IE43517B1 - Substituted imidazoles and their use as fungicides - Google Patents

Substituted imidazoles and their use as fungicides

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Publication number
IE43517B1
IE43517B1 IE226/76A IE22676A IE43517B1 IE 43517 B1 IE43517 B1 IE 43517B1 IE 226/76 A IE226/76 A IE 226/76A IE 22676 A IE22676 A IE 22676A IE 43517 B1 IE43517 B1 IE 43517B1
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Ireland
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substituted
imidazole
phenyl
joined
acid addition
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IE226/76A
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IE43517L (en
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Rohm & Haas
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Priority claimed from US05/642,041 external-priority patent/US4105762A/en
Priority claimed from US05/647,039 external-priority patent/US4073921A/en
Application filed by Rohm & Haas filed Critical Rohm & Haas
Publication of IE43517L publication Critical patent/IE43517L/en
Publication of IE43517B1 publication Critical patent/IE43517B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/2637—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions between a compound containing only oxygen and possibly halogen as hetero-atoms and a halogenated hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/50—Halogenated unsaturated alcohols containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

1530172 Substituted imidazoles ROHM & HAAS CO 2 Feb 1976 [5 Feb 1975 12 March 1975 18 Dec 1975 7 Jan 1976] 04011/76 Heading C2C [Also in Division A5] The invention comprises a substituted imidazole or metal salt complex or an agronomically acceptable acid addition salt thereof, said substituted imidazole being of the formula: wherein: Z (when not joined to R2) is a group containing up to 18 carbon atoms and is aryl; substituted aryl; aryl so substituted as to form a fused carbocyclic or heterocyclic ring; saturated carbocyclic so substituted as to form a fused aryl ring; or a heterocyclic group; R1(when not joined to R2) is hydrogen (except when R2 is hydrogen), cyano, (C 1 -C 20 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 12 )alkenyl, (C 5 -C 8 )- cycloalkenyl, (C 3 -C 6 )alkynyl or aralkyl of up to 24 carbon atoms which aralkyl group is optionally substituted with up to 3 substituents which may be the same or different; R2 (when not joined to Z or R1) is hydrogen or a group containing up to 20 carbon atoms and which is (C 1 -C 20 )alkyl, (C 2 -C 12 )alkenyl, (C 3 - C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 8 )cycloalkenyl, aryl or aralkyl, the last two groups being optionally substituted; R1 and R2 (when joined together) form, together with attached carbon atom, a (C 3 -C 8 )- cycloalkyl residue; Z and R2 (when joined together) form the group A is a (C 1 -C 5 )alkylene group X is halogen, nitro or (C 1 -C 4 )alkyl, the X substituents being the same or different when more than one is present; a is zero, 1 or 2, and n is zero or 1. Methods of preparation of these compounds and their precursors are given. The compounds may be used as fungicides.

Description

This invention concerns novel substituted imidazoles, fungicidal products containing them, the preparation of the new compounds and their use as fungicides.
The novel substituted imidazoles concerned in this invention are those of Formula I below as well as agronomically acceptable acid addition salts and metal complexes of the imidazoles of Formula I.
The Formula I compounds are: Z-C-CH. (A) -N ι z n < •(X).
(I) wherein Z (when not joined to R ) is a group containing up to 18 carbon atoms, preferably up to 14 carbon atoms, and is aryl; substituted aryl and preferably aryl substituted with up to 3 substituents which may be the same or different and which are selected from halo, cyano, (C^-C2)alkoxy, methylthio, nitro, amino and (in the case when R1 is cyano) trihalomethyl, benzoyl and methylenedioxy; aryl so substituted as to form a fused carbocyclic or heterocyclic ring; saturated carbocyclic so substituted as to form one or two fused aryl rings; or a hetercyclie group; 2 R (when not joined to R ) is hydrogen (except 2 when R is hydrogen), cyano, (C^-C^Jalkyl (typically (C^-Cg)alkyl), (C3-Cg)eyeloalkyl, (c2"c12)alkenyl, (Cg-Cg)cycloalkenyl, (C^-Cg)alkynyl or aralkyl of up to 24, preferably of up to 11, carbon atoms which aralkyl group is optionally substituted with up to 3 substituents which may be the same or different and which are preferably selected from halo, nitio, cyano, (C.-C_)alkoxy, amino and methylthio; * π y R (when not joined to Z or R ) is hydrogen or a group containing up to 20 carbon atoms and which is (C^-C20)alkyl (typically (C^-C^alkyl), (c2c12)alkenyl (preferably (C-Cg)alkenyl), (C^CgJalkynyl, (Cg-Cg) eycloalkyl, (C,.-Cg) cycloalkenyl, aryl or aralkyl, the last two groups being optionally substituted and preferably with up to 3 substituents which may be different and which are selected from halo, nitro, cyano, (Cn-c,)alkoxy, trihalomethyl, amino and methylthio; R and R (when joined together) form, together with the attached carbon atom, a (Ο^-Οθ)eycloalkyl residue; Z and R (when joined together) form the group A is a (C.-C.)alkylene group; X is halogen, nitro or (C^-Cj)alkyl, the X substituents being the same or different when more than one is present; a is zero, 1 or 2 and n is zero or 1.
The alkyl, alkenyl and alkylene groups which may be present in the compounds of Formula I may be straight or branch chained.
In Formula I, Z when aryl may be phenyl optionally substituted with up to three (preferably one or two) (C^-C^Jalkyl groups (e.g. tolyl or xylyl), biphenyl or naphthyl. When Z is aryl so substituted as to form a fused carbocylic or heterocyclic ring, it may be indanyl, acenapthenyl, methylenedioxyphenyl or indolyl. When Z is saturated carbocyclic so substituted as to form one or two aryl rings it may be indanyl or acenaphthenyl. When Z is a heterocyclic group, it may be thienyl, pyrryl, furyl, pyridyl, pyrimidyl or indolyl. When Z is substituted aryl, it may be phenyl substituted with up to three (preferably one or two) of the same or different substituents selected from halo, methoxy, ethoxy, nitro, amino and methylthio.
The term aryl used throughout this specification means an aromatic hydrocarbon group having a monovalent aromatic ring.
A sub-class of compounds in which the carbon atom vicinal to the Z group does not contain a cyano group are compounds of Formula IA below and acid addition salts of compounds of Formula IA. Compounds in which said vicinal carbon atom does not contain a cyano group will be designated herein by formulae, table and example numbers in which the letter A is appended.
R' ........fl Z—C-CH2— n (IA) I - 5 Wherein Z is phenyl, naphthyl, biphenyl, acenaphthenyl, indanyl, indolyl, pyridyl, pyrimidyl, pyrryl, furyl, thienyl or phenyl substituted with up to three of the same or different substituents selected from (C^-C^) alkyl, methoxy, eth'jx., halo, n.itrc., amino and methyl1 2 thio; R (when not joined to R ) is hydrogen (except 2 when R is hydrogen), (C^-σ^θ)alkyl, (C2"C12)alkenyl, (C7-Cg)aralkyl, (C7-Cg)aralkyl substituted with up to two of the same or different substituents selected from methoxy, ethoxy, halo, nitro, amino and methylthio, (Cg-C?)cycloalkyl or (Cg-C^)cycloalkenyl; R (when not joined to R1) is (C^-C^)alkyl, (Cg-C.^) alkenyl, (C^-Cg)aralkyl, (C7~Cg)aralkyl substituted with up to two of the same or different substituents selected from methoxy, ethoxy, halo, nitro, amino and methylthio, phenyl optionally substituted with up to two of the same or different substituents selected from methoxy, ethoxy, halo, nitro, amino and methylthio, 2 (Cg-C^Jcycloalkyl or (Cg-C?)cycloalkenyl; R and R (when joined together) form, together with the attached carbon atom, a (C3-Cg)cycloalkyl residue.
Compounds of Formula IA which may be singled out for mention are those in which 2 is phenyl optionally substituted with up to three of the same or different substituents selected from methyl, methoxy, . . 2,. halo and nitro. R is not joined to R and is hydrogen or, less preferably, (C^-C.^)alkyl (e.g.
(C^-Cg)alkyl and R2 is (C4"C1Q)alkyl, phenyl, benzyl, phenethyl each of the last three groups being option30 ally substituted in the ring with methyl or halo.
An example of a compound of the class just mentioned is one in which Z is 2,6-dichlorophenyl, R1 is hydrogen and R is n-butyl. - 6 Typical metal salt complexes of compounds of Formulae I and IA are those represented generally by Formula II below Z —C —CH_(A) — N . 4 n MY (II) 2 wherein Z, R , R , A, η, X and a are as defined above, M is a metal cation, Y is an anion counterion and m is 1 to 4. In Formula II above, the metal cation M is generally selected from Groups IIA, IVA, VA, IB, IIB, VIB, VIIB and VIII of the Periodic Table. Y is gener ally a solubilizing counterion.
The metal salt complexes can be prepared by bringing together in a suitable medium, usually a solvent, an appropriate metal salt and an appropriate substituted imidazole in the free base or acid addition salt form. Preparation of the substituted imidazole precursors is described in more detail later.
The invention also encompasses mixtures of (A) one or more compounds of Formula I or acid addition salts thereof and (B) one or more metal salts capable of complexing with said compounds or salts and/or at least one metal-containing fungicide.
The substituted imidazoles of this invention possess eradicant fungicidal properties which are significant in that they kill phytopathogenic fungi in infected plant tissues and therefore can be utilized after fungal infection has already occurred. 3 517 The systemic properties of these compounds are equally unique in that the compounds will move both acropetally and basipetally in plant tissues. Furthermore, these compounds possess protectant properties against phytoj pathogenic fungi when applied to >he plants prior to infection.
Typical compounds of Formula IA includes 1-[β-(2,4-dichlorophenyl)hexyl]imidazole 1-[β-(2-chlorophenyl)hexyl] imidazole 1 - [ β-(4-bromophenyl)hexyl]imidazole 1-[β-(3-iodophenyl)hexyl]imidazole 1-[β-(2,6-dichlorophenyl) decyl]imidazole l-[β-(2,4-dichlorophenyl)β-(ρ-chlorophenyl) ethyl] imidazole l-[p-(2,4-dichlorobenzyl)hexyl]imidazole l-[p-(2-methyl-41-chlorophenyl)heptyl]imidazole 1-[β-(2,4-dichlorophenethyl)hexyl]imidazole 1-[β-(2,4-dichlorophenyl)nonyl]imidazole 1-[β-(2,4-dimethylthiophenyl)hexyl] imidazole 1-[β-(4-(nitrophenyl)hexyl]imidazole 1-[β-(3,4-dichlorophenyl)hexyl]imidazole l-[^-(4-tolyl)hexyl]imidazole l-|^-(4-anisyl)hexyl]imidazole 1-[β-(2,4-dichlorophenyl)-β-cyclopropyl ethyl] imidazole 1-[β-(2,4-dichlorophenyl)-β-cyelopentyl ethyl] imidazole 1-[β-(2,4-dichlorophenyl)-β-cycloheptyl ethyl] imidazole l-[ β, β-^ίΐΛθω·^1θηβ-β-(2' ,4' -dichlorophenyl) ethyl] imidazole 1-[β, β-ρβηηηπιβί)ιγ1θηβ-β-(21,3' -dibromophenyl)ethyl] imidazole 1-[β, β-1ιβρΐ3πιβ^γ1θηβ-β-(3', 51 -difluorophenyl)ethyl] imidazole 3 31) The compounds of Formula I (where R^ is other than cyano, the cyano-substituted compounds being dealt with later on in this specification) can be prepared by standard methods of synthesis. Typical methods of preparation which can be utilized in the preparation of these compounds include the following general syntheses, the temperatures given unless indicated otherwise are in degrees centigrade. l-(P-substituted alkyl) imidazoles When an acetate derivative (IIIA) is reacted with sodium hydride in tetrahydrofuran (THF) or 1,2dimethoxyethane (glyme) it forms the corresponding sodium salt (IVA). The reaction of (IVA) with an organic halide affords the ester (VA). z-ch2c°2c2h5 (ΙΙΙΑ) NaH Z-CHNaCO2C2H5 (IVA) I (VII IA) Na These esters (VA) are converted to the corresponding carbinol derivatives (VIA) by a reduction with reagents such as lithium aluminum hydride (LiAlH^) in ether or bis(2-methoxyethoxy) aluminum hydride in benzene.
The subsequent treatment of (VIA) with methane sulfonyl chloride in the presence of triethyl amine in an aromatic hydrocarbon solvent such as benzene or toluene provides the sulfonate (VIIA). Treatment of (VIA) with thionyl chloride or phosphorus pentachloride in an aromatic hydrocarbon such as benzene 4351) - 10 or toluene provides the chloride (VIlaA). The reaction of (VIIA) with excess of an imidazole or (VIlaA) with the sodium salt of an imidazole either neat or in the presence of such solvents as benzene, glyme or N,Ndimethylformamide (DMF) gives the alkylated imidazole products (VIIIA).
Methylene Chain Extepsion The methylene chain can be extended from the methane sulfonate (VIIA) via the preparation Of the nitrile (IXA) The hydrolysis of (IX)A in boiling 50% sulfuric acid provides the acid (X)A which is subsequently reduced with LiAlH^ to provide the alcohol (XI)A. The imidazole derivative is then formed via the sulfonate in the usual way.
Compounds in which R in Formula I is phenyl The synthesis of these compounds involves a Darzen1 a reaction. A substituted benzophenone is reacted with ethyl chloroacetate in the presence of sodium hydride to give the glycidic ester (XII;A.
Z—C=O + NaH C1CH_COCH I _z Z Z 3 /\ Z-C"CHCO C„H I 2 2 5 C,H_ 6 5 Vs (XIX)A Z-CHCHO V5 (XXII)A 160 Hydrolysis Ψ OH I Z-C=CCO.H ι z C H 6 5 LiAlH.
Z-CHCH„OH I 2 c6H5 (XIV)A ch3so2ci/(c2h5)3n Z-CHCH„0S0„CH I z i 3 C.H6 5 (X).
Ni H Z-CHCH-N I Vs (XVjA (X). e d 5 17 A hydrolysis and a subsequent decarboxylation of (XII)A gives the diaryl acetaldehyde (XIII)A. This aldehyde (XIII)A is reduced to the corresponding alcohol (XIV)A by LiAlH^, and the latter is then converted to the imidazole product (XV)A by the usual route. β,β-disubstituted alkyl imidazoles When the appropriate sodium alkyl acetate derivative (XVl)A prepared as previously described is reacted at elevated temperatures in a solvent such as ether, tetrahydrofuran or dimethylformamide with an iodoalkane the desired trisubstituted acetate (XVII)A is obtained.
Z-CR NaCOgC^Hg (XVI)A R2X Z-CCH2OSO2CH3 ^CE[3SO2C1/(C2H5>3N (X). 2Y°2C2H5 R2 (XVII)A LiAlH4 I Z-CCH,OH >2 2 (XVIII)A ‘Ν' k Z-CCH-N (XIX)A -(X). * 3 5 1 Reduction of (XVII)A with LiAlH^ in anhydrous ether gives the alcohol (XVIIl)A. Formation of the sulfonate followed by the imidazole reaction as previously described gives the desired product (XIX)A.
Alternate Routes for Compounds in which R in Formula I is Optionally Substituted Phenyl The reduction of a substituted phenylacetic acid (XX)A with LiAlH4 in tetrahydrofuran gives the alcohol (XXI )A.
Z-CHCO-H I C.H_ R 6 5-n n (XX)A /' Z-CHCHLN I \CA-A LiAlH. -4-> H (X) a Z-CHCH-OH I C,H_ R 6 5-n n (XXI)A CH.SO 01/ Ψ Z-CHCH2OSO2CH3 (XXII)A Formation of the sulfonate by reaction with an imidazole gives the desired produot (XXII)A. l-(P-substituted diarylalkyl)imidazoles The reaction of chloroacetaldehyde diethylacetal with a substituted aromatic hydrocarbon in the presence of sulfuric aoid at room temperature gives the substituted arylethylchloride (XXIII)A. The reaction of (XXIII)A with the sodium salt of an imidazole as previously described affords the product (XXIV)A. j a 1 '7 - 14 z + (c2h5o)2chch2ci H SO 2 ‘ =Z-CHCH.C1 I 2 Z (XXIII) A I Na V Z-CHCH„N'/--(X) I 2 \ a z \=) (XXIV)A When a benzene substituted with electron donating groups is treated with 1,2-epoxyhexane in the presence of stannic chloride the hexanol (XXVjA is obtained.
/°\ Z + CH- CH.
SnCl, Z-CHCH2OH C4H9 C4H9 (XXV)A The imidazole derivative is formed via the route from the methane sulfonate. l-r~(methylthio substituted phenyl)alkyl]imidazoles The alkylthio derivatives are prepared from the aldehyde (XXVI )A. 43317 ch3s CH S * (XXVII)A ch2oh CH3SO2C1/(C2H5)3N ch3s CH2CN (XXIX)A NaCN ch3s CH2OEO2CH3 (XXVIIl)A CH3S 1. NaH 2. R'X h2so4 ch3s r~ . CHCN ROH I R' (XXX)A -> \ CHCO R I 2 R’ ch3s (XXXIIl)A (XXXI) A CHCELN I 2 R' a3517 The aldehyde (XXVI)A is reduced to the alcohol (XXVII)A with LiAlHj. The alcohol (XXVII)A is reacted with methane sulfonyl chloride in the presence of triethylamine to form the sulfonate (XXVIII)A. Treatment of the methane sulfonate (XXVIII)A with sodium cyanide gives the benzyl nitrile derivative (XXIX)A. Alkylation of the nitrile (XXIX)A via NaH metallation followed by treatment with alkylhalide gives the α-alkyl benzylnitrile derivative (XXX)A. Hydrolysis of the nitrile (XXX)A with sulfuric acid in an alcoholic solvent gives the α-alkyl phenylacetic acid ester (XXXI)A which upon reduction with LiAlH^ gives the phenethyl alcohol (XXXII)A. The imidazole product is formed via the methane sulfonate as shown above. l-Γβ-(nitro substituted phenyl)alkyl]imidazole The nitro substituted phenyl derivatives (XXXV)A are formed by nitration of the unsubstituted or substituted analogs (XXXIV)A. 4351? l-fB-(amino substituted phenyl)alkyl imidazole The amino substituted phenyl derivatives (XXXVI)A are formed by reduction of the nitro substituted phenyl derivative (XXXV)A.
Acid Addition Salts Z-C-CH (A) — N , 2 Π /= \= (X).
HA (XXXVII)A Z-C-CH. (A) — N . 2 π /L (X).
HA (XXXVIII)A The salts of substituted imidazole derivatives are prepared by treating an ether solution of the imidazole (XXXVll)A with an equivalent amount of the desired inorganic or organic acid dissolved in ether or alcohol followed by filtration or concentration then filtration to give the desired salt. 3517 - 18 Metal Complexes Z-C— CH. (A) - Ν' , 2 n /= /= V (XXXIX)A Z-C —CH_ (A) — N , z n.
