Cyano-substituted 1-(or 4-)phenylalkyl-1,2,3-triazole derivatives,their preparation and fungicidal compositions containing them

This invention concerns noVel substituted

1,2,4-triazoles and acid addition salts and metal salt complexes thereof, as well as their method of prepara tion and their use as broad-spectrum systemic fungicides.

This invention provides new compounds of the formula:

R¹

C -— CH₂ — Q (I) wherein

Z is phenyl which is optionally substituted with lor 2 halo atoms

R¹ is 2

R is cyano;

(C₁-C^)'-alkyl or (C₂~Ωθ)alkenyl; and 1-(1,2,4-triazolyl) '׳or .4-(1,2,4-triazolyl);

or an agronomically acceptable acid addition salt, or an

Q is agronomically acceptable metal salt complex, of a compound of Formula I>

Representative compounds according to the invention are a compound of Formula I (or acid addition salt or metal, salt complex) wherein Z is phenyl, R² is . n-C₄H_g and Q is unsubstituted 1-(1,2,4-triazolyl).

. The term alkyl as used herein encompasses both branched and straight chained alkyl groups.

2־54669 . The acids which can be utilized in making the acid addition salts of the. present invention include hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, hydroiodic, hydrofluoric,, perchloric, < p-toluenesulfonic, methanesulfonic, acetic, citric, tartaric, malic, maleic, oxalic, fumaric and phthalic.

The metal salt complexes of the invention are typified by those of the formula

R¹

10;

^Z“<^CH2)m wherein Z, R־¹־

-C — (CH,)״— Q

A; .

.

R , Q, m and n are as defined in

MX (II)

Formula (1) above, Mis a cation selected from Groups

IIA, IB, IIB, VIB, VIIB, and VIII of the Periodic

Table and X is an anion counterion selected in such a manner that the. sum of the valence charges of the cation M and anion X equal zero. Typical cations are magnesium, manganese, copper, nickel, zinc, iron, cobalt, calcium, tin, cadmium, mercury, chromium, lead and barium. Typical anions are chloride, bromide, iodide, fluoride, sulfate, bisulfate, perchlorate, nitrate, nitrite, phosphate, carbonate, bicarbonate, acetate, citrate, oxalate, tartarate, malate, maleate, fumarate, p-toluenesulfonate, methanesulfonate, (mono) or 25 . (di) (Cj-C^alkyl-dithiocarbamate and (c^-C^)alkylenebis-dithio carbamate. The Periodic Table referred to • herein is that appearing in the Merck Index, ninth edition.

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The substituted 1,2,4-triazoles of the invention can be . prepared by standard synthetic routes particularly those known per se for analogous compounds.

A preferred method for preparing compounds within the scope of.this invention is as follows:

R¹ . I metal ^z ----C — CH₂ ------Y + jQjsalt -----> Formula (1).

' R (Ill)

סך . In this reaction sequence Z, R , R and Q are as defined.in.Formula (1); Y may be halide, alkane sulfonate., or arylsulfonate and the metal salt is . ... . .' . ׳ ׳ : ׳'׳ ^; . preferably a sodium׳ or potassium salt. This reaction : can be run either without'solvent or in an appropriate .15 solvent such as benzene, toluene, xylene, glyme,

N,N-dimethylformamide, or dimethyl sulfoxide. Reaction . . temperatures may be from 0°C to 15O°C.

'׳ When the starting material of Formula (ill) is reacted with the 1H-1,2,4-triazole free base instead of

2.0 : its metal salt, (usually at temperatures from 50°C to .180°C) a mixture.of 1-substituted and 4-substituted . 1,2,4-triazoles. is obtained and these triazoles can be easily separated,by conventional chemical separation techniques such as extraction, chromatography, or crystallization.

Another preferred method for preparing the substituted triazoles is represented as follows:

2־54669

Z---C --CH״----NH״ + CH״CH״ . 3 ² 2 . ״

I \/

R² 'N-CR³=N-N=CR⁴-N -»Formula (1) / < Compound ^CH3CH . . (IV) )(V)

In this reaction sequence Z, R and R are as defined in Formula (1) and R and R are selected from hydrogen, halogen.,. (C^C^)alkyl, nitro or cyano. This reaction is usually run in an

10/. appropriate inert solvent such as benzene, toluene or xylene. .The reaction is usually carried out at temperatures from 0 C to 150 C with or without the ^; presence of a suitable catalyst such as p-toluenesulfonic acid, benzene sulfonic acid or methane sulfonic acid.

