CA2048001A1 - 2-substituted-1-hydroxyindoles - Google Patents

Abstract

Abstract of the Disclosure The present invention relates to 2-substituted-1-hydroxyindoles of the following formula:

Description

2 ~ 3 ~3 ~

2-SUBSTITUTED-l-~YDROX~I~DOLES
Field of the Invention The present invention relates to compounds useful as fungicides.
Background of the Invention In view of world hunger, it is useful to provide the public with a variety of fungicides for use in food agriculture.
The general structure of l-hydroxy-2-indoles is known in the art. Use of l-hydroxy indoles as fungicides is not known in the art. Although a number of N-substituted indoles have been described as active fungicides, none listed as active fungicides had an oxygen substituent, as found in l-hydroxy indoles.
US-A-3,296,277 discloses 3-cyano-1-hydroxy-2-phenylindole in which the phenyl group at the 2-position of the indole nucleus bears a nitro lower alkoxy substituent at either the ortho, meta, or para position. These compounds are disclosed as having pharmacological activity9 not as fungicides.-Loudon, et al., Journal of the ChemicalSociety, 3466 (1960) disclose the preparation of 3-cyano-1-hydroxy-2-phenylindole. Only phenyl, however, is discussed as a substituent in the 2-position of l-hydroxyindole. Other substituents in the 2-position are not disclosed.

. : :

-2~ 2 ~
Summary of the Invention The present invention relates to novel 2-substitu.ted-1-hydroxyindoles having the following formula:
R
I

R3 - ~ o ~ ._R2 wherein, Rl is an electron withdrawing group, R2 is selected from the group consisting of alkenyl having 2-10 carbon atoms, an N-substituted a-iminobenzyl group wherein the substituents are selected from the group consisting of phenyl, anilino and dimethylamino, and an unsubstituted or substituted aromatic group having meta or para substituents selected from the group consisting of nitro, trifluoromethyl, fluoro, formyl, hydroxyiminomethyl and carbamoyl, R is selected from the group consisting of halogen atoms, and n is 0, 1 or 2 provided that when R2 is either phenyl or nitro substituted phenyl and n is 0, then Rl is not cyano.
In one aspeet of the invention, a l-hydroxyindole is provided comprising the structure as shown above wherein Rl is cyano, and R2, R3, and n are defined as above.
Detailed Description of the Preferred Embodiments The compounds of the present invention are useful in controlling foliar phytopathogenic fungi.
The fungi are controlled by applying a fungicidally .
:

effective amount of one or more of the inventive compounds having the following formula:
Rl I

Rn - ~ ~ ~_R2 OH
wherein, Rl is an electron withdrawing group, such as carbamoyl, for example, carbamoyl, t-butylcarbamoyl, and dimethylcarbamoyl, carboxy, cyano and nitro;
R2 is selected from the group consisting of alkenyl having 2-10 carbon atoms, such as vinyl, allyl or butenyl, an N-substituted a-iminobenzyl group wherein the substituents are attached to said imino group and are selected from the group consisting of phenyl, anilino and dimethylamino, such as ~-(phenylimino)benzyl, ~-(N'-phenylazino)benzyl and a-(N', N'-dimethylazino)ben~yl, and an unsubstituted or substituted aromatic group having meta or para substituents selected from the group consisting of nitro, trifluoromethyl, fluoro, formyl, hydroxyiminomethyl and carbamoyl, such as phenyl, 4-nitrophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 4-formylphenyl, 4-carbamoylphenyl and 4-hydroxyiminomethylphenyl;
R is a halogen atom, such as chloro, bromo, iodo or fluoro; and n is 0, 1 or 2.
In the compounds of this invention, when R2 is either phenyl or nitro substituted phenyl and n is O, then Rl is not cyano.

Preferred compounds of the invention h~ve the above structure wherein Rl is cyano and ~2, R3 and n are as described above.
Other preferred compounds of the invention have the above structure wherein, Rl is cyano;
R2 is 3-trifluoromethylphenyl, 4-fluorophenyl, 4-formylphenyl, 4-carbamoylphenyl, phenyl, 2-furyl, vinyl, 4-pyridyl, 2-pyridyl, a-(phenylimino)benzyl or hydroxyiminomethylphenyl;
and n is O and represents no substituents at R3.
Even more preferred compounds of the invention have the above structure wherein Rl is cyano;
R2 is phenyl, 4-nitrophenyl or methyl; and R3 is chloro and n is 1 or 2 so that R3 represents 5,6-dichloro or 6-chloro.
n Even further preferred compounds of the invention have the above structure wherein Rl is cyano;
R is phenyl, 3-nitrophenyl, or 4-nitrophenyl;
R3 is 6-chloro; and n is 1.
The most preferred compounds of the invention are compounds wherein R is 3-nitrophenyl or 4-nitrophenyl.
Compounds representative of the present invention include:
3-cyano-1-hydroxy-2-(3-trifluoromethylphenyl)indole, 3-cyano-1-hydroxy-2-(4-fluorophenyl~indole, 3-cyano-1-hydroxy-2-(formylphenyl)indole, 3-cyano-1-hydroxy-2-(4-hydroxyiminome-thylphenyl)indole, 3-cyano-6-chloro-1-hydroxy-2-(4-nitrophenyl)indole, 3-cyano-5,6-dichloro-1-hydroxy-2-phenylindole, ~, ,; :
, ,; :
'~ '-' ~

