Process for the preparation of insecticidal acaridical and nematicidal 2-aryl-5-(trifluoromethyl) pyrrole compounds and intermediates thereof

PROCESS FOR THE PREPARATION OF INSECTICIDAL, ACARICIDAL AND NEMATICIDAL 2-ARYL-5-(TRIFLUOROMETHYL)PYRROLE COMPOUNDS AND INTERMEDIATES THEREOF

BACKGROUND OF TIIE lNVENTlON

99177 (B2 88/03788)

Israeli I’uldicaii«87222 ״ anWcscrlbes certain atylpynole compound» useful as Insecticides, iicmMnddcs, and acaricides and .lie preparation !hereof by Ute reaction of an eznlactonc will! an a-lialo-a.ll-uiisaluialed nitrile, ester or nitro compound in the presence of a nonpolar solvent. The process ot .aald publication is useful for the prcparaiion of said arylpyrroles. However die reaction produces only moderate product yields, uses leige excesses of die a-11alo-a,!Unsaturated nittile, ester or nhio compound and requites long reaction times.

It is an object of the present invention to provide a more efficient process for the preparation of Insecticidal, nematlcldal and acarlcldal 2-aryl-5-(trirjuoromethyl)pyrrole compounds which reduces excess starting materials and reaction time and Increases product yield. ...

it Is a further object of the invention to provide an efficient method of preparing the 1,1,1trl£luoro-2-propene compounds of the present invention.

UUMHAWt OF THE 1HVEHTWH

The present Invention relates to a process lor the preparation of insecticidal, nematlcldal and acarlcldal 2-aryl-5-(trHluoromethyl) pyrrole compounds of formula 1

<img file="IL98235A_D0001.tif" />

wherein

W is C_x-C₄ alkyl, CF₃ or H;

Y is CN, NO₂, . CO₂Rj cor׳

R is C^-C^ alkyl;

L is H, F, Cl or Br;

M is H, F, Cl, Br, I, CF_, NO- or OR-; and J a X

R₁ is C₁-C₃ alkyl or ^C₂F₄H by a single step reaction between an azalactone compound of formula II

<img file="IL98235A_D0002.tif" />

(II) wherein L and M are as described above and an a-haloa, ^-unsaturated nitrile, ester or nitro compound of formula III

<img file="IL98235A_D0003.tif" />

(III) wherein W and Y are as described above; X is Cl, Br, I or

0cch₃ and the cis and trans isomers thereof in the presence of a polar solvent and a base.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation in good yield of insecticidal, nematicidal and acaricidal compounds of formula I

<img file="IL98235A_D0004.tif" />

(I) wherein

W is C₁־C₄ alkyl, CF₃ or H;

Y is CN, NO- or CO_R; C(C)R,

R is alkyl;

L is H, F, Cl or Br;

M is H, F, Cl, Br, I, CF_, NO״ or OR.; and W 4£ X

Rj is C^-C^ alkyl or C₂F₄H by an efficient single step reaction between an azalactone compound of formula II

<img file="IL98235A_D0005.tif" />

(II) wherein L and M are as described above and an a-haloa,£-unsaturated nitrile, ester or nitro compound of formula III

<img file="IL98235A_D0006.tif" />

(III) wherein W and Y are as described above; X is Cl, Br, I or

0cch₃and the cis and trans isomers thereof in the presence of a polar solvent and a base.

The process preferably comprises reacting a formula II azalactone as described above with at least about one molar equivalent, preferably about one to five molar equivalents, of a formula III a-halo-a,j9unsaturated nitrile, ester or nitro compound as described above and at least about one molar equivalent, preferably about one to five molar equivalents, of a base in the presence of a polar solvent preferably at a temperature range of about 20°C to 180°C to form

2-aryl-5-(trifluoromethyl)pyrrole compounds of formula

I. Naturally, it is especially preferred to use as little excess reactants as possible. Advantageously, stoichiometric quantities may be used in the present invention and still maintain good yields.

The product formula I compounds may be isolated by conventional techniques such as dilution of the reaction mixture with water and filtration of the formula I product or extraction of said product with a suitable solvent. In the isolation procedure any suitable extraction solvents may be employed, including water-immiscible solvents such as ether, ethyl acetate, methylene chloride and the like.

Bases suitable for use in the process of the invention include bases such as alkali metal carbonates, trialkylamines, alkali metal hydroxides and pyridine. Preferred bases are pyridine, triethylamine and sodium carbonate.