Either.reactant can'be used in excess in this preparation and. the mode of addition is not critical.

The starting materials of Formula (ill) can be prepared by standard synthetic methods. Examples of . such preparative methods can be found in Belgian Patent

No. 838,928 or its West German equivalent OLS P2604047.

The starting materials of Formula (IV) can be prepared by.making the corresponding Formula (ill) starting materials wherein Y is chlorine or bromine and reacting them with ammonia, either without solvent or in an appropriate solvent such as diethyl ether, tetrahydrofuran or methanol at temperatures usually from -40°C to 100°C.

./.ν.;.λ.Χ.'.':Τ.'?\.'τίϊβ addition salts of the substituted 1,2,4-

'- 5^: - י'. י :

5. 46 69-2 triazoles of this invention can be prepared by standard techniques well-known in the art. For example, a.compound of Formula (1) can be dissolve^ in an appropriate solvent such as diethyl ether, tetrahydrofuran, ethanol or methanol, and treated with' an equivalent or excess amount of a mineral or organic acid . which may or may not be dissolved in an appropriate solvent. The mixture is then either cooled or evaporated to give the salt which can either be used as such Or recrystallized from an appropriate solvent or combination of. appropriate solvents.

The metal salt complexes of compounds of Formula I can be prepared by adding dropwise, with stirring, a stoichiometric amount of a׳ metal' salt (dissolved in an 15. . appropriate solvent) to a solution of a compound of . Formula׳(!)dissolved in an appropriate solvent.

. The reaction.mixture may be briefly stirred and the .solvent removed under reduced pressure to give the . desired metal salt.

'יי The metal salt complexes can also be prepared by mixing stoichiometric or excess amounts of the metal . salt and a .compound of Formula (!) in the desired amount of solvent containing the appropriate adjuvants just prior to spraying plants to combat fungi. Adjuvants that may be- included in this in-situ preparation may be .detergents, emulsifiers, wetting agents, spreading agents, dispersing agents, stickers, adhesives and ; other, adjuvants which are. used, in agricultural . . applications.

Solvents that can be utilized in such an in situ

2־54669 procedure include any polar solvent e.g., water, methanol, ethanol, isopropanol or ethylene glycol and any aprotic dipolar solvent e.g., dimethylsulfoxide, acetonitrile, dimethylformamide, nitromethane or acetone.

. Metal containing fungicides can also act as ־ safening agents (i.e.,to reduce phytotoxicity) in place of non-fungicidal metal salts. Typical metal . containing fungicides that can be utilized in these . .׳׳ in situ procedures are: a) dithiocarbamates and . derivatives such as: ferric dimethyldithiocarbamate (ferbam), zinc dimethyldithiocarbamate (ziram), manganese ethylenebisdithiocarbamate (maneb) and its' : coordination product with zinc ion (mancozeb), zinc , ethylenebisdithiocarbamate (zineb); b) copper-based fungicides.such as cuprous oxide, copper naphthenate, .. and Bordeaux mixture; and c) miscellaneous fungicides . , such as: . phenylmercuric acetate, N-ethylmercuri-1,2,3, ' 6-tetrahydro-3,6-endomethano-3,4,5,6,7,7»-hexachlorophthalmide, phenylmercuri monoethanolammonium lactate,

20, . nickel-containing compounds and calcium cyanamide.

The compounds of this invention possess an asymmetric carbon atom and thus exist as racemic mixtures. The d and 1 enantiomorphs in these racemic

25, . mixtures can be separated via standard techniques, such as fractional crystallization with d-tartaric acid, 1_tartaric acid or 1-quinic acid, followed by basification .and.extraction of the d or 1 enantiomorph free base.

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The following working Examples 1-4 are presented to show illustrative preparations of compounds of the invention. The compounds prepared by Examples 6-9, as well as other analogous compounds which have been prepared by following one of the procedures given herein, are.listed below in Table I, appropriate analytical data being given in Table

Example •

(Compound 1, Table l)

A mixture of 12 g (0.036 mole) of 2-cyano-2(2,4-dichlorophenyl)hexyl bromide and 10 g (0.145 mole) of 1H-1,2,4-triazpie is heated at 185° overnight. The reaction is cooled and poured ihto water and extracted '’.'; .'<.. with ether., When the combined ether extracts are washed with water, white precipitate separate from the . ether layer. . This precipitate is filtered and dried in vacuum to give .1 g of a white solid, mp 46-9°. Glc , and nmr analysis reveal this material to be 4- [2-cyano-220 . . (2,4-dichlorophenyl)hexylJ -1,2,4-triazole.