, _5_ 2 ~ 3 3-cyano-6-chloro-1-hydroxy-2-phenylindole, 3-cyano-2-(2-furyl)-1-hydroxyindole, 3-cyano-1-hydroxy-2-vinylindole, 3-cyano-1-hydroxy-2-(4-pyridyl)indole, 3-cyano-1-hydroxy-2-(2-pyridyl)indole, 3-cyano-2-(3,4-dimethoxybenzoyl)-~-hydroxyindole, 3-cyano-1-hydroxy-2-[a-~phenylimino)benzyl]indole, 3-cyano-1-hydroxy-2-[a-(phenylazino)benzyl]indole and 3-cyano-2-[~-(dimethylazino)benzyl]-1-hydroxyindole.
The 2-substituted l-hydroxyindoles are generally obtainable as colorless to yellow crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents. They are appreciably soluble in many organic solvents such as methanol, ethanol, acetone, chloroform, benzene, dioxane, dimethyl sulfoxide and N,N-dimethyl~ormamide, but are relatively insoluble in water.
The compounds of the invention can be prepared in general through minor modifications of literature procedures.
The synthesis of l-hydroxy-3-cyano-2-phenylindole was first described by Loudon and Tennant in 1~ Ç~Lem. ~Q~, 3466(1960). This preparation is represented by the ~ollowing reaction scheme:
:CN
lNo2 ~ /CN CN
I O l I
~. Ph ~ Ph ~!~ ,!~ 1H
I O i ~./ Ph :CN

The preparation involved the cyanide induced cyclization of either of two 2-nitrophenyl-substituted cyanostilbenes.
Further development towards the preparation of l-hydroxyindoles is seen in the work of F.J.
Petracek shown in US-A-3,296,277 which discloses the preparation of indoles containing substituted phenyls in the 2-position as seen in the following reaction scheme:
NO CN NO CN
1 2 1 ¦ 2 ¦/C02Et I `o \C02Er ArCH2Br > ~ \ ~ \CH Ar I~ 0~. - Ar < ~Na2C3 OE
This synthesis involves the condensation of ethyl 2-nitrophenylcyano acetate with various benzyl halides under basic conditions followed by aqueous alkaline rearrangement providing 2-aryl-3-cyano-1-hydroxyindoles. The free hydroxyl group is preferred for activity. Other compounds can be prepared by the acid rearrangement of the well known benzoin oximes through the method described by E. Fischer in Chemische Berichte, 28,585 (1985~.
The compounds of the invention can be prepared by using a slight modification of the method of Petracek as discussed hereinabove in reference to US-A-3,296,277. 2-Halonitrobenzene can be condensed with ethyl cyanoacetate in the presence of excess potassium hydroxide affording a good yield of the 2 ~

ethyl 2-cyano-2-nitrophenylacetate as can be seen by the following reaction scheme:
Cl /CN l2 IN

5~ \ ~ 2 Co2Et ~.\ /.
./ KOH DMA ~ /

¦2 CN TMG*,DMA*
loNa2C3 1 I~ ~o~I~o2Et <
MeOH ¦ ~ / Ar H20 \o/
CN
I
*ArCH2X where X is halo I~ ,O~o - Ar preferably chloro or bromo I *TMG=1,1,3,3,-tetramethylguanidine OH *DMA=N,N-dimethylacetamide Various benzyl halides can then be condensed with the acetate ester followed by cyclization to the aryl-substituted indole as shown. Bromides are preferred.
The compounds of the invention were particularly tested for activity against Colletotrichum lagenarium (Anthracnose on cucumbers), Puccinia xecondit_ (wheat leaf rust), Erisiphe polygoni (powdery mildew on beans), Phytophthora in~estans (late blight on tomatoes), Rhizoctonia solani (Rhizoctonia on cotton), Pythium sp. (damping off on peas) and Botrytis Cinerea (gray mold). They showed particularly enhanced activity against rust disease, including Puccinia recondita (wheat leaf rust).
The introduction of highly hydrophilic groups such as carboxylate or sulfamoyl was found to decrease activity. Further, the introduction of highly hydrophobic groups such as 4-phenylsulfonylphenyl, benzophenonyl, t-butylphenyl were also found to decrease activity.