-(X).
(X).
MY MY The metal complex salts of the aralkyl imidazole derivatives (XXXIX)A are prepared by the treatment of an alcoholic or aqueous solution of the imidazole (XXXVII)A with a metal salt at temperatures from about 15°C to about 60°C.
The following examples are provided merely to illustrate the methods of preparation of novel compounds of Formula I (where R1 is other than cyano) and their acid addition salts and metal complexes.
The actual working examples are illustrative preparations of compounds of the invention and which are listed and identified in Tables IA and IIA which follow later .
EXAMPLE IA 1—f6-(2,4-dichlorophenyl)hexyl)imidazole 1. ethyl-8-(2,4-dichlorophenyl)hexanoate To 58.6 g (1.22 mole) of 50% sodium hydride in liter of anhydrous tetrahydrofuran (THF) is added 3 317 - 19 at 40°, 50.0 g (0.215 mole) of ethyl-2,4-dichlorophenyl acetate, and the mixture is stirred for 10 min. When the evolution of H2 gas begins the temperature of the reaction is lowered to 10°, and 200.0 g (0.858 mole) of additional ester is added dropwise. When this addition is complete, the reaction is allowed to stir and to slowly warm up to ambient temperature. The reaction mixture is then heated at 40° for 1 hour and then it is cooled to ambient temperature. To the mixture is added at 20°, 198.0 g (1.076 mole) of 1-iodobutane, and when this addition is complete, the reaction is stirred at 40° for 16 hours. The mixture is cooled, stripped down in volume, and poured into 1.5 liters of water.
The insoluble oil is separated, and the aqueous layer is extracted with ether. The extract is combined with the oil. The ether solution is washed with 100 ml. of dilute hydrochloric acid, 100 ml. of sodium bicarbonate and finally 100 ml. of water. The solution is dried and concentrated to give 324.3 g of crude product. Distillation of the product gives 223.0 g (72%) of pure ester (115-20°/.25mm). The material is identified by ir and its purity is determined by glc. 2, 2-(2,4-dichlorophenyl)hexan-I-ol To 11.7 g. (0.308 mole) of lithium aluminum hydride in one liter of anhydrous ether at 5-10° is slowly added 140,0 g (0.486 mole) of the prepared ethyl~P-(2,4-dichlorophenyl)hexanoate. When the addition is complete, the reaction is allowed to stir and slowly warm to ambient temperature. The slurry is slowly added to iced water as H2 gas vigorously evolves. When this addition is complete, the mixture - 20 is made acidic with concentrated hydrochloric acid. The organic layer which forms is separated and the aqueous layer is extracted with ether. This extract is combined with the organic phase, and the solution is washed with water and then with dilute sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the ether solution is concentrated and distilled (118-23°/.2 mm) to give 110.8 g (92%) of product. 3. 2-(2,4-dichlorophenyl)hexyl methane sulfonate To 24.7 g (0.1 mole) of the 2-(2,4-diohlorophenyl)hexan-2-ol and 13.8 g (0.12 mole) of methane sulfonyl chloride in 200 ml, of benzene at 10° is slowly added 14.2 g (0.14 mole) of triethylamine.
When the addition is complete, the reaction mixture is stirred, and allowed to come up to ambient tempera ture over a 30 minute period. The reaction slurry is then heated to reflux for 30 minutes, cooled and poured into water. The organic solution is washed with dilute hydrochloric acid then with water and finally with dilute sodium bicarbonate solution.
After drying over anhydrous magnesium sulfate, the benzene is stripped off to yield 31.8 g (98%) of the crude product. This material is identified by ir and nmr. The purity is determined by glc. 4. Imidazole Reaction To 27.2 g (0.4 mole) of imidazole at 95° is added 31.8 g (0.098 mole) of the 2-(2,4-dichlorophenyl) hexyl methane sulfonate, and the materials are stirred at 95° for 16 hours. At the end of this 4351? - 21 period the reaction mixture is cooled, and poured into 500 ml. of water. After stirring for one hour the organic material is separated, and the aqueous layer is extracted with ether. The ether is combined with the organic phase, and after a water wash is dried and concentrated to give 24.4 g (88%) of product. The imidazole product is identified by ir, nmr, and elemental analysis. Its purity of greater than 95% is determined by glc.
EXAMPLE 2A 1-Γ P-(2,4-dichlorophenyl)hexyl 1 -imidazole hydrochloride In 30.0 g (0.101 mole) of l-[p-(2,4-diehlorophenyl)hexyljimidazole dissolved in 200 ml. of ether is bubbled dry hydrogen chloride gas until the mixture is acidic to litmus. A colourless solid forms which is separated by filtration to give 24.5 g of the hydrochloride salt which is identified by nmr.
EXAMPLE 3A l-Γ 6-(2,4-dichlorophenyl)hexyll imidazole zinc chloride Method A To a solution of 2.0 g (0.0067 mole) of 1-[P(2,4-dichlorophenyl)hexyl]imidazole in 10 ml. of absolute ethanol is added dropwise a solution of 0.46 g (0.0036 mole) of zinc chloride in 30 ml. of absolute ethanol. The reaction mixture is stirred at room temperature for 10 minutes and the solvent is removed under vacuum. A white glass-like solid is isolated as the product and is identified by nmr.
Method B 1-[$-(2,4-dichlorophenyl)hexyl]imidazole 2.0 g (0.0067 mole) and zinc chloride 0.92 g (0.0067 mole) iSSD are mixed in an acetone:methanol:water (1:1:2) solvent system, 40 ml. This preparation is immediately applied to plant foliage.
EXAMPLE 4A l-Γ0-(2,4-dichlorophenyl)hexyl] imidazole oxalate To a solution of 4 g (0.0135 mole) of l-[0-(2,4dichlorophenyl)hexyl] imidazole in ether is added dropwise a solution of 1.7 g (0.0135 mole) of oxalic acid dissolved in 10 ml. of methanol. A white precipitate forms immediately. The precipitate is collected by filtration and dried under vacuum to give 3.37 g of a solid, m.p. 126-128°.
EXAMPLE 25A l-Γ β-(p-methylthiophenyl)hexyl]imidazole 1. p-Methylthiophenyl methanol To 19.8 g (0.521 mole) of lithium aluminum hydride (LiAlH4) in 750 ml. of anhydrous ether is slowly added 98 g (0.64 mole) of p-methyl mercaptobenzaldehyde in 250 ml. of anhydrous ether at less than 10°C. When the addition is complete the reaction is stirred for 0.5 hour at 1O°C. and then the reaction is stopped by slowly adding 100 ml. of acetone to remove unreacted LiAlH4· To this mixture is added 500 ml. of water and the reaction is made acidic by the addition of cone, hydrochloric acid. The ether layer is separated, dried over anhydrous magnesium sulfate, and concentrated to give 89.6 g of the crude product. This residue is crystallized from ether-hexane to give 75.8 g, m.p. 38-40° (76% yield). 4351? 2. ^-Methylthiophenyl acetonitrile To 73.0 g (0.47 mole) of p-methylthiophenyl methanol and 59.6 g (0.52 mole) of methane sulfonyl chloride in 250 ml of benzene is slowly added 59.6 g (0.59 mole) of tra.ethylamme over a period of one hour at less than 15°C. When the addition is complete, the reaction is stirred for one hour and allowed to warm up to ambient temperature.
The reaction mixture is combined with 400 ml of dilute hydrochloric acid. The benzene layer is separated, washed with 250 ml of Hj0' dried and concentrated to give 74.7 g of the crude mesylate product.
This residue is added to 25.5 g (0.52 mole) of sodium cyanide in 300 ml of dimethyl sulfoxide, and allowed to stir for one hour. The reaction is poured into iced water and the yellow-tinted solid which forms is filtered and recrystallised from benzene-hexane to give 60.8 g (79%) of the product, m.p. 44-5°. 3. 2 -(p-Methylthiophenyl)hexanenitrile To 12.5 g (0.25 mole) of 50% sodium hydride in 300 ml of anhydrous, distilled tetrahydrofurane is added 60.0 g (0.258 mole) of the p-methylthiophenyl acetonitrile over a period of one hour. The reaction mixture is allowed to stir for one hour then 48.8 g (0.265 mole) of 1-iodobutane is slowly added. When the addition is complete, the reaction is stirred for two hours. The mixture is combined with 500 ml of water and the organic phase is separated, washed with water and concentrated to give 80.1 g of crude product. Upon distillation - 24 65.7 g (85%) of the product is isolated (126-30°/.01 mm). The imidazole derivative is then prepared by the procedures described in parts 2, 3, 4 and 5 of Example 89A.
EXAMPLE 27A l-Γ B-(p-nitrophenyl)hexyl]imidazole To a mixture of 20 ml of nitric acid and 10 ml of sulfuric acid at 5° is slowly added 10.0 g (0.044 mole) of l-[B-phenylhexyl]imidazole in 10 ml of sulfuric acid. As soon as the addition is complete, the reaction is poured into iced water and the oil product settles out. The acidic solution is decanted and the remaining oil is washed with water, and then made basic with dilute sodium hydroxide. The product is extracted out with ether, dried and treated with nitric acid to precipitate the salt. The salt is recrystallised from acetoneether to give 4.8 g m.p. 98-100°. Treatment of the salt with dilute sodium hydroxide gives the free base product.
EXAMPLE 28A l-Γ B-(p-aminophenyl)hexyl]imidazole To 5.0 g (0.0183 mole) of l-[β-(ρ-nitrophenyl)hexyl] imidazole in 50 ml of methanol is added 2.0 g of cone, hydrochloric acid. The solution is heated to reflux and 4 one gram portions of iron filings are added at five minute intervals. When the additions are complete, the reaction slurry is stirred at reflux for 14 hours. The reaction is cooled, and then poured into water. The organic material is extracted out with toluene, dried and concentrated to give 4.5 g of the crude product.
The oil is dissolved in ether, and the solution is treated with nitric acid. The salt settles out as an oil. The oil is treated with dilute sodium hydroxide, extracted with ether, dried and concentrated to give 3.5 g of the imidazoxe product.
EXAMPLE 29A 1-f β-(2,4-dichloro-5-nitrophenyl)hexyl] imidazole To a solution of 40 ml of nitric acid and 10 ml of sulfuric acid, 14.8 g (0.0498 mole) of 1-[β-(2,4dichlorophenyl)hexyl] imidazole in 30 ml of sulfuric acid is added at less than 5°. The reaction is stirred for % hour and then it is poured into iced water. The oily solid which separates is isolated by decanting off the dilute acid solution. The residue is washed and then treated with ammonium hydroxide solution.
The organic product is extracted out with ether, and the extract is dried and treated with dry hydrogen chloride. The hydrochloride salt precipitates out and is filtered to give 9.4 g of the crude product.
A recrystallisation of 2.7 g of this material from methanol gives 1.8 g of the purified hydrochloride salt, m.p. 99-100°.
EXAMPLE 44A ' l-Γg-(2,4-dimethylphenyl)hexyl)imidazole 1. 2,(2,4-dimethylphenyl)hexan-l-ol To a stirred, 0°C mixture of m-xylene 173 g (1.63 mole) and anhydrous stannic chloride 78.0 g (0.30 mole) which is constantly swept with nitrogen, is added dropwise, 1,2-epoxy-hexane, 30.Og (0.30 mole) in 50 g m-xylene. The exothermic temperature is ί & maintained at 3°C by the rate of addition. After the addition is completed, the reaction which now contains 223 g (2.0 mole) m-xylene is stirred for 30 minutes at 0°c then poured into iced concentrated hydrochloric acid. The aqueous and organic layers are separated. After extracting the aqueous portion with ethyl ether, this organic layer is combined with the previous organic fraction. This combined organic material is washed successively with water, sodium bicarbonate and again water. The dried organic solvent mixture of ethyl ether and excess unreacted m-xylene is then removed on rotary evaporator. The concentrated residue is fractionally distilled in vacuo. The third fraction, 112°C/.5 mm, is shown to be the desired product by spectral and analytical data.
The yield is 35.6 g (57.6% theory). 2. 1-Γ 6-(2,4-dimethylphenyl)hexvl1 imidazole The imidazole is formed from the alcohol by the method of Example IA parts 3 and 4.
EXAMPLE 60A l-Γ 6-(2,4-dlchlorophenyl)phenethvl1 imidazole 1. a-(2,4-dichlorophenyl)phenyl acetaldehyde To 47.1 g (0.188 mole) of 2,4-dichlorobenzophenone and 36.2 g (0.289 mole) of ethyl chloroacetate ls slowly added 14.9 g (0.31 mole) of 50% sodium hydride at 15°. The reaction is allowed to stir and slowly come up to ambient temperature overnight.
The reaction is added to iced water, and made acidic, with dilute hydrochloric aoid. The organic material is extracted out with three 200 ml portions of benzene. The extracts are combined, washed twice with 100 ml - 27 4 S * t 7 of water and dried over anhydrous magnesium sulfate.
The benzene is stripped off, and the crude product is added to 35.3 g (0.53 mole) of 85% potassium hydroxide in 350 ml of water. This mixture is refluxed for 20 hours, cooled a.ui washed twice with 200 ml of benzei.a. The aqueous solution is acidified and the organic acid settles out as an oil. The oil is separated and the aqueous solution is extracted twice with 200 ml of ether. The extracts are combined with the oil, dried over anhydrous magnesium sulfate and concentrated to give 30.7 g of the hydroxy acid. This residue is heated for 3 hours at 140° to decompose it to the crude aldehyde product (24.3 g ). Distillation (128-137°/ .05 mm) gives 16.3 g (33%) of the aldehyde. 2. (i-(2,4-dichlorophenyl)phenethanol To 2.4 g (0.0615) mole of LiAlH^ in 140 ml of anhydrous THF is added dropwise, at 0°, 16.3 g (0.0615 mole) of the a-(2,4-dichlorophenyl)phenyl acetaldehyde in 60 ml of anhydrous THF. When the addition is complete, the reaction is stirred for 2 hours at 0° and then for 16 hours at ambient temperature. The reaction is then heated up to reflux for two hours, cooled and poured into ice water. The mixture is acidified with concentrated hydrochloric aeid, and the organic material is extracted out twice with 200 ml portions of ether. The extracts are combined, dried over anhydrous magnesium sulfate and concentrated to give 15.5 g of crude product. Distillation (125-39°/ .025 mm) gives 10.6 g (65%) of the purified alcohol product. The material is identified by ir, and its purity is determined by glc. - 28 3. β-(2,4-dichlorophenyl)phenethyl methane sulfonate The methane sulfonate is prepared according to the method of Example IA part 3, the product is identified by ir and its purity is determined by gle. 4. 1-Γ 8-(2,4-dichlorophenyl)phenethyl)imidazole The imidazole is prepared by the method of Example IA part 4, the product is recrystallised from ether-acetone to give 2.6 g (32%) of the hydrochloride salt, m.p. 197-8°.
EXAMPLE 61A l-Γ8-butyl-8-(2,4-dichlorophenyl)hexyll imidazole hydrochloride 1· ethyl α-butyl- a- (2,4-dichlorophenyl)hexanoate To 4.3 g (0.09 mole) of 50% sodium hydride in 200 ml of anhydrous tetrahydrofuran is added 23.6 g (0.0816 mole) of ethyl a-(2,4-diehlorophenyl)hexanoate, and the reaction is heated at reflux for 72 hours.
The reaction is then stirred for 72 hours at ambient temperature. At the end of this period 16.6 g (0.09 mole) of iodobutane are added, and the reaction is heated at reflux for 24 hours. The reaction is cooled and poured into iced water, and the oil which forms is separated. The aqueous phase is extracted with ether, and the extract is combined with the oil.
The ether solution is dried and concentrated to give 14.2 g of crude product. A distillation (150-70°/ .25 mm) gives 13.3 g of the ester product. 2. 2-butyl-2-(2,4-dichlorophenyl)hexan-1-ol The alcohol is formed by the method of Example IA part 2, the pure product 4.8 g distils at 133-8°/O.O5 mm and is identified by nmr. t ? - 29 3· Imidazole Reaction The imidazole is formed via the methane sulfonate according to the methods of Example IA parts 3 and 4.
The final product 1.5 g (28%) m.p. 103-5° is recrystallised from acetone-ether and is identified by nmr and elemental analysis.
EXAMPLE 62A l-f β,β-bis(p-chlorophenyl)ethyl 1 imidazole 1. 2,2-bis(p-chlorophenyl) ethanol To 15.1 g (0.397 mole) of lithium aluminum hydride in 750 ml of anhydrous tetrahydrofuran at less than 5° is added portionwise over a 2 hour period 95.0 g (0.338 mole) of fcis(p-chlorophenyl)acetic acid. When the addition is complete, the reaction is stirred at 5° for 4 hours and then allowed to warm up to ambient temperature overnight. The reaction is slowly poured into iced water with resulting evolution of hydrogen. The mixture is made acidic with hydrochloric acid, and the organic phase which forms is separated. The aqueous phase is extracted twice with 200 ml of ether and the extracts are combined with the organic phase. The ether solution is dried and concentrated to give 74.9 g of crude product.
This residue is distilled (157-62°/.05 mm) to give .3 g (39%) of the product. 2. Formation of Imidazole.