Reaction solvents suitable for use in the above process include any polar solvents, for example solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, ethanol, methanol and isopropanol. Acetonitrile and dimethylformamide are preferred reaction solvents.

Certain starting formula III compounds are described below.

The l,l,l-trifluoro-2-propene compounds of the present invention have the structural formula Illa:

<img file="IL98235A_D0007.tif" />

(Illa) wherein X is Cl, Br or I;

Z is CN, CO R or C(O)R ;

X X

R and R, are C_-C. alkyl; and the cis and

*־14 1 trans isomers thereof.

Preferred l,l,l-trifluoro-2-propene compounds of the invention are those in which X is Cl or Br; Z is CN or C(O)R₁״_׳ and is C^C^ allcyl.

Formula Illa compounds may be prepared by reacting trifluoroacetaldehyde with (triphenylphosphoranylidene)acetonitrile in a solvent to give 4,4,4trifluorocrotononitrile. The said 4,4,4-trifluorocrotononitrile or other compound having the structural formula IV:

Η H

<img file="IL98235A_D0008.tif" />

(IV) wherein

Z is CN, COjR, C(O)R_1׳.

R and R, are C,-C. alkyl,. and the cis and trans isomers 1 14 thereof;

is reacted with at least about two molar equivalents, preferably about two to five molar equivalents of a halogenating agent in the presence of a solvent to form 2,3-dihalo-l,l,l-trifluoropropane compounds of formula V:

F₃CCHXCHXZ (V) wherein

X is Cl, Br or I; and Z is as described above. Halogenating agents that may be employed include bromine, chlorine, iodine, and the like. Reaction solvents suitable for use in the above-described reaction include tetrahydrofuran, carbon tetrachloride and the like. The resultant 2,3-dihalo-1,1,1,trifluoropropane is then reacted with at least about one molar equivalent, preferably about one to three molar equivalents, of a base in the presence of a solvent to form 1,1,1-trifluoro-2-propene compounds of formula ma.Bases suitable for use in the reaction include triethylamine, pyridine and sodium carbonate and the like, solvents such as ether and tetrahydrofuran may be preferably employed. This reaction scheme is illustrated as follows:

Η H HZ \ / X₂ B- \/

C=C —cf₃chxchxz > c=c f₃(/ \ F₃(/\ (IV) (V) (Illa)

The preparation of formula Illa compounds was illustrated in the previous reaction scheme, except when R is hydrogen. To prepare the formula Illa compounds when R is hydrogen an additional hydrolysis step may be required. Hydrolysis of a formula Illa compound when R is not hydrogen yields another formula Illa compound having the same structure except that R is now hydrogen.

In order to facilitate a further understanding of the invention, the following examples are presented to illustrate more specific details thereof. The invention is not to be limited thereby except as defined in the claims.

EXAMPLE

Preparation of 2-Phenvl-5-(trifluoromethyl)pyrrole-3carbonitrile in the presence of a base.

<img file="IL98235A_D0009.tif" />

Triethylamine (4.5g, 0.044 mol) is added dropwise to a mixture of 4-phenyl-2-(trifluoromethyl)־. 5(2H)-oxazolone (10.0g, 0.043 mol), 2-chloroacrylonitrile (3.51g, 0.43 mol) and acetonitrile (50 mL).

The temperature of the reaction mixture rises to 65°C and carbon dioxide gas evolves during the addition. After the addition is complete the reaction mixture is heated at reflux temperature for one hour, cooled to room temperature and poured into water (150 ml!). The solids are collected by filtration, air-dried and dried under vacuum at 60°C to give the title compound as a white solid (10.05g, 97%). Identified by NMR spectral analyses.

The process described affords a nearly quantitative yield of the product pyrrole using stoichiometric amounts of reagents and short reaction time.

EXAMPLE

Preparation of 2-Phenvl-5-ftrifluoromethvl)pvrrole-3carbonitrile without added base

<img file="IL98235A_D0010.tif" />

4-Phenyl-2-(trifluoromethyl)-5(2H)-oxazolone (13.5g, 0.059 mol), 2-chloroacrylonitrile (26 mL, 0.295 mol) and acetonitrile (250 mL) are heated at reflux temperature for 52 hours. The reaction mixture is then cooled to room temperature and concentrated in vacuo to give a solid. Recrystallization of the solid from toluene gives the title product as a yellow solid (10.1g, 73%). Identified by NMR spectral analyses.