• nmr (CDC1₃): £ 80.7-3.2 (complex multiplets, 9H), . 5.0 (q, 2H), 7.2-7.8 (m, 3H),

8.15 (s, 2H) . Example 2 ־ Preparation of 1- [2-Cyano-2-(2_>4-dichlorophenyl)hexyl] -1,

2,4-triazolium nitrate (Compound 3, Table I)

A. . 2-Cyano-2-(2,4-dichlorophenyl)hexyl bromide

A solution containing 1.0 mole of n-butyl bromide and‘1,0 mole of 2,4-dichlorophenyl cyanide in 250 ml of 30 methylene chloride is added into a 25% aqueous solution of .

־ .

2־54669 sodium hydroxide (500 ml) with 5.0 g of tetraethylammonium bromide. The reaction mixture is stirred vigorously under reflux for 3 hours to give

90% yield of desired product which is shown to be . 90% pure by glc analysis and nmr spectroscopy. The cyanide is then mixed with 1.3 moles of methylene bromide and added into a 50% aqueous solution of sodium hydroxide with either tetraethylammonium bromide . or benzyl triethyl ammonium chloride as catalyst. The 10 reaction mixture is heated to reflux (90°) for three hours until 95% of the starting material consumed.

There is always.about .5% ofcX-n-butyl 2,4-dichlorobenzyl cyanide remain unreacted in this reaction.

.B. 1- [2-Cyano-2-(2_>4-dichlorophenyl)hexyl]-l, . 2,4-triazole

To a dimethyl sulfoxide solution (25 ml) of sodium 1,2,4-triazole, generated from 3.2 g (0.046 m) of 1H-1,2,4-triazole and 1.85 g (0.046 m) of sodium hydroxide, is added 2-cyano-2-(2,4-dichlorophenyl) ׳ hexyl bromide dropwise at 110°. The whole is stirred at 110° for 1 1/2 hours. The reaction mixture is poured into 400 ml of water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO^. Drying agent was filtered and to the filtrate is added cone, nitric acid dropwise until no more precipitates form. The precipitate (8.0 g) is filtered and is characterized as ., the nitric acid salt (RH 45,136) 0> the desired product.

nmr (DMS0): £0.6-2.5 (complex multiplets, 9H, 5.2

'. .- 9 -

2־ 69 6 4 5 (q, 2H), 7.5-7.9 (m, 3H), 8.3 (s, 1H),

8.7 (s, 1H), 14.7 (s, 1H).

Example 3

The free base (Compound 4; Table I.) is obtained when the nitrate salt of Example 2 is back neutralized with 10% ammonium hydroxide solution.

. . nmr .(CDClg): $ 0.7-2.8 (complex multiplets, 9H), 5.0 (q, 2H), 7.1-7.6 (m, 3H), 7.9 (s, 1H), 8.0 (s, 1H)

-j_q Example 4

Zinc chloride complex of 1-[2-cyano-2-phenylhexyl]-1,2,4.triazole (Compound , Table I)־

To 6.5' g (0.0256 mole) of. 12 ך-cyano-2-phenylhexyl -1,2,4-triazole in 120 ml of methanol is added

151.5 ;־ g (0.0111 mole) of zinc chloride and let stir for minutes. The methanol is stripped to give 9.6 g . of residue. This material is taken up in warm ethanol, and the. solid product precipitates. The material is . separated by filtration to give 5.9 g (59%) of the product, mp 175-177°. .

Tables I and Ii referred to above now follow.