The imidazole derivative (m.p. 80-2°) is formed by the usual route. 3517 EXAMPLE 63A l-ΓS-(oapBchlorophenyl)-p-chlorophenethyll imidazole 1- 2-(o&p-chlorophenyl)-p-chlorophenethyl chloride To a mixture of 12.5 ml of 30% oleum in 25 ml of sulfuric acid is added dropwise at less than 35°, 11.6 g (0.76 mole) of chloroacetaldehyde diethyl acetal in 34.0 g (0.30 mole) of chlorobenzene. When the addition is complete, the reaction is stirred for 1 hour, and warmed up to ambient temperature. The reaction mixture is poured into iced water, and the organic phase is extracted out twice with 200 ml of ether. The extracts are dried and concentrated to give 17.3 g of the yellow-orange crude product. The material is distilled to give 9.8 g (165-8°/.4 mm) of the isomeric product. 2. Reaction with Imidazole To 75 ml of methanol is added 1.05 g (0.0458 mole) of sodium to form a solution. To this solution is then added 3.1 g (0.0458 mole) of imidazole, and the reaction is stripped to dryness. To the wet solid residue is added 50 ml of N,N-dimethylformamide. The resulting solution is heated up to 130°, and the remaining methanol is distilled off. To this dimethylformamide solution is added 8.7 g (0.0305 mole) of the 2- (o&p-chlorophenyl)-p-chlorophenethyl chloride, and the reaction is heated up to 130° for 48 hours. The reaction is cooled, poured into iced water and the organic material is extracted out with ether. The ether extract is cooled and treated with hydrogen chloride gas. The oil salt which forms is separated, and treated with a sodium bicarbonate solution. The resulting mixture is extracted with ether and the ether solution is dried and concentrated to give 0.6 g of the product. 4S51? EXAMPLE 64A 1-Γ β,g-tetramethylene-6-(2,4-dichlorophenyl)ethyl] imidazolium nitrate 1. a, ct-tetramethylene-2,4-dichlorobenzyl cyanide Into a 500 ml three-necked flask is placed 200 ml of 25% sodium hydroxide solution and 4 g of tetraethyl ammonium bromide. To this suspension is added dropwise a solution of 33.5 g (0.2 mole) of 2,4-dichlorobenzyl cyanide and 43 g (0.2 mole) of 1,4-dibromobutane in 200 ml of methylene chloride under nitrogen. When the addition is over, the reaction mixture is heated to reflux for 1.5 hours. It is then poured into water and the layers are separated. The aqueous layer is extracted with 100 ml of methylene chloride. The combined organic extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. Solvent is evaporated to give a light yellow oil. Vacuum distillation 130-140°/0.2 mm) gives 30.4 g (63%) of pure product, which is identified by nmr. 2. a, ra-tetramethylene-2,4-dlchlorophenyl acetic acid A mixture of 14 g (.06 mole) of a,a-tetramethylene2,4-dichlorobenzyl cyanide, 160 ml of 40% potassium hydroxide solution, and 120 ml of diethylene glycol is heated under reflux for 3 days. The reaction mixture is poured into water and extracted with ether. [The aqueous layer is then made acidic with hydrochloric acid followed by extraction with ether] . The combined ether extracts from the acidic solution are washed with water, saturated sodium chloride solution and 3517 then dried over magnesium sulfate. Solvent is evapor ated to give 12.4 g of crude acid which is recrystallized from hexane-benzene to give 8 g of pure acid, m.p. 136-138°. 3. 2,2-tetramethylene-2-(2,4-dichlorophenyl) ethyl alcohol To a suspension of 3g (0.08 mole) of lithium aluminum hydride in 300 ml of anhydrous ether is added dropwise 13 g (0.05 mole) of a, a-tetramethylene-2,4dichlorophenyl acetic acid in 50 ml of ether under nitrogen. The reaction mixture is then heated to reflux for one hour.· Excess lithium aluminum hydride is carefully decomposed by dropwise addition of 10% hydrochloric acid into the reaction mixture. The two layers are separated and the aqueous layer is extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate Solvent is evaporated to give 9.8 g of alcohol, which is identified by nmr. 4. 2,2-tetramethylene-2-(2,4-dichlorophenyl) ethyl methane sulfonate To a mixture of 9.8 g (.04 mole) of 2,2-tetramethylene 2-(2,4-dichlorophenyl)ethyl alcohol and 5 g (.04 mole) of methane sulfonyl chloride in 30 ml of benzene is added dropwise 5 g (.05 mole) of triethyl amine. The reaction mixture is stirred at.room temperature overnight. The precipitate formed is filtered. The benzene solution is washed with water then dilute hydrochloric acid and dried over magnesium sulfate. Solvent is evaporated to give 12 g of product, which is identified by nmr. ^3517 . 1-Γ β,g-tetramethylene-p-(2,4-dichlorophenyl)ethyl imidazole A mixcure of 12 g (.037 mole) of 2,2-tetramethylene2-(2,4-dichlorophenyl)ethyl methane sulfonate, 10 g (0.1 5 mole) of h.iidazole, i.nd 1 ml cf dimethyl formariide is heated at 140° for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. The drying agent is filtered and to the ethereal solution is added cone, nitric acid dropwise. The white precipitate which forms is collected by filtration and dried under vacuo. A total of 3.7 g of the salt is obtained m.p. 176-179°, which is identified by nmr.
EXAMPLE 85A 1- ίQ-(2,4-dichlorophenyl)hexyl]-4-nitroimidazole To 1.3 g (0.0307 mole) of sodium hydroxide in 150 ml of methanol is added 3.5 g (0.0307 mole) of 4-nitroimidazole, and the solution is heated and the methanol distilled off. To the concentrate is added 100 ml of dimethyl formamide and the solution is heated up to 120° to remove the excess methanol and water. This dimethyl formamide solution is then cooled to less than 90° and 10.0 g (0,0307 mole) of 2- (2,4-dichlorophenyl)hexyl methane sulfonate is added.
The reaction mixture is heated up to 145° for two hours and then cooled and poured into water. The organic material is extracted out with ether and after drying, the extract is stripped to give 11.2 g of residue. The concentrate is triturated with hexane and then dissolved in 25 ml of methanol. The methanol solution is poured slowly into water and a gummy <2317 solid forms. This solid is separated by filtration, dried and recrystallized from acetone-hexane to give 4.2 g (41%) of the product, m.p. 67-9°.
EXAMPLE 86A 1-Γ 6-(2,4-dichlorophenyl)hexyl14,5-dichloroimidazole To 100 ml of methanol is added 1.7 g (0.0735 mole) of sodium. When the sodium dissolves, 10 g (0.0735 mole) of 4,5-dichloroimidazole is added. The mixture is stirred until a solution forms, and then the methanol is stripped off. The wet residue is then added to 50 ml of dimethyl formamide and the solution heated up to 125° to remove the remaining methanol and water. The solution is cooled to less than 100° and 2.5 g (0.0735 mole) of 2-(2,4-dichlorophenyl)hexyl methane sulfonate is added. The reaction is heated up to 130° for two hours and then cooled. The reaction is poured into water and the organic material extracted three times with 200 ml of benzene. The combined extracts are washed twice with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated to obtain 15.8 g of the crude product. The residue is dissolved in ether, and treated with dry hydrogen chloride gas. The ether solution is decanted from the oil which forms and the oil is triturated twice with 150 ml of ether. The oil is then treated with 10% sodium hydroxide, and the product extracted out twice with 200 ml of ether. The ether solution is dried and concentrated to give 12.6 g (47%) of the oil product. ' ι - 35 - 4ii5i7 EXAMPLE 87A l-(g-(2,4-dichlorophenyl)hexyl1 -3-butylimidazolium iodide 1-[β-(2,4-dichlorophenyl)hexyl]imidazole 5.0 g (0.0168 mole) is heated for two hours on a steam bath with 3.1 g (0.0168 mole) of 1-iodobutane. The reaction is cooled and triturated three times with 50 ml of ether. The oil residue is stripped to dryness to give .3 g (66%) of the oil product.
EXAMPLE 88A 1-(0-(2,4-dichloro-5-nitrophenyl)hexyl]nitro imidazole To l-[p-(2,4-diehlorophenyl)hexyl] imidazole 20.0 g (0.067 mole) in 40 ml of sulfuric aeid is slowly added 80 ml of nitric acid and 40 ml of sulfuric acid. The reaction is heated on a steam bath for 14 hours, cooled and poured into water. The aqueous acidic solution is decanted from the oil which forms. The residue is washed twice with 75 ml of water, and then taken up in acetone-benzene, dried and concentrated to give 14.9 g of the crude product. To purify, 3.0 g of the crude product is dissolved in hot methanol. Upon cooling the product precipitates out, is separated by filtration and dried to give 1.6 g of the nitro imidazole derivative.
EXAMPLE 89A 1-f3-(2,4-dichlorophenyl)heptyl] imidazole · 2-(2,4-dichlorophenyl)hexyl cyanide To a suspension of 11.3 g (0.23 mole) of sodium cyanide in 100 ml of dry dimethyl formamide (DMP) is added dropwise a solution of 50 g (0.154 mole) of 2,2-(2,4-dichlorophenyl)-hexylmethane sulfonate in 50 ml of DMP. The reaction mixture is stirred at 70° overnight. It is then poured into 500 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated saline solution and finally dried over magnesium sulfate. Solvent is evaporated under reduced pressure to give 37 g of crude product which is further purified by vacuum distillation (107.5-110°/0.05 mm) to give 33.9 g (86%) of expected product. 2. 2-(2,4-dichlorophenyl)heptanoic acid A mixture of 15 g (0.0596 mole) of 2-(2,4-dichloro phenyl)hexyl cyanide and 100 ml of 50% sulfuric acid is heated at 110° overnight. The reaction mixture is cooled and diluted with 500 ml of water. This aqueous portion is extracted with ether ahd the combined ether extracts are dried over magnesium sulfate. Solvent is removed under reduced pressure to give 15.02 g (93.7%) of a white solid, m.p. 65-68°. 3. 3-(2,4-dichlorophenyl)-heptan-l-ol To a suspension of 2.07 g (0.0545 mole) of lithium aluminum hydride in 100 ml of ether is added dropwise a solution of 15 g (0.054 mole) of 2-(2,4-dichlorophenyl)heptanoic acid in 50 ml of ether. The resulting mixture is stirred at room temperature for 3 hours.
The excess lithium aluminum hydride is decomposed carefully with 100 ml of saturated ammonium chloride solution followed by 100 ml of dilute sulfuric acid solution. The ether layer is separated from the aqueous layer and the aqueous layer is again extracted with ether. The combined ether layers are washed with 10% sulfuric aoid, water, saturated sodium bicarbonate solution, saturated saline solution and dried - 37 ΛϊίΒί? over magnesium sulfate. Solvent is evaporated under reduced pressure to give 12 g of an oil which is further purified by vacuum distillation (120-125°/0.1 mm) to give 10.2 g (72%) of desired product. 4. 3-(2,4-dichlorophenyl)heptyl methane sulfonate To 10.2 g (0.039 mole) of the 3-(2,4-dichlorophenyl )heptan-l-ol and 4.8 g (0.042 mole) of triethylamine. When the addition is complete, the reaction is stirred and allowed to come up to ambient temperature over a 30 minute period. The reaction slurry is then heated to reflux for 30 minutes, cooled and poured into water. The organic solution is washed with dilute hydrochloric aeid, then with water and finally with dilute sodium bicarbonate solution.
After drying over anhydrous magnesium sulfate, the benzene is stripped off to give 10.6 g of crude sulfonate product. . l-Γ 3-(2,4-dichlorophenyl)heptyl]imidazole To 10.6 g (0.160 mole) of imidazole at 95° is added 10.9 g (0.042 mole) of the crude 3-(2',4'dichlorophenyl)heptyl methane sulfonate. The starting materials are stirred at 95° for 16 hours, cooled and poured into 500 ml of water. After stirring for 1 hour, the organic material is separated and the aqueous layer is extracted with ether. The ether is combined with the organic phase, and after a water wash, it is dried and concentrated to give .6 g of the crude product.
The following Tables IA and IIA present some of the compounds prepared by procedures presented in the preceding examples. These tables are - 38 4 2 517 presented as a further illustration Of the types of compounds encompassed by the present invention.
TABLE <22517 o Cl ffi CJ ϋ rt X . / Λ N rt rf 0) CJ CI CJ CJ r-l o H o H u ffl ω ϋ ω ϋ c 3 3 0 •r| Φ N U ϋ U ffl fa cj I Cl ci Cl pi X X X X X X r-l H H H H rd Pl ixT d* csl M* □ Gl cn o Pl ΟΪ ϋ Pl u Pl sT « u PI af d* Pl sT o Pl σι Oi d* Sflfflfflfflfflfflfflfflffl fO M co cn .. CO in rn (Ώ w w w ffl ffl ffl ffl fflrt ®Λ Φ Φ Φ kD vo k0 kO u u u o υ a t) U u Cl CJ CJ CJ CJ CJ CJ CI CJ r-1 H H H rd H H H H u □ u t υ t v v V V V 1 <φ 1 1 1 * «, «» k ci Cl CJ Cl Cl Cl CJ CI rf CJ rf m rf rf tn ji - 40 42517 r-4 rH Cl J* a Ti u Ci am d* Cl J* 4* U cl hf d* Cl ttP d* cl M0' υ* cl aw d* cl sf d* Cl a® d* cl w0' d* cl a* d* waaaaaaaaaa CO CO a a Β- iO 10 M* tf ω u ϋ a a a ϋ -SP CM CM Ό ID ie a a„ ffi art rH H □ o u o IX) IX) ID io U ϋ co co m « u a υ ϋ 1 1 a a a a in r-l H H Η Φ 0 u V 9 φ υ □ φ s * l 1 T 7 7 1 1 I CM CM CM co <4· ϋ «? CO CM Example H < r-l CM Ss $ ?S CO Q I |.
TABLE IA (continued) cl cl cl cl cl cl cl cl cn σι σι σι σι cn jσι σ> 8 8 a a a 8 a 8 xj· «* ># v M1 χΡ O υ u o ϋ O o O 8 a a a a 8 a 8 8 xt* Md 8 CO □ ID 8 CI xi1 O D o 8 »—» xf xi1 u co xt* <0 σ» a 8λ CJ 8 xf 8 Q 8 10 VD r-4 O 8 vD w M* u ϋ D u ro U N CJ I 1 o M 8 I. o w *a* Tf fc « φ 4-)1 a H * * 1 1 1 -**· 1 I CO Cl xf xt< Xf X# xh Φ H CJ < rf! rtj ci co xj* CJ CJ Cl *3 *3 d? *3 tn CJ CJ CJ ci 42S1? cl a01 d* cl J* 3* Cl nP d* At :· Cl af d* Ct d* cl a01 d* OI ffi VO υ OJ a o VO $3 o 1 OJ in 1 (Ί OJ s H □ 9 s·» 1 <# 1 vo * * OJ OJ I in a" IS υ (M W VO Example si σ» o cm cn rt! m tn TABLE IA (continued) . ·ί 7 j o ’ < Example TABLE IA (Continued) 435X7 Example TABLE IA (continued) - 48 -.Sai? ai ! rH rH & rH tf u rH ? tf* u I CM el m U fil b"ω a CO KO co ίΰ KO CO tt Λ KO CO as KO CO KO tt KO υ tn □ a o o U w tt CM KO a tt a CM CM CM CM CM ko KO rH υ 40 KO 40 rH H rH H rH U υ y co a a □ □ υ φ υ 9 H rH T tt P Η 1-1 I ! 1 1 T 9 a u « φ o «tf «tf •tf 1 1 1 1 I 1 * te * CM *tf M1 CM CM N CM CM Example rtj «ί rf (=C ¢4 itf Λ < < CM ro tf in Γ· on o CM oo KO KO KO KO ko KO ko KO r· r* rH I o ι as rH H υ ι u a ι a ra cn a o o ? CN Nf TABLE IA (continued) CN «Η 1 fc» co CM ti 53 Φ 0 1 CN X til CN ffi Φ rH w ffi y .ti CN υ 0 0 w CN in m cn H in m o ffi ffi a ffi 0 a ffi rH y ko ra MO >1 ra ko u T υ U u 0 u y si si σι ra ra a a a Nf nj> CJUO as a a cn cn n co CO y co ffi ffi ffi ffi ffi rH ffi ko Ό ko kO KO Nf υ KO υ a O O y a 1 ** y CN CN CN CN CN ra xf ffi CN rH rH rH rH H a KO rH y Q y y υ 1 M φ Q T 1 I 1 1 m rH m 0 1 T xi· xf sj· xf Xf ffi y ffi rH xf K *. *. * K kO I KO 1 y * CN CN CN CN CN y xf a CN xf CN rf! σ» r* g co ί ra CN ra rt! ra ra s co 4-Cl, u*) ¢0 - 50 3SX7 H ffi H υ ι w Al σϊ ffi TABLE IA (Continued) til Al Al Al ic01 &£ / o* o* o* o* H U I co CM «Λ κΏ □ CM CO ffi ffi o Ί □ CM CM CM H «-1 H U I v O 1 1 Tf * CM CM CM Φ g S δ $ ω ω co oo m—S *—s CO m Q o· o co O xt co CO in O o* Γ* xt VO rd Ol OJ « » • · • • • * * co co ο» xt co o· ω in xt *—’ H W-* **-* II II II II II £ 3 3 0 •H N a □ u a vo CO (J) Φ xt rd in Xt *41 in co • • · • in xt vO in co O · rd rd rd CO «**» χ> ιη 0· VO 04 σ» ο 00 Γ* νθ co ο» ιη Η C0 Μ* co Η Ο* rd 00 V 00 VO m Οί 00 00 ιη xt • • Φ Xt • • • • • • • · • · 00 φ • • cn cn ο· ra νθ 0· Γ* Ο* ιη νο γ* r* Ο] οι νο Elemental Analyses (Calc'd) x-x Η νθ Ο Γ* O rd O 1—1 vO xt co rd vo CO ο 00 CO co Ο» rd N CO Ol co 0 00 O co cn Ol • • » • • • » » rd O* • • Μ* <0 0 rd φ Φ Φ ω vo H 00 • · co m οι OJ co CO Ol OJ rd rd rd rd Ol rd > Γ- rd rd sm* »·*» s_z νο 0 Ο xt xt O· CO rd OJ V 00 rd VO rd xt rd rd VO Γ* σ» φ CO C4 φ M· co 00 rd O 00 00 « • • • « • « • • • • • • · « • νθ νθ in in xt xt in in co xt in xt in in Xt xt s«* s_> Sm» *-* Sm» Xt Ol 00 φ m rd Ol co O ra in φ 00 in in in VO VO ra o> CO OJ O' O 0 co 0- VO !