The procedure without added base gives only a

73% yield of the title product despite the use of a large excess of 2-chloroacrylonitrile and a long reaction time.

EXAMPLE

Preparation of Methyl 2-(p-chlorophenvl)-5-(trifluoromethyl)pyrrole-3-carboxylate

<img file="IL98235A_D0011.tif" />

<img file="IL98235A_D0012.tif" />

Triethylamine (5.58g, 0.055 mol) is added dropwise to a mixture of 4-(p-chlorophenyl)-2-(trifluoromethyl)-5(2H)-oxazolone (15.6g, 0.054 mol), methyl a-chloroacrylate (6.52.g, 0.054 mol) and acetonitrile (50 mL). The reaction mixture heats up to 55°C during the addition. After the addition is complete, the reaction mixture is heated at reflux temperature for one hour, cooled to room temperature and filtered. The filtrate is poured into an ether/water mixture and extracted with ether. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a black residue. Recrystall10 ization of the residue from hexane gives the title compound as an orange solid (8.25g, 50.2%). Identified by NMR spectral analyses.

EXAMPLE Preparation Using Non-Polar Solvent Instead of Polar Solvent

This example shows the necessity of using a polar solvent. Surprisingly, the base-catalyzed reaction when run in the presence of a non-polar solvent such as toluene does not result in the desired pyrrole.

<img file="IL98235A_D0013.tif" />

<img file="IL98235A_D0014.tif" />

2-chloroacrylonitrile (3.85g, 0.044 mol) is added to a 0°C mixture of 4-phenyl-2-(trifluoromethyl)5(2H)-oxazolone (10.0g, 0.044 mol) and toluene (50 mL). Triethylamine (4.49g, 0.044 mol) is added dropwise to the reaction mixture and the temperature rises to 25°C. When the addition is complete, water is added to the reaction mixture and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give alpha-chloro-5-oxo-

4-phenyl-2-(trifluoromethyl)-3-oxazoline-2-propionitrile as an amber liquid (8.37g, 60%). Identified by NMR spectral analyses.

EXAMPLE 5

This example demonstrates that with the addition of a base and a polar solvent such as acetonitrile to the product formed in Example 4 the desired pyrrole is formed.

<img file="IL98235A_D0015.tif" />

<img file="IL98235A_D0016.tif" />

Triethylamine (0.077g, 0.76 mmol) is added dropwise to a refluxing mixture of alpha-chloro-5-oxo-

4-phenyl-2-(trifluoromethyl)-3-oxazoline-2-propionitrile (0.24g, 0.76 mmol) and acetonitrile (25 mL). The reaction mixture is refluxed for 2 hours, cooled to room temperature and poured into water. The solids are collected by filtration and dried to give the title compound as a white solid (0.16g, 88%). Identified by NMR spectral analyses.

EXAMPLE

Solvent and base effects upon 2-arvl-5-(trifluoromethyl)pyrrole formation

The effects of solvent and base changes on the synthesis of 2-phenyl-5-(trifluoromethyl)pyrrole-3carbonitrile from 4-phenyl-2-(trifluoromethyl)-5(2H)oxazolone and 2-chloroacrylonitrile are shown in Table

I. The percentages shown represent area percent determined by HPLC analysis of the reaction mixture after refluxing for 1/2 hour.

TABLE

Solvent and Base Effects

<td> Solvent</td><td> Base</td><td> % Yield Arylpyrrole</td>

<td> Toluene</td><td> Triethylamine</td><td> 11</td>

<td> Toluene</td><td> Pyridine</td><td> 8</td>

<td> Tetrahydrofuran</td><td> Triethylamine</td><td> 39</td>

<td> Ethanol</td><td> Triethylamine</td><td> 80</td>

<td> Acetonitrile</td><td> Triethylamine</td><td> 96</td>

<td> Acetonitrile</td><td> —</td><td> 4*</td>

<td> Dimethylformamide</td><td> Pyridine</td><td> 100</td>

<td> Dimethylformamide</td><td> Sodium carbonate</td><td> 74</td>

<td> D imethy1formamide</td><td> Triethylamine</td><td> 100</td>

<td> * 1 hour refluxing</td><td></td><td></td>

EXAMPLE

Base effects in 2-arvl-5-ftrifluoromethvl)pyrrole formation Base effects on the synthesis of 2-aryl-5-(trifluoromethyl)pyrroles are shown in Table II. Acetonitrile is the solvent in all reactions.

