 1986, and incorporated herein by reference), and it is reported as the concentration of fungicide required to protect (pcf-pounds of fungicide impregnated per cubic foot or Kg/m³-kilograms of fungicide impregnated per cubic meter).

Gloeophyllum trαbeum 0.018-0.020 pcf

Coriol s versicolor 0.020-0.022 pcf

Coniophorα puteαnα 0.053-0.055 pcf

Poriα placenta ) 0.042 pcf Serpula lacrymans 0.6-0.9 kg/m³ The preceding examples are provided by way of illustration and are not

intended to limit the scope of this invention. The teaching of the present disclosure will no doubt suggest numerous variations to those skilled in the art, and these variations are within the contemplation of the present invention, which is limited only by the appended claims.

Claims

What is claimed is:

1. A compound of the formula

R.

I

[XC as C-[C]_n-N-CO-NH]_mR

in which n and m are a whole number integers between 1 and 3, R is H or a substituted or unsubstituted alkyl, branched alkyl, cycloalkyl, alkenyl, branched alkenyl or cycloalkenyl group having from one to not more than 20 carbon atoms and having from one to three linkages (valences) corresponding to m, -R, to R,. are independently H or a substituted or unsubstituted alkyl, branched alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, or alkenyl group having from one to not more than 20 carbons and R,. is H or alkyl when R„ or R_b is aryl, and X is I or Br.

2. The compound according to claim 1 in which R is substituted alkyl, branched alkyl or cycloalkyl and the substituents are selected from the group consisting of hydroxyl, halogen, cyano and nitro.

3. The compound according to claim 1 in which at least one of R, R_a, R_b, and R,. is substituted with at least one substituent selected from the group consisting of hydroxyl, halogen, cyano and nitro.

4. The compound according to claim 1 in which none of R, R_a, R_b, and R_c have more than 8 carbons.

5. The compound according to claim 1 in which X is I.

6. The compound according to the formula of claim 1 in which n is 1.

7. The compound according to claim 6 where R is selected from the group consisting of ethyl and propyl.

8. The compound according to claim 1 which is 3-Iodo-2-propynyl-butyl urea.

9. The compound according to claim 1 which is 3-Iodo-2-propynyl-tert-butyl urea.

10. The compound according to claim 1 which is 3-Iodo-2-propynyl-hexyl urea.

11. The compound according to claim 1 which is 3-Iodo-2-propynyl-methyl urea.

12. The compound according to claim 1 which is 3-Iodo-2-propynyl-isopropyl urea.

13. The compound according to claim 1 which is 3-Iodo-2-propynyl-isobutyl urea.

14. The compound according to the formula of claim 1 in which n is 2.

15. The compound according to claim 1 wherein R is H.

16. A method of making the compound of claim 15 comprising the steps of: a. reacting hydrocyanic acid with an amine of the formula

R.

I

HC≡C-[C]_n-NHR_c

wherein R_t to R,. are independently H or a substituted or unsubstituted alkyl, aryl, alkaryl or cycloalkyl group having 1-20 carbons and n is a whole number integer between 1 and 3; b. reacting the product of step (a) with a halogen molecule selected from the group consisting of I₂ and Br₂.

17. A fungicidal composition comprising a compound of claim 1 and a diluent.

18. The composition according to claim 17 in which X is I.

19. The composition according to claim 17 in which n is 1.

20. The composition according to claim 19 where R is selected from the group consisting of ethyl and propyl.

21. The fungicidal composition according to claim 17 comprising 3-Iodo-2-propynyl-butyl urea and a diluent.

22. The fungicidal composition according to claim 17 comprising 3-Iodo-2-propynyl-tert-butyl urea and a diluent.

23. The fungicidal composition according to claim 17 comprising

3-Iodo-2-propynyl-hexyl-urea and a diluent.

24. The fungicidal composition according to claim 17 comprising 3-Iodo-2-propynyl-methyl-urea and a diluent.

25. The fungicidal composition according to claim 17 comprising

3-Iodo-2-propynyl-isopropyl urea and a diluent.

26. The fungicidal composition according to claim 17 comprising 3-Iodo-2-propynyl-isobutyl urea and a diluent.

27. The composition according to claim 17 in which n is 2.

28. The composition according to claim 17 wherein R is H.

29. The composition according to claim 17 in which R is substituted alkyl, branched alkyl or cycloalkyl and the substituents are selected from the group consisting of hydroxyl, halogen, cyano and nitro.

30. The composition according to claim 17 in which at least one of R, R,, R_b, and R,. is substituted with at least one substituent selected from the group consisting of hydroxyl, halogen, cyano and nitro.

31. The composition according to claim 17 in which none of R, R,, R_b, and R_c have more than 8 carbons.