> 0- 0 0 0 rd CO 00 Φ xt Ol 00 xt Ol σ» Φ m 00 vO VO m in xt xt in in CO xt m xt V xt xt V Sm* *-* S-* 'S*' Sm*» 'r' s«X *** co rd rd rd Xt CO 00 OJ rd 1 VO 1 1 Tt 00 1 Φ 1 VO Φ t 1 O’ CO O’ Ol rd rd CO O rd m rd Ol Ό in rd CM CO rij xt in vo • jtf « %. ύ o x 7 o <ύ* Ρ» CM CM * ♦ • • tn CO VO 11 II 0) M PM υ ρ* σ» CD CM oo r* H I-I tn > CO H 00 CM VO in VO in o P Γ* CM r* w r* VO CD co in Ρ» in in O CM CO 00 CM rH vo CD p- • CM CO • • • • P • • » • • σν co • • o rH • • rH rH rH r-l • O fl 0 H CM • • P- r-i rH 00 00 rH rH H H CD H H rH H rH 00 CD ·>—* %-* *—* Xm* ’W’ -»·»* CM σ» 00 CO CD > rH rH H P O P> CO • · II 1 °i P* O CD vo p* rH rH N CM CO CM rH H CO CO H rH •tf O CM P* cm co CM CM CO co rH VO •tf H in h m P- CM N ¢0 o co vo •tf rH o co co P- P* CM rH r-t H •tf CO Kf in P> 00 CM P* in in >tf -tf in tn CD CD CD CD 00 CO CO 00 00 00 VO vo P- VO P* 00 co CD co CD VO CD m CM CD o VO o PJ H P* σ> vo CM vo CD σι CM co CM vo CD CD •tf co CD 00 Cm i • « • • « < I • • • < • • • I • CD CD o CO co CO p* σ> ω co co CM ’tf Ρ» 00 vo o •tf 3 •tf tf in tn P* P- P* Ps—* vo VO P- r- P- P* in vo ·»—* o νθ 00 m σ» 1 1 1 1 vo in «tf in CM M· •tf rH rH ? CM P* Example < σ» ί rH CM rH rf3 CO H rij m H Ol vO VO in OJ VO VO CO VO in • • • OJ co • o O o CO • σ» rH rH H ov O cs CO -tf VO in Ol O O* cs CO in VO rH • • • • tn O' OJ co cn cn • • OJ Ol 0- Γ~ il ω ffl σ» οι oo oj co sp H r-J oo cn co co o VO m » co cn cs CO CS in o sp m m • 1 • vO rH • • o· co o o o rH • • co cs • • H rH H rH O' co rH rH cn cn Elemental Analyses (Calc 1d) 0) cs OV 00 OV OV O rH 0* si1 Ο» sp o ov Sp CO OJ co cs co sp H rH rH rH cs ts OJ OJ in co H* O OV H m CS cs ·»—» vo Ov ov cs Sp O' O VO sp m o- s & rH O' O Ol rH • cs co o> CS H • « sp Sp • · o O; O 00 « · 00 CO • · / o · O' r* VO VO vo vO ov ov oo o· vo in vO vO H Ov VO e-> CO VO vo rH in rH vo Sp vo sp Ol oj co in vo cn in O in O' CS CS vo O vo O rH vo sp sp ov ov Ol co Φ 00 VO O ο ό co cs cn rH CS VO vo OV ό VO vo vO in vo vo VO O' > O' O' in in in in Ο» co vO co O I O cs 3517 CJ 00 xt VD « · to co rH rH I! tn to rH CJ cn Xt rH tn to in C* p* O Cl O in ω • • » • « CJ rH rH Cl VD p* O rH H »h rH r-H ci CJ CJ Cl *»«» »—» Cl Ph M* C* in tt P* (0 xt to O tn Φ rH 00 VP to CO Cl in in tt in tt m o > tt tt pH 00 Μ» • • « • » « • • p* ci • • • • • • in tn VP pH - O o O o O O • · rH H tt tt H rH H rH r-l rH rH rH H rH rH H co cn rH rH rH rH rH rH to p* • vp CJ KO CJ .19 s Cl O tt p* rH VD rH O in xt 00 Xi ffi sf rH in r> tt tt xt Ph Ρ». VO VD O tt cn o xt vo P* P* p- co co in in tt tt tt tt Ρ· P* > p* vd in lfl lfl >··«. Ο H xt to Ρ* rH to xt P* Xt cn in VD Cl co oj O pH Xt tt VD o tO Xt Cl VD tt VD p* oo xt VD ro ro tt Cl in tn (O xt in W 00 tt 00 Φ tt Cl VO VD Ρ* Ρ» rH CJ VD VD > pH P- P* P* ΓΗ r* co VD VD Ίί rt VD VO O o O in to rjl 1 (O 1 00 tt O Cl tt rH rH 8 ί£ Cl a Cl cn ci ό co co Cl to to (O fi! Xt to tn to 517 Elemental Analyses (Calc'd) V*) LO io Xf CN X··* rt rt rt Ό kD kD rt O in O Xf in r- rt t*- Xf rt tin iH cn xf m rt σι » o Ol 1 » O rt CO * Φ « O oo d d d • 0 d d H d d H cn ι—1 cn cn cn rH cn H ‘w’ rH rH rH rH —w* «Η «Η rH rH 'mh' in o in co rt rH cn K 0 xf kO Xf O m rt xf rH en co cn cn Cft in ID xf O in xf Xf Xf rt η • · N xf d s n· d cn cn cn cn s^» cn cn σ» cn *<>«/ σ» cn Ch ✓*— 1-. ¢) in O O rt οΐ rt tn kO xf rt Xf o co rH Xf Nf O cn o rt CN in in kO m rt KO « < 00 kO t I in • rt « CO ID r « » » tH CN CO CN co o xf cn cn o kp cn (D C"i t** co ω cn CO CO s co > ω ι-, [-« r- co w is r- r- r— r- s —-« IS IS S rt <4 cn rt ί Nf Nf rt! ra Nf Nf ;i7 o a in r~ Sp Tp II fc sp tn sp σι » CO CO Η H I I I I I tt m xx CN H xx ^-χ ^a. CN cn w cn r* in cn O CO o Φ CN tf KO > H a) > cn O cn co co H • KO CN • · tf KO r-ί O > o » • • • • • • o i • H CN • • · • · H co co co co co σ» H sx cn σ» Η H r· Ν t*· r* r* «Η h H ι—1 H r4 tf o Φ KO kO CO cn O Ο H XX cn m co co • · KO KO • O O co σ» KO KO KO KO CN CN CN CN CN CN CN CN xx· sx x.' σ» m tf φ .21 .95) .44 tt co XX tf CO in H CO tf in m cn in KD CO o KO cn tf .23 .05) .16 CO tt co s CO IS tf tf tf tf sp sp in m CO tt tt tt s Φ sx SX SX SX XX XX xx Xte o o CN m IS in ω cm tf co in m tn ko CN KD tt m co O «Η co CO co κο H o o O m sp sp CO cn CN co ω cn H CN ω co. co cn > r> CN H tf tt KO s CN CO r- oo CO co tf sP in in in in in in px fx s s KO KO XX XX XX XX SX XX , XX SX XX O T co o ? CM tn H rH H rH Example a) in sP S f£ & sp SP sp 3$ in in tn '0 Elemental Analyses (Calc* VO 0« in cm νθ Φ Φ O rd Ol iN CO rd H r-j i—} Tt r> vo M-S >-x r— r* CM Xt tn O' co in in xt CM Ο Ch tTj 1 • rd ω CM « co co O σ» > rd vo rd CM « • t O • • * • • « ♦ rd rd cn r-d 00 CO > vo r- 00 X-* Sm» x-' x-z x_^ xt Ρ» xt Ch rd in xt O Xt CM 00 CO • » • • • · 00 o in rd CM CM CO CM CM Sm» CM CM (O 'x M-X, <-s z-x z~x 00 CO xt vo xt co O CM Ο φ ω cm 00 CO xt co xt m rd co m xt φ 00 • Ch Γχ vo 00 co CM in ch xt xt t « · • · o · • « • · t · • · • · Φ co co ω 00 00 rd Φ φ φ σ» ch Xt xt vO VO Xt xt X-' x-z —· x·'- x-* ω 3 Xt VO rd O in CO σ» CO CM CO co in ch P* xt ch rd Xt r> ch co CM xt Ch CM CM 00 P· « ch m • · m CO 00 ω ps 00 Ρχ co φ o Φ CO 6 00 xt 00 xt xt px ρ* px h· Ρχ r* Ρ* CO Ρχ px Ρχ co m in in in vO VO Sm* XmZ 00 I in l CM px co 1 ch O O rd rd CO ω rf! ra in px co φ m m m in g vO CM VO kD O 00 sp co CO rd in o kO CT CI M ffl o kD σι > in kD η Cl σι Cl m m O r-l rd rd 00 σι Cl O r-l 5p « • Γ* σι ΟΙ r-l kD σι Ο ω kO kD • • • * r-l rd • • • • • • • · • • rd o o o rd H co ω 00 σι r- 00 00 01 σι rd rd rd rd <··» <·> »—x ·*-» Γ* σι in cq ϋ\ r*· rt o r* > r- σι k0 o rd cq CD O rt ’Φ O -tf m r* OI CQ • • ♦ 1 • « « · a « • · « ♦ o Φ r-l rd σι O Ol Ol CO 10 Γ* Ο» kD kD Cl rd rd oi m oi oi - rn m Ol Ol Ol Ol «Μ» X*» <*· ·*>«, l 00 r* rt r- rd O rd cq O rt σι 00 M1 CQ Ίφ 0* o- CD C* Ο N rd Ol kD tP tn CO c* CQ Ol a » • M· kD kD kD φ kO Μ· «Φ «Φ in in «·"·» -«"X co Oi os «41 O -4« O ro co o O Ol co σι tn rd r- CI sf 01 kD O > w ω Ol ^p kD σι Q m O σι oi r> co co r* CO σι σι kD kD kD 00 «Φ in kD r* in in in in kD kD <φ ># in in in in o •s K»Z s—* 01 1 Ο- Ι in t kO 1 kD in 00 CQ σι «· kD rd rd Ol rd Example kD rf σι kD g 0» - 59 Λ +J O Elemental Analyses (Calc'd) l> rd ρ- cn xp in in m cn ω t-d rd co cn ro O rd in ra rd Φ 03 ra CM XP r-ί «t Ρ* rd m ro co σ> ra ra ώ oo px px m p* Ch Φ co co > CO Ρ* Ρχ co co Φ cn r* Γ) Tp Ρ* m in VO O in rd in xp rd cn ro m rd XP CM 00 in O ω vO rd Φ co xp ps in σ> p· Φ τΡ oo in • · CM H Φ O 00 00 m cn rd rd o o ro ra rd CM CM CM CM CM H CM CM CM CM CM CM CM CM CM rd rd rd rd s/ Sm* s* Tt< CM ΓΩ CM m vo νθ Ρχ rd P* h in Φ in 00 CM rd m CO 00 CM Xf o oo rn O • · O CO « · rn cm rn rn ra O xp cn VO \O P« P- co r* νθ vO m xp in in in in VO VO in mS— s* s* *—» CM Ρ* Φ Ch CM O nJ O CM P* rd Ch rn oo nj O 00 rd Φ Ρ* h in cn o Φ vo XP CM rn rd « · cn o • · VO px • « cn cm • ( «-Ι CM m xp m vo r- 0 xp in xp vo xp Ρχ CM rd rd CM Φ VD ra ra ra ra tn vo VD VO ra ra in in ra Γ' Ρχ Ρ* Xm* P* 1 m in 1 Ρχ m rd 00 < rtj C CM m Tp in VO Ρχ 00 φ o px px P* ρ- Ρχ P- Ρχ Ρχ co - 60 σν ο* cn cn sp vo cs cs sp cn in cn cn m rH rH O cn O m O' vo rH rH vo cn CO cn cn cn cn P* r-V ·»> O' m oo in ov rH cn VO o vo VO OV in P* (S cn sp cn o • a • 00 o a a in vo ω 00 a rH o cs rH rH rt rH o a a rH rH « a a a sp sp • • rH rH i-H rH rH rH P* OV rH rH vo o- in in rH rH co v> *—* v> *-* •«-X «V 00 σι O ω in σι co tn Ο CS sp ov cn sp rt ov co VO OV Ο rt rH rH p' P- cn ρ- VO Ρ* cn p* cn cn σν P> tn sp m in in VO cn cs σι σν 00 00 in sp co co M cs rt rt rH rH CS CS cs cs rH Η cn cn rH rH rt rt CS cs Vi* v> ν»· ν* V-i rv sp sp sp sp tn in O p- Ο cn rt Ο 00 vo O rt rt co vo CS O- sp r-l σι P sp σν cs CO Sp ov vo CS rt cs sp « a a · a i a a VO o· vo vo vo in VO VO Tf m Tf Tf m in Tf Tf vo VO V-» V* v«x V V V/ V v> CS in O rt ω co cn sp «η m m rH r· cs O cn VO sp σν ov p* tn in m > tv νο ο in cs VO sp vo tn Tf prt co in in vo cn p* ω p-ι ο ο Ο σι rt rt vo vo O rt in vo vo vo m in in vo ιη ιη in sp Tf Tf Tf Tf vo VO V> V> *—* ν' V-* Vi* v> Vi* V* m TJ r> 1 σν m co I vo VO P- rt rt vo Example a co $ co sp co «5 in rtj O' <0 Φ co - 61 The metal salt complexes of Formula II and those individual complexes identified in foregoing Table IA and subsequently in this specification can be prepared by adding dropwise, with stirring, a stoichiometric amount of a metal salt dissolved in an appropriate solvent to a solution of the 1-substituted imidazole free base dissolved in a similarly appropriate solvent. The reaction mixture is briefly stirred and the solvent is removed under reduced pressure to give the metal IO salt complex of the respective 1-substituted imidazole. Identification and purity are determined by elemental analysis.
Mixtures of an appropriate metal salt and an appropriate substituted imidazole (in free base or acid addition salt form) may also be formed and used, by addition of a suitable liquid, to form a metal salt complex in situ. Thus a metal salt complex can also be prepared by mixing stoichiometric or excess amounts of the metal salt and 1-substituted imidazole in the desired amount of solvent containing the appropriate adjuvants just prior to spraying the plants. Adjuvants that may be included in this in situ" preparation may be detergents, emulsifiers, wetting agents, spreading agents, dispersing agents, stickers, adhesives, and the like which are used in agricultural applications.
Solvents that can be utilized in these procedures 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. 3517 The metal salt cations that may be used in these procedures can be selected from the group consisting of calcium, magnesium, manganese, copper, nickel, zinc, iron, cobalt, tin, cadmium, mercury, chromium, lead and barium.
Any appropriate anion e.g., chloride, bromide, iodine, sulfate, bisulfate, phosphate, nitrate, perchlorate, carbonate, bicarbonate, hydrosulfide, hydroxide, acetate, oxalate, malate, citrate, or tartrate may be utilized as the counterion in the metal salt.
The substituted imidazoles when complexed with a metal salt are safened, i.e. have reduced phytotoxicity, and it has also been found that any metal containing fungicides can also act as safening agents when used in place of metal salts. Typical metal containing fungicides that can be utilized in these procedures are: a) dithiocarbamates and derivatives (particularly metal salts of ethylenebisdithioearbamic acid) 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-ethylmercuri1,2,3,6-tetrahydro-3,6-endomethano-3,4,5,6,7,7-hexachlorophthalimide, phenylmercuric monoethanolammonium lactate, nickel-containing.compounds and calcium cyanamide. - 63 The compounds of Formula I (wherein is other than cyano) and metal salt complexes of Formula II (wherein R^ is other than cyano) are excellent as systanic protectant.eradicant fungicide and possess a high degree of activity against assorted phytopathogenic fungi. Certain compounds are particularly effective for the control of grey mold of faba beans (Botrytis cinerea), rice blast (Piricularia oryzae) on rice plants, tomato late blight (Phytophtora infestans) on tomato seedlings, bean powdery mildew (Erysiphe polygon!) on bean plants, barley net blotch (Helminthosporium teres) on barley plants, grape downy mildew (Plasmopora yiticola) on grape seedlings, citrus decay (Penicillium digitatum) On citrus fruit, apple scab (Venturia inaequalis) on apple seedlings, wheat powdery mildew (Erysiphe graminis) on wheat plants, wheat black point (Alternaria tenuis) on wheat plants, black rot of grapes (Guiqnardia bidwellii) on grape seedlings, cucumber powdery mildew (Erysiphe cichqraceatum) on cucumber plants, and the organism responsible for the production of aflatoxin (Aspergillus flavus). The compounds eradicant fungicidal properties are significant in that they kill Helminthosporium tores in infected plant tissues, a property not possessed by current fungicides used to control diseases incited by Helminthosporium spp.
The systemic properties possessed by these compounds are equally unique in their ability to move both aeropetally and basipetally in plant tissues.
As the free base the compounds under discussion can be used to control seed-borne Helminthosporium oryzae, a property which is found in no fungicides >317 - 64 other than the organic mercury compounds. These free base compounds possess growth regulatory activity in both dicotyledonous and monocotyledonous plants, the most pronounced effect being a retardation of plant growth. In some cases, particularly in dicotyledonous plants, some of the growth regulatory properties may be considered adverse. When this occurs, the growth regulatory and phytotoxic plant responses may be suppressed by metal salt complexation of the imidazole compounds with elements selected from Groups IIA, IVA, IB, IIB, VIB, VIIB, and VIXI of the Periodic Table.
In evaluating the compounds under discussion, a preliminary fungicidal evaluation was carried out using the compounds at 300 ppm and spraying the plants to run off in a carrier volume of about 150 gallons/acre.
The general procedure was 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 and allow to dry. The proper plants were then inoculated with the fungal spores and then allowed to incubate until the disease had developed and the control read or estimated. The percent disease control is reported by the following rating system: A = 97-100% control B = 90-96% control C = 70-89% control D = 50-69% control E = Inactive 50% control % disease control = disease of untreated-disease of treated x 100 disease of untreated The phytopathogenic fungi used in the evaluation of the 5 fungicidal activity of the compounds of Table IA are described below: BH - barley net blotch (Helminthosporium teres) BOT - grey mold of faba beans (Botrytis cinerea) BPM - bean powdery mildew (Erysiphe polygoni) GDM - grape downy mildew (Plasmopora viticola) TLB - tomato late blight (Phytophtora infestans) RB - rice blast (Piricularia oryzae) WSR - wheat stem rust (Puccinia qraminis f. sp. tritici) WLR - wheat leaf rust (Puccinia recondita) Table III presents the results of the application of most of the compounds of Table IA at a rate of 300 ppm evaluated against the above fungi. 42517 - 66 Table ΙΙΙΑ Example No. BH BOT BPM GDM TLB RB WSR WLR IA A B A B E B - A 2A A B A A B A - A 3A A A A A B B - A 4A E B A A A B - A 5A A C A A B E - A 6A A A A B B E - A 7A A A A A A A - A 8A A A A A B B - A 9A A . A A A A A - A IGA A A A A B A - A 11A E E A B B B - A 12A A E A E B A - A 13A E E A - E E - E 14A A E A B A - - E 15A A E A B Ξ B - C 16A A E E E C A - C 17A A E A B A E - B 18A A E A A A E - A 19A E E A B B B - A 20A A E A B A E - A 21A A B A B B B - A 22A A E A A A B - A 23A A C A C E - c - 24A A C A E E - E - 25A E c A E E - E - 26A - E A E B - B - 27A A c A C E - C - 28A E E B C E A A - 29A E C A E E - E - 30A B A A E E - C - «35ί7 Sxample No. BH BOT BPM GUM TLB RB WSR WLR 31A E C A C B - E - 32A E C A C E - B - 33A A E A C E - E - 34A 35A E E A E E E 36A 37A A E A B A B 38A A E A E E - E - 39A E C A E - - E - 4QA E E A C A - C - 41A E C A C E - E - 42A E E A B A - E - 43A E E A E E A E - 44A A E A A E - C - 45A A C E E E - C - 46A A C A A E A A - 47A E B E C E - B - 48A A B A B E - A - 49A B A A B B - B - SOA A A A B E A A - 51A E E A E E E C - 52A E E A E E - E - 53A E E A E E - E 54A A E A E E - E - 55A E C A E E - E - 56A A A E E E C E - 57A A E A E E B B - 58A E C A E E B E - 59A E G A E E - E - 60A A A A B A A - A «ο- & 3517 Example No. 61A 62A 63A 64A 65A 66A 67A 68A 69A 70A 71A 72A 73A 74A 75A 76A 77A 78Ά 79A 80A 81A 82A 83A 84A 85A 86A 87A 88A 89A BH BOT BPM GDM TLB RB WSR WLR Ε B A B A A A A Ε E Ε E A A Ε B A C A C A E E C A C A C Ε E E C Ε B A B Ε E A E Ε E Ε E A E Ε E Ε E Ε E E A Ε E A E A E Β E A A A A A B A C A E A B A A A B A E A E A E Ε E A E A B A B A B A E A E Ε E Ε E A E Ε E A C A C A B Β B B A Ε B Β B A E A A Β B E Β B B C E Β E Ε E E A Ε B Ε B Ε B Β B Β B Β B Β B Β B Ε B Ε B E Β B E A E A B E A Β E A A A B E E - A A E B B A A A A A A A E A E E A E A A E A C ί 35 t? There will now be described novel products involving cyano-substituted compounds of Formula I (and their metal complexes and acid addition salts) and, in referring to such compounds, formulae, example, table numbers etc., will have added thereto the letter B to distinguish 1 them from those given above in which R in Formula I is other than cyano.
