Synthesis of 2-aryl-5-(trifluoromethyl)pyrroles useful as pesticidal agents and as intermediates for the preparation of said agents

Abstract: There is provided a synthesis of 2-aryl-5-(trifluoromethyl)pyrrole compounds of formula I via the condensation of a suitable enamine with an α-haloketone.

Description: Arylpyrrole compounds are highly effective insecticidal, acaricidal and nematocidal agents. The present invention is directed to a process for the preparation of arylpyrrole compounds of formula I wherein A is hydrogen, phenyl or C₁-C₆ alkyl optionally substituted with phenyl; W is CN, NO₂, CO₂R₁ or SO₂R₂; L is hydrogen or halogen; M and R are each independently hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, CN, NO₂, Cl, Br, F, I, CF₃, R₃CF₂Z, R₄CO or NR₅R₆ and when M and R are on adjacent positions they may be taken together with the carbon atoms to which they are attached to form a ring in which MR represents the structure -OCH₂O-, -OCF₂O- or -CH=CH-CH=CH-; R₁ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl; R₂ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl; R₃ is hydrogen, F, CHF₂, CHFCl or CF₃; R₄ is C₁-C₄ alkyl, C₁-C₄ alkoxy or NR₅R₆; R₅ is hydrogen or C₁-C₄ alkyl; R₆ is hydrogen, C₁-C₄ alkyl or R₇CO; R₇ is hydrogen or C₁-C₄ alkyl; Z is S(O) n or O and n is an integer of 0, 1 or 2 which comprises reacting a compound of formula II wherein A, W, L, M and R are described above with at least one molar equivalent of a compound of formula III wherein X is Cl, Br or I in the presence of an acid and a solvent. The arylpyrrole compounds of formula I are highly useful as insecticidal, acaricidal and nematocidal agents and, further, are important intermediates in the manufacture of certain insecticidal arylpyrrole compounds. Surprisingly, it has been found that pyrrole rings substituted at the α-positions may be effectively prepared in a single step process via the condensation of a suitable enamine with an α-haloketone. Thus, pyrrole compounds of formula I may be prepared by reacting an enamine of formula II with about one molar equivalent of an α-haloketone of formula III in the presence of an acid and a solvent at preferably an elevated temperature. The reaction is illustrated in flow diagram I. The solvents suitable for use in the process of the present invention include organic solvents such as hydrocarbons and aromatic hydrocarbons having a boiling range of about 80 o to 250 o C, such as benzene, toluene, xylene and the like, preferably toluene. Acids suitable for use in the invention include organic acids such as acetic acid, propionic acid and the like, preferably acetic acid. Reaction temperatures of about 80 o to 150 o C are suitable, with 90 o -130 o C. being preferred. The compounds of formula II wherein A is hydrogen may be prepared by reacting the appropriate benzonitrile of formula IV with a compound of formula V in the presence of a base as shown in flow diagram II. The compounds of formula II wherein A is other than hydrogen may be prepared by reacting the appropriate aroyl compound of formula VI with a suitable amine of formula VII as shown in flow diagram III. Arylpyrrole compounds of formula I may be useful as intermediates in the manufacture of insecticidal arylpyrroles. For example, compounds of formula I may be halogenated using a suitable halogenating agent such as a halogen, a hypohalite or the like to afford the corresponding 2-aryl-4-halopyrrole insecticidal agents of formula VIII. The reaction is shown in flow diagram IV. By varying the substituents, A, W, L, M and R and the halogen, X, numerous possible arylpyrroles may be prepared from the intermediate compounds of formula I. Preferred is the process according to the present invention wherein W is CN or NO₂; W is CN, A is hydrogen or methyl, L and R are hydrogen and M is halogen; W is CN, A is hydrogen or methyl, L is hydrogen and M and R are halogen. In order to facilitate a further understanding of the present invention, the following examples are set forth primarily