"

-8- ~ ~L~8 Preparation of Ethyl Cyano-2-nitrophenvl-acetate A mixture of 2-chloronitrobenzene (47.2 g, 0.300 mole) and ethyl cyanoacetate (40 ml, 0.38 mol) in N,N-dimethylacetamide (DMA, 250 ml) was treat~d at once with potassium hydroxide pellets (120 g, 2.14 mole). The mixture was mechanically stirred and heated for ten minutes at 110 - 120C (caution:
minimal heat `application may be needed, exothermic reaction) then poured into ice-cold dilute hydrochloric acid. Ether extractive workup gave an oil. The oil was passed through silica gel eluting with toluene to provide a yellow oil, which was dissolved in 100 ml methanol then chilled. The solid was filtered to afford ethyl cyano-2-nitrophenylacetate as a yellow solid (51.4 g, 73.2%) mp 57-61C (literature 59-60C).
~xample 1: Preparation of l-~ydroxy-3-cyano-2-(4-tri-fluoromethylphenyl)indole A mixture of ethyl cyano-2-nitrophenylacetate (4.68 g, 20.0 mmole), 4-trifluoromethylbenzyl bromide (4.77 g, 20.0 mmole), 1,1,3,3-tetramethylguanidine (TMG, 2.81 ml, 22.4 mmole) in DMA (50 ml) was heated to 100C. Two additional 0.2 ml portions of the benzyl bromide were added at 15 min intervals. After a final 15 min the mixture was poured into water.
Ethyl acetate extractive workup afforded the alkylated product as an oil. This oil in methanol ~80 ml) with aqueous sodium carbonate (20 ml, 1.0 M) was heated at reflux for 5 h then poured into ice-cold dilute hydrochloric acid. The solid was filtered, air dried then recrystallized twice from toluene to afford N-hydroxy-3-cyano-2-(4-trifluoromethylphenyl)indole as a cream solid (3.81 g, 63.1%) mp 202-203C (at which temperature it decomposed.).

2 ~

Examples 2 to ll:
The compounds described in the following Tabes I and II, which also contain the melting points and elemental analyses for these compounds, were prepared by the procedure of Example l and the hereinabove described modified procedures of Petracek, except using the appropriate starting materials in equivalent amounts.

2 ~

TABLE I

CN
I

X ~ =. ~ Y

OH
(% Found~
Elemental Analysis (%Calculated~
Example X Y ~p(oc~a N C H

3 H 3-CF3 187-188 9.2 63.6 3.0 9.3 63.6 3.0 4 H 4-F 208-209 10.5b 72.4 3.9 10.7 72.1 3.8 H 4-CH0 207-209 ll.lC 72.5 4.0 11.8 72.5 4.0 6 H 4-CH=NOH 200-205 15.668.9 4.1 15.2 69.3 4.0 7 6-C1 4-No2 252 13.2d 56.7 2.6 13.2 56.6 2.3 8 5,6-C12 H 223-224 lo.oe 59.3 2.9 10.1 59.4 2.8 9 6-Cl H 225-227 10.5 67.1 3.5 10.4 67.0 3.4 - . i , , . .

. . .~ ,... ' .
. ~ ' :.

TABLE II
CN
., I
t ~ ~ - R
~ / \N /
I

OE
(% Fo~nd) Elemental Analysis (%Calculated~
10 Example R mp(C)a N C E

-CH=C~2 182-183 14.9 71.4 4.5 15.2 71.7 4.4 ~ 219-220 12.8f 69.0 3.8 15-- ~ 12.9 69.4 3.7 Key to Table I and II footnotes:
a) All compounds melted with decomposition.
b) through f): Although all samples were dried in vacuo, certain samples retained solvent of crystallization. Therefore, the calculated values of the elements (N, C and H) for certain examples were based on retentions of specific molar ratios of solvent as follows:
Molar Ratio of Footno~e Example _~olventCompound/Solvent b 4 Toluene 15/2 c 5 Acetonitrile 3/1 d 7 Water 4/1 e 8 Acetonitrile 4/1 30 f 11 Acetonitrile 10/1 : . :
~.
- -.
, 2 ~

Example 12: Preparation of 3-cyano-1-hydroxy-2-~a-(phenylimino)-benzylJindole CN

I~,O~ N~

~ ~

A mixture of 3-cyano-2-benzoyl-1-hydroxy-indole (2.62 g, 10.0 mmole) and aniline (1.0 g, 10.8 mmole) were heated at reflux in toluene (50 ml) undex a trap for 16 hours. Concentration in vacuQ
afforded a solid. Recrystallization from methylcyclohexane provided dark crystals, m.p. 188-190C. Analysis (dry 25C): Fd(calculated) N, 12.2 (12.4), C, 78.2 (78.3) H, 4.7 (4.5).
Example 13: Preparation of 3-cyano-1-hydroxy-2-[a-(phenylazino)-benzyl]indo~e CN