One cyano-substituted sub-class of compounds have the general formula Z-C-CH2(CH2)n-N --(X) (IB) wherein Z (when not joined to R ) is phenyl, naphthyl. thienyl, pyrryl, furyl, pyridyl, pyrimidyl or phenyl substituted with up to three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl, propyl, butyl, trihalomethyl, phenyl, benzoyl or methylenedioxy? R (when not joined to Z) is hydrogen, (C^-C2Q)alkyl, (C^-Cg)cycloalkyl, (Cg-Cg)cycloalkenyl, (Cg-Cg)alkenyl, (C^-Cg)alkynyl, phenyl, benzyl, naphthylmethyl, phenethyl or each of the last four groups ring substituted with up to three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl and trihalomethyl; R and Z (when joined together) form the group .251) X is halogen; a is zero, 1 or 2 and n is zero or 1.
A sub-class of compounds of Formula IB are those 2 in which 2 is not joined to R and is phenyl or naphthyl or phenyl substituted with up to two or three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl and trihalomethyl 2 and R is hydrogen, )alkyl, (Cg-Cg)cycloaikyl, (C5-Cg)cycloalkenyl, (Cg-Cg)alkenyl, (Cg-Cg)aikynyl, phenyl, benzyl or phenethyl or phenyl, benzyl or phenethyl each ring substituted with up to two or three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl and trihalomethyl. Examples of another sub-class of compounds are those in which 2 (when not joined to R ) is phenyl, naphthyl, thienyl, pyridyl, or phenyl substituted with up to three of the same or different substituents selected from methyl, bromine, chlorine, fluorine, trifluoromethyl, phenyl, methoxy, nitro, methylenedioxy 2 and benzoyl; R (when not joined to Z) is halogen, (C^-Cg)alkyl, (Cg-Cg)cycloalkyl, (Cg-Cg)alkenyl, (Cg-Cg)cycloalkenyl, (Cg-Cg)aikynyl, phenyl, benzyl or phenethyl (each of the last three groups being optionally substituted with up to two or three of the same or different halogen atoms) or naphthylmethyl; Z and R (when joined together) form the group X is chlorine; a is zero, 1 or 2 and n is 2ero or 1. preferred are compounds in which 2 is phenyl optionally substituted with up to two of chlorine and/or methyl, £3517 R is not joined to Z and is (C.-C ) alkyl and a and n X s are both zero, e.g. the compound of Formula IB in which Z is phenyl, R is n-butyl and a and n are both zero.
Acid addition salts of compounds of Formula IB are also provided and these are of an agronomically acceptable character, i.e. do not harm crops to which they may be applied.
Typical metal salt complexes of compounds of Formula IB may be represented by the general formula CN m Z-C-CH.(CH) -N , ζ z n (X) a MY (IIB) wherein Z, R‘ X and a are as defined for Formula IB; M is a metal cation selected from Group IIA, IVA, IB, IIB, VIB, VIIB or VIII of the Periodic Table; Y is an anion counterion; and m is an integer from one to four. M may, for example, be selected from the following metals; calcium, magnesium, barium, tin, lead, copper, zine, cadmium, chromium, manganese, iron, cobalt or nickel. Y may be an anion selected from chloride, bromide, iodide, sulfate, bisulfate, phosphate, nitrate, perchlorate, carbonate, bicarbonate, hydrosulfide, hydroxide, acetate, oxalate, malate, citrate and tartrate.
Typical cyano-substituted compounds of Formula I and IB are tabulated below; 1-[2-cyano-2-(2-ehlorophenyl)propyl]imidazole 1-[2-cyano-2-(3-fluorophenyl)butyl]-2-methylimidazole 1-(2-cyano-2-(4-bromophenyl)pentyl]imidazole 1-[2-cyano-2-(2,3-difluorophenyl)3,3-dimethylbutyl] imidazole 1-[2-cyano-2-(5-bromo-2-ehlorophenyl)dodecyl]imidazole 1-[3-cyano-3-(2,5-dichlorophenyl)tetradecyl] -2-methylimidazole 1-[2-cyano-2-(2-cyanophenyl)doco syl] -2-nitroimidazole 1-[2-cyano-2-(2-methoxyphenyl)hexyl]imidazole 1-[2-cyano-2-(4-chloro-2-nitrophenyl)butyl]-2-methylimidazole 1-[2-cyano-2-phenyl-2-(2-ehlorophenyl) ethyl]imidazole 1-[2-cyano-2-(2-bromophenyl)-2-(2-nitrophenyl) ethyl] imidazole 1-(2-cyano-2-(2-chloro-4-methylphenyl)-2-(4-methoxyphenyl) ethyl]imidazole l-[3-cyano-3-(2,6-diethylphenyl)propyl] -2-nitroimidazole l-[2-cyano-2-(4-trifluoromethylphenyl) ethyl] imidazole 1-[3-cyano-3-(2-bromophenyl)-3-(4-ehlorophenyl) propyl]-2-methyl imidazole 1-(2-allyl-2-cyano-2-(2,4-dichlorophenyl) ethyl]imidazole 1-(2-crotyl-2-cyano-2-(2,4-dichlorophenyl) ethyl]imidazole 1-(2-methallyl-2-cyano-2-(2,4-dichlorophenyl) ethyl]imidazole 1-(2-(5-hexenyl)-2-cyano-2-(2,4-dichlorophenyl) ethyl]imidazole 1-(2-propargyl-2-cyano-2-(2,4-dichlorophenyl)ethyl]imidazole l-[2-(4-pentynyl)-2-cyano-(2,4-dichlorophenyl)ethyl]imidazole 3517 1-(2-(5-hexynyl)-2-cyano-(2,4-dichlorophenyl) ethyl]imidazole l-(2-cyano-2-(4-trifluoromethylphenyl)hexyl] -2nitroimidazole 1-(2-cyano-2-(2,4-difluorophenyl)-1-(2,4-dimethylphenyl)hexyl]-2-nitroimidazole 1-(2-cyano-2-(4-iodophenyl)octyl]imidazole l-(2-cyano-2-(3,5-dinitrophenyl)hexyl]imidazole 1-(2-cyano-2-(2,3-dimethylphenyl)hexyl]imidazole 1-(2-cyano-2-phenyl-2-(4-ethylphenyl) ethyl]imidazole 1-(2-cyano-2-(4-pyridyl)-2-phenylethyl]imidazole 1-(2-cyano-2-(4-pyrimidyl)-2-phenylethyl]imidazole l-[2-cyano-2-(3-pyridyl)-2-phenyldecyl] imidazole 1-(2-cyano-2-(2-pyrimidyl)-2-phenylethyl] imidazole 1-(2-cyano-2-(1-naphthyl)hexyl]imidazole 1-[2-cyano-2-(1-(2,4-diehloronaphthyl) ] hexyl}imidazole and the acid addition salts and metal salt complexes thereof.
Compounds of Formula IB can be prepared by various synthetic routes including the following procedures. Compounds of Formula IB can be prepared by alkylating a substituted acetonitrile of the formula Z-CH2CN (IIIB) with an alkyl halide and sodium hydride in a solvent such as ether, tetrahydrofuran or dioxane at temperatures from about 20°C. to about 1OO°C. to give a substituted acetonitrile of Formula IVB Z-CH(R2)CN (IVB) The substituted acetonitrile (Formula IVB) is hydroxyalkylated by reacting it with an aldehyde or ketone in a solvent such as pyridine or N,N-dimethylformamide at temperatures from about 0°C. to about 150°C. for periods from about 10 to about 40 hours to give the alcohol of Formula VB, i.e.
CN I ο Z-C(R )CH2OH (VB) The resultant alcohol (Formula VB) is converted to the chloride via phosphorous pentachloride or thionyl chloride in a solvent such as benzene or toluene at temperatures from about 10°C. to about 110°C. The alcohol can also be converted to the methane sulfonate ester by reacting it with methane sulfonyl chloride in a solvent such as benzene or toluene at temperatures from about 10°C. to about 110°C. Either the chloride or the methane sulfonate ester can be reacted with an imidazole either neat or in a solvent such as N,Ndimethylformamide, dimethylsulfoxide or diglyme at temperatures from about 50°C. to about 180°C. for periods from about 10 to about 40 hours to give the desired product of Formula IB.
Compounds of Formula IB can be prepared by reacting an aldehyde vzith an arylmagnesium halide in an anhydrous ethereal solvent such as ether, tetrahydrofuran or dioxane at temperatures from about 25°C. to about 100°C. for periods from about 1 to about 24 hours to give an alcohol of Formula VIB.
Z-CH(R2)OH (VIB) The alcohol (Formula VIB) ia converted to the halide by reacting it with phosphorous tribromide or thionyl chloride in a solvent such as benzene or toluene at temperatures of from about 25°C. to about 110°C.
The alcohol can also be converted to the methane sulfonate ester by reacting it with methane sulfonyl chloride in a solvent such as benzene or toluene at temperatures of from about 25°C. to about 11O°C.
Either the halide or the methane sulfonate ester oan be reacted with a metal cyanide in a solvent such as dimethylsulfoxide or Ν,Ν-dimethylformamide at temperatures from about 50°C. to about 180°C. for periods from about 4 to about 24 hours to give the substituted acetonitrile of Formula VIIB.
Z-CH(R2)CN (VIIB) The substituted acetonitrile (Formula VIIB) is hydroxyalkylated by reacting it with an aldehyde or ketone in a solvent such as pyridine or Ν,Ν-dimethylformamide at temperatures from about 0°C. to about 150°C. for periods from about 10 to about 40 hours to give the corresponding alcohol of Formula VB. The alcohol is converted as above to the halide or methane sulfonate. Either the halide or the methane sulfonate ester can be similarly reacted as above, with an imidazole either neat or in a solvent such as Ν,Ν-dimethylformamide, dimethylsulfoxide or diglyme at temperatures from about 50°C. to about 180°C. for periods from about 10 to about 40 hours to give the desired product of Formula IB. The compounds of Formula IB can also be prepared by utilizing the procedure of Markosza and Serafin, - 76 Roczniki Chem.. 39, 1223 (1965)? ibid. 40, 1839 (1966), and Brandstrom and Junggren, Tet. Letters, 473 (1972) wherein the quaternary ammonium salt of an arylacetonitrile carbanion (formed by the action of a 25 to 50% solution of sodium hydroxide on an arylacetonitrile of Formula IIIB followed by treatment with a quaternary ammonium halide) is extracted into an aprotic solvent such as chloroform or methylene chloride and alkylated by adding an alkyl halide to the solution to give an aralkylacetonitrile of Formula IVB.
The carbanion of a substituted acetonitrile (Formula IVB) can be bromoalkylated with a dibromo alkane under conditions similar to Markosza and Brandstrom to give the bromide (Formula VIIIB) CN I ο Z-C(R)CH„(CH„) Br (VIIIB) ί n The bromide (Formula VIIIB) is then reacted with an imidazole either neat or in a solvent such as Ν,Νdimethylformamide, dimethylsulfoxide or diglyme at temperatures from about 50°C. to about 180°C. for periods from about 10 to about 40 hours to give the desired product of Formula IB The carbanion of a substituted acetonitrile Formula IVB can be bromoalkylated with a dibromoalkane under conditions similar to Markosza and Brandstrom to give the bromide (Formula IXB) CN I p 2-C(ir)CH_(CiI,) Br 2 z n (IXB) - η This bromide (Formula IXB) is then reacted with an imidazole either neat or in a solvent such as N,Ndimethylformamide, dimethylsulfoxide or diglyme at temperatures from about 50°C. to about 180°C. for periods from about 10 to about 40 hours to give the desired product of Formula IS.
An improved process for the preparation of compounds of Formula IB involves the addition of a solution of an arylacetonitrile and alkyl halide in dimethylsulfoxide to a 50% aqueous solution of sodium hydroxide at room temperature. To this reaction mixture is then added a dibromoalkane and the desired product (Formula VIIIB) is isolated in good yield.
The bromide (Formula VIIIB) is then reacted with an imidazole either neat or with a small quantity of a high boiling solvent at temperatures from about 50°C. to about 180°C. for periods from about 10 to about 40 hours to give the desired product of Formula IB.
The compounds of Formula IB can be similarly prepared by adding a dibromoalkane to a solution of a diarylacetonitrile in dimethylsulfoxide and 50% sodium hydroxide holding the reaction temperatures at about 20°C. to about 50°C. for periods from about 1 to about 8 hours. The resultant bromide is then converted to the imidazole yia prior reaction conditions.
The acid addition salts of the compounds of Formula IB can be prepared by adding aqueous alcoholic or ethereal solutions of organic or mineral acids to aqueous, alcoholic or ethereal solutions of the compounds of Formula IB. The resultant precipitate is then filtered, washed with solvent and dried to give the desired acid addition salt. Typical acids 3 517 which can be utilized in the above preparation include hydrochloric, nitric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, oxalic, malic, tartaric and citric.
The metal salt complexes of the compounds of Formula IB can be prepared by treating an aqueous or alcoholic solution of a compound of Formula IB or its acid addition salt with an aqueous or alcoholic solution of a metal salt. The precipitate is filtered, washed with solvent and dried to give the desired metal salt complex (Formula IIB).
The metal salts that can be utilized in the above procedure include those which are formed by the combination of a metal cation, for example Mg, Ca, Ba, Sn, Pb, Cu, Zn, Cd, Cr, Mn, Fe, Co or Ni and an anion, for example, chloride, bromide, iodide, sulfate, bisulfate, phosphate, nitrate, perchlorate, carbonate, bicarbonate, hydrosulfide, hydroxide, acetate, oxalate, malate, citrate or tartrate.
A metal salt complex of Formula IIB can also be prepared by mixing stoichiometric or excess amounts of the metal salt and a substituted imidazole in the desired amount of solvent containing the appropriate adjuvants just prior to spraying the plants. Adjuvants that may be included in this in-situ11 preparation may be detergents, emulsifiers, wetting agents, spreading agents, dispersing agents, stickers, adhesives, and the like which are used in agricultural applications. Complexing with a metal salt provides a safening effect which reduces the phytotoxicity while retaining fungicidal efficacy.
It has also been found that metal containing fungicides can also act as safening agents for compounds 3517 of Formula IB when used in place of metal salts.
Typical metal containing fungicides that can be utilized in these procedures are: а. 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-ethylmercuri15 1,2,3,6-tetrahydro-3,6-endomethano-3,4,5, б, 7,7-hexachlorophthalimide, phenylmercur ic monoethanolammonium lactate, nickelcontaining compounds and calcium cyanamide.
Solvents that can be utilized in the above procedures 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.
The following examples are provided to illustrate methods of the preparation of compounds of Formulae IB (and acid addition salts) and IIB. The actual working examples are illustrative preparations Of compounds of the invention and which are listed and identified in Tables IB and IIB which follow later . 42517 - 80 Example 15B l-r2-cyano-2-(2,4-dichlorophenyl)hexyl1 imidazole hydrochloride a) α-n-butyl-2,4-dichlorobenzyl cyanide Sodium hydride (0.3 mole as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature a solution of 2,4dichlorobenzyl cyanide (55.8 g., 0.3 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed, the temperature is maintained at 30°C. for an additional 0.5 hours. A solution of n-butyl iodide is then added dropwise and the resultant reaction mixture is stirred at 40°C. overnight under nitrogen.
The reaction mixture is poured into 1 liter of water and extracted with (3 x 200 ml.) of ether. The combined ether extracts are washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 71 g. of a brown crude product which is further purified by vacuum distillation (lO5-7°/O.l mm) to give 61.7 g (85%) of product which is identified by nmr. b) 2-cyano-2-(2,4-dichlorophenyl)hexan-l-ol To an ice cold stirred solution of g-n-butyl2,4-dichlorobenzyl cyanide (5 g., 0.02 mole) in 20 ml. of pyridine containing a suspension of paraformaldehyde (2.4 g., 0.08 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under iSS!7 nitrogen at room temperature for 16 hours. The reaction mixture is poured into 300 ml. of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 5.6 g. of a thick oil, which is identified by nmr. c) 2-cyano-2-(2t4-dichlorophenyl)hexyl methane sulfonate A mixture of 2-cyano-2-(2,4-dichlorophenyl)hexanl-ol (5.6 g., 0.02 mole) and methane sulfonyl chloride (2.9 g., 0.025 mole) in 200 ml. of benzene is added dropwise at 10°C., 2.8 g. (0.027) of triethylamine.
The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 6.3 g. of product. d) 1-(2-cyano-2-(2,4-dichlorophenyl) hexyl) imidazole hydrochloride A mixture of 2-eyano-2-(2,4-dichlorophenyl)hexyl methane sulfonate (100 g., 0.29 mole), imidazole (100 g., 1.5 mole) and N,N-dimethylformamide (5 ml.) is heated with stirring at 135°C. overnight. The reaction mixture is poured into water and extracted with ether . The combined ether extracts are dried over magnesium sulfate. The drying agent is filtered and into the ethereal solution is bubbled 3 517 - 82 dry hydrogen chloride gas. The white solid which precipitates is collected and dried to give 70.4 g. (68%) of the expected product, which is identified by nmr.
EXAMPLE 24B Zinc Chloride Complex of l-r2-cyano-2,4-dichlorophenyl)hexyl] imidazole To an ethanolic solution of l-[2-cyano-2-(2,4dichlorophenyl)hexyl] imidazole (3 g., 0.01 mole) is added a solution of zinc chloride (0.63 g., 0.01 mole) dissolved in 10 ml. of absolute ethanol. The white precipitate which is formed is filtered, washed with ethanol and dried to give 3.1 g. of desired product, m.p. 196-198°C, which is identified by nmr.
EXAMPLE 27B l-r2-cyano-l-(4-chlorophenyl)propyl]imidazole hydrochloride a) 2-cyano-2-(4-chlorophenyl)propan-1-ol To an ice cold stirred solution of a-methyl-4chlorobenzyl cyanide * (50 g., 0.3 mole) in 500 ml. of pyridine containing a suspension of paraformaldehyde (36 g., 1.2 mole) is added 1 ml, of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaotion mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil, 58.4 g., which is identified by nmr. *-commercially available. b) 2-cyano-2-(4-chlorophenyl)propyl methane sulfonate To a mixture of 2-cyano-2-(4-chlorophenyl)propanl-ol (68 g., 0.3 mole) and methane sulfonyl chloride (37.5 g., 0.33 mole) in 2 liters of benzene is added dropwise at 10°C., 36 g. (0.36 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 63 g. of product. c) 1-(2-cyano-2-(4-chlorophenyl)propyl] imidazole hydrochloride A mixture of 2-cyano-2-(4-chlorophenyl)propyl methane sulfonate (63 g. 0.23 mole), imidazole (62.6 g., 0.9 mole) and N,N-dimethylformamide (3 ml.) is heated with stirring at 130°C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. Into the ethereal solution is bubbled dry hydrogen chloride gas. The white solid which precipitates is collected and dried to give 38 g. (58.6%) of the expected product, which is identified by nmr.