for the purpose of illustrating certain more specific details thereof. The invention is not to be limited, thereby except as defined in the claims. The terms IR and NMR designate infrared and nuclear magnetic resonance, respectively. The term HPLC designates high pressure liquid chromatography. EXAMPLE 1 2-(p-Chlorophenyl)-5-(trifluoromethyl)-pyrrole-3-carbonitrile A solution of p -chloro-β-(methylamino)cinnaminitrile (10.0 g, 0.052 mol) in toluene and acetic acid is treated dropwise with 3-bromo-1,1,1-trifluoro-2-propanone (10.0 g, 0.052 mol) at room temperature, heated at reflux temperature for about 1 hour or until the disappearance of starting material by thin layer chromatography, cooled to room temperature and diluted with ethyl acetate. The organic phase is washed sequentially with water and 5N NaOH, dried (Na₂SO₄) and concentrated in vacuo to give a brown oil residue. The residue is flash chromatographed (silica gel, hexanes/ethyl acetate, 80/20) to give the title product as a pale yellow solid 6.7 g (48% yield) mp 129.5 o C to 130.5 o C, identified by IR and NMR spectral analyses. EXAMPLE 2 Preparation of 2-(3,4-Dichlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile A solution of 3,4-dichloro-β-(methylamino)-cinnaminitrile (7.0 g, 0.031 mol) in toluene and acetic acid is treated dropwise with 3-bromo-1,1,1-trifluoro-2-propanone (6.0 g, 0.031 mol) at room temperature, heated at reflux temperature for 5 hours, cooled and diluted with ethyl acetate. The organic phase is washed sequentially with water and aqueous sodium hydroxide, dried (Na₂SO₄) and concentrated in vacuo to give a brown oil residue. The residue is flash chromatographed (silica gel, hexanes/ethyl acetate, 80/20) to give the title compound as a pale yellow solid, mp 130.2 o C, identified by mass spectral, IR and NMR analyses. EXAMPLE 3 Preparation of 1-Methyl-2-(2-naphthyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile A solution of β-(methylamino)-2-naphthalene-acrylonitrile (2.5 g, 0.012 mol) in toluene and acetic acid is treated dropwise with 3-bromo-1,1,1-trifluoro-2-propanone (2.3 g, 0.012 mol) at room temperature, heated at reflux temperature for 6 hours, cooled and diluted with ethyl acetate. The organic phase is washed sequentially with water and 5N NaOH, dried (Na₂SO₄) and concentrated in vacuo to give a brown oil residue. The residue is flash chromatographed (silica gel, hexanes/ethyl acetate, 80/20) to give the title compound as a yellow solid, mp 134 o C, identified by mass spectral, IR and NMR analyses. EXAMPLE 4 A mixture of β-amino- p -chlorocinnaminitrile potassium salt (2.2 g, 0.01 mol) in acetic acid is treated dropwise with 3-bromo-1,1,1-trifluoro-2-propanone (1.91 g, 0.01 mol) at room temperature, heated at 100 o C for 1 1/2 hours, stirred at room temperature for 16 hours and diluted with water and ethyl acetate. The organic phase is washed sequentially with water and aqueous sodium hydroxide, dried (Na₂SO₄) and concentrated in vacuo to give a semi-solid residue. The residue is crystallized in ethyl acetate/heptane to give the title compound as a brown solid, mp 238 o C to 240 o C, identified by ¹³C and l HNMR analyses. EXAMPLE 5 A mixture of p -chlorobenzoylacetonitrile (18.0 g, 0.1 mol), methylamine hydrochloride (10.13 g, 0.15 mol) and sodium acetate (12.3 g, 0.15 mol) in toluene is heated at reflux temperature (with a Dean Stark trap) for 5-6 hours, cooled to room temperature and diluted with water and ethyl acetate. The organic phase is separated and concentrated in vacuo to a residue which is crystallized from toluene/heptane to give the title product as a pale yellow solid, 17.1 g, (89% yield), mp 111.0 o C to 113.0 o C, identified by ¹³C and l HNMR spectral analyses. EXAMPLE 6 A solution of p -chlorobenzonitrile (13.8 g, 0.1 mol) in dimethoxyethane is treated with acetonitrile (4.93 g, 0.012 mol) at room temperature, treated portionwise with potassium t-butoxide (11.8 g, 0.105 mol), heated at reflux temperature for 1 hour, cooled to room temperature, diluted