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TABLE I

CN

I Z-C-CH₂-Q.Y

<td> 5</td><td> Compound ^No.</td><td> Z ־.’</td><td> י</td><td> Q</td><td> Y</td>

<td></td><td> 1</td><td> 2,4-ClC.H״ 0 3</td><td> C₄K₉-n</td><td> 4-(1,2,4-triazolyl)</td><td> *.</td>

<td></td><td> . 2</td><td> 2,4-C1C_aH_ גם</td><td>^C4^H9־־Ii</td><td> 1&amp;4-(1,2,4-triazolyl)</td><td>^HN03</td>

<td></td><td> 3 \</td><td> 2,4-CldH״ 4 ם</td><td>^c4^h₉־H</td><td> 1-(1,2,4-triazolyl)</td><td>^HN03</td>

<td> 10</td><td> ' . 4</td><td> 2,4-ClC.H״ 0 3</td><td> C₄H₉-n</td><td> 1-(1,2,4-triazolyl)</td><td> —</td>

<td></td><td> ־5</td><td> 4-dC₆^H₄ .</td><td>^CH3</td><td> 1-(1,2,4-triazolyl)</td><td> —</td>

<td></td><td> • . . 6</td><td>⁴־^c1c6^h4 . .</td><td>^CH3</td><td> 1-(1,2,4-triazolyl)</td><td> HNO o</td>

<td></td><td> 7.</td><td>^C6^H5 : '</td><td></td><td> 1-(1,2,4-triazolyl)</td><td> HC1</td>

<td></td><td> 8</td><td>^C6^H5 \</td><td> C^g-n</td><td> 1-.(4,2,4-triazolyl)</td><td> —</td>

<td> 15</td><td>⁹ ׳</td><td>^C6^H5 </td><td>^c4^H9-n</td><td> 1-(1,2,4-triazolyl)</td><td> 1/2znc!₂</td>

<td></td><td> 10 ..׳'.</td><td> 2,4-ClC₆H₃</td><td>^C8^H17“~</td><td> 1-(1,2,4-triazolyl)</td><td> HC1</td>

<td></td><td> 11</td><td> 2,4-C1C,H_o. . . 0 3</td><td>^C8^H17”-</td><td> 1-(1,2,4-triazolyl)</td><td> —</td>

<td></td><td> 12.</td><td> 2,4-010^, 0 3</td><td> ch₂ch=</td><td> 1-(1,2,4-triazolyl)</td><td> —</td>

<td></td><td></td><td></td><td> ch₂</td><td></td><td></td>

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TABLE II

Elemental Analysis: Calc'd (found)

<td></td><td> Compound No.</td><td> mp .¾</td><td> C</td><td> H</td><td> Cl</td><td colspan="2"> N 0 or Zn</td>

<td> 5</td><td> 1.</td><td> . 46-9</td><td> 55.74 (55.40)</td><td> 4.99 (5.12)</td><td> 21.94 (21.82)</td><td> 17.33 (17.18)</td><td></td>

<td></td><td> 2</td><td> 110-120</td><td> 46.65 (46.41)</td><td> 4.44 (4.30)</td><td> 18.36 (18.55)</td><td> 18.13 (18.36)</td><td> 12.43 (12.77)</td>

<td></td><td> . 3' . .</td><td> 156-8</td><td> 46.65 (46.30)</td><td> 4.41 (4.61)</td><td> 18.36 (18.50)</td><td> 18.13 (18.27)</td><td> 12.43 (12.54)</td>

<td> 10:</td><td> 4</td><td> oil</td><td> 55.74 (55.91)</td><td> 4.99 (5.09)</td><td> 21.94 (22.07)</td><td> 17.33 (17.21)</td><td></td>

<td></td><td> 5,'</td><td> 114-6</td><td> 58.43 (57.40)</td><td> 4.49 (5.03)</td><td> 14.37 (13.37)</td><td> 22.71 (19.48)</td><td></td>

<td> 15</td><td> 6</td><td colspan="2"> 16 3( dec. )4554 .י (47.28)</td><td> 3.90 (3.90)</td><td> 11.45 (11.50)</td><td> 22.61 (21.97)</td><td> I5.5O (16.00)</td>

<td></td><td> 7 י' ’</td><td> 162-65</td><td> 6Ί.95 ' (61.10)</td><td> י¹ 6.59 (6.35)</td><td> 12.19 (10.49)</td><td> 19.27 (17.91)</td><td></td>

<td></td><td> 8</td><td> oil</td><td> 70.84 (71.36)</td><td> 7.13 (7.19)</td><td> -</td><td> 22,03 (20.82)</td><td></td>

<td> 20. ^:</td><td> 9</td><td> 175-77.</td><td> 55.87 (56.10)</td><td> 5.60 (5.70)</td><td> 10.99 (12.05)</td><td> 17.37 (17.01)</td><td> 10.13 (9.04)</td>