EXAMPLE 28B 1-1' (2-cyano-2-(2-chlorophenyl) -2-(4-chlorophenyl) ethyl]imidazolium nitrate a) 2,4-dichlorobenzhvdrol To 12.7 g. (0.52 mole) of magnesium turnings in 200 ml. of anhydrous ether is added 10.0 g. (0.052 mole) of p-bromochlorobenzene, and the mixture is warmed to reflux. When the Grignard reaction begins, the heat is removed and 80.0 g. (0.47 mole) of additional p-bromochlorobenzene in 80 ml. of ether is added dropwise as the refluxing continues. When the addition is completed, the reaction is heated at reflux for 2 hours, cooled, and 73.4 g. (0.52 mole) of_o-chlorobenzaldehyde are slowly added. The reaction is refluxed for 2 hours, cooled and poured into iced water. The resulting mixture is made acidic with hydrochloric acid, and the organic phase is separated. The aqueous layer is extracted with ether, and the extract is added to the organic phase. This solution is washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oily solid.
The material is crystallized from petroleum ether to give 109.4 g. (83%) of the product, m.p. 68-70°. b) 2,41-dichlorodiphenyl bromomethane To 109.4 g. (0.432 mole) of 2,41-dichlorobenzyhydrol in 125 ml. of benzene is slowly added 68.4 g. (0.253 mole) of phosphorus tribromide at 10°C. When the addition is complete the reaction is stirred for 2 hours. The benzene is then stripped off at atmospheric pressure with the pot temperature reaching 115°C. The reaction is cooled, and poured into iced water . After stirring for 15 minutes, the organic material is extracted out with ether (3 x 100 ml.).
The extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and then concentrated to give 116.5 g. of the crude product. A distillation 435iz gives 97.2 g. (69%) of the pure bromomethane product (140-5°C./0.1 mm). c) 2,41-dichlorodiphenylacetonitrile To 85.0 g. (0.27 mole) of the prepared bromomethane derivative is added at 125°C., 25.5 g. (0.285 mole) of anhydrous cuprous cyanide. The temperature gradually exothermed to 140°C. before it is cooled back to 125°C. After stirring for 1 hour at 125°C., the reaction is heated up to 150°C. for an additional hour. The insoluble solid is filtered, and the filtrate is stripped to dryness giving 70.6 g. of the crude product.
A distillation provided 63.3 g. (90%) of the acetonitrile derivative (140-4°C/0.1 mm). d) 2-cyano-2-(2-chlorophenyi)-2-(4-chlorophenyi) ethanol To an ice cold stirred solution of 2,41-dichlorodiphenylacetonitrile (20 g., 0.08 mole) in 100 ml. of pyridine containing a suspension of paraformaldehyde (9.2 g., 0.3 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 60 hours. The reaction mixture is poured into 1.5 liters of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate.
The solvent is evaporated to give 18 g. of a thick oil, which is identified by nmr. e) 2-cyano-2-(2-chlorophenyi)-2-(4-chlorophenyl) ethyl methane, sulfonate To a mixture of 2-cyano-2-(2-chlorophenyi)-2(4-chlorophenyl)ethanol (18 g. 0.06 mole) and methane 3517 sulfonyl chloride (7.8 g., 0.07 mole) in 200 ml. of benzene is added dropwise at 10°C., 7.5 g. (0.08 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 22 g. of product; m.p. 124-7°C, which is identified by nmr. f) l-r2-cyano-2-(2-chlorophenyl)-2-(4-chl6rophenylethyl]imidazolium nitrate A mixture of 2-cyano-2-(2-chlorophenyl)-2-(4chlorophenyl)ethyl methane sulfonate (22 g., 0.06 mole), imidazole (16.3 g., 0.24 mole) and H,N-dimethylformamide (1 ml.) is heated with stirring at 150°C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. Into the ethereal solution is poured, with rigorous stirring, an excess of concentrated nitric acid solution. The resultant precipitate is filtered and washed with ether and dried to give 10.8 g. (44.4%) of product, which is identified by nmr.
EXAMPLE 31B l-r2-cyano-2-(2,4-dichlorophenyl)decyl]imidazole hydrochloride a) g-n-octyl-2,4-dichlorobenzyl cyanide Sodium hydride (0.13 mole as a 50% dispersion in mineral oil) is washed with 100 ml. of dry r-hexare to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature, a solution of 2,4-dichlorobenzyl cyanide (25 g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed the temperature is maintained at 30°C. for an additional 0.5 hours. A solution of n-octylbromide (27 g., 0.14 mole) is then added dropwise and the resultant reaction mixture is poured into 1 liter of water and extracted with (3 x 200 ml.) of ether. The combined ether extracts are washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated to give 39.8 g. (100%) of product. b) 2-cyano-2-(2,4-dichlorophenyl) decan-1-ol To an ice cold stirred solution of a-n-octyl20 2,4-dichlorobenzyl cyanide (40 g., 0.14 mole) in 250 ml. of pyridine containing a suspension of paraformaldehyde (21 g., 0.7 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours.
The reaction mixture is poured into 2 liters of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate.
The solvent is evaporated to give 40 g. of a thick oil. - 88 c) 2-cyano-2-(2,4-dichlorophenyl)decyl methane sulfonate To a mixture of 2-cyano-2-(2,4-dichlorophenyl)decan-1-ol (40 g., 0.12 mole) and methane sulfonyl chloride (15.3 g., 0.13 mole) in 2 liters of benzene is added dropwise at 10°C., 14.8 g., (0.14 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric aeid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 41.3 g. of product, which is identified by nmr. d) 1-Γ 2-cyano-2-(2,4-dichlorophenyl) decyl] imidazole hydrochloride A mixture of 2-cyano-2-(2,4-dichlorophenyl)decyl methane sulfonate (41.3 g., 0.1 mole), imidazole (27.7 g., 0.4 mole) and N,N-dimethylformamide (1.5 ml.) is heated with stirring at 130°C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over sodium sulfate. Into the ethereal solution is bubbled dry hydrogen chloride gas. The white solid which precipitates is collected and dried to give 11.7 g. (28%) of the expected product, which is identified by nmr.
EXAMPLE 37B 1-Γ2-cyano-2-(2-pyridyl)-2-phenylethyl] imidazole a) 2-cyano-2-(2-pyridyl)-2-phenyl ethanol To an ice cold stirred solution of phenyl-2pyridyl acetonitrile * (50 g., 0.26 mole) in 350 ml. of pyridine containing a suspension of paraformaldehyde (31 g., 1.0 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours.
The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil 58 g, which is identified by nmr. *-commercially available. b) 2-cyano-2-(2-pyridyl)-2-phenyl ethyl methane sulfonate To a mixture of 2-cyano-2-(2-pyridyl)-2-phenyl ethanol (25 g., 0.1 mole) and methane sulfonyl chloride (14 g., 0.11 mole) in 600 ml. of benzene is added dropwise at 10°C., 13.5 g. (0.12 mole) of triethyiamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 19.5 g. of product; m.p. 83-5°C. which is identified by nmr. c) l-r2-cyano-2-(2-pyridyl)-2-phenylethyl]imidazole A mixture of 2-cyano-2-(2-pyridyl)-2-phenyl ethyl methane sulfonate (11 g., 0.037 mole), imidazole (10 g., 0.15 mole) and Ν,Ν-dimethylformamide (1 ml.) is heated with stirring at 140°C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over sodium sulfate. When the solvent is evaporated, a total of 3.4 g. (34%) of product is obtained, which is identified by nmr.
EXAMPLE 41B l-r2-cyano-2-(2,4-dichlorophenyl)-4-phenyl butyl]imidazolium nitrate a) g-phenethyl-2,4-dichlorobenzyl cyanide Sodium hydride (0.13 mole as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature a solution of 2,4-dichlorobenzyl cyanide (25 g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed, the temperature is maintained at 30°c. for an additional 0.5 hours. A solution of phenethylbromide (26 g., 0.14 mole) is then added dropwise and the resultant reaction mixture is stirred at 40°C. overnight under nitrogen. The reaction mixture is poured into 1 liter of water and extracted with (3 x 200 ml.) of ether. The combined ether extracts are washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated and the crude product distilled (144-56°/O.O3 mm) to give 26.6 g. (70.5·'!.·' of product, which is identified by nmr. b) 2-cyano-2-(2,4-dichlorophenyl-4-phenyl butan-l-ol To an ice cold stirred solution of ci-phenethyl2,4-dichlorobenzyl cyanide (26.5 g., 0.09 mole) in 200 ml. of pyridine containing a suspension of paraformaldehyde (11 g,, 0.35 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours.
The reaction mixture is poured into 1 liter of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate.
The solvent is evaporated to give 25.4 g. of a thick oil, which is identified by nmr. c) 2-cyano-2-(2,4-dichlorophenyl)-4-phenyl butyl methane sulfonate To a mixture of 2-cyano-2-(2,4-dichlorophenyl)4-phenyl butan-l-ol (25.4 g., 0.08 mole) and methane sulfonyl chloride (10 g., 0.09 mole) in 1 liter of benzene is added dropwise at 1O°C, 9.6 g. (0.09 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 25.1 g. of product, which is identified by nmr. d) 1-Γ 2-cyano-2-(2,4-dichlorophenyl)-4-phenyl butyl imidazole nitrate A mixture of 2-cyano-2-(2,4-dichlorophenyl)-4phenyl butyl methane sulfonate (25 g., 0.063 mole), imidazole (17 g., 0.25 mole) and Ν,Ν-dimethylformamide (1 ml.) is heated with stirring at 150°C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. Into the ethereal solution is poured, with rigorous stirring, an excess of concentrated nitric acid solution. The resultant precipitate is filtered and washed with ether and dried to give 17.5 g. (64%) of product, which is identified by nmr.
EXAMPLE 48B l-Γ6-cyano-6-(2,4-dichlorophenyl)decyl] imidazole a) ot-n-butyl-2,4-dichlorobenzyl cyanide This compound is prepared in Example 15B, part a. b) 6-cyano-6-(2,4-dichlorophenyl)decyl bromide To 30 ml. of 50% sodium hydroxide solution containing 1 g. of benzyl triethylammonium chloride is added dropwise at room temperature, a mixture of 11 g. (0.045 mole) of α-η-butyl benzyl cyanide and 13.6 g. (0.6 mole) of 1,5-dibromobutane. The mixture is heated to 80°C. with rigorous stirring overnight.
It is then poured into water and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. Solvent is evaporated and the unreacted 1,5-dibromobutane is removed under vacuum to give 14.2 g. of product, which is identified by nmr. c) l-f6-cyano-6-(2,4-dichlorophenyl)decyl] imidazole A mixture of 6-cyano-6-(2,4-dichlorophenyl)decyl bromide (14.2 g., 0.036 mole) imidazole (10 g., 0.15 mole) and 5 ml. Ν,Ν-dimethylformamide is heated at 120°C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are dried over magnesium sulfate and filtered. Into the ethereal solution is bubbled dry hydrogen chloride gas until no more oily precipitate forms. The solvent is then decanted and the oily residue is taken up in acetone and neutralized with dilute ammonium hydroxide solution. The purified free base is extracted into ether and dried over magnesium sulfate. When the solvent is evaporated, a total of 6.5 g. (47.8%) of product is obtained, which is identified by nmr.
In Table IB a number of the more representative cyano-substituted compounds of this invention are presented; their melting points and elemental analysis have been provided in Table IIB. η a rt O rt rt 2 rt rt -' - U I I u ffl ι ι a I I I I I I I I 1 I ι ι ι ι ι ι ι ι ι ι oooooooo oo TABLE IB \ / ffl β OJ s 1 u-o N ω rt & fil J* a_Tf u in ω VO Q a rt «I of Tf o «r a71 fil uf Tf ϋ «tf « SJ ffl V U O cn c a1 8 δ vO o i OJ ffl ffl cn ffl «tf fil a0' o* fil a51 Tf u fil a c? fil ω a Tf u fil o* «tf «tf «tf ffl ffl «tf ffl vo vo ffl «tf VO o 0 vo ffl ϋ in cn o VO cn ffl ffl M □ Pm vo o ffl ‘r o o | «tf tf sp en 1 «tf ffl in ffl vo ffl r* ffl co β| ΐ ο* Tf a ω a a0' +•1 Tf a a OT O rt - 95 rt rt rH ffi ti ooo cl cl til til cl cl cl cl til OJ σι cn σ» σ σ tn _σ σι ffi ffi ffi ffi ffi ffi ffi ffi ffi Nf Nf Xf Xf Nf Nf Nf ‘M· xf υ a υ u u u a U u til xf U CM nt «—I r-1 r-1 o o o w s a cl hf o* cl uP o'* cl „01 a in jsC a o o ra a. ra - 97 42 517 tt H Si! Example m CQ fl) a CQ ffl 00 tt o rH Cl co CJ CJ a ro co o m tf ω HO=HO HO- ETTO-t'Z HSE rt in I ' I cl ta0' u cl σι <# υ cl <5 M tf υ cl σι ffl Φ o Cl hF ffl 1# o M ro M (Q ffl ffl ffl ffl kO kD kD kD u U □ υ H r-l rd H 9 V V o I 1 si si si si fe * π N fM N N ω ffl ffl ffl ffl ffl <0 si in kD si si si si •s4 3Si'7 100 Example Theory Found Theory Found Theory Found Ko. M.P. C H HALOGEN tf rH CO W co F o VO tf tf CM in cn fO cn cn in CO rH ω σ» CD f 0 • • • β • • • « • • CM rH rH o rH co o o o rH σι co rH rH rH CM rH rH rH rH rH CM CM rH F F CM rH tf in CD CD O in rH VO VO CM in F CM O in O vo tf • • • • • • • rH rH O rH F o rH O CM CD CO H H CM rH rH H H rH CM CM rH O in f f cn f « tf cn rH cn c o o 9 vo cn co cn O H rH cn tf in vo co O σι • VO rH tn O • cn VO f vo vo F f tn vo in F co vo in vo in in tf VO in • vo CD • rH F « O cn O cn » co « CM CM 1 rn vo < tf o β VO H • cn CM F σι tf • rH cn • o o • F rH f vo VO F f tf vo in F CO VO tn vo in in tf VO vo Ό CM • o rH CD tf •tf •tf • CM CD t tf co • CM O cn tf in O 1 cn rH CD O co vo CM tf • tn cn • in in • cn in CM vo tf CO rH cn 00 VO CM tf vo cn σι F vO vO VO VO tf vO vo F vo VO tn F in in tf vo o n n CM cn tf o tf tn o o cn co co co cn on CM CM VO tf in CM .tf co tf cn vo in 00 m vO F F co CM o CD cn F F σι cn σι F vo vo VO VO •tf VO vo GO VO vo in F tn in tf 7 F CM rH 7 CO 1 CO 1 tf 1 tf VO 1 tn in in 7 cn 1 rH o in in tn VO CM rH 1 CM CM m 1 1 o rH •rl vo CM vo vO cn F •H cn rH CM H o cn F tf 0 rH rH rH rH rH rH 0 tf CM rH rH tf co rH rH « rH 148-150 62.77 63.12 7.02 7.01 tt tt tt tt tt tt (4 tt tt m tt w tt in vo F co σι o H CM cn tf m vo Γ- H H rH rH H rH rH Η «I Ol - 101 oo η ω i£> iO o- O o <$ rH O 00 vo ο φ Γ- 04 • • « · * • rH 04 H H rH H St? TABLE IIB xt 00 VD vo VD Xf H tt tn Xt Xt tt 04 xt tt Xf OJ tn rH rH rH o H «φ H σι in • X· > [- tn xi* tn tn tn V0 tt H tn Φ m VO OJ Γ- rH X* rH in OJ O VD 00 VO m tn tt in tt in « ΙΌ rH VD Xt1 0* tn ro xi tn rH rH rH OJ in o Ol rH 'Φ VD H rH rH rH rH rH rH rH rH rH rH rH rH H rH H rH Kl tt in O m • VD tt tn 00 • rn ω » Ο- Η in vo 00 o in 0- • in H • xt H tn o- vO 0« • xt O • H Γ- xt in O- OJ vD xt vD tn rn tn tn OJ OJ tn vD H tn Η xt VD rH H H H H H H H H H H H H H H H H r- o N „ - .