TABLE II

<img file="IL98235A_D0017.tif" />

Equivalents

<td> JL</td><td> JL.</td><td> Y</td><td> X</td><td> of triethvlamlns</td><td> Time</td><td> ו Yield</td>

<td> H</td><td> 4-C1</td><td> CN</td><td> Cl</td><td> 0</td><td> 78^a</td><td> 79</td>

<td> H</td><td> 4-C1</td><td> CN</td><td> Cl</td><td> 1</td><td> l/2^a</td><td> 96</td>

<td> cf₃</td><td> H</td><td>^c°₂c₂h₅</td><td> Br</td><td> 0</td><td> 24^a b</td><td> 2</td>

<td>^CF3</td><td> H</td><td>^CW5</td><td> Br</td><td> 1</td><td> 2° a ׳</td><td>²⁰.</td>

<td> H</td><td> 4-C1</td><td> 00_Λ</td><td> Cl</td><td> 0</td><td> 4 l/2^a .a</td><td> 27</td>

<td> H</td><td> 4-C1</td><td> CO.CH,</td><td> Cl</td><td> 1</td><td> 1</td><td> 50</td>

^a Hours reaction mixture is refluxed.

b Hours reaction mixture is stirred at room temperature.

EXAMPLE Solvent effects in 2-arvl-5-(trifluoromethvlלpyrrole formation

Solvent effects in the formation of 2-(p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile from 4-(p-chlorophenyl)-2-(trifluoromethyl)-5(2H)-oxazolone and

2-chloroacrylonitrile are shown in Table III.

TABLE

Solvent effects in 2-arvl-5-(trifluoromethylלpyrrole formation

<td> Solvent</td><td> Equivalents of 2-Chloroacrylonitrile</td><td> Time^a</td><td> % Yield</td>

<td> Nitromethane</td><td> 10</td><td> 21</td><td> 14</td>

<td> Toluene</td><td> 10</td><td> 17</td><td> 17</td>

<td> Trifluoroacetic</td><td> Anhydride 10</td><td> 17</td><td> 17</td>

<td> Acetonitrile</td><td> 10</td><td> 17</td><td> 46</td>

Hours reaction mixture is refluxed

The results of these experiments show that even with polar solvents and long times, yields are generally poor in the absence of added base.

EXAMPLE

Preparation of 4.4.4-Trifluorocrotononitrile (ElandfZ)Trifluoroacetaldehyde (47.4g, 0.48 mol), generated by addition of l-ethoxy-2,2,2-trifluoroethanol (77.6g, 0.48 mol) to polyphosphoric acid (300 mL) heated to 150-180°C, is swept with nitrogen over 2 hours into a slurry of (triphenylphosphoranylidene) acetonitrile (97.3g, 0.32 mol) in ether (400 mL). The reaction mixture is stirred overnight under nitrogen. After filtering off the solid triphenylphosphine oxide, the ether is distilled off to obtain an orange solution. Bulb to bulb distillation of the solution affords 2 fractions of the title compound as a clear colorless oil (14.3g, 37%). Fraction 1 (bp 20-40°C , 14mm) contains a 6:1 mixture of (E):(Z). Fraction 2 (bp 40-50°C, 14mm) contains a 2:1 mixture of (Z):(E). The fractions are identified by NMR analyses.

EXAMPLE

Preparation of 2,3-Dibromo-4,4.4-Trifluorobutvronitrile

F₃C Η γ CN \=C\ + Br₂ ---> r₃C—C—C—H

CN h Br (E) and (Z)

Bromine (4.57g, 0.029 mol) is added over a 5 minute period to a solution of 4,4,4-trifluorocrotononitrile (3.46g, 0.029 mol) and carbon tetrachloride (70 mL). The resulting dark red solution is refluxed for 5 hours, then water (70 mL) is added to terminate the reaction. The organic layer is separated, washed sequentially with water, 5% sodium thiosulfate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the title product as a yellow oil (6.1g, 76%), identified by NMR spectral analyses.

Following the procedure of example 10, but substituting the appropriately substituted 1,1,1-trifluoro-2-propene for 4,4,4-trifluorocrotononi-16trile yields the following compounds.