I~ ,O~ /~ N NHPh OH

A mixture of 3-cyano-2-benzoyl-1 hydroxy-indole (2.62 , 10.0 mmole) and phenylhydrazine (1.1 ml, 11.1 mmole) was heated at reflux in ethanol (35 ml) for fifteen minut.es. The mixture was treated with additional phenylhydrazine (0.25 ml, 2.5 mmole) and stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo then triturated , ! ' , .-:' ': '' ' ' ~ ~'' ,` ,~ ''' ' .
, -13- 2 ~ Q ~
with ether-ligroin mixture to give a yellow solid.
Recrystallization from acetic acid yielded a bright yellow solid which was dried in vacuo at 800C, mp 154-158C. Analysis (dry 25C): Fd(calculated 12.5 mole % acetic acid) N, 15.7 (15.5), C, 74.2 (74.2), H, 4.6 (4.7).
Example 14: Preparation of 3-cyano-2-[a-(dimethylazino)benzyl]-l-hydroxyindole.

CN
I

I~ ,0~ ~N-N(CE3)2 OH

This compound was prepared as described for Example 13. A yellow solid, mp 164-165C, was obtained. Analysis (dry 25C): Fd (Calculated 11 mole % methanol) N, 18.2 (18.2), C, 70.5 (70.6), H, 5.3 (5.4)

Claims (9)

1. A compound having the following formula:

wherein, R1 is carbamoyl, t-butylcarbamoyl, dimethylcarbamoyl, carboxy, nitro or cyano;
R2 is an alkenyl having 2-10 carbon atoms, an N-substituted .alpha.-iminobenzyl group wherein the substituents are selected from the group consisting of phenyl, anilino and dimethylamino, an unsubstituted aromatic group or an aromatic group having meta or para substituents selected from the group consisting of nitro, trifluoromethyl, fluoro, formyl, hydroxyiminomethyl and carbamoyl;
R3 is a halogen atom; and n is 0, 1 or 2 provided that when R2 is either phenyl or nitro substituted phenyl and n is 0, then R1 is not cyano.

2. The compound of claim 1 wherein R1 is cyano; and R2 is alkenyl, the unsubstituted aromatic group or the aromatic group with meta or para substituents.

3. The compound of claim 1 wherein R1 is cyano, R2 is 3-trifluoromethylphenyl,

4-methoxyphenyl, 4-fluorophenyl, 4-formylphenyl, 4-carbamoylphenyl, 2-furyl, vinyl, 4-pyridyl, 2-pyridyl, and .alpha.-(phenylimino)benzyl; and n is 0.

4. The compound of claim 1 wherein R1 is cyano, R2 is phenyl, 4-nitrophenyl, 3-nitrophenyl or methyl;
R3 is chloro and n is 1 or 2.

5. The compound of claim 4 wherein R3 is 6-chloro and n is 1.

6. The compound of claim 5 wherein R2 is 4-nitrophenyl.

7. The compound of claim 5 wherein R2 is 3-nitrophenyl.

8. The compound of claim 1 selected from the group consisting of:
3-cyano-1-hydroxy-2-(3-trifluoromethylphenyl)indole, 3-cyano-1-hydroxy-2-(4-fluorophenyl)indole, 3-cyano-1-hydroxy-2-(formylphenyl)indole, 3-cyano-1-hydroxy-2-(4-hydroxyiminomethylphenyl)indole, 3-cyano-6-chloro-1-hydroxy-2-(4-nitrophenyl)indole, 3-cyano-5,6-dichloro-1-hydroxy-2-phenylindole, 3-cyano-6-chloro-1-hydroxy-2-phenylindole, 3-cyano-2-(2-furyl)-1-hydroxyindole, 3-cyano-1-hydroxy-2-vinylindole, 3-cyano-1-hydroxy-2-(4-pyridyl)indole, 3-cyano-1-hydroxy-2-(2-pyridyl)indole, 3-cyano-2-(3,4-dimethoxybenzoyl)-1-hydroxyindole, 3-cyano-1-hydroxy-2-[.alpha.-(phenylimino)benzyl]indole, 3-cyano-1-hydroxy-2-[.alpha.-(phenylazino)benzyl]indole and 3-cyano-2-[.alpha.-(dimethylazino)benzyl]-1-hydroxyindole.

9. The compound of claim 8 is 3-cyano-6-chloro-1-hydroxy-2-(4-nitrophenyl) indole or 3-cyano-6-chloro-1-hydroxy-2-phenylindole.