Ol 1 Tl r- J 00 t tt 1 xt 1 m xt 1 VO in in in Ol tn 1 o in in m VD Ol Η 1 OJ Ol tn 1 • O H vO OJ vO vO m Ο- •h tn H 04 H O tn Ο- Xf H H H H H Η O Xi1 OJ H H Xt co Η H CQ m CQ Η (M CO ffl η η η n in io co tt tt tt tt m tt tt tt o H Ol m m VO Ο- H H H H H H Η 102 Exajnple Theory Found Theory Found Theory Found Φ rH Μ* O CO in m CD px XP xp VD m rn r> ω X? xl1 XP ω CM cn cn CM CM CM » • « « • « * ♦ » « • « O o VD CM xi· in p* cn m O p* O rH rH CM rH rH CM H H cn CM CM CM CM CM CM xp XP r-i t—i o O in xp VD in ω VD in CM xp cn H LO in I-i vo cn VD xP • • • • • • • • • • o P* Η xP m px P* in in o P* o «-Η H CM H rH CM r-i r-i cn CM CM CM CM m CM o CM t—i 00 CM r-{ in co in VD in xp o r-i xp Φ CM 00 P* φ CM rH 00 in vD P* φ CM in xP o P* in px· xp m VD xp* in m xp cn cn cn VD in in in cn xp co Φ CM cn oo o xp 00 00 cn i—i o xP in cn o Φ m VD H cn CM P· VO xp xP cn m in CM φ px VD VD M· in xP in in xp cn tn cn vD m in V CM o VD o CO CM rH Xp in xp o rH CD VD rH Φ rH cn xP Xp w cn Φ in p> o in m 00 cn rH VD in d P- Ρχ CM co co ω CM xP CM cn in Ρ* CM VO H VD VD Ρχ vD in vo Xp VD vo in in in XP in VD in VD in px Ρχ Xp VD cn CM Φ cn rH in in cn rH Ρχ φ xp xi* rH H CM rH 00 CM P* O cn cn cn VD Φ O rH Tp • vo rH Φ o CM o Φ OS «η in cn cn Ρχ CM VD CM vD VD Ρχ Ρχ in px VD vD in m in xp m vD in VD CM 0) rH rH UJ 00 xp CM **-* px m 1 VD 1 Xp 1 ? x|· Φ ί 1* Φ 1 O px 1 o rH o 1 rH VD cn rH CM O CM Ρχ Φ Ρχ in 1 in rH •ri in cn •ri Φ CM m rH Ρχ Φ in m cn CM CM 0 CM φ 0 rH CM CM CM H rH H H H Λ in co (0 CO CO cq CO co co CO CQ CO CO M CO CQ OQ « co Φ o rH CM cn xi· in VD Ρχ 00 Φ O rH CM cn d1 i—i rH CM CM CM CM CM CM CM CM CM CM ra cn cn cn ra 103 2 517 Theory Found Theory Found Theory Found Theory Found o tf o rH w| tf cn • cn Bl Φ rH Oi * H o rH CO r- t-» in H co rH 6 rH c- O « in H tf CJ rH CJ CJ rH r* CO CD tf SI tt in 00 CO CO CO tt tf rH rH rH rH H rH CO tf CO in C· CO KO P* rH in o rH tt KO d CO tt 00 tf CN m rH KO co CN 00 co tt CJ tt tt rH O tt rH CO co Cl r-' O d CO KO in o CO Cl tt CJ rH H rH H rH rH rH Cl rH rH rH rH H H rH H rH CO CO in in > Cl KO KO KO ra CO CO tt Cl P* CJ Tp CN in 00 KO co o m tt co co co CO rH O tt rH Cl Cl co co d o CO KO tf co CO CO d CN o Cl rH rH rH rH rH Cl rH rH rH H H rH H rH rH rH H CN u H rH Φ tf Cl TJ 00 in KO tf CO tf tt rH tt 1 p* I l | 1 1 1 1 I 1 o p* rH o rH o rH kO co rH Cl O CJ r* tt P* in 1 •rl rH •rj m co •H tt Cl CO rH I- tt in CO CO Cl in 0 Cl O CN tt 0 rH CN CN CJ rH H H rH rH Λ in ra £0 n m 00 tt tt CO tt o rH Cl CO tf rH rH CM Cl Cl CN CN tt tt tt tt tt a ffl tt tt tt in KO co tt o rH CN CO tf CN CN CN Cl CJ a CO CO co CO 104 Π3 φ rt rt Γ* Φ xf r- φ H xf ti co rt co O xf in σι H rt in ti • « • * 4 * ♦ co ♦ • 0 § σι Ch Γ- Γ- Γ- co xf Φ Φ fe K o o H H Η Η Η H H rt rt H Λ ffi O i—J O H Φ Φ O xf Φ σ 0 a rt rt tn σι rt rt H in rt rt Q) • • • • » • • • • • X5 σι σι Γ- Φ Φ co in co Φ Γ- ei i—l H Η H H H H rt rt Η Φ H H r- φ H O ω cn H rt O O σι rt tn r* in rt tn σι xf H rt in Γ- » • • • • 4 rt rt rt rt rt Xf xf rt in xf xf xf in «I ol rt σι co xf H σι in Φ H r- tn kD co rt Xf CO Φ H H CO xf CO rt φ H 4 4 4 4 • rt rt rt rt rt xf xf rt in rt xf xf Φ σι σι σι 1-» rt rt rt σι xf kD CO kD xf co in H rt Xf φ O σι σι 0 in Xf H co r- rt xf Γ- in H co xf co in H Ol xf Xf in tn ιο tn Φ in m xf xf in in oi kD in rt H Xf r- Φ co rt o rt kD Γ* O rt Xf xf Xf co CO H kD xf σι • 4 4 4 « 4 4 a » 4 4 ω 01 rt xf 03 m H co Xf σι in rt rt Xf Xf in in tn in kD in in Nf xf in kD α υ rt H rt QJ Q) H m γ- 01 Ό τ) in kD H rt H kD η H Su/ h 1 1 1 1 kD 1 rt l 1 1 Xf 01 o rt 1 rt I 00 oi H xf o 0i LO xf kD CO σι tn 0 Φ 00 «Η rt rt xf H H H H xf H xf H H 0 rt H H φ Η ffi ffi « ιη φ γrt rt rt ffi ω rt ffi ffi σ» o rt xf ffi ffi H rt xf xf ffi rt xf ffi ffi ffi xf tn φ Xf Xf Xf ffi Γxf 105 fa Ο®*? Theory Found Theory Found Theory Found Theory Found «I Ol ISl ffl Ch CO CO CN si m m rd > rd m m CQ O in si o si id O' 01 CQ Ol co CN H 6 O CQ rd rd id id id rd rd CN o rs si si 00 CN CN si O o 00 si o CN in kO • rt CQ id id rd o in 00 r—! »d id id rd rd «d rd 01 m O si « CQ 01 r* o rd rd CN CQ id kO r*· rd si si kD CQ 8 00 01 rs O si in CN CQ d CN o rd rd rd 6 oi rd rd id id rd id id rd rd td rd id td N kD CQ kD m CQ CN CQ kD si kO σι si rd CN 00 CQ r* Oi 00 01 r* 01 id CN « * W in CQ CQ o CN o td td O σι o CN td id td td rd id rd rd td id id td CN *d CN υ 0 rd m r* 01 φ in kO rd CQ si id kD td d Ό id I I 1 ! kO 1 CN 1 1 •w> I si oi O CQ 1 CQ 1 00 Oi id si o 01 in si kO CO 01 in o kO CO •rj CN CQ M* td rd id rd si rd si rd td 0 CN id rd ffl ffl ffl ffl ffl m ffl ffl ffl m ffl ffl « in hs CO Oi o rd CN fQ Ί1 \D t·» cn CQ CQ CQ CQ <φ si si si <Φ si ’φ . 4&-5Ί-7. - 106 Some of the substituted nitriles which are used as intermediates in the preparation of the compounds of this invention are commercially available materials.
In Table IIIB below some of the representative substit5 uted nitriles which are prepared via the methods herein-described are given along with their melting points or bpiling points and elemental analyses. - 107 al ta u a ν u — a TABLE IIIB o o in co cn OJ O co vo vO O OI o- • • • • • • • in ω in tf in Ο» O' GO GO co tf tf VO co O t"» cn cn ov tf « • • • a • • in co in in in VO 0* tf in vo vO ω cn co OJ co ov VO O' CS OJ OJ OJ GO 00 m m OJ OJ O O • 1 1 • » Ov ov O' O' OJ OI OJ OJ O o cn cn rt o co vo ov O· in tf 00 o • • • « • « in 00 m cn cn ov ov rt cn rt vO V£> rt in tf 0* tf tf tf in rt in co in cn cn ov OV m cn 00 tf m o OJ in tf co O vo Ol tf • • I • • • • ov ov tf cn cn cn in co m VO vo 00 00 cs ov OJ tn in cn O' in rt m rt rt in cn • • « • • ov cn ov tf tf cn cn in 00 in in VO co co o cn cn O O X tf in 0 00 vo cn r^l T* 00 I tf O' o tf co rt rt ω o < § in o οι ov vo rt Iti 0 fi} •H rt M 3 rt g & K I £ ffl cs rt ffl OJ rt ffl Ol ffl OJ u ffl U rt rt ffl ffl cn in cn u U σν 0* rt rt rt σν σν rt rH ffl ffl ffl ffl ffl ffl ffl OJ OJ OJ tf tf tf cn rt rt rt rt rt rt rt υ u o u □ υ a cl cil cl cl cl Ov cn σν Tf ID ov σν ffl a ffl a y su ffl tf Tf tf ω □ tf tf ϋ u o υ T T> a υ rt Ol Ol Ol cn rt rt rt r i ffl r ι V V V rt T tf vO tf φ tf ·» ·» 1 * o a CS CS Tf cs 43S17 - 108 The compounds of Formula I (wherein R is cyano) their acid addition salts and their metal salt complexes (particularly those of Formula IIB) are highly active broad spectrum fungicidal agents. These compounds are particularly effective against phytopathogenic fungi such as grey mold (Botrytis cinerea) on broad bean plants (Vicia faba), bean powdery mildew (Erysiphe polygoni) on broad bean plants (var. Dwarf Hort.), tomato late blight (Phytophthora infestans) on tomato LO seedlings, rice blast (Piricularia oryzae) on rice plants, grape downy mildew (Plasmopora viticola) on grape seedlings, barley net blotch (Helminthosporium teres) on barley plants, wheat leaf rust (Puccinia recondita) on wheat plants and wheat stem rust (Puccinia qraminis f. sp. tritici) on wheat plants.
The following test procedures were used to evaluate the compounds under discussion, acid addition salts and metal salt complexes. In the evaluation of these fungicidal agents against Botrytis cinerea the following procedure is followed. Broad beans are trimmed to a height of approximately 4-5 inches 24 hours prior to chemical application, the plants are sprayed to run off with the chemical agent and allowed to dry. The plants are inoculated with Botrytis cinerea and incubated in a humid environment at 75-85°F. for 66 hours. The plant lesions are evaluated 66 to 68 hours after inoculation.
The effect of these fungicidal agents against Erysiphe polygon! is evaluated via the following procedure. In this test, bean plants (var. Dwarf Hort.) are thinned to two plants per pot 24 hours prior to chemical application. Erysiphe polygon! 43S17 - 109 is cultured on bean leaves for 20-21 days under existing greenhouse conditions. Spores are harvested by adding deionized water containing 0.05 ml. of Tween 80 (Tween is a registered Trade Mark) per 500 ml. water to a quart jar containing excised mildew infected bean leaves.
The spores are loosened from the leaf surface by shaking the jar. The resulting suspension is filtered through cheesecloth to remove plant debris and adjusted to 4 2-2.5 x 10 spores per ml. Bean plants are inoculated by spraying the leaves and stems with inoculum until a film of inoculum is observed on the plants. Inoculated plants are maintained under existing greenhouse conditions. Treatment comparisons are made 8-10 days after inoculation. Typical bean powdery mildew symptoms are circular white mycelial mats (fructifications) on the leaf surface.
In evaluating these fungicidal agents against Phytophthora infestans the following procedure is utilized. Tomato seedlings are sprayed to run-off with suspensions of agents under evaluation in the given dosage series. The sprayed plants are allowed to dry and are then inoculated with a suspension of Phytophthora infestans fungal spores. The plants are maintained at 60 to 62°F. temperature and 100% relative humidity for about 40 hours to incubate.
The plants are then stored under greenhouse conditions for 5 or 6 days at which time treatment comparisons are made.
The test for evaluating these fungicidal agents against Piricularia oryzae is given below. Rice plants are trimmed to a height of approximately 5 - 110 inches 24 hours prior to chemical application. The plants are sprayed to run-off with the chemical agent, allowed to dry, and then inoculated with Piricularia oryzae and maintained in a humid environment (75-85°F.) for 24 hours. The plants are then maintained in a greenhouse environment for 7-8 days after inoculation at which time disease readings are made.
The effect of these fungicidal agents against Plasmopora viticola. is evaluated via the following procedure. Grape seedlings are sprayed to run-off with suspensions of agents under evaluation in the given dosage series. The sprayed plants are allowed to dry and then inoculated with a suspension of the Plasmopora viticola fungal spores. The inoculated plants are incubated in a humid environment at 65-7O°F. for 48 hours then stored in light for 4 days and replaced into a humid environment (65-7O°F.) for 24 hours. The plants are then evaluated for fungal growth.
In evaluating these fungicidal agents against Helminthosporium teres the following procedure is followed. Barley plants are trimmed to a height of approximately 2.5 inches 24 hours prior to chemical application. The plants are sprayed to run-off with the chemical agent and allowed to dry. The plants are then inoculated with Helminthosporium teres and incubated in a humid environment at 75 to 80°F. for 24 hours. The plants are then transferred to a greenhouse (7O-75°F.) for 6 to 7 days prior to determining disease control levels.
Another test used to evaluate the broad spectrum of activity possessed by these fungicidal agents is - Ill their control of Puccinia recondita. In this test the wheat plants are trimmed to approximately 2.5 inches prior to chemical application to afford uniform height and ease of inoculation. The plants are sprayed to run-off as before and dried before inoculation. The inoculated plants are placed in humid environment at 7O-75°F. for 24 hours then placed in the greenhouse at 7O-75°F. for 6 to 8 days. The occurrence of rustcoloured pustules on the surface of the leaves is evaluated. In the test for Puccinia qraminis f. sp. tritici, seven-day-old wheat plants (var. Monon) are trimmed to approximately 2.5 inches, 24 hours prior to chemical application. The plants are sprayed to run-off and dried before inoculation. The wheat plants are then inoculated by applying a stem rust 5 spore suspension containing a minimum of 2.5 x 10 spores per ml. until run-off. After inoculation the plants are placed into a humid environment at approximately 68°F., and the temperature is not allowed to exceed 85°F. After two weeks, treatment comparisons are made. The wheat stem rust is characterized by brick red spores in irregularly-shaped sori on the leaves and stems of the wheat seedlings.
The results of the above tests in evaluating the cyano-substituted imidazoles, and their acid addition salts and metal salt complexes are shown in Table IVB.
In compiling this table, the following codes are used; BOT = Grey mold of broad beans (Botrytis cinerea) BPM = Bean powdery mildew (Erysiphe polygoni) TLB = Tomato late blight (Phytophthora infestans) RB = Rice blast (Piricularia oryzae) GDM = Grape downy mildew (Plasmopora viticola) 517 - 112 BH = Barley Net Blotch (Helminthosporium tergal WLR = Wheat leaf rust (Puccinia recondita) WSR = Wheat stem rust (Puccinia graminis f. sp. tritici) The following disease rating scale is used for evaluating these fungicidal agents: A = 97-100% disease control B = 90-96% disease control C = 70-89% disease control D = 50-69% disease control E = <50% disease control SSI 7 - 113 rf! rf! W rf! rf! W W rf! rf! Ο H rf! W ffl < H Η M W rf! ffl W HmmmmwwwwwmWHramfflMM rfJrtJrflrflsJriJrfiWriJrfirfJrfirfJrfJrfirfJrtiW uwmwfiuwuffluwWrijrawwwo rfJWrfirtJrflWWWrflW rf! rfirfjrfjrfiw tt tt tt tt tt tt tt tt tt ffl tt tt tt ffl tt tt tt tt H CS cn xp in Φ r· 00 cn o H CS cn V m Φ Γ- 00 rH H H H H rH rH Η H /2517 114 ο o m tt η ffl «ι < tt rtjHHttOHMffl HtteCWHWfflfflWHMttfflfflfflMW ffl Hfflfflfflfflfijmffl < HWaWWMttttmfflfflHttttHOH OfflWOttrfJttrtittWOttiaJflJrtJMffl Httffl^.ttrtifSRiJnittrfittUttrtJisJffl Example fflfflfflfflfflfflfflnfflfflfflfflfflfflfflfflffl CJiOHMM'tftnfflNffleiOHtMM'tftt rHMMNOnlNfMMNNMMMMnm 4,3 517 - 115 λ! m m m tn m n < < < < < Wfflrf!rf!fflUUHWrf!fflri: rfJWriJrfirfJrfJrilHHrfJrfJri: WHUfflrfJrfJfflWHfflrfjW UrfjWCQrflWHWHrfJrfJrf! co co PQ « PQ PQ CQ CQ PQ CQ PQ VO r* co Φ o H CM co xP m Φ P· cn co co co Xp xp xp XP xP xP XP xp 517 - 116 The compounds of Formula I (wherein R^ is cyano) and their metal complexes and acid addition salts are not only broad spectrum fungicides but possess protectant and eradicant activity as well. The eradicant fungicidal properties of such compounds are particularly significant in that they kill phytopathogenic fungi in infected plant tissues and therefore can be utilized after fungal infection has already occurred.
The compounds under discussion also possess excellent fungicidal control of wheat stem rust (Puccinia graminis) and barley net blotch (Helminthosporium teres) and exhibit excellent eradicant activity on barley net blotch (Helminthosporium teres) and wheat yellow spot (Helminthosporium tritici-vulgaris).
In general, the invention provides a method of combating fungi on plants which are capable of giving rise to a vendible agronomic crop and which are infested, or liable to infestation, with phytopathogenic fungi, which method comprises applying to said plants, or their habitat, a fungicidally effective amount of (1) a substituted imidazole as defined in foregoing Formula I (or an agronomically acceptable acid addition salt thereof) or (2) a substituted imidazole as defined in foregoing Formula I (or an agronomically i acceptable acid addition salt thereof) complexed, or in admixture, with (a) a metal salt or (b) a metalcontaining fungicide. The invention also provides fungicidal compositions containing components (1) or (2) defined above and an agronomically acceptable J carrier. Usually, the fungicidal compositions will be in the form of (a) an emulsifiable concentrate, flowable emulsion concentrate or a wettable powder <2517 - 117 each containing a surfactant or (b) granules or a dust.
Fungicidal components (1) or (2) can be applied to various loci such as the seed, the soil, or the foliage. For such purposes the products can be used in the technical or pure form as prepared, as solutions or as formulations. Components (1) or (2) are usually taken up in an agronomically acceptable carrier; or are formulated so as to render them suitable for subsequent dissemination as fungicides. For example, they can be formulated as wettable powders, emulsifiable concentrates, dusts, granular formulations, aerososl, or flowable emulsion concentrates. In such formulations, the fungicidal products are extended with a liquid or solid carrier and, when desired, suitable surfactants are incorporated.
It is usually desirable, particularly in the case of foliar spray formulations, to include adjuvants, such as wetting agents, spreading agents, dispersing agents, stickers, or adhesives, in accordance with agricultural practices. Such adjuvants commonly used in the art can be found in the John W. McCutcheon, Inc. publication Detergents and Emulsifiers, Annual.
In general, the fungicidal agents of this invention can be dissolved in certain solvents such as acetone, methanol, ethanol, dimethylformamide, pyridine or dimethyl sulfoxide and such solutions extended with water. The concentration of the solution can vary from 1% to 90% by weight with a preferred range being 5 to 50% by weight.
For the preparation of emulsifiable concentrates the fungicidal agents can be dissolved in suitable »17 - 118 organic solvents, or a mixture of solvents, together with an emulsifying agent which permits dispersion of the fungicide in water. The concentration of the active ingredient in emulsifiable concentrates is usually 10% to 90% by weight and in flowable emulsion concentrates, this can be as high as 75% by weight.
Wettable powders suitable for spraying can be prepared by admixing the fungicidal product with a finely divided solid, such as clays, inorganic silicates and carbonates, and silicas and incorporating wetting agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such formations is usually in the range of 20% to 98% by weight preferably 40% to 75% by weight. A typical wettable powder is made by blending 50 parts by weight of the zinc chloride complex of l~[2-cyano2,2-diphanylethyl]imidazole or l-[p-(2,4-dichlorophenyl)hexyl]imidazole with 45 parts of a synthetic precipitated hydrated silicon dioxide sold as Hi-Sil (Hi-Sil is a registered Trade Mark), and 5 parts by weight of sodium lignosulfonate (Marasperse N-22). in another preparation of kaolin type (Barden) clay is used in place of the Hi-Sil in the above wettable powder, and in another such preparation 25% of the Hi-Sil is replaced with a synthetic sodium silico aluminate sold under the trademark Zeolex (Zeolex is a registered Trade Mark).