Br Z

F₃C—C—C—H

H Br

Z State

II

COCH₂CH₃ colorless oil

2CH₃ yellow oil

I

CH yellow oil

EXAMPLE

Preparation of 2-Bromo-4.4.4- Trifluorocrotononitrile (El- and fZ)Br CN

I I

F₃C—C—C—H + N(CH_gCH₃>₃

H Br

<img file="IL98235A_D0018.tif" />

Br

CN (E) and (Z) Triethylamine (3.7g, 0.037 mol) is added dropwise to a solution of 2,3-dibromo-4,4,4-trifluorobutyronitrile (5.32g, 0.023 mol) and tetrahydrofuran (100 mL). A voluminous white precipitate forms during the addition. Stirring is continued for 1 hour, then the solid is filtered off and washed with tetrahydrofuran. The tetrahydrofuran is distilled off to give a dark brown oil. Bulb to bulb distillation (15 mm, 24°C) of the oil yields the title product as a clear colorless liquid (3.1g, 82%). NMR spectral analyses identifies a 6:1 mixture of E:Z .

Following the procedure described in example 11, but using the appropriately substituted 1,2-dibromo-3,3,3-trifluoropropane for 2,3-dibromo-4,4,4-trifluorobutyronitrile yields the compounds shown below.

<img file="IL98235A_D0019.tif" />

<E) and <Z>

_Z^ 0 II COCHgCHg

II cch₃

State clear yellow oil red oil

EXAMPLE

Preparation of 2-fp-chlorophenvl)-4.5-bisftrifluoromethyl)pyrrole-3-carbonitrile

<img file="IL98235A_D0020.tif" />

Cl

<img file="IL98235A_D0021.tif" />

4-(p-Chlorophenyl)-2-(trifluoromethyl)-2oxazolin-5-one (2.0g, 7.59 mmol) and 2-bromo-4,4,4-trifluorocrotononitrile (0.81g, 4.05 mmol) are dissolved in acetonitrile (10 mL). To the resulting yellow solution triethylamine (0.45g, 4.46 mmol) is added dropwise while the reaction flask is cooled with a water bath. After stirring at 25°C overnight, the reaction mixture is poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic extracts are washed sequentially with water, 5% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid. The solid is chromatographed using silica gel and eluted with hexane/ethyl acetate 3:1 to yield the title compound as yellow crystals (1.26g, mp 208°C).

Following the procedure of example 12, but substituting 3-bromo-5,5,5-trifluoro-3-penten-2-one for

2-bromo-4,4,4-trifluorocrotononitrile yields 2-(p- chlorophenyl)-4,5-bis (trifluoromethyl)pyrrol-3-yl methylketone as yellow crystals.

EXAMPLE

Preparation of Ethyl 2-(p-chlorophenvl)- 4,5-bis f trifluoromethyl)pvrrole-3-carboxylate

<img file="IL98235A_D0022.tif" />

COCHpCH, II 0 (E) and (Z)

<img file="IL98235A_D0023.tif" />

<img file="IL98235A_D0024.tif" />

Triethylamine (1.1g, 0.011 mol) is added dropwise to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-2-oxazolin-5-one (2.64g, 0.01 mol) and acetonitrile (25 mL). After stirring for 10 minutes at room temperature, a solution of ethyl 2-bromo-4,4,4trifluorocrotonate (2.47g, 0.01 mol) and acetonitrile (1 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 2 hours then poured into water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an orange oil which solidifies upon standing. Trituration with hexanes gives the title product as a yellow solid (2.36g, 61.3%, mp 138°-140°c).

EXAMPLE

Preparation of 2-(3,4-dichlorophenvl)-4.5-bis ftrifluoromethvl)pvrrole-3-carbonitrile

<img file="IL98235A_D0025.tif" />

+ N(CH₂CH₃)₃ ---->

ci

Cl mmol) is added dropwise to a solution of 2,3-dibromo-4,4,4-trifluorobutyronitrile (1.63g, 10.2 mmol) and tetrahydrofuran (20 mL). Stirring is continued for 15 minutes then a solution of 4-(3,4-dichlorophenyl)-2-(trifluoromethyl)-

2- oxazlin-5-one (2.6g, 8.72 mmol), triethylamine (0.88g, 8.7 mmol) and acetonitrile (5 ml) is added dropwise to the reaction mixture. The reaction mixture is stirred overnight at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown oil. Chromatography of the oil using silica gel and hexanes/ ethyl acetate 3:1 yields the title product as a pale yellow solid (1.49g, 67%, mp 205-208°C).

The foregoing description might include matter which is not claimed but which is retained herein for the sake of completeness.