with ether and filtered. The solid filter cake is air dried and a 10 g sample is recrystallized from ethanol to give the title compound as a white solid, 3.9 g, identified by IR, ¹³C and l HNMR spectral analyses. EXAMPLE 7 Preparation of β-(Methylamino)-2-naphthaleneacrylonitrile A solution of β-oxo-2-naphthalenepropionitrile (5.0 g, 0.0256 mol) in toluene is treated with methylamine hydrochloride ()2.6 g, 0.0384 mol), sodium acetate (3.15 g, 0.0386 mol) and a catalytic amount of acetic acid, heated at reflux temperature (fitted with a Dean Stark trap) for 6 hours, cooled, diluted with ethyl acetate and dilute hydrochloric acid. The organic phase is dried over Na₂SO₄ and concentrated in vacuo to give a residue which is triturated under hexanes to give the title compound as a yellow solid, 3.1 g (58% yield) mp 138 o C, identified by IR, l NHMR and mass spectral analyses. EXAMPLE 8 A solution of 2-( p -chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (5.70 g, 0.02 mol) in chlorobenzene is treated with bromine (3.52 g, 0.022 mol), heated at 80 o C for 20 hours, cooled to room temperature, treated with additional bromine (3.52 g, 0.022 mol) and heated at 100 o C until reaction is complete by HPLC analysis. The reaction mixture is cooled to room temperature and diluted with ethyl acetate and water. The organic phase is washed with aqueous sodium metabisulfite, dried (MgSO₄) and concentrated in vacuo to afford a solid residue. The residue is recrystallized from ethyl acetate/heptane to give the title product as a white solid, 6.50 g (89.4% yield), mp 126 o C to 129 o C. EXAMPLE 9 A solution of 2-( p -chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (20.0 g, 0.0739 mol) in monochlorobenzene is treated with t -butylhypochlorite (19.6 g, 0.087 mol), heated at 70 o C for 2 hours, treated with additional t -butylhypochlorite (2.0 g, 0.009 mol), heated at 80 o C to 82 o C for 1 hour, cooled to room temperature, diluted with heptane and filtered. The filter cake is air-dried to give the title product as a pale solid, 18.5 g, (82.5% yield), mp 242.5 o C to 243.0 o C, identified by ¹⁹F and l HNMR spectral analyses.

Claims: A process for the preparation of a compound of formula I wherein A is hydrogen, phenyl or C₁-C₆ alkyl optionally substituted with phenyl; W is CN, NO₂, CO₂R₁ or SO₂R₂; L is hydrogen or halogen; M and R are each independently hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, CN, NO₂, Cl, Br, F, I, CF₃, R₃CF₂Z, R₄CO or NR₅R₆ and when M and R are on adjacent positions they may be taken together with the carbon atoms to which they are attached to form a ring in which MR represents the structure -OCH₂O-, -OCF₂O- or -CH=CH-CH=CH-; R₁ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl; R₂ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl; R₃ is hydrogen, F, CHF₂, CHFCl or CF₃; R₄ is C₁-C₄ alkyl, C₁-C₄ alkoxy or NR₅R₆; R₅ is hydrogen or C₁-C₄ alkyl; R₆ is hydrogen, C₁-C₄ alkyl or R₇CO; R₇ is hydrogen or C₁-C₄ alkyl; Z is S(O) n or O and n is an integer of 0, 1 or 2 characterized by reacting a compound of formula II wherein A, W, L, M and R are described above with at least one molar equivalent of a compound of formula III wherein X is Cl, Br or I in the presence of an acid and a solvent. The process according to claim 1 wherein the reaction takes place at an elevated temperature. The process according to claim 2 wherein the elevated temperature is about 90 o C to 130 o C. The process according to claim 1 wherein the acid is acetic acid. The process according to claim 1 wherein W is CN. The process according to claim 1 wherein W is NO₂. The process according to claim 5 wherein A is hydrogen or methyl, L and R are hydrogen and M is halogen. The process according to claim 5 wherein A is hydrogen or methyl, L is hydrogen and M and R are halogen.

Inventors: KAMESWARAN VENKATARAMAN, KAMESWARAN, VENKATARAMAN
Applicants: AMERICAN CYANAMID CO, AMERICAN CYANAMID COMPANY
Application year: 1991
Main classification: C07D207
IPC codes: A01N43, C07D207