Dusts are prepared by mixing the fungicidal products with finely divided inert solids which can be organic or inorganic in nature. Materials useful for this purpose include botanical flours, silicas, silicates, carbonates and clays. One convenient 3 517 - 119 method of preparing a dust is to dilute a wettable powder with a finely divided carrier. Dust concentrates containing 20% to 80% by weight of the active ingredient are commonly made and are subsequently diluted in 1% to 10% by weight use concentration.
The fungicidal compositions provided by this invention can be applied as fungicidal sprays by methods commonly employed, such as conventional highgallonage hydraulic sprays, low-gallonage sprays, air-blast spray, aerial sprays and dusts. The dilution and rate of application will depend upon the type of equipment employed, the method of application and diseases to be controlled, but the preferred effective amount is usually about 0.1 lb to 25 lbs. per acre of the active ingredient.
As a seed protectant, active fungicidal agent of the invention coated on the seed is usually applied at a dosage rate of about 0.1 to 20 ounces per hundred pounds of seed. As a soil fungicide the fungicidal agent can be incorporated in the soil or applied to the surface usually at a rate of 0.1 to 50 lbs. per acre.
As a foliar fungicide, the fungicidal agent is usually applied to growing plants at a rate of 0.25 to 10 lbs. per acre.
Fungicides which can be used in combination with the fungicidal agents of this invention include: 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 2 5 t 7 - 120 (zineb), zinc propylenebisdithiocarbamate (propineb), sodium methyldithiocarbamate (metham), tetramethylthiruam disulfide (thiram), and 3,5-dimethyl-1,3,5-2H-tetrahydrothiadiazine-2-thione (dazomet); b) Nitrophenol derivatives such as: dinitro(1-methylheptylJphenyl crotonate (dinocap), 2-sec-butyl-4,6-dinitrophenyl 3,3-dimethyl acrylate (binapacryl), and 2-sec-butyl-4,6-dinitrophenyl isopropyl carbonate; c) heterocyclic structures such as: N-trichloromethylthiotetrahydro-phthalimide (captan), N-trichloromethylthiophthalimide (folpet), 2-heptadecyl-2-imidazoline acetate (glyodin), 2-octyli sothiazolone-3, 2,4-diehloro-6-(o-chloroanilino)-s-triazine, diethyl phthalimidophosphorothioate, ) 4-butyl-1,2,4-triazole, -amino-l-[bis(dimethylamino)phosphinyl] -3phenyl-1,2,4-triazole -ethoxy-3-trichloromethyl-l,2,4-thiadiazole, 2,3-dicyano-1,4-dithiaanthraquinone (dithianon) 2-thio-l,3-dithio-4,5-b quinoxaline (thioquinox), methyl 1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl), 2-(4-thiazolyl)benzimidazole (thiabendazole) 4-(2-chlorophenylhydrazono)-3-methyl-5 0 isoxazolones, pyridine-2-thiol-1-oxide, - 121 3 517· 8-hydroxyquinoline sulfate, 2,3-dihydro-5-carboxanilido-6-methyl-1,4oxathiin-4,4-dioxide, 2.3- dihydro-5-carboxanilido-6-methyl-1,4oxathiin, a(phenyl)-a(2,4-dichlorophenyl)-5-pyrimidinylmethanol (triarimol), cis-N,(1,1,2,2-tetrachloro ethyl)thio-4cyclohexene-1,2-dicarboximide, 3-(2-(3,5-dimethyl-2-oxcyclohexyl)-2-hydroxyethyl] glutarimide (cycloheximide), dehydroacetic acid, N-(1,1,2,2-tetrachloroethylthio)-3a,4,7,4atetrahydrophthalimide (captafol), 6-butyl-2-ethylamino-4-hydroxy~6-methylpyrimidine (ethirimol), acetate of 4-cyclododecyl-2,6-dimethylmorpholine (dodemorph), and 6-methyl-2-oxo-l,3-dithiolo(4,5-b]-quinoxaline (quinomethionate). miscellaneous halogenated fungicides such as: tetrachloro~2_-benzoquinone (chloranil), 2.3- dichloro-1,4-napthoquinone (dichlone), 1.4- dichloro-2,5-dimethoxybenzene (chloroneb), 3.5.6- trichloro-o-anisic acid (tricamba), 2.4.5.6- tetrachloroisophthalonitrile (TCPN), 2.6- dichloro-4-nitroaniline (dicloran), 2-chloro-1-nitropropane, polychloronitrobenzenes such as: pentachloronitrobenzene (PCNB) and tetrafluorodichloroacetone; - 122 - ·. κ 1 7 e) fungicidal antibiotics such as: griseofulvin, kasugamycin and streptomycin; f) copper-based fungicides such as: cuprous oxide, basic cupric chloride, basic copper carbonate, copper naphthenate, and Bordeaux mixture; and g) miscellaneous fungicides such as: diphenyl, dodecylguanidine acetate (dodine), phenylmercuric acetate, N-ethylmercuri-1,2,3,6LO tetrahydro-3,6-endomethano-3,4,5,6,7,7hexachlorophthalimide, phenylmercuric monoethanol ammonium lactate, ρ,-dimethylaminobenzenediazo sodium sulfonate, methyl isothiocyanate, l-thiocyano-2,4-dinitrobenzene, L5 1-phenylthiosemicarbazide, nickel-containing compounds, calcium cyanamide, lime sulfur, sulfur, and 1,2-bis(3-methoxycarbonyl-2thioureido)benzene (thiophanate-methyl).
The fungicidal agents provided by this invention can be advantageously employed in various ways.
Since these agents possess inherent systemicity and broad spectrum fungicidal activity, they ean be employed in the storage of cereal grain. The fungicdal agents can also be employed as fungicides in turf and fruit orchard applications.

Claims (33)

1. CLAIMS:1. A substituted imidazole or metal salt complex or an agronomically acceptable acid addition salt thereof, said substituted imidazole being of the formula: (X). (I) 2. . wherein: Z (when not joined to R ) is a group containing up to 18 carbon atoms and is aryl; substituted aryl? aryl so substituted as to form a fused carbocyclic or heterocyclic ring; saturated carbocyclic so substituted as to form a fused aryl ring; or a heterocyclic group; 1 2 R (when not joined to R ) is hydrogen (except when R is hydrogen), cyano, (C -C 2Q )alkyl, (C 3 -C g )cycloalkyl, (C 2 -C 12 )alkenyl, (Cg-Cgjcycloalkenyl, (C,-C_)alkynyl or aralkyl of up to 24 carbon atoms which aralkyl group is optionally substituted with up to 3 substituents which may be the same or different; 2 1 R (when not joined to 2 or R ) is hydrogen or a group containing up to 20 carbon atoms and which is ( C 1-C 2O )alkyl, (C 2 -0^) alkenyl, (C^-Cg)alkynyl, (C,-C 0 )cycloalkyl, (C c -C n )cycloalkenyl, aryl or aralkyl, the last two groups being optionally substituted; 1 2 R and R (when joined together) form, together with attached carbon atom, a (Cg-Cgjcycloalkyl residue; Z and R (when joined together) form the group - 124 - A is a (C n -C c )alkylene group; X □ X is halogen, nitro or (C^-C^)alkyl, the x substituents being the same or different when more than one is present; a is zero, 1 or 2; and n is zero or 1.
2. A substituted imidazole, or an agronomically acceptable acid addition salt thereof, said substituted imidazole being of the formula; Z -C —CEL / n' \=2 (IA) wherein Z is phenyl, naphthyl, biphenyl, acenaphthenyl, indanyl, indolyl, pyridyl, pyrimidyl, pyrryl, furyl, thienyl or phenyl substituted with up to three of the same or different substituents selected from (C^-C^)alkyl, methoxy, ethoxy, halo, nitro, amino and methyl1 2 thio; R (when not joined to R ) is hydrogen (except 2 when R is hydrogen), (C^-Ο^θ)alkyl, (C 2 “C^ 2 )alkenyl, (C 7 -c g )aralkyl, (C^-Cglaralkyl substituted with up to two of the same or different substituents selected from methoxy, ethoxy, halo, nitro, amino and methylthio, (Cg-C?)cycloalkyl or (Cg-C^)cyoloalkenyl, R (when not joined to R^) is (C^-C^q)alkyl, (c^-C^j)alkenyl, 125 42517 (C-C Q )aralkyl, (C_-C„)aralkyl substituted with up to 7 y / y two of the same or different substituents selected from methoxy, ethoxy, halo, nitro, amino and methylthio, phenyl optionally substituted with up to two of the same or different substituents selected from methoxy, ethoxy, halo, nitro, amino and methylthio, (C -C_)1 cyeloalkyl or (Cg-C?)cycloalkenyl and R and R (when joined together) form, together with the attached carbon atom, a (c-c)cyeloalkyl residue. 3. o
3. A compound (including acid addition salts) according to Claim 2, wherein 2 is phenyl optionally substituted with up to three of the same or different substituents selected from methyl, methoxy, halo and 1 2 nitro, R is not joined to R and is hydrogen or 2 (C^-C^Jalkyl and R is (C 4 -C 1Q )alkyl or phenyl optionally substituted with methyl or halo.
4. A compound according to Claim 3, wherein Z 1 2 is 2,6-dichlorophenyl, R is hydrogen and R is n-butyl.
5. A metal salt complex of the formula R' --N Z-C-CH O (A) —N , 2 Π (X) MY (II) 1 2 wherein Z, R , R , A, η, X and a are as defined in Claim 1, M is a metal cation, Y is an anion counterion and m is 1 to 4.
6. A complex according to Claim 5, wherein M is selected from Groups IIA, IVA, VA, IB, IIB, VIB, VIIB and VIII of the Periodic Table. - 126 43 5--7
7. A complex according to Claim 6, wherein M is calcium, magnesium, manganese, copper, nickel, zinc, iron, cobalt, tin, cadmium, mercury, chromium, lead or barium.
8. A complex according to Claim 6 or 7, wherein Y is an anion selected from chloride, bromide, iodide, sulfate, bisulfate, phosphate, nitrate, perchlorate, carbonate, bicarbonate, hydrosulfide, hydroxide, acetate, oxalate, malate or citrate.
9. A complex according to any of Claims 5 to 8, wherein the substituted imidazole portion is as defined in Claim 2.
10. A complex according to any of Claims 5 to 8, substituted imidazole portion is as defined in Claim 3 or 4.
11. A substituted imidazole or metal salt complex or an agronomieally acceptable acid addition salt thereof, said substituted imidazole being of the formula: CN Z-C_CH 2 (CH 2 ) n —1 \l (X). (IB) wherein 2 (when not joined to R ) is phenyl, naphthyl, thienyl, pyrryl, furyl, pyridyl, pyrimidyl or phenyl substituted with up to three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl, propyl, butyl, trihalomethyl, 2 t phenyl, benzoyl or methylenedioxy; R (when not joined to Z) is hydrogen, alkyl, (C 3 -C s )cycloalkyl, - 127 4 2517 (C-C-,)cycloalkenyl, (C-C)alkenyl, (C -C )alkynyl, phenyl, benzyl, naphthylmethyl, phenethyl or each of the last four groups ring substituted with up to three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl 2 and trihalomethyl; R and Z (when joined together) form the group X is halogen; a is zero, 1 or 2 and n is zero or 1.
12. A substituted imidazole, or an agronomically acceptable acid addition salt thereof, said substituted imidazole being of Formula IB in Claim 11, wherein Z is not joined to R and is phenyl or naphthyl or phenyl substituted with up to two or three of the same or different substituents selected from halo, nitro, cyano, methoxy, 2 ethoxy, methyl, ethyl and trihalomethyl and R is hydrogen, (C^C^) alkyl, (Cg-Cgjcycloalkyl, (C 5 -C g )cycloalkenyl, (C-C,.)alkenyl, (C.-C,)alkynyl, phenyl, do do benzyl or phenethyl or phenyl, benzyl or phenethyl each ring substituted with up to two or three of the same or different substituents selected from halo, nitro, cyano, methoxy, ethoxy, methyl, ethyl and trihalomethyl.
13. A compound, including acid addition salts, according to Claim 11, wherein Z (when not joined to 2 R ) is phenyl, naphthyl, thienyl, pyridyl or phenyl substituted with up to three of the same or different substituents selected from methyl, bromine, chlorine. - 128 fluorine, trifluoromethyl, phenyl, methoxy, nitro, methylenedioxy and benzoyl; R (when not joined to Z) is hydrogen, (C.-C„)alkyl, (C-C)cycloaikyl, (C,-C r )~ X o J B Jo alkenyl, (C-C )cycloalkenyl, (C,-C 3aikynyl, phenyl, □ o JO benzyl, phenethyl (each of the last three groups being optionally substituted with up to two or three of the same or different halogen atoms) or naphthylmethyl; Z and R (when joined together) form the group X is chlorine; a is zero, 1 or 2 and n is zero or 1.
14. A compound, including addition salts, according to Claim 13, wherein Z is phenyl optionally substituted with up to two of chlorine and/or methyl, R is not joined to Z and is (C-C Jalkyl and a and n X 8 are both zero.
15. A compound according to Claim 14, including 2 . addition salts thereof, wherein Z is phenyl and R is n-butyl.
16. A metal salt complex of the formula; CN Z-C-CH„(CH„) — N 2 2 n •(x). MY (IIB) wherein Z, R , η, X and a are as defined in Claim 11, M is a metal cation, Y is an anion counterion and m is 1 to 4. 4251 7 - 129
17. A complex according to Claim 16, wherein M is selected from Group IIA, IVA, IB, IIB, VIB, VIIB or VIII of the Periodic Table.
18. A complex according to Claim 17, wherein M is calcium, magnesium, barium, tin, lead, copper, zinc, cadmium, chromium, manganese, iron, cobalt or nickel.
19. A complex according to Claim 17 or 18, wherein Y is an anion selected from chloride, bromide, iodide, sulfate, bisulfate, phosphate, nitrate, perchlorate, carbonate, bicarbonate, hydrosulfide, hydroxide, acetate, oxalate, malate, citrate and tartrate.
20. A complex according to any of Claims 16 to 19, wherein the substituted imidazole portion is as defined in Claim 13.
21. A complex according to any of Claims 16 to 19, wherein the substituted imidazole portion is as defined in Claim 12, 14 or 15.
22. A substituted imidazole, acid addition salt or metal salt complex according to Claim 1, being any one of those individual compounds disclosed in the foregoing descriptive portion of this specification with the exception of the compounds claimed in Claims 4 and 15.
23. A fungicidal composition containing as an active ingredient, A(l) a substituted imidazole as defined in claim 1 (or an agronomically acceptable acid addition salt thereof) or (2) a substituted imidazole as defined in Claim 12 (or an agronomically acceptable acid addition salt thereof) complexed, or in admixture, with (a) a metal salt or (b) a metalcontaining fungicide and (B) an agronomically acceptable carrier. 517 - 130
24. A composition according to Claim 23 in the form of (a) an emulsifiable concentrate, a flowable emulsion concentrate or a wettable powder each contain ing a surfactant or (b) granules or a dust.
25. A method of combating fungi on plants which are capable of giving rise to a vendible agronomic crop and which are infested, or liable to infestation, with phytopathogenic fungi, which method comprises applying to said plants, or their habitat, a fungicidally effective amount of an active ingredient which is (1) a substituted imidazole as defined in Claim 1 (or an agronomically acceptable acid addition salt thereof) or (2) a substituted imidazole as defined in Claim 1 (or an agronomically acceptable acid addition salt thereof) complexed, or in admixture, with (a) a metal salt or (b) a metal-containing fungicide.
26. A method according to Claim 25, wherein said active ingredient is applied to plant foliage, plant seeds or soil.
27. A method according to Claim 25 or 26, wherein said active ingredient includes a dithiocarbonate as a metal-containing fungicide.
28. A composition according to Claim 23 or 24, or a method according to any of claims 25-27, wherein said active ingredient contains a substituted imidazole, acid addition salt or metal salt complex as defined in claim 2 or 9.
29. A composition according to Claim 23 or 24, or a method according to any of claims 25-27, wherein said active ingredient contains a substituted imidazole, acid addition salt or metal salt complex as defined in Claims 3, 4 and 10. 3 a ι 7 - 131
30. A composition according to Claim 23 or 24, or a method according to any of Claims 25-27, wherein said active ingredient contains a substituted imidazole, acid addition salt or metal salt complex as defined in any of Claims 11, 13 and 16-20.
31. A composition according to Claim 23 or 24, or a method according to any of Claims 25-27, wherein said active ingredient contains a substituted imidazole, acid addition salt or metal salt complex as defined in any of Claims 12, 14, 15 and 21.
32. A substituted imidazole as defined in Claim 1, or a metal salt complex or agronomieally acceptable acid addition salt thereof, whenever prepared by any of the general methods described in the foregoing descriptive portion of this specification.
33. A substituted imidazole as defined in Claim 1, or a metal salt complex or agronomieally acceptable acid addition salt thereof, whenever prepared by a method substantially as hereinbefore described with reference to any of Examples 1A-4A, 25A, 27A to 29A, 44A, 15B, 24B, 27B, 28B, 31B, 37B, 41B and 48B.
IE226/76A 1975-02-05 1976-02-04 Substituted imidazoles and their use as fungicides IE43517B1 (en)

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US54729175A 1975-02-05 1975-02-05
US55754675A 1975-03-12 1975-03-12
US05/642,041 US4105762A (en) 1975-02-05 1975-12-18 Metal salt complexes of 1-substituted aralkyl imidazoles, and methods and compositions for controlling phytopathogenic fungi using them
US05/647,039 US4073921A (en) 1975-03-12 1976-01-07 Substituted arylcyanoalkyl and diarylcyanoalkylimidazoles and fungical compositions and methods utilizing them

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FR2300081A1 (en) 1976-09-03
DD124098A5 (en) 1977-02-02
AR226407A1 (en) 1982-07-15
NL7601206A (en) 1976-08-09
HU178950B (en) 1982-07-28
AR220522A1 (en) 1980-11-14
FR2300081B1 (en) 1981-04-30
GR58522B (en) 1977-10-29
NZ179937A (en) 1978-09-25
IL48975A0 (en) 1976-04-30
OA05234A (en) 1981-02-28
AU1087376A (en) 1977-08-11
BR7600736A (en) 1976-08-31
IL48975A (en) 1980-03-31
ES444918A1 (en) 1977-11-01
IT1061007B (en) 1982-10-20
DE2604047A1 (en) 1976-09-16
ES458202A1 (en) 1978-08-16
JPS51143667A (en) 1976-12-10
AU502679B2 (en) 1979-08-02
PT64778A (en) 1976-03-01
DK48076A (en) 1976-08-06
MX4047E (en) 1981-11-23

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