<td></td><td> 10</td><td> 125-31</td><td> 54.88 (54.80)</td><td> 6.60 (5.95)</td><td> 25.-58 (24.77)</td><td> 13.48 (13.76)</td><td></td>

<td> 25</td><td> 11</td><td> - oil</td><td> 60.16 (56.97)</td><td> 6.37 (6.48).</td><td> 18,70 (17.93)</td><td> 14.77 (14.25)</td><td></td>

<td></td><td> 12</td><td> 88-90</td><td> 54.74 (54.97)</td><td> 3.94 (3.97)</td><td> 23.08 (22.85)</td><td> 18.24 (18.59)</td><td></td>

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The substituted 1,2,4-triazoles, acid addition . salts and metal;salt complexes of this invention are broad-spectrum fungicides which possess a high degree .of activity against assorted phytopathogenic fungi.

These compounds, salts and complexes are particularly effective at rates of application from about 50 to about 2000 ppm in controlling barley net blotch (Helminthosporium teres) on barley plants, grey mold (Botrytis cinerea) on faba beans, bean powdery mildew (Erysiphe. polygon!) on bean plants, grape downy mildew (Plasmopora viticola) on grape seedlings, rice blast . (Piricularia oryzae) on.rice plants, tomato late blight (Phytophthora infestans) on tomato seedlings, and wheat stem rust'(Puccinia graminis f. s^. tritici race 15B-2) on wheat seedlings.?

In evaluating these compounds, a preliminary fungicidal evaluation is carried out using the compounds in a carrier at a concentration of 300 ppm and spraying the. plants to run off in a carrier volume of about . 150 gallons/acre. ׳

The general, procedure is to take potted plants in proper condition of growth for susceptibility to the ' fungal disease to be evaluated, to spray these on a . moving belt with the fungicidal agents and allow them to dry. The plants are then inoculated with the appropriate fungal spores which are then allowed to . incubate until the disease has developed and the percent control is read or estimated.

Typical compounds, acid addition salts and metal

־ י.'.. י

2־54669 ׳ salt complexes of the invention.

have (when evaluated by the general procedure given above at 300 ppm concentration) shown complete or 70-90% fungicidal control of j (1) Helminth□sporium teres on barley plants (var. Wong), (2) Botrytis cinerea on broad bean plants (var. Vicia faba), (3) Erysiphe polygon! on bean plants (var. Drawf Hort), (4) Plasmopora viticola on grape seedlings (var. Siebel 1000), (5) Piricularia oryzae on rice plants (var. Nova 66), (6)

1q Phytophthora infestans on tomato plants (var. Rutgers) and (7) Puccinia graminis(f. sp. tritici race 15B-2) on

.. wheat, plants.

.'. The compounds of Formula I and their acid addition salts and metal salt complexes find a wide variety of uses !5 .1./ as broad, spectrum fungicides, e.g. in the storage of cereal grain and as fungicides on turf, fruit orchards, vegetables and golf courses.

In their use as fungicides, the active ingredients provided by the invention are usually applied to combat ' : phytopathogenic fungi on plants by applying them to growing plants, plant seeds or the plant habitat, e.g. soil, in a fungicidally effective amount.

The substituted 1,2,4-triazoles, acid additon salts and metal salt complexes of the present invention . . in their application as agricultural fungicides can be applied to. various loci such as the seed, the soil or the foliage, .particularly where a vendible agronomic crop is concerned. For such purposes these compounds can be used, in the technical or pure form as prepared,

יי. -'.14 - ' .

2־54669 as solutions or as formulations. The compounds are usually used in admixture with an agronomically acceptable diluent or carrier so as to render .them suitable for subsequent dissemination as fungicides, 5; For example, the'active fungicidal ingredients can be formulated with a carrier or diluent as dusts, .granules, aerosols, emulsifiable concentrates, wettable powders,'or f-lowable emulsion concentrates, the last ; ' three formulations usually containing a surfactant with a liquid or solid carrier and, when desired, suitable surfactants are incorporated. Details of suitable methods of making formulations, and other pesticides which mayJ5e used in conjunction with the . fungicidally active compounds concerned in the present 15 ' invention are to be found in the specification of

W. German OLS P2604047, and its various counterparts ' in other countries, which patent specifications are incorporated herein by reference.